inibidores da integrase do hiv em população com idade mais...
TRANSCRIPT
Marcia Rachid
bull Membro do Comitecirc Assessor para Terapia Antirretroviral do Departamento Nacional de ISTAIDSHepatites Virais do Ministeacuterio da Sauacutede
bull Coordenadora da Cacircmara Teacutecnica de AIDS do CREMERJbull Poacutes-graduada em Imunologia Cliacutenica ndash Instituto de Poacutes-Graduaccedilatildeo Meacutedica Carlos Chagasbull Mestre em Doenccedilas Infecciosas e Parasitaacuterias ndash UFRJ
marciarachidgmailcom
Inibidores da Integrase do HIV em Populaccedilatildeo com Idade mais Avanccedilada
Polifarmaacutecia e Comorbidades
Conflito de Interesses
bull Sem conflito de interesses a declarar
Aspectos que devem ser considerados
bull O estigma e a discriminaccedilatildeo em relaccedilatildeo ao HIV permanecem altamente
prevalentes em qualquer faixa etaacuteria
bull Fatores geneacuteticos hormonais nutricionais e o estilo de vida podem interferir
negativamente e podem piorar com o passar do tempo
bull Problemas de sauacutede mental satildeo comuns e podem progredir com a idade
bull Comorbidades e polifarmaacutecia satildeo questotildees crescentes na populaccedilatildeo com
mais de 50 anos e podem comprometer adesatildeo
bull As interaccedilotildees medicamentosas satildeo frequentes e uma preocupaccedilatildeo
significativa com maior risco de toxicidade
bull Os esquemas terapecircuticos baseados em inibidores da integrase satildeo eficazes
bem tolerados tecircm menos interaccedilotildees medicamentosas menor toxicidade e
alta barreira agrave resistecircncia
Risco de adoecimento por Tuberculose eacute de doze a vinte
vezes maior do que na populaccedilatildeo geral
Karim Lancet 2009
Coinfecccedilatildeo
HIV-Tuberculose
Coinfecccedilatildeo
HIV-Hepatite CClausen LN et al World J Gastroenterol 2014 2012132ndash12143
Alteraccedilotildees Metaboacutelicas Endoacutecrinas e Lipodistrofia
bull Alteraccedilotildees metaboacutelicas (dislipidemia hiperglicemia diabetes) costumam ser associadas agrave esteatose hepaacutetica e ao maior risco de eventos cardiovasculares
bull Podem ocorrer pancreatite ou hiperamilasemia acidemia ou acidose laacutetica
bull Se houver depoacutesitos de gordura satildeo centrais abdome tronco mamas giba regiatildeo cervicofacial (lipohipertrofia) Se houver lipoatrofia eacute perifeacuterica (face e membros)
bull Podem ocorrer hipotireoidismo e hipogonadismo (alteraccedilotildeeshormonais costumam ser mais comuns nos homens com reduccedilatildeo de niacuteveis de testosterona)
Disfunccedilatildeo mitocondrial
bull lipodistrofia
bull neuropatias
bull esteatose
hepaacutetica
bull miopatia
bull pancreatite
bull acidose laacutetica
bull intoleracircncia agrave
glicose
resistecircncia agrave
insulina diabetes
TG e de LDL
reduccedilatildeo HDL
ARV (ITRN)
ITRcitocinas
HIV
bull Gama-DNA polimerasebull transportebull estresse oxidativobull apoptosebull fosforilaccedilatildeobull proteoacutelisebull glicosilaccedilatildeo
Alteraccedilotildees associadas aos Inibidores da Protease
resistecircncia agrave
insulina
GLUT4
GLUT1
reduccedilatildeo do armazenamento
de gordura nos adipoacutecitos
Interferecircncia na
utilizaccedilatildeo da glicose
nos muacutesculos e
adipoacutecitos
aumento de lipiacutedeos no
fiacutegado maior produccedilatildeo e
secreccedilatildeo de VLDL
hiperlipidemia
lipodystrophy
Interferecircncia na adipogecircnese
Siacutentese de TG
apoB VLDL
HIV e IPlipodistrofia
Alteraccedilotildees Metaboacutelicas Endoacutecrinas e Risco Cardiovascular
Infecccedilatildeo pelo HIV e Risco Cardiovascular
- 60 das pessoas com HIV tecircm placas nas arteacuterias cardiacuteacas mesmo semsinaissintomas
- Haacute relaccedilatildeo direta com a inflamaccedilatildeo decorrente da infecccedilatildeo pelo HIV
HIV e Aterosclerose
HIV-1-Associated Atherosclerosis Unraveling the Missing LinkJ Am Coll Cardiol 2017 Jun 2769(25)3084-3098 doi 01016jjacc201705012Kearns A Gordon J Burdo TH Qin X
Doenccedila cardiovascular incluindo aterosclerose e outras complicaccedilotildees associadas eacute causa
crescente de morbidade e mortalidade nos pacientes infectados pelo HIV na era poacutes-
HAART
Terapia antirretroviral comorbidades associadas tais como dislipidemia abuso de drogas
infecccedilotildees oportunistas e outros fatores de risco relacionados a haacutebitos de vida satildeo
importantes tanto para precipitar como para piorar a aterosclerose
Tipo 1 resulta espontaneamente da instabilidade da placa ateroscleroacutetica
Tipo 2 ocorre por desequiliacutebrio entre consumooferta de oxigecircnio vasoespasmo (por exemplo infecccedilatildeo ou uso de cocaiacutena)
EVENTOS CARDIOVASCULARES
Infarto Agudo do Miocaacuterdio
FatoresAnos Perdidos de Vida Idade 35 a 80 anos (95 CI)
Risco de morte
HIV + que nunca fumaram
(HIV + nunca que fumaram vs controlesque nunca fumaram)
51 (44ndash58) 03
Controles fumantes
(controles fumantes vs controles quenunca fumaram)
36 (31ndash40) 344
HIV + fumantes
(HIV + fumantes vs HIV + que nuncafumaram)
123 (115ndash130) 615
Tabagismo Mortalidade e HIV Helleberg Clin Infect Dis 2013
Nuacutemero de Anos Perdidos e Risco de Morte Atribuiacutedo agrave Populaccedilatildeo de Fumantes e com HIV
Em um local onde o tratamento da infecccedilatildeo pelo HIV eacute organizado e gratuito pessoas portadoras do HIV e
fumantes perdem mais anos de vida para o tabagismo do que para o proacuteprio viacuterus Satildeo 123 anos de vida
perdidos para o cigarro O excesso de mortalidade de fumantes eacute triplicado e o risco de morte associado
ao tabagismo eacute duplicado entre HIV + em comparaccedilatildeo agrave populaccedilatildeo natildeo fumante mesmo com HIV
NA-ACCORD Fumo hipertensatildeo arterial e niacuteveis de colesterol aumentam
risco de IAM em portadores do HIV
bull Metanaacutelise retrospectivabull Eventos validados de 7 coortes cliacutenicas
NA-ACCORD 12000 -122013 bull N = 29515[1]
ndash Fraccedilatildeo atribuiacutevel agrave populaccedilatildeo proporccedilatildeo de IM evitaacuteveis pela prevenccedilatildeo de fatores de risco modificaacuteveis relacionados com o HIV e tradicionais
ndash 347 pacientes (12) apresentavam IM de tipo 1 devido agrave ruptura da placa
ndash A anaacutelise de sensibilidade foi feita para 16687 pacientes (57) com dados de IMC 227 apresentaram IM tipo 1
ndash ~ 40 de reduccedilatildeo IM possiacutevel atraveacutes da prevenccedilatildeo do tabagismo TC elevado ou hipertensatildeo independentemente do IMC
1 Althoff KN et al CROI 2017 Abstract 130 2 Shepherd L et al CROI
2017 Abstract 131 Slide credit
clinicaloptionscom
bull Em outra anaacutelise separada (DAD) a interrupccedilatildeo do fumo reduziu as taxas globaisde cacircncer apoacutes 1 ano (exceto pulmatildeo quepermaneceu alta mesmo apoacutes 5 anos)[2]
Ajuste para idade sexo raccedila e fatores de risco
listados daggerP lt 05
Adjusted Population Attributable Fractions for MI[1]
MI
BMI Subgrou
p
Traditional MI risk factors
Smoking 38dagger 36
Elevated TC 43dagger 39dagger
HTN 41dagger 39dagger
All 3 (smoking TC HTN) 86
HIV-related MI risk factors
DM 2 4
CKD 3 3
CD4+ cell count 10dagger 14dagger
VL 6 8
AIDS 2 -1
HCV coinfection 8dagger 14dagger
bull Uso recente de ABC associado com ~70 aumento risco de IM
ndash Uso recente definido como ainda em uso ou interrupccedilatildeo dentrodos uacuteltimos seis meses
bull Exposiccedilatildeo cumulativa
ndash ao ABC foi associada com pequeno aumento do risco de IM
ndash ao Lopinavirr foi associada com aumento do risco de IM
Estudo DAD
Risco Cardiovascular
Abacavir e Risco de Infarto Agudo do Miocaacuterdio e Doenccedila Cerebrovascularna era HAART
R Bedimo12 A Westfall3 H Drechsler12 P Tebas41VA North Texas Healthcare System Medicine Dallas United States 2University of Texas Southwestern MedicalCenter Medicine Dallas United States 3University of Alabama at Birmingham Medicine Birmingham United
States 4University of Pennsylvania Medicine Philadelphia United States
19424 pacientes acompanhados por cerca de 4 anos (75311 pessoas-ano) 278 IAM e 868 AVC entre pessoas com mais fatores de risco para DCV incluindo hepatite C e doenccedila renal
Taxa global IAM 369 por 1000 pessoas-ano AVC 1168 por 1000 pessoas-ano
Abacavir associado a maior risco de IAM (hazard ratio [HR] 127 ou 27 aumento do risco) e de AVC (HR 117)
Anaacutelise foi repetida apoacutes controle dos fatores de risco conhecidos paraDCV e condiccedilotildees coexistentes (idade hiperlipidemia hipertensatildeo diabetes tabagismo) e a associaccedilatildeo entre abacavir e IAM ou AVC deixou de ser forte e deixou de ser estatisticamente significante
Pacientes HIV+ com problemas renais satildeo mais medicados com abacavir comoalternativa ao tenofovir e jaacute tecircm maior risco de DCV e de AVC o que passoua ser considerado fator de confusatildeo na anaacutelise
DAD exposiccedilatildeo ao ATVRTV ou DRVRTV e risco
cardiovascular
bull Prospectivo Jan2009 (BL) ateacute o primeiro evento CV uacuteltima visita + 6 meses ou 01022016
bull (N = 35711)
ndash 1157 pts (32) apresentaram DCV (IM AVE morte suacutebita) ou se submeteram a um procedimento cardiacuteaco invasivo
bull Exposiccedilatildeo cumulativa a DRVRTV estaacute associada a risco CV - anaacutelisemultivariada 59 risco aumentadocom 5 anos de uso
ndash Associaccedilatildeo natildeo parece ser mediada pordislipidemia
bull Limitaccedilotildees Fatores de confusatildeo potencialmente natildeomensuraacuteveis num estudo observacional ndash Natildeo foipossiacutevel diferenciar entre DRVRTV 800100 QD vs DRVRTV 600100 BID
bull Natildeo avaliou uso de estatinas natildeo ajustou para supressatildeo viral Fumo atual apenas Exposiccedilatildeo aotabaco em maccedilosano natildeo foi avaliada exposiccedilatildeopreacutevia a IP de primeira geraccedilatildeo natildeo avaliada
Ryom L et al CROI 2017 Abstract 128LB
Incidence Rates of CVD andCumulative Exposure to ATV+RTV and DRV+RTV
ATV+RTV DRV+RTV
Cumulative years of drug exposure
200
150
100
50
40
30
20
0
Incid
en
ce r
ate
1000 P
YF
U (
95
CI)
Incidecircncia de Doenccedilas Crocircnicas
Aumenta Exponencialmente com a Idade
Idade
INC
IDEcirc
NC
IA
Idade eacute o maior fator de riscoSlide cortesia de Peter Reiss
Schouten J et al Clin Infect Dis 2014
Comorbidades relacionadas agrave idade
A IDADE Eacute FATOR DE RISCO INDEPENDENTE E NAtildeO MODIFICAacuteVEL PARA DCV
J GUNTER ET AL ACTA CLINICA BELGICA INTERNATIONAL JOURNAL OF CLINICAL AND LABORATORY MEDICINE
Prevalecircncia de Fatores Predisponentes
para Fragilidade
KKooij et al 8th Netherlands Conference on HIV Pathogenesis Epidemiology Prevention and Treatment Amsterdam November 2014
Causas de Morte 1999-2011
Continuous Increase of Cardiovascular Diseases Diabetes and Non-HIV Related Cancers
as Causes of Death in HIV-Infected Individuals in Brazil An Analysis of Nationwide Data
Paula AA Schechter M Tuboi SH Faulhaber JC Luz PM et al (2014) PLOS ONE 9(4)
e94636 httpsdoiorg101371journalpone0094636
bull 12366853 atestados
bull 151706 (123) HIVAIDS
ATVr DRVr EFV RPV DTG RAL ABC FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Antihypert
ensiv
eagents
Amlodipine
Atenolol
Bisoprolol
Enalapril
Felodipine
Indapamide
Lisinopril
Losartan
Nifedipine
Olmesartan
Perindopril
Valsartan
Interaccedilotildees com Antihipertensivos
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Potential interaction
no dose adjustment
required
ATVr DRVr EFV RPV DTG RAL
AB
C FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Lip
id-l
ow
ering a
gents
Atorvastatin
Fluvastatin
Lovastatin
Pravastatin
Rosuvastatin
Simvastatin
Antidia
betic a
gents
Glibenclamid
e (Glyburide)
Linagliptin
Metformin
Nateglinide
Saxagliptin
Sitagliptin
Interaccedilotildees Medicamentosas com Hipolipemiantes e Hipoglicemiantes
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Do not co-
administer
Potential interaction
no dose adjustment
required
Interaccedilotildees com Medicamentos que atuam no SNC
BOOSTED FREE AGENTS BOOSTED AGENTS
DTGII RAL EFV ETV RPV EVGc DRVr
Stim
ula
nts
amyl nitrate
cocaine
ecstasy (MDMA)
mephedrone
methamphetamine
Dep
ress
ants
alcohol
alprazolam
codeine
diazepam
GHB (gamma hydroxybutyrate)
heroin (diamorphone)
hydrocodone
hydromorphone
ketamine
pethidine (meperideine)
methadone
midazolam (oral)
morphine
oxycodone
temazepam
triazolam
Hal
luci
no
gen
s
cannabis
lysergic acid dietheylamide (LSD)
phencyclidine (PCP angle dust)
Further information (in vivo in vitro or from label) at wwwhiv-druginteractionsorg
These drugs should not be co-administered
Potential interaction-may require close monitoring alteration of drug dosage or timing of administration
No clinically significant expected
Dose do DTG interfere nos niacuteveis de Metformina
Haacute aumento da exposiccedilatildeo plasmaacutetica da metformina
quando coadministrada com DTG e o efeito produzido
(PK) no niacutevel de metformina eacute dose-dependente do DTG
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50 mgq24h
Metf
orm
in c
on
cen
trati
on
(microg
mL
)
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q24h
Metformin alone Period
3
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50mg q12h
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q12h
Metformin alone Period
3
bull Anaacutelise retrospectiva de adultos HIV+ que mudaram o esquema para
outros contendo DTG e fazendo uso concomitante de metformina
(n=15)
bull DTG natildeo alterou a resposta ao uso da metformina nos pacientes
diabeacuteticos
ndash Natildeo houve diferenccedila significante nos niacuteveis de glicose em jejum nem
na concentraccedilatildeo de HbA1 observados antes e depois da troca para
DTG
Na vida real natildeo houve diferenccedila significativa na glicemia de jejum nem na Hb glicada antes e depois da troca para DTG
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
BHIVA 2016 April Manchester UKCB Jones1 J Tan1 J Robinson1 H Tate1 H Lamba1
1Merck Sharp ampDohme Limited Hertford Road Hoddesdon Hertfordshire
- Comorbidades satildeo frequentes
- 70 das pessoas fazem uso de outros medicamentos
- Supressatildeo viral alcanccedilada em cerca de 85 dos casos
independentemente da idade das comorbidades e do uso
de outros medicamentos
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
n=19215 RAL em 83 dos esquemas (n=1428)
Switching From a Boosted Protease Inhibitor (PIr) Based Regimen to a
Dolutegravir (DTG) Regimen in Virologically Suppressed Patients With
High Cardiovascular Risk (Framingham Score gt10 or Age gt 50 Years) Is
Non-Inferior and Decreases Lipids The NEAT 022 Study
JM Gatell1 L Assoumou2 G Moyle3 L Waters4 E Martinez5 H-J
Stellbrink6 G Guaraldi7 S de Wit8 F Raffi9 A Pozniak10 on behalf of
NEAT022 Study Group
1Hospital ClinicIDIBAPS University of Barcelona Infectious Diseases Barcelona Spain 2Sorbone Universites INSERM
UPMC Univ Paris 06 IPLESP UMRS 1136 Paris France 3Chelsea and Westminster Hospital London United Kingdom4Mortimer Market Center London United Kingdom 5Hospital ClinicIDIBAPS University of Barcelona Barcelona Spain6Infectiologisches Centrum Hamburg Germany 7University of Modena and Reggio Emilia Modena Italy 8Saint Pierre
University Hospital Universiteacute Libre de Bruxelles Brussels Belgium 9CHU
Hotel-Dieu Nantes Nantes France 10Chelsea amp Westminster Hospital London United Kingdom
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
Conflito de Interesses
bull Sem conflito de interesses a declarar
Aspectos que devem ser considerados
bull O estigma e a discriminaccedilatildeo em relaccedilatildeo ao HIV permanecem altamente
prevalentes em qualquer faixa etaacuteria
bull Fatores geneacuteticos hormonais nutricionais e o estilo de vida podem interferir
negativamente e podem piorar com o passar do tempo
bull Problemas de sauacutede mental satildeo comuns e podem progredir com a idade
bull Comorbidades e polifarmaacutecia satildeo questotildees crescentes na populaccedilatildeo com
mais de 50 anos e podem comprometer adesatildeo
bull As interaccedilotildees medicamentosas satildeo frequentes e uma preocupaccedilatildeo
significativa com maior risco de toxicidade
bull Os esquemas terapecircuticos baseados em inibidores da integrase satildeo eficazes
bem tolerados tecircm menos interaccedilotildees medicamentosas menor toxicidade e
alta barreira agrave resistecircncia
Risco de adoecimento por Tuberculose eacute de doze a vinte
vezes maior do que na populaccedilatildeo geral
Karim Lancet 2009
Coinfecccedilatildeo
HIV-Tuberculose
Coinfecccedilatildeo
HIV-Hepatite CClausen LN et al World J Gastroenterol 2014 2012132ndash12143
Alteraccedilotildees Metaboacutelicas Endoacutecrinas e Lipodistrofia
bull Alteraccedilotildees metaboacutelicas (dislipidemia hiperglicemia diabetes) costumam ser associadas agrave esteatose hepaacutetica e ao maior risco de eventos cardiovasculares
bull Podem ocorrer pancreatite ou hiperamilasemia acidemia ou acidose laacutetica
bull Se houver depoacutesitos de gordura satildeo centrais abdome tronco mamas giba regiatildeo cervicofacial (lipohipertrofia) Se houver lipoatrofia eacute perifeacuterica (face e membros)
bull Podem ocorrer hipotireoidismo e hipogonadismo (alteraccedilotildeeshormonais costumam ser mais comuns nos homens com reduccedilatildeo de niacuteveis de testosterona)
Disfunccedilatildeo mitocondrial
bull lipodistrofia
bull neuropatias
bull esteatose
hepaacutetica
bull miopatia
bull pancreatite
bull acidose laacutetica
bull intoleracircncia agrave
glicose
resistecircncia agrave
insulina diabetes
TG e de LDL
reduccedilatildeo HDL
ARV (ITRN)
ITRcitocinas
HIV
bull Gama-DNA polimerasebull transportebull estresse oxidativobull apoptosebull fosforilaccedilatildeobull proteoacutelisebull glicosilaccedilatildeo
Alteraccedilotildees associadas aos Inibidores da Protease
resistecircncia agrave
insulina
GLUT4
GLUT1
reduccedilatildeo do armazenamento
de gordura nos adipoacutecitos
Interferecircncia na
utilizaccedilatildeo da glicose
nos muacutesculos e
adipoacutecitos
aumento de lipiacutedeos no
fiacutegado maior produccedilatildeo e
secreccedilatildeo de VLDL
hiperlipidemia
lipodystrophy
Interferecircncia na adipogecircnese
Siacutentese de TG
apoB VLDL
HIV e IPlipodistrofia
Alteraccedilotildees Metaboacutelicas Endoacutecrinas e Risco Cardiovascular
Infecccedilatildeo pelo HIV e Risco Cardiovascular
- 60 das pessoas com HIV tecircm placas nas arteacuterias cardiacuteacas mesmo semsinaissintomas
- Haacute relaccedilatildeo direta com a inflamaccedilatildeo decorrente da infecccedilatildeo pelo HIV
HIV e Aterosclerose
HIV-1-Associated Atherosclerosis Unraveling the Missing LinkJ Am Coll Cardiol 2017 Jun 2769(25)3084-3098 doi 01016jjacc201705012Kearns A Gordon J Burdo TH Qin X
Doenccedila cardiovascular incluindo aterosclerose e outras complicaccedilotildees associadas eacute causa
crescente de morbidade e mortalidade nos pacientes infectados pelo HIV na era poacutes-
HAART
Terapia antirretroviral comorbidades associadas tais como dislipidemia abuso de drogas
infecccedilotildees oportunistas e outros fatores de risco relacionados a haacutebitos de vida satildeo
importantes tanto para precipitar como para piorar a aterosclerose
Tipo 1 resulta espontaneamente da instabilidade da placa ateroscleroacutetica
Tipo 2 ocorre por desequiliacutebrio entre consumooferta de oxigecircnio vasoespasmo (por exemplo infecccedilatildeo ou uso de cocaiacutena)
EVENTOS CARDIOVASCULARES
Infarto Agudo do Miocaacuterdio
FatoresAnos Perdidos de Vida Idade 35 a 80 anos (95 CI)
Risco de morte
HIV + que nunca fumaram
(HIV + nunca que fumaram vs controlesque nunca fumaram)
51 (44ndash58) 03
Controles fumantes
(controles fumantes vs controles quenunca fumaram)
36 (31ndash40) 344
HIV + fumantes
(HIV + fumantes vs HIV + que nuncafumaram)
123 (115ndash130) 615
Tabagismo Mortalidade e HIV Helleberg Clin Infect Dis 2013
Nuacutemero de Anos Perdidos e Risco de Morte Atribuiacutedo agrave Populaccedilatildeo de Fumantes e com HIV
Em um local onde o tratamento da infecccedilatildeo pelo HIV eacute organizado e gratuito pessoas portadoras do HIV e
fumantes perdem mais anos de vida para o tabagismo do que para o proacuteprio viacuterus Satildeo 123 anos de vida
perdidos para o cigarro O excesso de mortalidade de fumantes eacute triplicado e o risco de morte associado
ao tabagismo eacute duplicado entre HIV + em comparaccedilatildeo agrave populaccedilatildeo natildeo fumante mesmo com HIV
NA-ACCORD Fumo hipertensatildeo arterial e niacuteveis de colesterol aumentam
risco de IAM em portadores do HIV
bull Metanaacutelise retrospectivabull Eventos validados de 7 coortes cliacutenicas
NA-ACCORD 12000 -122013 bull N = 29515[1]
ndash Fraccedilatildeo atribuiacutevel agrave populaccedilatildeo proporccedilatildeo de IM evitaacuteveis pela prevenccedilatildeo de fatores de risco modificaacuteveis relacionados com o HIV e tradicionais
ndash 347 pacientes (12) apresentavam IM de tipo 1 devido agrave ruptura da placa
ndash A anaacutelise de sensibilidade foi feita para 16687 pacientes (57) com dados de IMC 227 apresentaram IM tipo 1
ndash ~ 40 de reduccedilatildeo IM possiacutevel atraveacutes da prevenccedilatildeo do tabagismo TC elevado ou hipertensatildeo independentemente do IMC
1 Althoff KN et al CROI 2017 Abstract 130 2 Shepherd L et al CROI
2017 Abstract 131 Slide credit
clinicaloptionscom
bull Em outra anaacutelise separada (DAD) a interrupccedilatildeo do fumo reduziu as taxas globaisde cacircncer apoacutes 1 ano (exceto pulmatildeo quepermaneceu alta mesmo apoacutes 5 anos)[2]
Ajuste para idade sexo raccedila e fatores de risco
listados daggerP lt 05
Adjusted Population Attributable Fractions for MI[1]
MI
BMI Subgrou
p
Traditional MI risk factors
Smoking 38dagger 36
Elevated TC 43dagger 39dagger
HTN 41dagger 39dagger
All 3 (smoking TC HTN) 86
HIV-related MI risk factors
DM 2 4
CKD 3 3
CD4+ cell count 10dagger 14dagger
VL 6 8
AIDS 2 -1
HCV coinfection 8dagger 14dagger
bull Uso recente de ABC associado com ~70 aumento risco de IM
ndash Uso recente definido como ainda em uso ou interrupccedilatildeo dentrodos uacuteltimos seis meses
bull Exposiccedilatildeo cumulativa
ndash ao ABC foi associada com pequeno aumento do risco de IM
ndash ao Lopinavirr foi associada com aumento do risco de IM
Estudo DAD
Risco Cardiovascular
Abacavir e Risco de Infarto Agudo do Miocaacuterdio e Doenccedila Cerebrovascularna era HAART
R Bedimo12 A Westfall3 H Drechsler12 P Tebas41VA North Texas Healthcare System Medicine Dallas United States 2University of Texas Southwestern MedicalCenter Medicine Dallas United States 3University of Alabama at Birmingham Medicine Birmingham United
States 4University of Pennsylvania Medicine Philadelphia United States
19424 pacientes acompanhados por cerca de 4 anos (75311 pessoas-ano) 278 IAM e 868 AVC entre pessoas com mais fatores de risco para DCV incluindo hepatite C e doenccedila renal
Taxa global IAM 369 por 1000 pessoas-ano AVC 1168 por 1000 pessoas-ano
Abacavir associado a maior risco de IAM (hazard ratio [HR] 127 ou 27 aumento do risco) e de AVC (HR 117)
Anaacutelise foi repetida apoacutes controle dos fatores de risco conhecidos paraDCV e condiccedilotildees coexistentes (idade hiperlipidemia hipertensatildeo diabetes tabagismo) e a associaccedilatildeo entre abacavir e IAM ou AVC deixou de ser forte e deixou de ser estatisticamente significante
Pacientes HIV+ com problemas renais satildeo mais medicados com abacavir comoalternativa ao tenofovir e jaacute tecircm maior risco de DCV e de AVC o que passoua ser considerado fator de confusatildeo na anaacutelise
DAD exposiccedilatildeo ao ATVRTV ou DRVRTV e risco
cardiovascular
bull Prospectivo Jan2009 (BL) ateacute o primeiro evento CV uacuteltima visita + 6 meses ou 01022016
bull (N = 35711)
ndash 1157 pts (32) apresentaram DCV (IM AVE morte suacutebita) ou se submeteram a um procedimento cardiacuteaco invasivo
bull Exposiccedilatildeo cumulativa a DRVRTV estaacute associada a risco CV - anaacutelisemultivariada 59 risco aumentadocom 5 anos de uso
ndash Associaccedilatildeo natildeo parece ser mediada pordislipidemia
bull Limitaccedilotildees Fatores de confusatildeo potencialmente natildeomensuraacuteveis num estudo observacional ndash Natildeo foipossiacutevel diferenciar entre DRVRTV 800100 QD vs DRVRTV 600100 BID
bull Natildeo avaliou uso de estatinas natildeo ajustou para supressatildeo viral Fumo atual apenas Exposiccedilatildeo aotabaco em maccedilosano natildeo foi avaliada exposiccedilatildeopreacutevia a IP de primeira geraccedilatildeo natildeo avaliada
Ryom L et al CROI 2017 Abstract 128LB
Incidence Rates of CVD andCumulative Exposure to ATV+RTV and DRV+RTV
ATV+RTV DRV+RTV
Cumulative years of drug exposure
200
150
100
50
40
30
20
0
Incid
en
ce r
ate
1000 P
YF
U (
95
CI)
Incidecircncia de Doenccedilas Crocircnicas
Aumenta Exponencialmente com a Idade
Idade
INC
IDEcirc
NC
IA
Idade eacute o maior fator de riscoSlide cortesia de Peter Reiss
Schouten J et al Clin Infect Dis 2014
Comorbidades relacionadas agrave idade
A IDADE Eacute FATOR DE RISCO INDEPENDENTE E NAtildeO MODIFICAacuteVEL PARA DCV
J GUNTER ET AL ACTA CLINICA BELGICA INTERNATIONAL JOURNAL OF CLINICAL AND LABORATORY MEDICINE
Prevalecircncia de Fatores Predisponentes
para Fragilidade
KKooij et al 8th Netherlands Conference on HIV Pathogenesis Epidemiology Prevention and Treatment Amsterdam November 2014
Causas de Morte 1999-2011
Continuous Increase of Cardiovascular Diseases Diabetes and Non-HIV Related Cancers
as Causes of Death in HIV-Infected Individuals in Brazil An Analysis of Nationwide Data
Paula AA Schechter M Tuboi SH Faulhaber JC Luz PM et al (2014) PLOS ONE 9(4)
e94636 httpsdoiorg101371journalpone0094636
bull 12366853 atestados
bull 151706 (123) HIVAIDS
ATVr DRVr EFV RPV DTG RAL ABC FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Antihypert
ensiv
eagents
Amlodipine
Atenolol
Bisoprolol
Enalapril
Felodipine
Indapamide
Lisinopril
Losartan
Nifedipine
Olmesartan
Perindopril
Valsartan
Interaccedilotildees com Antihipertensivos
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Potential interaction
no dose adjustment
required
ATVr DRVr EFV RPV DTG RAL
AB
C FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Lip
id-l
ow
ering a
gents
Atorvastatin
Fluvastatin
Lovastatin
Pravastatin
Rosuvastatin
Simvastatin
Antidia
betic a
gents
Glibenclamid
e (Glyburide)
Linagliptin
Metformin
Nateglinide
Saxagliptin
Sitagliptin
Interaccedilotildees Medicamentosas com Hipolipemiantes e Hipoglicemiantes
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Do not co-
administer
Potential interaction
no dose adjustment
required
Interaccedilotildees com Medicamentos que atuam no SNC
BOOSTED FREE AGENTS BOOSTED AGENTS
DTGII RAL EFV ETV RPV EVGc DRVr
Stim
ula
nts
amyl nitrate
cocaine
ecstasy (MDMA)
mephedrone
methamphetamine
Dep
ress
ants
alcohol
alprazolam
codeine
diazepam
GHB (gamma hydroxybutyrate)
heroin (diamorphone)
hydrocodone
hydromorphone
ketamine
pethidine (meperideine)
methadone
midazolam (oral)
morphine
oxycodone
temazepam
triazolam
Hal
luci
no
gen
s
cannabis
lysergic acid dietheylamide (LSD)
phencyclidine (PCP angle dust)
Further information (in vivo in vitro or from label) at wwwhiv-druginteractionsorg
These drugs should not be co-administered
Potential interaction-may require close monitoring alteration of drug dosage or timing of administration
No clinically significant expected
Dose do DTG interfere nos niacuteveis de Metformina
Haacute aumento da exposiccedilatildeo plasmaacutetica da metformina
quando coadministrada com DTG e o efeito produzido
(PK) no niacutevel de metformina eacute dose-dependente do DTG
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50 mgq24h
Metf
orm
in c
on
cen
trati
on
(microg
mL
)
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q24h
Metformin alone Period
3
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50mg q12h
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q12h
Metformin alone Period
3
bull Anaacutelise retrospectiva de adultos HIV+ que mudaram o esquema para
outros contendo DTG e fazendo uso concomitante de metformina
(n=15)
bull DTG natildeo alterou a resposta ao uso da metformina nos pacientes
diabeacuteticos
ndash Natildeo houve diferenccedila significante nos niacuteveis de glicose em jejum nem
na concentraccedilatildeo de HbA1 observados antes e depois da troca para
DTG
Na vida real natildeo houve diferenccedila significativa na glicemia de jejum nem na Hb glicada antes e depois da troca para DTG
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
BHIVA 2016 April Manchester UKCB Jones1 J Tan1 J Robinson1 H Tate1 H Lamba1
1Merck Sharp ampDohme Limited Hertford Road Hoddesdon Hertfordshire
- Comorbidades satildeo frequentes
- 70 das pessoas fazem uso de outros medicamentos
- Supressatildeo viral alcanccedilada em cerca de 85 dos casos
independentemente da idade das comorbidades e do uso
de outros medicamentos
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
n=19215 RAL em 83 dos esquemas (n=1428)
Switching From a Boosted Protease Inhibitor (PIr) Based Regimen to a
Dolutegravir (DTG) Regimen in Virologically Suppressed Patients With
High Cardiovascular Risk (Framingham Score gt10 or Age gt 50 Years) Is
Non-Inferior and Decreases Lipids The NEAT 022 Study
JM Gatell1 L Assoumou2 G Moyle3 L Waters4 E Martinez5 H-J
Stellbrink6 G Guaraldi7 S de Wit8 F Raffi9 A Pozniak10 on behalf of
NEAT022 Study Group
1Hospital ClinicIDIBAPS University of Barcelona Infectious Diseases Barcelona Spain 2Sorbone Universites INSERM
UPMC Univ Paris 06 IPLESP UMRS 1136 Paris France 3Chelsea and Westminster Hospital London United Kingdom4Mortimer Market Center London United Kingdom 5Hospital ClinicIDIBAPS University of Barcelona Barcelona Spain6Infectiologisches Centrum Hamburg Germany 7University of Modena and Reggio Emilia Modena Italy 8Saint Pierre
University Hospital Universiteacute Libre de Bruxelles Brussels Belgium 9CHU
Hotel-Dieu Nantes Nantes France 10Chelsea amp Westminster Hospital London United Kingdom
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
Aspectos que devem ser considerados
bull O estigma e a discriminaccedilatildeo em relaccedilatildeo ao HIV permanecem altamente
prevalentes em qualquer faixa etaacuteria
bull Fatores geneacuteticos hormonais nutricionais e o estilo de vida podem interferir
negativamente e podem piorar com o passar do tempo
bull Problemas de sauacutede mental satildeo comuns e podem progredir com a idade
bull Comorbidades e polifarmaacutecia satildeo questotildees crescentes na populaccedilatildeo com
mais de 50 anos e podem comprometer adesatildeo
bull As interaccedilotildees medicamentosas satildeo frequentes e uma preocupaccedilatildeo
significativa com maior risco de toxicidade
bull Os esquemas terapecircuticos baseados em inibidores da integrase satildeo eficazes
bem tolerados tecircm menos interaccedilotildees medicamentosas menor toxicidade e
alta barreira agrave resistecircncia
Risco de adoecimento por Tuberculose eacute de doze a vinte
vezes maior do que na populaccedilatildeo geral
Karim Lancet 2009
Coinfecccedilatildeo
HIV-Tuberculose
Coinfecccedilatildeo
HIV-Hepatite CClausen LN et al World J Gastroenterol 2014 2012132ndash12143
Alteraccedilotildees Metaboacutelicas Endoacutecrinas e Lipodistrofia
bull Alteraccedilotildees metaboacutelicas (dislipidemia hiperglicemia diabetes) costumam ser associadas agrave esteatose hepaacutetica e ao maior risco de eventos cardiovasculares
bull Podem ocorrer pancreatite ou hiperamilasemia acidemia ou acidose laacutetica
bull Se houver depoacutesitos de gordura satildeo centrais abdome tronco mamas giba regiatildeo cervicofacial (lipohipertrofia) Se houver lipoatrofia eacute perifeacuterica (face e membros)
bull Podem ocorrer hipotireoidismo e hipogonadismo (alteraccedilotildeeshormonais costumam ser mais comuns nos homens com reduccedilatildeo de niacuteveis de testosterona)
Disfunccedilatildeo mitocondrial
bull lipodistrofia
bull neuropatias
bull esteatose
hepaacutetica
bull miopatia
bull pancreatite
bull acidose laacutetica
bull intoleracircncia agrave
glicose
resistecircncia agrave
insulina diabetes
TG e de LDL
reduccedilatildeo HDL
ARV (ITRN)
ITRcitocinas
HIV
bull Gama-DNA polimerasebull transportebull estresse oxidativobull apoptosebull fosforilaccedilatildeobull proteoacutelisebull glicosilaccedilatildeo
Alteraccedilotildees associadas aos Inibidores da Protease
resistecircncia agrave
insulina
GLUT4
GLUT1
reduccedilatildeo do armazenamento
de gordura nos adipoacutecitos
Interferecircncia na
utilizaccedilatildeo da glicose
nos muacutesculos e
adipoacutecitos
aumento de lipiacutedeos no
fiacutegado maior produccedilatildeo e
secreccedilatildeo de VLDL
hiperlipidemia
lipodystrophy
Interferecircncia na adipogecircnese
Siacutentese de TG
apoB VLDL
HIV e IPlipodistrofia
Alteraccedilotildees Metaboacutelicas Endoacutecrinas e Risco Cardiovascular
Infecccedilatildeo pelo HIV e Risco Cardiovascular
- 60 das pessoas com HIV tecircm placas nas arteacuterias cardiacuteacas mesmo semsinaissintomas
- Haacute relaccedilatildeo direta com a inflamaccedilatildeo decorrente da infecccedilatildeo pelo HIV
HIV e Aterosclerose
HIV-1-Associated Atherosclerosis Unraveling the Missing LinkJ Am Coll Cardiol 2017 Jun 2769(25)3084-3098 doi 01016jjacc201705012Kearns A Gordon J Burdo TH Qin X
Doenccedila cardiovascular incluindo aterosclerose e outras complicaccedilotildees associadas eacute causa
crescente de morbidade e mortalidade nos pacientes infectados pelo HIV na era poacutes-
HAART
Terapia antirretroviral comorbidades associadas tais como dislipidemia abuso de drogas
infecccedilotildees oportunistas e outros fatores de risco relacionados a haacutebitos de vida satildeo
importantes tanto para precipitar como para piorar a aterosclerose
Tipo 1 resulta espontaneamente da instabilidade da placa ateroscleroacutetica
Tipo 2 ocorre por desequiliacutebrio entre consumooferta de oxigecircnio vasoespasmo (por exemplo infecccedilatildeo ou uso de cocaiacutena)
EVENTOS CARDIOVASCULARES
Infarto Agudo do Miocaacuterdio
FatoresAnos Perdidos de Vida Idade 35 a 80 anos (95 CI)
Risco de morte
HIV + que nunca fumaram
(HIV + nunca que fumaram vs controlesque nunca fumaram)
51 (44ndash58) 03
Controles fumantes
(controles fumantes vs controles quenunca fumaram)
36 (31ndash40) 344
HIV + fumantes
(HIV + fumantes vs HIV + que nuncafumaram)
123 (115ndash130) 615
Tabagismo Mortalidade e HIV Helleberg Clin Infect Dis 2013
Nuacutemero de Anos Perdidos e Risco de Morte Atribuiacutedo agrave Populaccedilatildeo de Fumantes e com HIV
Em um local onde o tratamento da infecccedilatildeo pelo HIV eacute organizado e gratuito pessoas portadoras do HIV e
fumantes perdem mais anos de vida para o tabagismo do que para o proacuteprio viacuterus Satildeo 123 anos de vida
perdidos para o cigarro O excesso de mortalidade de fumantes eacute triplicado e o risco de morte associado
ao tabagismo eacute duplicado entre HIV + em comparaccedilatildeo agrave populaccedilatildeo natildeo fumante mesmo com HIV
NA-ACCORD Fumo hipertensatildeo arterial e niacuteveis de colesterol aumentam
risco de IAM em portadores do HIV
bull Metanaacutelise retrospectivabull Eventos validados de 7 coortes cliacutenicas
NA-ACCORD 12000 -122013 bull N = 29515[1]
ndash Fraccedilatildeo atribuiacutevel agrave populaccedilatildeo proporccedilatildeo de IM evitaacuteveis pela prevenccedilatildeo de fatores de risco modificaacuteveis relacionados com o HIV e tradicionais
ndash 347 pacientes (12) apresentavam IM de tipo 1 devido agrave ruptura da placa
ndash A anaacutelise de sensibilidade foi feita para 16687 pacientes (57) com dados de IMC 227 apresentaram IM tipo 1
ndash ~ 40 de reduccedilatildeo IM possiacutevel atraveacutes da prevenccedilatildeo do tabagismo TC elevado ou hipertensatildeo independentemente do IMC
1 Althoff KN et al CROI 2017 Abstract 130 2 Shepherd L et al CROI
2017 Abstract 131 Slide credit
clinicaloptionscom
bull Em outra anaacutelise separada (DAD) a interrupccedilatildeo do fumo reduziu as taxas globaisde cacircncer apoacutes 1 ano (exceto pulmatildeo quepermaneceu alta mesmo apoacutes 5 anos)[2]
Ajuste para idade sexo raccedila e fatores de risco
listados daggerP lt 05
Adjusted Population Attributable Fractions for MI[1]
MI
BMI Subgrou
p
Traditional MI risk factors
Smoking 38dagger 36
Elevated TC 43dagger 39dagger
HTN 41dagger 39dagger
All 3 (smoking TC HTN) 86
HIV-related MI risk factors
DM 2 4
CKD 3 3
CD4+ cell count 10dagger 14dagger
VL 6 8
AIDS 2 -1
HCV coinfection 8dagger 14dagger
bull Uso recente de ABC associado com ~70 aumento risco de IM
ndash Uso recente definido como ainda em uso ou interrupccedilatildeo dentrodos uacuteltimos seis meses
bull Exposiccedilatildeo cumulativa
ndash ao ABC foi associada com pequeno aumento do risco de IM
ndash ao Lopinavirr foi associada com aumento do risco de IM
Estudo DAD
Risco Cardiovascular
Abacavir e Risco de Infarto Agudo do Miocaacuterdio e Doenccedila Cerebrovascularna era HAART
R Bedimo12 A Westfall3 H Drechsler12 P Tebas41VA North Texas Healthcare System Medicine Dallas United States 2University of Texas Southwestern MedicalCenter Medicine Dallas United States 3University of Alabama at Birmingham Medicine Birmingham United
States 4University of Pennsylvania Medicine Philadelphia United States
19424 pacientes acompanhados por cerca de 4 anos (75311 pessoas-ano) 278 IAM e 868 AVC entre pessoas com mais fatores de risco para DCV incluindo hepatite C e doenccedila renal
Taxa global IAM 369 por 1000 pessoas-ano AVC 1168 por 1000 pessoas-ano
Abacavir associado a maior risco de IAM (hazard ratio [HR] 127 ou 27 aumento do risco) e de AVC (HR 117)
Anaacutelise foi repetida apoacutes controle dos fatores de risco conhecidos paraDCV e condiccedilotildees coexistentes (idade hiperlipidemia hipertensatildeo diabetes tabagismo) e a associaccedilatildeo entre abacavir e IAM ou AVC deixou de ser forte e deixou de ser estatisticamente significante
Pacientes HIV+ com problemas renais satildeo mais medicados com abacavir comoalternativa ao tenofovir e jaacute tecircm maior risco de DCV e de AVC o que passoua ser considerado fator de confusatildeo na anaacutelise
DAD exposiccedilatildeo ao ATVRTV ou DRVRTV e risco
cardiovascular
bull Prospectivo Jan2009 (BL) ateacute o primeiro evento CV uacuteltima visita + 6 meses ou 01022016
bull (N = 35711)
ndash 1157 pts (32) apresentaram DCV (IM AVE morte suacutebita) ou se submeteram a um procedimento cardiacuteaco invasivo
bull Exposiccedilatildeo cumulativa a DRVRTV estaacute associada a risco CV - anaacutelisemultivariada 59 risco aumentadocom 5 anos de uso
ndash Associaccedilatildeo natildeo parece ser mediada pordislipidemia
bull Limitaccedilotildees Fatores de confusatildeo potencialmente natildeomensuraacuteveis num estudo observacional ndash Natildeo foipossiacutevel diferenciar entre DRVRTV 800100 QD vs DRVRTV 600100 BID
bull Natildeo avaliou uso de estatinas natildeo ajustou para supressatildeo viral Fumo atual apenas Exposiccedilatildeo aotabaco em maccedilosano natildeo foi avaliada exposiccedilatildeopreacutevia a IP de primeira geraccedilatildeo natildeo avaliada
Ryom L et al CROI 2017 Abstract 128LB
Incidence Rates of CVD andCumulative Exposure to ATV+RTV and DRV+RTV
ATV+RTV DRV+RTV
Cumulative years of drug exposure
200
150
100
50
40
30
20
0
Incid
en
ce r
ate
1000 P
YF
U (
95
CI)
Incidecircncia de Doenccedilas Crocircnicas
Aumenta Exponencialmente com a Idade
Idade
INC
IDEcirc
NC
IA
Idade eacute o maior fator de riscoSlide cortesia de Peter Reiss
Schouten J et al Clin Infect Dis 2014
Comorbidades relacionadas agrave idade
A IDADE Eacute FATOR DE RISCO INDEPENDENTE E NAtildeO MODIFICAacuteVEL PARA DCV
J GUNTER ET AL ACTA CLINICA BELGICA INTERNATIONAL JOURNAL OF CLINICAL AND LABORATORY MEDICINE
Prevalecircncia de Fatores Predisponentes
para Fragilidade
KKooij et al 8th Netherlands Conference on HIV Pathogenesis Epidemiology Prevention and Treatment Amsterdam November 2014
Causas de Morte 1999-2011
Continuous Increase of Cardiovascular Diseases Diabetes and Non-HIV Related Cancers
as Causes of Death in HIV-Infected Individuals in Brazil An Analysis of Nationwide Data
Paula AA Schechter M Tuboi SH Faulhaber JC Luz PM et al (2014) PLOS ONE 9(4)
e94636 httpsdoiorg101371journalpone0094636
bull 12366853 atestados
bull 151706 (123) HIVAIDS
ATVr DRVr EFV RPV DTG RAL ABC FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Antihypert
ensiv
eagents
Amlodipine
Atenolol
Bisoprolol
Enalapril
Felodipine
Indapamide
Lisinopril
Losartan
Nifedipine
Olmesartan
Perindopril
Valsartan
Interaccedilotildees com Antihipertensivos
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Potential interaction
no dose adjustment
required
ATVr DRVr EFV RPV DTG RAL
AB
C FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Lip
id-l
ow
ering a
gents
Atorvastatin
Fluvastatin
Lovastatin
Pravastatin
Rosuvastatin
Simvastatin
Antidia
betic a
gents
Glibenclamid
e (Glyburide)
Linagliptin
Metformin
Nateglinide
Saxagliptin
Sitagliptin
Interaccedilotildees Medicamentosas com Hipolipemiantes e Hipoglicemiantes
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Do not co-
administer
Potential interaction
no dose adjustment
required
Interaccedilotildees com Medicamentos que atuam no SNC
BOOSTED FREE AGENTS BOOSTED AGENTS
DTGII RAL EFV ETV RPV EVGc DRVr
Stim
ula
nts
amyl nitrate
cocaine
ecstasy (MDMA)
mephedrone
methamphetamine
Dep
ress
ants
alcohol
alprazolam
codeine
diazepam
GHB (gamma hydroxybutyrate)
heroin (diamorphone)
hydrocodone
hydromorphone
ketamine
pethidine (meperideine)
methadone
midazolam (oral)
morphine
oxycodone
temazepam
triazolam
Hal
luci
no
gen
s
cannabis
lysergic acid dietheylamide (LSD)
phencyclidine (PCP angle dust)
Further information (in vivo in vitro or from label) at wwwhiv-druginteractionsorg
These drugs should not be co-administered
Potential interaction-may require close monitoring alteration of drug dosage or timing of administration
No clinically significant expected
Dose do DTG interfere nos niacuteveis de Metformina
Haacute aumento da exposiccedilatildeo plasmaacutetica da metformina
quando coadministrada com DTG e o efeito produzido
(PK) no niacutevel de metformina eacute dose-dependente do DTG
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50 mgq24h
Metf
orm
in c
on
cen
trati
on
(microg
mL
)
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q24h
Metformin alone Period
3
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50mg q12h
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q12h
Metformin alone Period
3
bull Anaacutelise retrospectiva de adultos HIV+ que mudaram o esquema para
outros contendo DTG e fazendo uso concomitante de metformina
(n=15)
bull DTG natildeo alterou a resposta ao uso da metformina nos pacientes
diabeacuteticos
ndash Natildeo houve diferenccedila significante nos niacuteveis de glicose em jejum nem
na concentraccedilatildeo de HbA1 observados antes e depois da troca para
DTG
Na vida real natildeo houve diferenccedila significativa na glicemia de jejum nem na Hb glicada antes e depois da troca para DTG
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
BHIVA 2016 April Manchester UKCB Jones1 J Tan1 J Robinson1 H Tate1 H Lamba1
1Merck Sharp ampDohme Limited Hertford Road Hoddesdon Hertfordshire
- Comorbidades satildeo frequentes
- 70 das pessoas fazem uso de outros medicamentos
- Supressatildeo viral alcanccedilada em cerca de 85 dos casos
independentemente da idade das comorbidades e do uso
de outros medicamentos
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
n=19215 RAL em 83 dos esquemas (n=1428)
Switching From a Boosted Protease Inhibitor (PIr) Based Regimen to a
Dolutegravir (DTG) Regimen in Virologically Suppressed Patients With
High Cardiovascular Risk (Framingham Score gt10 or Age gt 50 Years) Is
Non-Inferior and Decreases Lipids The NEAT 022 Study
JM Gatell1 L Assoumou2 G Moyle3 L Waters4 E Martinez5 H-J
Stellbrink6 G Guaraldi7 S de Wit8 F Raffi9 A Pozniak10 on behalf of
NEAT022 Study Group
1Hospital ClinicIDIBAPS University of Barcelona Infectious Diseases Barcelona Spain 2Sorbone Universites INSERM
UPMC Univ Paris 06 IPLESP UMRS 1136 Paris France 3Chelsea and Westminster Hospital London United Kingdom4Mortimer Market Center London United Kingdom 5Hospital ClinicIDIBAPS University of Barcelona Barcelona Spain6Infectiologisches Centrum Hamburg Germany 7University of Modena and Reggio Emilia Modena Italy 8Saint Pierre
University Hospital Universiteacute Libre de Bruxelles Brussels Belgium 9CHU
Hotel-Dieu Nantes Nantes France 10Chelsea amp Westminster Hospital London United Kingdom
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
Risco de adoecimento por Tuberculose eacute de doze a vinte
vezes maior do que na populaccedilatildeo geral
Karim Lancet 2009
Coinfecccedilatildeo
HIV-Tuberculose
Coinfecccedilatildeo
HIV-Hepatite CClausen LN et al World J Gastroenterol 2014 2012132ndash12143
Alteraccedilotildees Metaboacutelicas Endoacutecrinas e Lipodistrofia
bull Alteraccedilotildees metaboacutelicas (dislipidemia hiperglicemia diabetes) costumam ser associadas agrave esteatose hepaacutetica e ao maior risco de eventos cardiovasculares
bull Podem ocorrer pancreatite ou hiperamilasemia acidemia ou acidose laacutetica
bull Se houver depoacutesitos de gordura satildeo centrais abdome tronco mamas giba regiatildeo cervicofacial (lipohipertrofia) Se houver lipoatrofia eacute perifeacuterica (face e membros)
bull Podem ocorrer hipotireoidismo e hipogonadismo (alteraccedilotildeeshormonais costumam ser mais comuns nos homens com reduccedilatildeo de niacuteveis de testosterona)
Disfunccedilatildeo mitocondrial
bull lipodistrofia
bull neuropatias
bull esteatose
hepaacutetica
bull miopatia
bull pancreatite
bull acidose laacutetica
bull intoleracircncia agrave
glicose
resistecircncia agrave
insulina diabetes
TG e de LDL
reduccedilatildeo HDL
ARV (ITRN)
ITRcitocinas
HIV
bull Gama-DNA polimerasebull transportebull estresse oxidativobull apoptosebull fosforilaccedilatildeobull proteoacutelisebull glicosilaccedilatildeo
Alteraccedilotildees associadas aos Inibidores da Protease
resistecircncia agrave
insulina
GLUT4
GLUT1
reduccedilatildeo do armazenamento
de gordura nos adipoacutecitos
Interferecircncia na
utilizaccedilatildeo da glicose
nos muacutesculos e
adipoacutecitos
aumento de lipiacutedeos no
fiacutegado maior produccedilatildeo e
secreccedilatildeo de VLDL
hiperlipidemia
lipodystrophy
Interferecircncia na adipogecircnese
Siacutentese de TG
apoB VLDL
HIV e IPlipodistrofia
Alteraccedilotildees Metaboacutelicas Endoacutecrinas e Risco Cardiovascular
Infecccedilatildeo pelo HIV e Risco Cardiovascular
- 60 das pessoas com HIV tecircm placas nas arteacuterias cardiacuteacas mesmo semsinaissintomas
- Haacute relaccedilatildeo direta com a inflamaccedilatildeo decorrente da infecccedilatildeo pelo HIV
HIV e Aterosclerose
HIV-1-Associated Atherosclerosis Unraveling the Missing LinkJ Am Coll Cardiol 2017 Jun 2769(25)3084-3098 doi 01016jjacc201705012Kearns A Gordon J Burdo TH Qin X
Doenccedila cardiovascular incluindo aterosclerose e outras complicaccedilotildees associadas eacute causa
crescente de morbidade e mortalidade nos pacientes infectados pelo HIV na era poacutes-
HAART
Terapia antirretroviral comorbidades associadas tais como dislipidemia abuso de drogas
infecccedilotildees oportunistas e outros fatores de risco relacionados a haacutebitos de vida satildeo
importantes tanto para precipitar como para piorar a aterosclerose
Tipo 1 resulta espontaneamente da instabilidade da placa ateroscleroacutetica
Tipo 2 ocorre por desequiliacutebrio entre consumooferta de oxigecircnio vasoespasmo (por exemplo infecccedilatildeo ou uso de cocaiacutena)
EVENTOS CARDIOVASCULARES
Infarto Agudo do Miocaacuterdio
FatoresAnos Perdidos de Vida Idade 35 a 80 anos (95 CI)
Risco de morte
HIV + que nunca fumaram
(HIV + nunca que fumaram vs controlesque nunca fumaram)
51 (44ndash58) 03
Controles fumantes
(controles fumantes vs controles quenunca fumaram)
36 (31ndash40) 344
HIV + fumantes
(HIV + fumantes vs HIV + que nuncafumaram)
123 (115ndash130) 615
Tabagismo Mortalidade e HIV Helleberg Clin Infect Dis 2013
Nuacutemero de Anos Perdidos e Risco de Morte Atribuiacutedo agrave Populaccedilatildeo de Fumantes e com HIV
Em um local onde o tratamento da infecccedilatildeo pelo HIV eacute organizado e gratuito pessoas portadoras do HIV e
fumantes perdem mais anos de vida para o tabagismo do que para o proacuteprio viacuterus Satildeo 123 anos de vida
perdidos para o cigarro O excesso de mortalidade de fumantes eacute triplicado e o risco de morte associado
ao tabagismo eacute duplicado entre HIV + em comparaccedilatildeo agrave populaccedilatildeo natildeo fumante mesmo com HIV
NA-ACCORD Fumo hipertensatildeo arterial e niacuteveis de colesterol aumentam
risco de IAM em portadores do HIV
bull Metanaacutelise retrospectivabull Eventos validados de 7 coortes cliacutenicas
NA-ACCORD 12000 -122013 bull N = 29515[1]
ndash Fraccedilatildeo atribuiacutevel agrave populaccedilatildeo proporccedilatildeo de IM evitaacuteveis pela prevenccedilatildeo de fatores de risco modificaacuteveis relacionados com o HIV e tradicionais
ndash 347 pacientes (12) apresentavam IM de tipo 1 devido agrave ruptura da placa
ndash A anaacutelise de sensibilidade foi feita para 16687 pacientes (57) com dados de IMC 227 apresentaram IM tipo 1
ndash ~ 40 de reduccedilatildeo IM possiacutevel atraveacutes da prevenccedilatildeo do tabagismo TC elevado ou hipertensatildeo independentemente do IMC
1 Althoff KN et al CROI 2017 Abstract 130 2 Shepherd L et al CROI
2017 Abstract 131 Slide credit
clinicaloptionscom
bull Em outra anaacutelise separada (DAD) a interrupccedilatildeo do fumo reduziu as taxas globaisde cacircncer apoacutes 1 ano (exceto pulmatildeo quepermaneceu alta mesmo apoacutes 5 anos)[2]
Ajuste para idade sexo raccedila e fatores de risco
listados daggerP lt 05
Adjusted Population Attributable Fractions for MI[1]
MI
BMI Subgrou
p
Traditional MI risk factors
Smoking 38dagger 36
Elevated TC 43dagger 39dagger
HTN 41dagger 39dagger
All 3 (smoking TC HTN) 86
HIV-related MI risk factors
DM 2 4
CKD 3 3
CD4+ cell count 10dagger 14dagger
VL 6 8
AIDS 2 -1
HCV coinfection 8dagger 14dagger
bull Uso recente de ABC associado com ~70 aumento risco de IM
ndash Uso recente definido como ainda em uso ou interrupccedilatildeo dentrodos uacuteltimos seis meses
bull Exposiccedilatildeo cumulativa
ndash ao ABC foi associada com pequeno aumento do risco de IM
ndash ao Lopinavirr foi associada com aumento do risco de IM
Estudo DAD
Risco Cardiovascular
Abacavir e Risco de Infarto Agudo do Miocaacuterdio e Doenccedila Cerebrovascularna era HAART
R Bedimo12 A Westfall3 H Drechsler12 P Tebas41VA North Texas Healthcare System Medicine Dallas United States 2University of Texas Southwestern MedicalCenter Medicine Dallas United States 3University of Alabama at Birmingham Medicine Birmingham United
States 4University of Pennsylvania Medicine Philadelphia United States
19424 pacientes acompanhados por cerca de 4 anos (75311 pessoas-ano) 278 IAM e 868 AVC entre pessoas com mais fatores de risco para DCV incluindo hepatite C e doenccedila renal
Taxa global IAM 369 por 1000 pessoas-ano AVC 1168 por 1000 pessoas-ano
Abacavir associado a maior risco de IAM (hazard ratio [HR] 127 ou 27 aumento do risco) e de AVC (HR 117)
Anaacutelise foi repetida apoacutes controle dos fatores de risco conhecidos paraDCV e condiccedilotildees coexistentes (idade hiperlipidemia hipertensatildeo diabetes tabagismo) e a associaccedilatildeo entre abacavir e IAM ou AVC deixou de ser forte e deixou de ser estatisticamente significante
Pacientes HIV+ com problemas renais satildeo mais medicados com abacavir comoalternativa ao tenofovir e jaacute tecircm maior risco de DCV e de AVC o que passoua ser considerado fator de confusatildeo na anaacutelise
DAD exposiccedilatildeo ao ATVRTV ou DRVRTV e risco
cardiovascular
bull Prospectivo Jan2009 (BL) ateacute o primeiro evento CV uacuteltima visita + 6 meses ou 01022016
bull (N = 35711)
ndash 1157 pts (32) apresentaram DCV (IM AVE morte suacutebita) ou se submeteram a um procedimento cardiacuteaco invasivo
bull Exposiccedilatildeo cumulativa a DRVRTV estaacute associada a risco CV - anaacutelisemultivariada 59 risco aumentadocom 5 anos de uso
ndash Associaccedilatildeo natildeo parece ser mediada pordislipidemia
bull Limitaccedilotildees Fatores de confusatildeo potencialmente natildeomensuraacuteveis num estudo observacional ndash Natildeo foipossiacutevel diferenciar entre DRVRTV 800100 QD vs DRVRTV 600100 BID
bull Natildeo avaliou uso de estatinas natildeo ajustou para supressatildeo viral Fumo atual apenas Exposiccedilatildeo aotabaco em maccedilosano natildeo foi avaliada exposiccedilatildeopreacutevia a IP de primeira geraccedilatildeo natildeo avaliada
Ryom L et al CROI 2017 Abstract 128LB
Incidence Rates of CVD andCumulative Exposure to ATV+RTV and DRV+RTV
ATV+RTV DRV+RTV
Cumulative years of drug exposure
200
150
100
50
40
30
20
0
Incid
en
ce r
ate
1000 P
YF
U (
95
CI)
Incidecircncia de Doenccedilas Crocircnicas
Aumenta Exponencialmente com a Idade
Idade
INC
IDEcirc
NC
IA
Idade eacute o maior fator de riscoSlide cortesia de Peter Reiss
Schouten J et al Clin Infect Dis 2014
Comorbidades relacionadas agrave idade
A IDADE Eacute FATOR DE RISCO INDEPENDENTE E NAtildeO MODIFICAacuteVEL PARA DCV
J GUNTER ET AL ACTA CLINICA BELGICA INTERNATIONAL JOURNAL OF CLINICAL AND LABORATORY MEDICINE
Prevalecircncia de Fatores Predisponentes
para Fragilidade
KKooij et al 8th Netherlands Conference on HIV Pathogenesis Epidemiology Prevention and Treatment Amsterdam November 2014
Causas de Morte 1999-2011
Continuous Increase of Cardiovascular Diseases Diabetes and Non-HIV Related Cancers
as Causes of Death in HIV-Infected Individuals in Brazil An Analysis of Nationwide Data
Paula AA Schechter M Tuboi SH Faulhaber JC Luz PM et al (2014) PLOS ONE 9(4)
e94636 httpsdoiorg101371journalpone0094636
bull 12366853 atestados
bull 151706 (123) HIVAIDS
ATVr DRVr EFV RPV DTG RAL ABC FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Antihypert
ensiv
eagents
Amlodipine
Atenolol
Bisoprolol
Enalapril
Felodipine
Indapamide
Lisinopril
Losartan
Nifedipine
Olmesartan
Perindopril
Valsartan
Interaccedilotildees com Antihipertensivos
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Potential interaction
no dose adjustment
required
ATVr DRVr EFV RPV DTG RAL
AB
C FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Lip
id-l
ow
ering a
gents
Atorvastatin
Fluvastatin
Lovastatin
Pravastatin
Rosuvastatin
Simvastatin
Antidia
betic a
gents
Glibenclamid
e (Glyburide)
Linagliptin
Metformin
Nateglinide
Saxagliptin
Sitagliptin
Interaccedilotildees Medicamentosas com Hipolipemiantes e Hipoglicemiantes
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Do not co-
administer
Potential interaction
no dose adjustment
required
Interaccedilotildees com Medicamentos que atuam no SNC
BOOSTED FREE AGENTS BOOSTED AGENTS
DTGII RAL EFV ETV RPV EVGc DRVr
Stim
ula
nts
amyl nitrate
cocaine
ecstasy (MDMA)
mephedrone
methamphetamine
Dep
ress
ants
alcohol
alprazolam
codeine
diazepam
GHB (gamma hydroxybutyrate)
heroin (diamorphone)
hydrocodone
hydromorphone
ketamine
pethidine (meperideine)
methadone
midazolam (oral)
morphine
oxycodone
temazepam
triazolam
Hal
luci
no
gen
s
cannabis
lysergic acid dietheylamide (LSD)
phencyclidine (PCP angle dust)
Further information (in vivo in vitro or from label) at wwwhiv-druginteractionsorg
These drugs should not be co-administered
Potential interaction-may require close monitoring alteration of drug dosage or timing of administration
No clinically significant expected
Dose do DTG interfere nos niacuteveis de Metformina
Haacute aumento da exposiccedilatildeo plasmaacutetica da metformina
quando coadministrada com DTG e o efeito produzido
(PK) no niacutevel de metformina eacute dose-dependente do DTG
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50 mgq24h
Metf
orm
in c
on
cen
trati
on
(microg
mL
)
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q24h
Metformin alone Period
3
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50mg q12h
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q12h
Metformin alone Period
3
bull Anaacutelise retrospectiva de adultos HIV+ que mudaram o esquema para
outros contendo DTG e fazendo uso concomitante de metformina
(n=15)
bull DTG natildeo alterou a resposta ao uso da metformina nos pacientes
diabeacuteticos
ndash Natildeo houve diferenccedila significante nos niacuteveis de glicose em jejum nem
na concentraccedilatildeo de HbA1 observados antes e depois da troca para
DTG
Na vida real natildeo houve diferenccedila significativa na glicemia de jejum nem na Hb glicada antes e depois da troca para DTG
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
BHIVA 2016 April Manchester UKCB Jones1 J Tan1 J Robinson1 H Tate1 H Lamba1
1Merck Sharp ampDohme Limited Hertford Road Hoddesdon Hertfordshire
- Comorbidades satildeo frequentes
- 70 das pessoas fazem uso de outros medicamentos
- Supressatildeo viral alcanccedilada em cerca de 85 dos casos
independentemente da idade das comorbidades e do uso
de outros medicamentos
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
n=19215 RAL em 83 dos esquemas (n=1428)
Switching From a Boosted Protease Inhibitor (PIr) Based Regimen to a
Dolutegravir (DTG) Regimen in Virologically Suppressed Patients With
High Cardiovascular Risk (Framingham Score gt10 or Age gt 50 Years) Is
Non-Inferior and Decreases Lipids The NEAT 022 Study
JM Gatell1 L Assoumou2 G Moyle3 L Waters4 E Martinez5 H-J
Stellbrink6 G Guaraldi7 S de Wit8 F Raffi9 A Pozniak10 on behalf of
NEAT022 Study Group
1Hospital ClinicIDIBAPS University of Barcelona Infectious Diseases Barcelona Spain 2Sorbone Universites INSERM
UPMC Univ Paris 06 IPLESP UMRS 1136 Paris France 3Chelsea and Westminster Hospital London United Kingdom4Mortimer Market Center London United Kingdom 5Hospital ClinicIDIBAPS University of Barcelona Barcelona Spain6Infectiologisches Centrum Hamburg Germany 7University of Modena and Reggio Emilia Modena Italy 8Saint Pierre
University Hospital Universiteacute Libre de Bruxelles Brussels Belgium 9CHU
Hotel-Dieu Nantes Nantes France 10Chelsea amp Westminster Hospital London United Kingdom
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
Alteraccedilotildees Metaboacutelicas Endoacutecrinas e Lipodistrofia
bull Alteraccedilotildees metaboacutelicas (dislipidemia hiperglicemia diabetes) costumam ser associadas agrave esteatose hepaacutetica e ao maior risco de eventos cardiovasculares
bull Podem ocorrer pancreatite ou hiperamilasemia acidemia ou acidose laacutetica
bull Se houver depoacutesitos de gordura satildeo centrais abdome tronco mamas giba regiatildeo cervicofacial (lipohipertrofia) Se houver lipoatrofia eacute perifeacuterica (face e membros)
bull Podem ocorrer hipotireoidismo e hipogonadismo (alteraccedilotildeeshormonais costumam ser mais comuns nos homens com reduccedilatildeo de niacuteveis de testosterona)
Disfunccedilatildeo mitocondrial
bull lipodistrofia
bull neuropatias
bull esteatose
hepaacutetica
bull miopatia
bull pancreatite
bull acidose laacutetica
bull intoleracircncia agrave
glicose
resistecircncia agrave
insulina diabetes
TG e de LDL
reduccedilatildeo HDL
ARV (ITRN)
ITRcitocinas
HIV
bull Gama-DNA polimerasebull transportebull estresse oxidativobull apoptosebull fosforilaccedilatildeobull proteoacutelisebull glicosilaccedilatildeo
Alteraccedilotildees associadas aos Inibidores da Protease
resistecircncia agrave
insulina
GLUT4
GLUT1
reduccedilatildeo do armazenamento
de gordura nos adipoacutecitos
Interferecircncia na
utilizaccedilatildeo da glicose
nos muacutesculos e
adipoacutecitos
aumento de lipiacutedeos no
fiacutegado maior produccedilatildeo e
secreccedilatildeo de VLDL
hiperlipidemia
lipodystrophy
Interferecircncia na adipogecircnese
Siacutentese de TG
apoB VLDL
HIV e IPlipodistrofia
Alteraccedilotildees Metaboacutelicas Endoacutecrinas e Risco Cardiovascular
Infecccedilatildeo pelo HIV e Risco Cardiovascular
- 60 das pessoas com HIV tecircm placas nas arteacuterias cardiacuteacas mesmo semsinaissintomas
- Haacute relaccedilatildeo direta com a inflamaccedilatildeo decorrente da infecccedilatildeo pelo HIV
HIV e Aterosclerose
HIV-1-Associated Atherosclerosis Unraveling the Missing LinkJ Am Coll Cardiol 2017 Jun 2769(25)3084-3098 doi 01016jjacc201705012Kearns A Gordon J Burdo TH Qin X
Doenccedila cardiovascular incluindo aterosclerose e outras complicaccedilotildees associadas eacute causa
crescente de morbidade e mortalidade nos pacientes infectados pelo HIV na era poacutes-
HAART
Terapia antirretroviral comorbidades associadas tais como dislipidemia abuso de drogas
infecccedilotildees oportunistas e outros fatores de risco relacionados a haacutebitos de vida satildeo
importantes tanto para precipitar como para piorar a aterosclerose
Tipo 1 resulta espontaneamente da instabilidade da placa ateroscleroacutetica
Tipo 2 ocorre por desequiliacutebrio entre consumooferta de oxigecircnio vasoespasmo (por exemplo infecccedilatildeo ou uso de cocaiacutena)
EVENTOS CARDIOVASCULARES
Infarto Agudo do Miocaacuterdio
FatoresAnos Perdidos de Vida Idade 35 a 80 anos (95 CI)
Risco de morte
HIV + que nunca fumaram
(HIV + nunca que fumaram vs controlesque nunca fumaram)
51 (44ndash58) 03
Controles fumantes
(controles fumantes vs controles quenunca fumaram)
36 (31ndash40) 344
HIV + fumantes
(HIV + fumantes vs HIV + que nuncafumaram)
123 (115ndash130) 615
Tabagismo Mortalidade e HIV Helleberg Clin Infect Dis 2013
Nuacutemero de Anos Perdidos e Risco de Morte Atribuiacutedo agrave Populaccedilatildeo de Fumantes e com HIV
Em um local onde o tratamento da infecccedilatildeo pelo HIV eacute organizado e gratuito pessoas portadoras do HIV e
fumantes perdem mais anos de vida para o tabagismo do que para o proacuteprio viacuterus Satildeo 123 anos de vida
perdidos para o cigarro O excesso de mortalidade de fumantes eacute triplicado e o risco de morte associado
ao tabagismo eacute duplicado entre HIV + em comparaccedilatildeo agrave populaccedilatildeo natildeo fumante mesmo com HIV
NA-ACCORD Fumo hipertensatildeo arterial e niacuteveis de colesterol aumentam
risco de IAM em portadores do HIV
bull Metanaacutelise retrospectivabull Eventos validados de 7 coortes cliacutenicas
NA-ACCORD 12000 -122013 bull N = 29515[1]
ndash Fraccedilatildeo atribuiacutevel agrave populaccedilatildeo proporccedilatildeo de IM evitaacuteveis pela prevenccedilatildeo de fatores de risco modificaacuteveis relacionados com o HIV e tradicionais
ndash 347 pacientes (12) apresentavam IM de tipo 1 devido agrave ruptura da placa
ndash A anaacutelise de sensibilidade foi feita para 16687 pacientes (57) com dados de IMC 227 apresentaram IM tipo 1
ndash ~ 40 de reduccedilatildeo IM possiacutevel atraveacutes da prevenccedilatildeo do tabagismo TC elevado ou hipertensatildeo independentemente do IMC
1 Althoff KN et al CROI 2017 Abstract 130 2 Shepherd L et al CROI
2017 Abstract 131 Slide credit
clinicaloptionscom
bull Em outra anaacutelise separada (DAD) a interrupccedilatildeo do fumo reduziu as taxas globaisde cacircncer apoacutes 1 ano (exceto pulmatildeo quepermaneceu alta mesmo apoacutes 5 anos)[2]
Ajuste para idade sexo raccedila e fatores de risco
listados daggerP lt 05
Adjusted Population Attributable Fractions for MI[1]
MI
BMI Subgrou
p
Traditional MI risk factors
Smoking 38dagger 36
Elevated TC 43dagger 39dagger
HTN 41dagger 39dagger
All 3 (smoking TC HTN) 86
HIV-related MI risk factors
DM 2 4
CKD 3 3
CD4+ cell count 10dagger 14dagger
VL 6 8
AIDS 2 -1
HCV coinfection 8dagger 14dagger
bull Uso recente de ABC associado com ~70 aumento risco de IM
ndash Uso recente definido como ainda em uso ou interrupccedilatildeo dentrodos uacuteltimos seis meses
bull Exposiccedilatildeo cumulativa
ndash ao ABC foi associada com pequeno aumento do risco de IM
ndash ao Lopinavirr foi associada com aumento do risco de IM
Estudo DAD
Risco Cardiovascular
Abacavir e Risco de Infarto Agudo do Miocaacuterdio e Doenccedila Cerebrovascularna era HAART
R Bedimo12 A Westfall3 H Drechsler12 P Tebas41VA North Texas Healthcare System Medicine Dallas United States 2University of Texas Southwestern MedicalCenter Medicine Dallas United States 3University of Alabama at Birmingham Medicine Birmingham United
States 4University of Pennsylvania Medicine Philadelphia United States
19424 pacientes acompanhados por cerca de 4 anos (75311 pessoas-ano) 278 IAM e 868 AVC entre pessoas com mais fatores de risco para DCV incluindo hepatite C e doenccedila renal
Taxa global IAM 369 por 1000 pessoas-ano AVC 1168 por 1000 pessoas-ano
Abacavir associado a maior risco de IAM (hazard ratio [HR] 127 ou 27 aumento do risco) e de AVC (HR 117)
Anaacutelise foi repetida apoacutes controle dos fatores de risco conhecidos paraDCV e condiccedilotildees coexistentes (idade hiperlipidemia hipertensatildeo diabetes tabagismo) e a associaccedilatildeo entre abacavir e IAM ou AVC deixou de ser forte e deixou de ser estatisticamente significante
Pacientes HIV+ com problemas renais satildeo mais medicados com abacavir comoalternativa ao tenofovir e jaacute tecircm maior risco de DCV e de AVC o que passoua ser considerado fator de confusatildeo na anaacutelise
DAD exposiccedilatildeo ao ATVRTV ou DRVRTV e risco
cardiovascular
bull Prospectivo Jan2009 (BL) ateacute o primeiro evento CV uacuteltima visita + 6 meses ou 01022016
bull (N = 35711)
ndash 1157 pts (32) apresentaram DCV (IM AVE morte suacutebita) ou se submeteram a um procedimento cardiacuteaco invasivo
bull Exposiccedilatildeo cumulativa a DRVRTV estaacute associada a risco CV - anaacutelisemultivariada 59 risco aumentadocom 5 anos de uso
ndash Associaccedilatildeo natildeo parece ser mediada pordislipidemia
bull Limitaccedilotildees Fatores de confusatildeo potencialmente natildeomensuraacuteveis num estudo observacional ndash Natildeo foipossiacutevel diferenciar entre DRVRTV 800100 QD vs DRVRTV 600100 BID
bull Natildeo avaliou uso de estatinas natildeo ajustou para supressatildeo viral Fumo atual apenas Exposiccedilatildeo aotabaco em maccedilosano natildeo foi avaliada exposiccedilatildeopreacutevia a IP de primeira geraccedilatildeo natildeo avaliada
Ryom L et al CROI 2017 Abstract 128LB
Incidence Rates of CVD andCumulative Exposure to ATV+RTV and DRV+RTV
ATV+RTV DRV+RTV
Cumulative years of drug exposure
200
150
100
50
40
30
20
0
Incid
en
ce r
ate
1000 P
YF
U (
95
CI)
Incidecircncia de Doenccedilas Crocircnicas
Aumenta Exponencialmente com a Idade
Idade
INC
IDEcirc
NC
IA
Idade eacute o maior fator de riscoSlide cortesia de Peter Reiss
Schouten J et al Clin Infect Dis 2014
Comorbidades relacionadas agrave idade
A IDADE Eacute FATOR DE RISCO INDEPENDENTE E NAtildeO MODIFICAacuteVEL PARA DCV
J GUNTER ET AL ACTA CLINICA BELGICA INTERNATIONAL JOURNAL OF CLINICAL AND LABORATORY MEDICINE
Prevalecircncia de Fatores Predisponentes
para Fragilidade
KKooij et al 8th Netherlands Conference on HIV Pathogenesis Epidemiology Prevention and Treatment Amsterdam November 2014
Causas de Morte 1999-2011
Continuous Increase of Cardiovascular Diseases Diabetes and Non-HIV Related Cancers
as Causes of Death in HIV-Infected Individuals in Brazil An Analysis of Nationwide Data
Paula AA Schechter M Tuboi SH Faulhaber JC Luz PM et al (2014) PLOS ONE 9(4)
e94636 httpsdoiorg101371journalpone0094636
bull 12366853 atestados
bull 151706 (123) HIVAIDS
ATVr DRVr EFV RPV DTG RAL ABC FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Antihypert
ensiv
eagents
Amlodipine
Atenolol
Bisoprolol
Enalapril
Felodipine
Indapamide
Lisinopril
Losartan
Nifedipine
Olmesartan
Perindopril
Valsartan
Interaccedilotildees com Antihipertensivos
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Potential interaction
no dose adjustment
required
ATVr DRVr EFV RPV DTG RAL
AB
C FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Lip
id-l
ow
ering a
gents
Atorvastatin
Fluvastatin
Lovastatin
Pravastatin
Rosuvastatin
Simvastatin
Antidia
betic a
gents
Glibenclamid
e (Glyburide)
Linagliptin
Metformin
Nateglinide
Saxagliptin
Sitagliptin
Interaccedilotildees Medicamentosas com Hipolipemiantes e Hipoglicemiantes
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Do not co-
administer
Potential interaction
no dose adjustment
required
Interaccedilotildees com Medicamentos que atuam no SNC
BOOSTED FREE AGENTS BOOSTED AGENTS
DTGII RAL EFV ETV RPV EVGc DRVr
Stim
ula
nts
amyl nitrate
cocaine
ecstasy (MDMA)
mephedrone
methamphetamine
Dep
ress
ants
alcohol
alprazolam
codeine
diazepam
GHB (gamma hydroxybutyrate)
heroin (diamorphone)
hydrocodone
hydromorphone
ketamine
pethidine (meperideine)
methadone
midazolam (oral)
morphine
oxycodone
temazepam
triazolam
Hal
luci
no
gen
s
cannabis
lysergic acid dietheylamide (LSD)
phencyclidine (PCP angle dust)
Further information (in vivo in vitro or from label) at wwwhiv-druginteractionsorg
These drugs should not be co-administered
Potential interaction-may require close monitoring alteration of drug dosage or timing of administration
No clinically significant expected
Dose do DTG interfere nos niacuteveis de Metformina
Haacute aumento da exposiccedilatildeo plasmaacutetica da metformina
quando coadministrada com DTG e o efeito produzido
(PK) no niacutevel de metformina eacute dose-dependente do DTG
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50 mgq24h
Metf
orm
in c
on
cen
trati
on
(microg
mL
)
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q24h
Metformin alone Period
3
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50mg q12h
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q12h
Metformin alone Period
3
bull Anaacutelise retrospectiva de adultos HIV+ que mudaram o esquema para
outros contendo DTG e fazendo uso concomitante de metformina
(n=15)
bull DTG natildeo alterou a resposta ao uso da metformina nos pacientes
diabeacuteticos
ndash Natildeo houve diferenccedila significante nos niacuteveis de glicose em jejum nem
na concentraccedilatildeo de HbA1 observados antes e depois da troca para
DTG
Na vida real natildeo houve diferenccedila significativa na glicemia de jejum nem na Hb glicada antes e depois da troca para DTG
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
BHIVA 2016 April Manchester UKCB Jones1 J Tan1 J Robinson1 H Tate1 H Lamba1
1Merck Sharp ampDohme Limited Hertford Road Hoddesdon Hertfordshire
- Comorbidades satildeo frequentes
- 70 das pessoas fazem uso de outros medicamentos
- Supressatildeo viral alcanccedilada em cerca de 85 dos casos
independentemente da idade das comorbidades e do uso
de outros medicamentos
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
n=19215 RAL em 83 dos esquemas (n=1428)
Switching From a Boosted Protease Inhibitor (PIr) Based Regimen to a
Dolutegravir (DTG) Regimen in Virologically Suppressed Patients With
High Cardiovascular Risk (Framingham Score gt10 or Age gt 50 Years) Is
Non-Inferior and Decreases Lipids The NEAT 022 Study
JM Gatell1 L Assoumou2 G Moyle3 L Waters4 E Martinez5 H-J
Stellbrink6 G Guaraldi7 S de Wit8 F Raffi9 A Pozniak10 on behalf of
NEAT022 Study Group
1Hospital ClinicIDIBAPS University of Barcelona Infectious Diseases Barcelona Spain 2Sorbone Universites INSERM
UPMC Univ Paris 06 IPLESP UMRS 1136 Paris France 3Chelsea and Westminster Hospital London United Kingdom4Mortimer Market Center London United Kingdom 5Hospital ClinicIDIBAPS University of Barcelona Barcelona Spain6Infectiologisches Centrum Hamburg Germany 7University of Modena and Reggio Emilia Modena Italy 8Saint Pierre
University Hospital Universiteacute Libre de Bruxelles Brussels Belgium 9CHU
Hotel-Dieu Nantes Nantes France 10Chelsea amp Westminster Hospital London United Kingdom
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
Disfunccedilatildeo mitocondrial
bull lipodistrofia
bull neuropatias
bull esteatose
hepaacutetica
bull miopatia
bull pancreatite
bull acidose laacutetica
bull intoleracircncia agrave
glicose
resistecircncia agrave
insulina diabetes
TG e de LDL
reduccedilatildeo HDL
ARV (ITRN)
ITRcitocinas
HIV
bull Gama-DNA polimerasebull transportebull estresse oxidativobull apoptosebull fosforilaccedilatildeobull proteoacutelisebull glicosilaccedilatildeo
Alteraccedilotildees associadas aos Inibidores da Protease
resistecircncia agrave
insulina
GLUT4
GLUT1
reduccedilatildeo do armazenamento
de gordura nos adipoacutecitos
Interferecircncia na
utilizaccedilatildeo da glicose
nos muacutesculos e
adipoacutecitos
aumento de lipiacutedeos no
fiacutegado maior produccedilatildeo e
secreccedilatildeo de VLDL
hiperlipidemia
lipodystrophy
Interferecircncia na adipogecircnese
Siacutentese de TG
apoB VLDL
HIV e IPlipodistrofia
Alteraccedilotildees Metaboacutelicas Endoacutecrinas e Risco Cardiovascular
Infecccedilatildeo pelo HIV e Risco Cardiovascular
- 60 das pessoas com HIV tecircm placas nas arteacuterias cardiacuteacas mesmo semsinaissintomas
- Haacute relaccedilatildeo direta com a inflamaccedilatildeo decorrente da infecccedilatildeo pelo HIV
HIV e Aterosclerose
HIV-1-Associated Atherosclerosis Unraveling the Missing LinkJ Am Coll Cardiol 2017 Jun 2769(25)3084-3098 doi 01016jjacc201705012Kearns A Gordon J Burdo TH Qin X
Doenccedila cardiovascular incluindo aterosclerose e outras complicaccedilotildees associadas eacute causa
crescente de morbidade e mortalidade nos pacientes infectados pelo HIV na era poacutes-
HAART
Terapia antirretroviral comorbidades associadas tais como dislipidemia abuso de drogas
infecccedilotildees oportunistas e outros fatores de risco relacionados a haacutebitos de vida satildeo
importantes tanto para precipitar como para piorar a aterosclerose
Tipo 1 resulta espontaneamente da instabilidade da placa ateroscleroacutetica
Tipo 2 ocorre por desequiliacutebrio entre consumooferta de oxigecircnio vasoespasmo (por exemplo infecccedilatildeo ou uso de cocaiacutena)
EVENTOS CARDIOVASCULARES
Infarto Agudo do Miocaacuterdio
FatoresAnos Perdidos de Vida Idade 35 a 80 anos (95 CI)
Risco de morte
HIV + que nunca fumaram
(HIV + nunca que fumaram vs controlesque nunca fumaram)
51 (44ndash58) 03
Controles fumantes
(controles fumantes vs controles quenunca fumaram)
36 (31ndash40) 344
HIV + fumantes
(HIV + fumantes vs HIV + que nuncafumaram)
123 (115ndash130) 615
Tabagismo Mortalidade e HIV Helleberg Clin Infect Dis 2013
Nuacutemero de Anos Perdidos e Risco de Morte Atribuiacutedo agrave Populaccedilatildeo de Fumantes e com HIV
Em um local onde o tratamento da infecccedilatildeo pelo HIV eacute organizado e gratuito pessoas portadoras do HIV e
fumantes perdem mais anos de vida para o tabagismo do que para o proacuteprio viacuterus Satildeo 123 anos de vida
perdidos para o cigarro O excesso de mortalidade de fumantes eacute triplicado e o risco de morte associado
ao tabagismo eacute duplicado entre HIV + em comparaccedilatildeo agrave populaccedilatildeo natildeo fumante mesmo com HIV
NA-ACCORD Fumo hipertensatildeo arterial e niacuteveis de colesterol aumentam
risco de IAM em portadores do HIV
bull Metanaacutelise retrospectivabull Eventos validados de 7 coortes cliacutenicas
NA-ACCORD 12000 -122013 bull N = 29515[1]
ndash Fraccedilatildeo atribuiacutevel agrave populaccedilatildeo proporccedilatildeo de IM evitaacuteveis pela prevenccedilatildeo de fatores de risco modificaacuteveis relacionados com o HIV e tradicionais
ndash 347 pacientes (12) apresentavam IM de tipo 1 devido agrave ruptura da placa
ndash A anaacutelise de sensibilidade foi feita para 16687 pacientes (57) com dados de IMC 227 apresentaram IM tipo 1
ndash ~ 40 de reduccedilatildeo IM possiacutevel atraveacutes da prevenccedilatildeo do tabagismo TC elevado ou hipertensatildeo independentemente do IMC
1 Althoff KN et al CROI 2017 Abstract 130 2 Shepherd L et al CROI
2017 Abstract 131 Slide credit
clinicaloptionscom
bull Em outra anaacutelise separada (DAD) a interrupccedilatildeo do fumo reduziu as taxas globaisde cacircncer apoacutes 1 ano (exceto pulmatildeo quepermaneceu alta mesmo apoacutes 5 anos)[2]
Ajuste para idade sexo raccedila e fatores de risco
listados daggerP lt 05
Adjusted Population Attributable Fractions for MI[1]
MI
BMI Subgrou
p
Traditional MI risk factors
Smoking 38dagger 36
Elevated TC 43dagger 39dagger
HTN 41dagger 39dagger
All 3 (smoking TC HTN) 86
HIV-related MI risk factors
DM 2 4
CKD 3 3
CD4+ cell count 10dagger 14dagger
VL 6 8
AIDS 2 -1
HCV coinfection 8dagger 14dagger
bull Uso recente de ABC associado com ~70 aumento risco de IM
ndash Uso recente definido como ainda em uso ou interrupccedilatildeo dentrodos uacuteltimos seis meses
bull Exposiccedilatildeo cumulativa
ndash ao ABC foi associada com pequeno aumento do risco de IM
ndash ao Lopinavirr foi associada com aumento do risco de IM
Estudo DAD
Risco Cardiovascular
Abacavir e Risco de Infarto Agudo do Miocaacuterdio e Doenccedila Cerebrovascularna era HAART
R Bedimo12 A Westfall3 H Drechsler12 P Tebas41VA North Texas Healthcare System Medicine Dallas United States 2University of Texas Southwestern MedicalCenter Medicine Dallas United States 3University of Alabama at Birmingham Medicine Birmingham United
States 4University of Pennsylvania Medicine Philadelphia United States
19424 pacientes acompanhados por cerca de 4 anos (75311 pessoas-ano) 278 IAM e 868 AVC entre pessoas com mais fatores de risco para DCV incluindo hepatite C e doenccedila renal
Taxa global IAM 369 por 1000 pessoas-ano AVC 1168 por 1000 pessoas-ano
Abacavir associado a maior risco de IAM (hazard ratio [HR] 127 ou 27 aumento do risco) e de AVC (HR 117)
Anaacutelise foi repetida apoacutes controle dos fatores de risco conhecidos paraDCV e condiccedilotildees coexistentes (idade hiperlipidemia hipertensatildeo diabetes tabagismo) e a associaccedilatildeo entre abacavir e IAM ou AVC deixou de ser forte e deixou de ser estatisticamente significante
Pacientes HIV+ com problemas renais satildeo mais medicados com abacavir comoalternativa ao tenofovir e jaacute tecircm maior risco de DCV e de AVC o que passoua ser considerado fator de confusatildeo na anaacutelise
DAD exposiccedilatildeo ao ATVRTV ou DRVRTV e risco
cardiovascular
bull Prospectivo Jan2009 (BL) ateacute o primeiro evento CV uacuteltima visita + 6 meses ou 01022016
bull (N = 35711)
ndash 1157 pts (32) apresentaram DCV (IM AVE morte suacutebita) ou se submeteram a um procedimento cardiacuteaco invasivo
bull Exposiccedilatildeo cumulativa a DRVRTV estaacute associada a risco CV - anaacutelisemultivariada 59 risco aumentadocom 5 anos de uso
ndash Associaccedilatildeo natildeo parece ser mediada pordislipidemia
bull Limitaccedilotildees Fatores de confusatildeo potencialmente natildeomensuraacuteveis num estudo observacional ndash Natildeo foipossiacutevel diferenciar entre DRVRTV 800100 QD vs DRVRTV 600100 BID
bull Natildeo avaliou uso de estatinas natildeo ajustou para supressatildeo viral Fumo atual apenas Exposiccedilatildeo aotabaco em maccedilosano natildeo foi avaliada exposiccedilatildeopreacutevia a IP de primeira geraccedilatildeo natildeo avaliada
Ryom L et al CROI 2017 Abstract 128LB
Incidence Rates of CVD andCumulative Exposure to ATV+RTV and DRV+RTV
ATV+RTV DRV+RTV
Cumulative years of drug exposure
200
150
100
50
40
30
20
0
Incid
en
ce r
ate
1000 P
YF
U (
95
CI)
Incidecircncia de Doenccedilas Crocircnicas
Aumenta Exponencialmente com a Idade
Idade
INC
IDEcirc
NC
IA
Idade eacute o maior fator de riscoSlide cortesia de Peter Reiss
Schouten J et al Clin Infect Dis 2014
Comorbidades relacionadas agrave idade
A IDADE Eacute FATOR DE RISCO INDEPENDENTE E NAtildeO MODIFICAacuteVEL PARA DCV
J GUNTER ET AL ACTA CLINICA BELGICA INTERNATIONAL JOURNAL OF CLINICAL AND LABORATORY MEDICINE
Prevalecircncia de Fatores Predisponentes
para Fragilidade
KKooij et al 8th Netherlands Conference on HIV Pathogenesis Epidemiology Prevention and Treatment Amsterdam November 2014
Causas de Morte 1999-2011
Continuous Increase of Cardiovascular Diseases Diabetes and Non-HIV Related Cancers
as Causes of Death in HIV-Infected Individuals in Brazil An Analysis of Nationwide Data
Paula AA Schechter M Tuboi SH Faulhaber JC Luz PM et al (2014) PLOS ONE 9(4)
e94636 httpsdoiorg101371journalpone0094636
bull 12366853 atestados
bull 151706 (123) HIVAIDS
ATVr DRVr EFV RPV DTG RAL ABC FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Antihypert
ensiv
eagents
Amlodipine
Atenolol
Bisoprolol
Enalapril
Felodipine
Indapamide
Lisinopril
Losartan
Nifedipine
Olmesartan
Perindopril
Valsartan
Interaccedilotildees com Antihipertensivos
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Potential interaction
no dose adjustment
required
ATVr DRVr EFV RPV DTG RAL
AB
C FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Lip
id-l
ow
ering a
gents
Atorvastatin
Fluvastatin
Lovastatin
Pravastatin
Rosuvastatin
Simvastatin
Antidia
betic a
gents
Glibenclamid
e (Glyburide)
Linagliptin
Metformin
Nateglinide
Saxagliptin
Sitagliptin
Interaccedilotildees Medicamentosas com Hipolipemiantes e Hipoglicemiantes
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Do not co-
administer
Potential interaction
no dose adjustment
required
Interaccedilotildees com Medicamentos que atuam no SNC
BOOSTED FREE AGENTS BOOSTED AGENTS
DTGII RAL EFV ETV RPV EVGc DRVr
Stim
ula
nts
amyl nitrate
cocaine
ecstasy (MDMA)
mephedrone
methamphetamine
Dep
ress
ants
alcohol
alprazolam
codeine
diazepam
GHB (gamma hydroxybutyrate)
heroin (diamorphone)
hydrocodone
hydromorphone
ketamine
pethidine (meperideine)
methadone
midazolam (oral)
morphine
oxycodone
temazepam
triazolam
Hal
luci
no
gen
s
cannabis
lysergic acid dietheylamide (LSD)
phencyclidine (PCP angle dust)
Further information (in vivo in vitro or from label) at wwwhiv-druginteractionsorg
These drugs should not be co-administered
Potential interaction-may require close monitoring alteration of drug dosage or timing of administration
No clinically significant expected
Dose do DTG interfere nos niacuteveis de Metformina
Haacute aumento da exposiccedilatildeo plasmaacutetica da metformina
quando coadministrada com DTG e o efeito produzido
(PK) no niacutevel de metformina eacute dose-dependente do DTG
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50 mgq24h
Metf
orm
in c
on
cen
trati
on
(microg
mL
)
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q24h
Metformin alone Period
3
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50mg q12h
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q12h
Metformin alone Period
3
bull Anaacutelise retrospectiva de adultos HIV+ que mudaram o esquema para
outros contendo DTG e fazendo uso concomitante de metformina
(n=15)
bull DTG natildeo alterou a resposta ao uso da metformina nos pacientes
diabeacuteticos
ndash Natildeo houve diferenccedila significante nos niacuteveis de glicose em jejum nem
na concentraccedilatildeo de HbA1 observados antes e depois da troca para
DTG
Na vida real natildeo houve diferenccedila significativa na glicemia de jejum nem na Hb glicada antes e depois da troca para DTG
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
BHIVA 2016 April Manchester UKCB Jones1 J Tan1 J Robinson1 H Tate1 H Lamba1
1Merck Sharp ampDohme Limited Hertford Road Hoddesdon Hertfordshire
- Comorbidades satildeo frequentes
- 70 das pessoas fazem uso de outros medicamentos
- Supressatildeo viral alcanccedilada em cerca de 85 dos casos
independentemente da idade das comorbidades e do uso
de outros medicamentos
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
n=19215 RAL em 83 dos esquemas (n=1428)
Switching From a Boosted Protease Inhibitor (PIr) Based Regimen to a
Dolutegravir (DTG) Regimen in Virologically Suppressed Patients With
High Cardiovascular Risk (Framingham Score gt10 or Age gt 50 Years) Is
Non-Inferior and Decreases Lipids The NEAT 022 Study
JM Gatell1 L Assoumou2 G Moyle3 L Waters4 E Martinez5 H-J
Stellbrink6 G Guaraldi7 S de Wit8 F Raffi9 A Pozniak10 on behalf of
NEAT022 Study Group
1Hospital ClinicIDIBAPS University of Barcelona Infectious Diseases Barcelona Spain 2Sorbone Universites INSERM
UPMC Univ Paris 06 IPLESP UMRS 1136 Paris France 3Chelsea and Westminster Hospital London United Kingdom4Mortimer Market Center London United Kingdom 5Hospital ClinicIDIBAPS University of Barcelona Barcelona Spain6Infectiologisches Centrum Hamburg Germany 7University of Modena and Reggio Emilia Modena Italy 8Saint Pierre
University Hospital Universiteacute Libre de Bruxelles Brussels Belgium 9CHU
Hotel-Dieu Nantes Nantes France 10Chelsea amp Westminster Hospital London United Kingdom
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
Alteraccedilotildees associadas aos Inibidores da Protease
resistecircncia agrave
insulina
GLUT4
GLUT1
reduccedilatildeo do armazenamento
de gordura nos adipoacutecitos
Interferecircncia na
utilizaccedilatildeo da glicose
nos muacutesculos e
adipoacutecitos
aumento de lipiacutedeos no
fiacutegado maior produccedilatildeo e
secreccedilatildeo de VLDL
hiperlipidemia
lipodystrophy
Interferecircncia na adipogecircnese
Siacutentese de TG
apoB VLDL
HIV e IPlipodistrofia
Alteraccedilotildees Metaboacutelicas Endoacutecrinas e Risco Cardiovascular
Infecccedilatildeo pelo HIV e Risco Cardiovascular
- 60 das pessoas com HIV tecircm placas nas arteacuterias cardiacuteacas mesmo semsinaissintomas
- Haacute relaccedilatildeo direta com a inflamaccedilatildeo decorrente da infecccedilatildeo pelo HIV
HIV e Aterosclerose
HIV-1-Associated Atherosclerosis Unraveling the Missing LinkJ Am Coll Cardiol 2017 Jun 2769(25)3084-3098 doi 01016jjacc201705012Kearns A Gordon J Burdo TH Qin X
Doenccedila cardiovascular incluindo aterosclerose e outras complicaccedilotildees associadas eacute causa
crescente de morbidade e mortalidade nos pacientes infectados pelo HIV na era poacutes-
HAART
Terapia antirretroviral comorbidades associadas tais como dislipidemia abuso de drogas
infecccedilotildees oportunistas e outros fatores de risco relacionados a haacutebitos de vida satildeo
importantes tanto para precipitar como para piorar a aterosclerose
Tipo 1 resulta espontaneamente da instabilidade da placa ateroscleroacutetica
Tipo 2 ocorre por desequiliacutebrio entre consumooferta de oxigecircnio vasoespasmo (por exemplo infecccedilatildeo ou uso de cocaiacutena)
EVENTOS CARDIOVASCULARES
Infarto Agudo do Miocaacuterdio
FatoresAnos Perdidos de Vida Idade 35 a 80 anos (95 CI)
Risco de morte
HIV + que nunca fumaram
(HIV + nunca que fumaram vs controlesque nunca fumaram)
51 (44ndash58) 03
Controles fumantes
(controles fumantes vs controles quenunca fumaram)
36 (31ndash40) 344
HIV + fumantes
(HIV + fumantes vs HIV + que nuncafumaram)
123 (115ndash130) 615
Tabagismo Mortalidade e HIV Helleberg Clin Infect Dis 2013
Nuacutemero de Anos Perdidos e Risco de Morte Atribuiacutedo agrave Populaccedilatildeo de Fumantes e com HIV
Em um local onde o tratamento da infecccedilatildeo pelo HIV eacute organizado e gratuito pessoas portadoras do HIV e
fumantes perdem mais anos de vida para o tabagismo do que para o proacuteprio viacuterus Satildeo 123 anos de vida
perdidos para o cigarro O excesso de mortalidade de fumantes eacute triplicado e o risco de morte associado
ao tabagismo eacute duplicado entre HIV + em comparaccedilatildeo agrave populaccedilatildeo natildeo fumante mesmo com HIV
NA-ACCORD Fumo hipertensatildeo arterial e niacuteveis de colesterol aumentam
risco de IAM em portadores do HIV
bull Metanaacutelise retrospectivabull Eventos validados de 7 coortes cliacutenicas
NA-ACCORD 12000 -122013 bull N = 29515[1]
ndash Fraccedilatildeo atribuiacutevel agrave populaccedilatildeo proporccedilatildeo de IM evitaacuteveis pela prevenccedilatildeo de fatores de risco modificaacuteveis relacionados com o HIV e tradicionais
ndash 347 pacientes (12) apresentavam IM de tipo 1 devido agrave ruptura da placa
ndash A anaacutelise de sensibilidade foi feita para 16687 pacientes (57) com dados de IMC 227 apresentaram IM tipo 1
ndash ~ 40 de reduccedilatildeo IM possiacutevel atraveacutes da prevenccedilatildeo do tabagismo TC elevado ou hipertensatildeo independentemente do IMC
1 Althoff KN et al CROI 2017 Abstract 130 2 Shepherd L et al CROI
2017 Abstract 131 Slide credit
clinicaloptionscom
bull Em outra anaacutelise separada (DAD) a interrupccedilatildeo do fumo reduziu as taxas globaisde cacircncer apoacutes 1 ano (exceto pulmatildeo quepermaneceu alta mesmo apoacutes 5 anos)[2]
Ajuste para idade sexo raccedila e fatores de risco
listados daggerP lt 05
Adjusted Population Attributable Fractions for MI[1]
MI
BMI Subgrou
p
Traditional MI risk factors
Smoking 38dagger 36
Elevated TC 43dagger 39dagger
HTN 41dagger 39dagger
All 3 (smoking TC HTN) 86
HIV-related MI risk factors
DM 2 4
CKD 3 3
CD4+ cell count 10dagger 14dagger
VL 6 8
AIDS 2 -1
HCV coinfection 8dagger 14dagger
bull Uso recente de ABC associado com ~70 aumento risco de IM
ndash Uso recente definido como ainda em uso ou interrupccedilatildeo dentrodos uacuteltimos seis meses
bull Exposiccedilatildeo cumulativa
ndash ao ABC foi associada com pequeno aumento do risco de IM
ndash ao Lopinavirr foi associada com aumento do risco de IM
Estudo DAD
Risco Cardiovascular
Abacavir e Risco de Infarto Agudo do Miocaacuterdio e Doenccedila Cerebrovascularna era HAART
R Bedimo12 A Westfall3 H Drechsler12 P Tebas41VA North Texas Healthcare System Medicine Dallas United States 2University of Texas Southwestern MedicalCenter Medicine Dallas United States 3University of Alabama at Birmingham Medicine Birmingham United
States 4University of Pennsylvania Medicine Philadelphia United States
19424 pacientes acompanhados por cerca de 4 anos (75311 pessoas-ano) 278 IAM e 868 AVC entre pessoas com mais fatores de risco para DCV incluindo hepatite C e doenccedila renal
Taxa global IAM 369 por 1000 pessoas-ano AVC 1168 por 1000 pessoas-ano
Abacavir associado a maior risco de IAM (hazard ratio [HR] 127 ou 27 aumento do risco) e de AVC (HR 117)
Anaacutelise foi repetida apoacutes controle dos fatores de risco conhecidos paraDCV e condiccedilotildees coexistentes (idade hiperlipidemia hipertensatildeo diabetes tabagismo) e a associaccedilatildeo entre abacavir e IAM ou AVC deixou de ser forte e deixou de ser estatisticamente significante
Pacientes HIV+ com problemas renais satildeo mais medicados com abacavir comoalternativa ao tenofovir e jaacute tecircm maior risco de DCV e de AVC o que passoua ser considerado fator de confusatildeo na anaacutelise
DAD exposiccedilatildeo ao ATVRTV ou DRVRTV e risco
cardiovascular
bull Prospectivo Jan2009 (BL) ateacute o primeiro evento CV uacuteltima visita + 6 meses ou 01022016
bull (N = 35711)
ndash 1157 pts (32) apresentaram DCV (IM AVE morte suacutebita) ou se submeteram a um procedimento cardiacuteaco invasivo
bull Exposiccedilatildeo cumulativa a DRVRTV estaacute associada a risco CV - anaacutelisemultivariada 59 risco aumentadocom 5 anos de uso
ndash Associaccedilatildeo natildeo parece ser mediada pordislipidemia
bull Limitaccedilotildees Fatores de confusatildeo potencialmente natildeomensuraacuteveis num estudo observacional ndash Natildeo foipossiacutevel diferenciar entre DRVRTV 800100 QD vs DRVRTV 600100 BID
bull Natildeo avaliou uso de estatinas natildeo ajustou para supressatildeo viral Fumo atual apenas Exposiccedilatildeo aotabaco em maccedilosano natildeo foi avaliada exposiccedilatildeopreacutevia a IP de primeira geraccedilatildeo natildeo avaliada
Ryom L et al CROI 2017 Abstract 128LB
Incidence Rates of CVD andCumulative Exposure to ATV+RTV and DRV+RTV
ATV+RTV DRV+RTV
Cumulative years of drug exposure
200
150
100
50
40
30
20
0
Incid
en
ce r
ate
1000 P
YF
U (
95
CI)
Incidecircncia de Doenccedilas Crocircnicas
Aumenta Exponencialmente com a Idade
Idade
INC
IDEcirc
NC
IA
Idade eacute o maior fator de riscoSlide cortesia de Peter Reiss
Schouten J et al Clin Infect Dis 2014
Comorbidades relacionadas agrave idade
A IDADE Eacute FATOR DE RISCO INDEPENDENTE E NAtildeO MODIFICAacuteVEL PARA DCV
J GUNTER ET AL ACTA CLINICA BELGICA INTERNATIONAL JOURNAL OF CLINICAL AND LABORATORY MEDICINE
Prevalecircncia de Fatores Predisponentes
para Fragilidade
KKooij et al 8th Netherlands Conference on HIV Pathogenesis Epidemiology Prevention and Treatment Amsterdam November 2014
Causas de Morte 1999-2011
Continuous Increase of Cardiovascular Diseases Diabetes and Non-HIV Related Cancers
as Causes of Death in HIV-Infected Individuals in Brazil An Analysis of Nationwide Data
Paula AA Schechter M Tuboi SH Faulhaber JC Luz PM et al (2014) PLOS ONE 9(4)
e94636 httpsdoiorg101371journalpone0094636
bull 12366853 atestados
bull 151706 (123) HIVAIDS
ATVr DRVr EFV RPV DTG RAL ABC FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Antihypert
ensiv
eagents
Amlodipine
Atenolol
Bisoprolol
Enalapril
Felodipine
Indapamide
Lisinopril
Losartan
Nifedipine
Olmesartan
Perindopril
Valsartan
Interaccedilotildees com Antihipertensivos
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Potential interaction
no dose adjustment
required
ATVr DRVr EFV RPV DTG RAL
AB
C FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Lip
id-l
ow
ering a
gents
Atorvastatin
Fluvastatin
Lovastatin
Pravastatin
Rosuvastatin
Simvastatin
Antidia
betic a
gents
Glibenclamid
e (Glyburide)
Linagliptin
Metformin
Nateglinide
Saxagliptin
Sitagliptin
Interaccedilotildees Medicamentosas com Hipolipemiantes e Hipoglicemiantes
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Do not co-
administer
Potential interaction
no dose adjustment
required
Interaccedilotildees com Medicamentos que atuam no SNC
BOOSTED FREE AGENTS BOOSTED AGENTS
DTGII RAL EFV ETV RPV EVGc DRVr
Stim
ula
nts
amyl nitrate
cocaine
ecstasy (MDMA)
mephedrone
methamphetamine
Dep
ress
ants
alcohol
alprazolam
codeine
diazepam
GHB (gamma hydroxybutyrate)
heroin (diamorphone)
hydrocodone
hydromorphone
ketamine
pethidine (meperideine)
methadone
midazolam (oral)
morphine
oxycodone
temazepam
triazolam
Hal
luci
no
gen
s
cannabis
lysergic acid dietheylamide (LSD)
phencyclidine (PCP angle dust)
Further information (in vivo in vitro or from label) at wwwhiv-druginteractionsorg
These drugs should not be co-administered
Potential interaction-may require close monitoring alteration of drug dosage or timing of administration
No clinically significant expected
Dose do DTG interfere nos niacuteveis de Metformina
Haacute aumento da exposiccedilatildeo plasmaacutetica da metformina
quando coadministrada com DTG e o efeito produzido
(PK) no niacutevel de metformina eacute dose-dependente do DTG
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50 mgq24h
Metf
orm
in c
on
cen
trati
on
(microg
mL
)
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q24h
Metformin alone Period
3
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50mg q12h
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q12h
Metformin alone Period
3
bull Anaacutelise retrospectiva de adultos HIV+ que mudaram o esquema para
outros contendo DTG e fazendo uso concomitante de metformina
(n=15)
bull DTG natildeo alterou a resposta ao uso da metformina nos pacientes
diabeacuteticos
ndash Natildeo houve diferenccedila significante nos niacuteveis de glicose em jejum nem
na concentraccedilatildeo de HbA1 observados antes e depois da troca para
DTG
Na vida real natildeo houve diferenccedila significativa na glicemia de jejum nem na Hb glicada antes e depois da troca para DTG
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
BHIVA 2016 April Manchester UKCB Jones1 J Tan1 J Robinson1 H Tate1 H Lamba1
1Merck Sharp ampDohme Limited Hertford Road Hoddesdon Hertfordshire
- Comorbidades satildeo frequentes
- 70 das pessoas fazem uso de outros medicamentos
- Supressatildeo viral alcanccedilada em cerca de 85 dos casos
independentemente da idade das comorbidades e do uso
de outros medicamentos
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
n=19215 RAL em 83 dos esquemas (n=1428)
Switching From a Boosted Protease Inhibitor (PIr) Based Regimen to a
Dolutegravir (DTG) Regimen in Virologically Suppressed Patients With
High Cardiovascular Risk (Framingham Score gt10 or Age gt 50 Years) Is
Non-Inferior and Decreases Lipids The NEAT 022 Study
JM Gatell1 L Assoumou2 G Moyle3 L Waters4 E Martinez5 H-J
Stellbrink6 G Guaraldi7 S de Wit8 F Raffi9 A Pozniak10 on behalf of
NEAT022 Study Group
1Hospital ClinicIDIBAPS University of Barcelona Infectious Diseases Barcelona Spain 2Sorbone Universites INSERM
UPMC Univ Paris 06 IPLESP UMRS 1136 Paris France 3Chelsea and Westminster Hospital London United Kingdom4Mortimer Market Center London United Kingdom 5Hospital ClinicIDIBAPS University of Barcelona Barcelona Spain6Infectiologisches Centrum Hamburg Germany 7University of Modena and Reggio Emilia Modena Italy 8Saint Pierre
University Hospital Universiteacute Libre de Bruxelles Brussels Belgium 9CHU
Hotel-Dieu Nantes Nantes France 10Chelsea amp Westminster Hospital London United Kingdom
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
Alteraccedilotildees Metaboacutelicas Endoacutecrinas e Risco Cardiovascular
Infecccedilatildeo pelo HIV e Risco Cardiovascular
- 60 das pessoas com HIV tecircm placas nas arteacuterias cardiacuteacas mesmo semsinaissintomas
- Haacute relaccedilatildeo direta com a inflamaccedilatildeo decorrente da infecccedilatildeo pelo HIV
HIV e Aterosclerose
HIV-1-Associated Atherosclerosis Unraveling the Missing LinkJ Am Coll Cardiol 2017 Jun 2769(25)3084-3098 doi 01016jjacc201705012Kearns A Gordon J Burdo TH Qin X
Doenccedila cardiovascular incluindo aterosclerose e outras complicaccedilotildees associadas eacute causa
crescente de morbidade e mortalidade nos pacientes infectados pelo HIV na era poacutes-
HAART
Terapia antirretroviral comorbidades associadas tais como dislipidemia abuso de drogas
infecccedilotildees oportunistas e outros fatores de risco relacionados a haacutebitos de vida satildeo
importantes tanto para precipitar como para piorar a aterosclerose
Tipo 1 resulta espontaneamente da instabilidade da placa ateroscleroacutetica
Tipo 2 ocorre por desequiliacutebrio entre consumooferta de oxigecircnio vasoespasmo (por exemplo infecccedilatildeo ou uso de cocaiacutena)
EVENTOS CARDIOVASCULARES
Infarto Agudo do Miocaacuterdio
FatoresAnos Perdidos de Vida Idade 35 a 80 anos (95 CI)
Risco de morte
HIV + que nunca fumaram
(HIV + nunca que fumaram vs controlesque nunca fumaram)
51 (44ndash58) 03
Controles fumantes
(controles fumantes vs controles quenunca fumaram)
36 (31ndash40) 344
HIV + fumantes
(HIV + fumantes vs HIV + que nuncafumaram)
123 (115ndash130) 615
Tabagismo Mortalidade e HIV Helleberg Clin Infect Dis 2013
Nuacutemero de Anos Perdidos e Risco de Morte Atribuiacutedo agrave Populaccedilatildeo de Fumantes e com HIV
Em um local onde o tratamento da infecccedilatildeo pelo HIV eacute organizado e gratuito pessoas portadoras do HIV e
fumantes perdem mais anos de vida para o tabagismo do que para o proacuteprio viacuterus Satildeo 123 anos de vida
perdidos para o cigarro O excesso de mortalidade de fumantes eacute triplicado e o risco de morte associado
ao tabagismo eacute duplicado entre HIV + em comparaccedilatildeo agrave populaccedilatildeo natildeo fumante mesmo com HIV
NA-ACCORD Fumo hipertensatildeo arterial e niacuteveis de colesterol aumentam
risco de IAM em portadores do HIV
bull Metanaacutelise retrospectivabull Eventos validados de 7 coortes cliacutenicas
NA-ACCORD 12000 -122013 bull N = 29515[1]
ndash Fraccedilatildeo atribuiacutevel agrave populaccedilatildeo proporccedilatildeo de IM evitaacuteveis pela prevenccedilatildeo de fatores de risco modificaacuteveis relacionados com o HIV e tradicionais
ndash 347 pacientes (12) apresentavam IM de tipo 1 devido agrave ruptura da placa
ndash A anaacutelise de sensibilidade foi feita para 16687 pacientes (57) com dados de IMC 227 apresentaram IM tipo 1
ndash ~ 40 de reduccedilatildeo IM possiacutevel atraveacutes da prevenccedilatildeo do tabagismo TC elevado ou hipertensatildeo independentemente do IMC
1 Althoff KN et al CROI 2017 Abstract 130 2 Shepherd L et al CROI
2017 Abstract 131 Slide credit
clinicaloptionscom
bull Em outra anaacutelise separada (DAD) a interrupccedilatildeo do fumo reduziu as taxas globaisde cacircncer apoacutes 1 ano (exceto pulmatildeo quepermaneceu alta mesmo apoacutes 5 anos)[2]
Ajuste para idade sexo raccedila e fatores de risco
listados daggerP lt 05
Adjusted Population Attributable Fractions for MI[1]
MI
BMI Subgrou
p
Traditional MI risk factors
Smoking 38dagger 36
Elevated TC 43dagger 39dagger
HTN 41dagger 39dagger
All 3 (smoking TC HTN) 86
HIV-related MI risk factors
DM 2 4
CKD 3 3
CD4+ cell count 10dagger 14dagger
VL 6 8
AIDS 2 -1
HCV coinfection 8dagger 14dagger
bull Uso recente de ABC associado com ~70 aumento risco de IM
ndash Uso recente definido como ainda em uso ou interrupccedilatildeo dentrodos uacuteltimos seis meses
bull Exposiccedilatildeo cumulativa
ndash ao ABC foi associada com pequeno aumento do risco de IM
ndash ao Lopinavirr foi associada com aumento do risco de IM
Estudo DAD
Risco Cardiovascular
Abacavir e Risco de Infarto Agudo do Miocaacuterdio e Doenccedila Cerebrovascularna era HAART
R Bedimo12 A Westfall3 H Drechsler12 P Tebas41VA North Texas Healthcare System Medicine Dallas United States 2University of Texas Southwestern MedicalCenter Medicine Dallas United States 3University of Alabama at Birmingham Medicine Birmingham United
States 4University of Pennsylvania Medicine Philadelphia United States
19424 pacientes acompanhados por cerca de 4 anos (75311 pessoas-ano) 278 IAM e 868 AVC entre pessoas com mais fatores de risco para DCV incluindo hepatite C e doenccedila renal
Taxa global IAM 369 por 1000 pessoas-ano AVC 1168 por 1000 pessoas-ano
Abacavir associado a maior risco de IAM (hazard ratio [HR] 127 ou 27 aumento do risco) e de AVC (HR 117)
Anaacutelise foi repetida apoacutes controle dos fatores de risco conhecidos paraDCV e condiccedilotildees coexistentes (idade hiperlipidemia hipertensatildeo diabetes tabagismo) e a associaccedilatildeo entre abacavir e IAM ou AVC deixou de ser forte e deixou de ser estatisticamente significante
Pacientes HIV+ com problemas renais satildeo mais medicados com abacavir comoalternativa ao tenofovir e jaacute tecircm maior risco de DCV e de AVC o que passoua ser considerado fator de confusatildeo na anaacutelise
DAD exposiccedilatildeo ao ATVRTV ou DRVRTV e risco
cardiovascular
bull Prospectivo Jan2009 (BL) ateacute o primeiro evento CV uacuteltima visita + 6 meses ou 01022016
bull (N = 35711)
ndash 1157 pts (32) apresentaram DCV (IM AVE morte suacutebita) ou se submeteram a um procedimento cardiacuteaco invasivo
bull Exposiccedilatildeo cumulativa a DRVRTV estaacute associada a risco CV - anaacutelisemultivariada 59 risco aumentadocom 5 anos de uso
ndash Associaccedilatildeo natildeo parece ser mediada pordislipidemia
bull Limitaccedilotildees Fatores de confusatildeo potencialmente natildeomensuraacuteveis num estudo observacional ndash Natildeo foipossiacutevel diferenciar entre DRVRTV 800100 QD vs DRVRTV 600100 BID
bull Natildeo avaliou uso de estatinas natildeo ajustou para supressatildeo viral Fumo atual apenas Exposiccedilatildeo aotabaco em maccedilosano natildeo foi avaliada exposiccedilatildeopreacutevia a IP de primeira geraccedilatildeo natildeo avaliada
Ryom L et al CROI 2017 Abstract 128LB
Incidence Rates of CVD andCumulative Exposure to ATV+RTV and DRV+RTV
ATV+RTV DRV+RTV
Cumulative years of drug exposure
200
150
100
50
40
30
20
0
Incid
en
ce r
ate
1000 P
YF
U (
95
CI)
Incidecircncia de Doenccedilas Crocircnicas
Aumenta Exponencialmente com a Idade
Idade
INC
IDEcirc
NC
IA
Idade eacute o maior fator de riscoSlide cortesia de Peter Reiss
Schouten J et al Clin Infect Dis 2014
Comorbidades relacionadas agrave idade
A IDADE Eacute FATOR DE RISCO INDEPENDENTE E NAtildeO MODIFICAacuteVEL PARA DCV
J GUNTER ET AL ACTA CLINICA BELGICA INTERNATIONAL JOURNAL OF CLINICAL AND LABORATORY MEDICINE
Prevalecircncia de Fatores Predisponentes
para Fragilidade
KKooij et al 8th Netherlands Conference on HIV Pathogenesis Epidemiology Prevention and Treatment Amsterdam November 2014
Causas de Morte 1999-2011
Continuous Increase of Cardiovascular Diseases Diabetes and Non-HIV Related Cancers
as Causes of Death in HIV-Infected Individuals in Brazil An Analysis of Nationwide Data
Paula AA Schechter M Tuboi SH Faulhaber JC Luz PM et al (2014) PLOS ONE 9(4)
e94636 httpsdoiorg101371journalpone0094636
bull 12366853 atestados
bull 151706 (123) HIVAIDS
ATVr DRVr EFV RPV DTG RAL ABC FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Antihypert
ensiv
eagents
Amlodipine
Atenolol
Bisoprolol
Enalapril
Felodipine
Indapamide
Lisinopril
Losartan
Nifedipine
Olmesartan
Perindopril
Valsartan
Interaccedilotildees com Antihipertensivos
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Potential interaction
no dose adjustment
required
ATVr DRVr EFV RPV DTG RAL
AB
C FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Lip
id-l
ow
ering a
gents
Atorvastatin
Fluvastatin
Lovastatin
Pravastatin
Rosuvastatin
Simvastatin
Antidia
betic a
gents
Glibenclamid
e (Glyburide)
Linagliptin
Metformin
Nateglinide
Saxagliptin
Sitagliptin
Interaccedilotildees Medicamentosas com Hipolipemiantes e Hipoglicemiantes
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Do not co-
administer
Potential interaction
no dose adjustment
required
Interaccedilotildees com Medicamentos que atuam no SNC
BOOSTED FREE AGENTS BOOSTED AGENTS
DTGII RAL EFV ETV RPV EVGc DRVr
Stim
ula
nts
amyl nitrate
cocaine
ecstasy (MDMA)
mephedrone
methamphetamine
Dep
ress
ants
alcohol
alprazolam
codeine
diazepam
GHB (gamma hydroxybutyrate)
heroin (diamorphone)
hydrocodone
hydromorphone
ketamine
pethidine (meperideine)
methadone
midazolam (oral)
morphine
oxycodone
temazepam
triazolam
Hal
luci
no
gen
s
cannabis
lysergic acid dietheylamide (LSD)
phencyclidine (PCP angle dust)
Further information (in vivo in vitro or from label) at wwwhiv-druginteractionsorg
These drugs should not be co-administered
Potential interaction-may require close monitoring alteration of drug dosage or timing of administration
No clinically significant expected
Dose do DTG interfere nos niacuteveis de Metformina
Haacute aumento da exposiccedilatildeo plasmaacutetica da metformina
quando coadministrada com DTG e o efeito produzido
(PK) no niacutevel de metformina eacute dose-dependente do DTG
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50 mgq24h
Metf
orm
in c
on
cen
trati
on
(microg
mL
)
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q24h
Metformin alone Period
3
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50mg q12h
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q12h
Metformin alone Period
3
bull Anaacutelise retrospectiva de adultos HIV+ que mudaram o esquema para
outros contendo DTG e fazendo uso concomitante de metformina
(n=15)
bull DTG natildeo alterou a resposta ao uso da metformina nos pacientes
diabeacuteticos
ndash Natildeo houve diferenccedila significante nos niacuteveis de glicose em jejum nem
na concentraccedilatildeo de HbA1 observados antes e depois da troca para
DTG
Na vida real natildeo houve diferenccedila significativa na glicemia de jejum nem na Hb glicada antes e depois da troca para DTG
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
BHIVA 2016 April Manchester UKCB Jones1 J Tan1 J Robinson1 H Tate1 H Lamba1
1Merck Sharp ampDohme Limited Hertford Road Hoddesdon Hertfordshire
- Comorbidades satildeo frequentes
- 70 das pessoas fazem uso de outros medicamentos
- Supressatildeo viral alcanccedilada em cerca de 85 dos casos
independentemente da idade das comorbidades e do uso
de outros medicamentos
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
n=19215 RAL em 83 dos esquemas (n=1428)
Switching From a Boosted Protease Inhibitor (PIr) Based Regimen to a
Dolutegravir (DTG) Regimen in Virologically Suppressed Patients With
High Cardiovascular Risk (Framingham Score gt10 or Age gt 50 Years) Is
Non-Inferior and Decreases Lipids The NEAT 022 Study
JM Gatell1 L Assoumou2 G Moyle3 L Waters4 E Martinez5 H-J
Stellbrink6 G Guaraldi7 S de Wit8 F Raffi9 A Pozniak10 on behalf of
NEAT022 Study Group
1Hospital ClinicIDIBAPS University of Barcelona Infectious Diseases Barcelona Spain 2Sorbone Universites INSERM
UPMC Univ Paris 06 IPLESP UMRS 1136 Paris France 3Chelsea and Westminster Hospital London United Kingdom4Mortimer Market Center London United Kingdom 5Hospital ClinicIDIBAPS University of Barcelona Barcelona Spain6Infectiologisches Centrum Hamburg Germany 7University of Modena and Reggio Emilia Modena Italy 8Saint Pierre
University Hospital Universiteacute Libre de Bruxelles Brussels Belgium 9CHU
Hotel-Dieu Nantes Nantes France 10Chelsea amp Westminster Hospital London United Kingdom
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
Infecccedilatildeo pelo HIV e Risco Cardiovascular
- 60 das pessoas com HIV tecircm placas nas arteacuterias cardiacuteacas mesmo semsinaissintomas
- Haacute relaccedilatildeo direta com a inflamaccedilatildeo decorrente da infecccedilatildeo pelo HIV
HIV e Aterosclerose
HIV-1-Associated Atherosclerosis Unraveling the Missing LinkJ Am Coll Cardiol 2017 Jun 2769(25)3084-3098 doi 01016jjacc201705012Kearns A Gordon J Burdo TH Qin X
Doenccedila cardiovascular incluindo aterosclerose e outras complicaccedilotildees associadas eacute causa
crescente de morbidade e mortalidade nos pacientes infectados pelo HIV na era poacutes-
HAART
Terapia antirretroviral comorbidades associadas tais como dislipidemia abuso de drogas
infecccedilotildees oportunistas e outros fatores de risco relacionados a haacutebitos de vida satildeo
importantes tanto para precipitar como para piorar a aterosclerose
Tipo 1 resulta espontaneamente da instabilidade da placa ateroscleroacutetica
Tipo 2 ocorre por desequiliacutebrio entre consumooferta de oxigecircnio vasoespasmo (por exemplo infecccedilatildeo ou uso de cocaiacutena)
EVENTOS CARDIOVASCULARES
Infarto Agudo do Miocaacuterdio
FatoresAnos Perdidos de Vida Idade 35 a 80 anos (95 CI)
Risco de morte
HIV + que nunca fumaram
(HIV + nunca que fumaram vs controlesque nunca fumaram)
51 (44ndash58) 03
Controles fumantes
(controles fumantes vs controles quenunca fumaram)
36 (31ndash40) 344
HIV + fumantes
(HIV + fumantes vs HIV + que nuncafumaram)
123 (115ndash130) 615
Tabagismo Mortalidade e HIV Helleberg Clin Infect Dis 2013
Nuacutemero de Anos Perdidos e Risco de Morte Atribuiacutedo agrave Populaccedilatildeo de Fumantes e com HIV
Em um local onde o tratamento da infecccedilatildeo pelo HIV eacute organizado e gratuito pessoas portadoras do HIV e
fumantes perdem mais anos de vida para o tabagismo do que para o proacuteprio viacuterus Satildeo 123 anos de vida
perdidos para o cigarro O excesso de mortalidade de fumantes eacute triplicado e o risco de morte associado
ao tabagismo eacute duplicado entre HIV + em comparaccedilatildeo agrave populaccedilatildeo natildeo fumante mesmo com HIV
NA-ACCORD Fumo hipertensatildeo arterial e niacuteveis de colesterol aumentam
risco de IAM em portadores do HIV
bull Metanaacutelise retrospectivabull Eventos validados de 7 coortes cliacutenicas
NA-ACCORD 12000 -122013 bull N = 29515[1]
ndash Fraccedilatildeo atribuiacutevel agrave populaccedilatildeo proporccedilatildeo de IM evitaacuteveis pela prevenccedilatildeo de fatores de risco modificaacuteveis relacionados com o HIV e tradicionais
ndash 347 pacientes (12) apresentavam IM de tipo 1 devido agrave ruptura da placa
ndash A anaacutelise de sensibilidade foi feita para 16687 pacientes (57) com dados de IMC 227 apresentaram IM tipo 1
ndash ~ 40 de reduccedilatildeo IM possiacutevel atraveacutes da prevenccedilatildeo do tabagismo TC elevado ou hipertensatildeo independentemente do IMC
1 Althoff KN et al CROI 2017 Abstract 130 2 Shepherd L et al CROI
2017 Abstract 131 Slide credit
clinicaloptionscom
bull Em outra anaacutelise separada (DAD) a interrupccedilatildeo do fumo reduziu as taxas globaisde cacircncer apoacutes 1 ano (exceto pulmatildeo quepermaneceu alta mesmo apoacutes 5 anos)[2]
Ajuste para idade sexo raccedila e fatores de risco
listados daggerP lt 05
Adjusted Population Attributable Fractions for MI[1]
MI
BMI Subgrou
p
Traditional MI risk factors
Smoking 38dagger 36
Elevated TC 43dagger 39dagger
HTN 41dagger 39dagger
All 3 (smoking TC HTN) 86
HIV-related MI risk factors
DM 2 4
CKD 3 3
CD4+ cell count 10dagger 14dagger
VL 6 8
AIDS 2 -1
HCV coinfection 8dagger 14dagger
bull Uso recente de ABC associado com ~70 aumento risco de IM
ndash Uso recente definido como ainda em uso ou interrupccedilatildeo dentrodos uacuteltimos seis meses
bull Exposiccedilatildeo cumulativa
ndash ao ABC foi associada com pequeno aumento do risco de IM
ndash ao Lopinavirr foi associada com aumento do risco de IM
Estudo DAD
Risco Cardiovascular
Abacavir e Risco de Infarto Agudo do Miocaacuterdio e Doenccedila Cerebrovascularna era HAART
R Bedimo12 A Westfall3 H Drechsler12 P Tebas41VA North Texas Healthcare System Medicine Dallas United States 2University of Texas Southwestern MedicalCenter Medicine Dallas United States 3University of Alabama at Birmingham Medicine Birmingham United
States 4University of Pennsylvania Medicine Philadelphia United States
19424 pacientes acompanhados por cerca de 4 anos (75311 pessoas-ano) 278 IAM e 868 AVC entre pessoas com mais fatores de risco para DCV incluindo hepatite C e doenccedila renal
Taxa global IAM 369 por 1000 pessoas-ano AVC 1168 por 1000 pessoas-ano
Abacavir associado a maior risco de IAM (hazard ratio [HR] 127 ou 27 aumento do risco) e de AVC (HR 117)
Anaacutelise foi repetida apoacutes controle dos fatores de risco conhecidos paraDCV e condiccedilotildees coexistentes (idade hiperlipidemia hipertensatildeo diabetes tabagismo) e a associaccedilatildeo entre abacavir e IAM ou AVC deixou de ser forte e deixou de ser estatisticamente significante
Pacientes HIV+ com problemas renais satildeo mais medicados com abacavir comoalternativa ao tenofovir e jaacute tecircm maior risco de DCV e de AVC o que passoua ser considerado fator de confusatildeo na anaacutelise
DAD exposiccedilatildeo ao ATVRTV ou DRVRTV e risco
cardiovascular
bull Prospectivo Jan2009 (BL) ateacute o primeiro evento CV uacuteltima visita + 6 meses ou 01022016
bull (N = 35711)
ndash 1157 pts (32) apresentaram DCV (IM AVE morte suacutebita) ou se submeteram a um procedimento cardiacuteaco invasivo
bull Exposiccedilatildeo cumulativa a DRVRTV estaacute associada a risco CV - anaacutelisemultivariada 59 risco aumentadocom 5 anos de uso
ndash Associaccedilatildeo natildeo parece ser mediada pordislipidemia
bull Limitaccedilotildees Fatores de confusatildeo potencialmente natildeomensuraacuteveis num estudo observacional ndash Natildeo foipossiacutevel diferenciar entre DRVRTV 800100 QD vs DRVRTV 600100 BID
bull Natildeo avaliou uso de estatinas natildeo ajustou para supressatildeo viral Fumo atual apenas Exposiccedilatildeo aotabaco em maccedilosano natildeo foi avaliada exposiccedilatildeopreacutevia a IP de primeira geraccedilatildeo natildeo avaliada
Ryom L et al CROI 2017 Abstract 128LB
Incidence Rates of CVD andCumulative Exposure to ATV+RTV and DRV+RTV
ATV+RTV DRV+RTV
Cumulative years of drug exposure
200
150
100
50
40
30
20
0
Incid
en
ce r
ate
1000 P
YF
U (
95
CI)
Incidecircncia de Doenccedilas Crocircnicas
Aumenta Exponencialmente com a Idade
Idade
INC
IDEcirc
NC
IA
Idade eacute o maior fator de riscoSlide cortesia de Peter Reiss
Schouten J et al Clin Infect Dis 2014
Comorbidades relacionadas agrave idade
A IDADE Eacute FATOR DE RISCO INDEPENDENTE E NAtildeO MODIFICAacuteVEL PARA DCV
J GUNTER ET AL ACTA CLINICA BELGICA INTERNATIONAL JOURNAL OF CLINICAL AND LABORATORY MEDICINE
Prevalecircncia de Fatores Predisponentes
para Fragilidade
KKooij et al 8th Netherlands Conference on HIV Pathogenesis Epidemiology Prevention and Treatment Amsterdam November 2014
Causas de Morte 1999-2011
Continuous Increase of Cardiovascular Diseases Diabetes and Non-HIV Related Cancers
as Causes of Death in HIV-Infected Individuals in Brazil An Analysis of Nationwide Data
Paula AA Schechter M Tuboi SH Faulhaber JC Luz PM et al (2014) PLOS ONE 9(4)
e94636 httpsdoiorg101371journalpone0094636
bull 12366853 atestados
bull 151706 (123) HIVAIDS
ATVr DRVr EFV RPV DTG RAL ABC FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Antihypert
ensiv
eagents
Amlodipine
Atenolol
Bisoprolol
Enalapril
Felodipine
Indapamide
Lisinopril
Losartan
Nifedipine
Olmesartan
Perindopril
Valsartan
Interaccedilotildees com Antihipertensivos
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Potential interaction
no dose adjustment
required
ATVr DRVr EFV RPV DTG RAL
AB
C FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Lip
id-l
ow
ering a
gents
Atorvastatin
Fluvastatin
Lovastatin
Pravastatin
Rosuvastatin
Simvastatin
Antidia
betic a
gents
Glibenclamid
e (Glyburide)
Linagliptin
Metformin
Nateglinide
Saxagliptin
Sitagliptin
Interaccedilotildees Medicamentosas com Hipolipemiantes e Hipoglicemiantes
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Do not co-
administer
Potential interaction
no dose adjustment
required
Interaccedilotildees com Medicamentos que atuam no SNC
BOOSTED FREE AGENTS BOOSTED AGENTS
DTGII RAL EFV ETV RPV EVGc DRVr
Stim
ula
nts
amyl nitrate
cocaine
ecstasy (MDMA)
mephedrone
methamphetamine
Dep
ress
ants
alcohol
alprazolam
codeine
diazepam
GHB (gamma hydroxybutyrate)
heroin (diamorphone)
hydrocodone
hydromorphone
ketamine
pethidine (meperideine)
methadone
midazolam (oral)
morphine
oxycodone
temazepam
triazolam
Hal
luci
no
gen
s
cannabis
lysergic acid dietheylamide (LSD)
phencyclidine (PCP angle dust)
Further information (in vivo in vitro or from label) at wwwhiv-druginteractionsorg
These drugs should not be co-administered
Potential interaction-may require close monitoring alteration of drug dosage or timing of administration
No clinically significant expected
Dose do DTG interfere nos niacuteveis de Metformina
Haacute aumento da exposiccedilatildeo plasmaacutetica da metformina
quando coadministrada com DTG e o efeito produzido
(PK) no niacutevel de metformina eacute dose-dependente do DTG
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50 mgq24h
Metf
orm
in c
on
cen
trati
on
(microg
mL
)
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q24h
Metformin alone Period
3
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50mg q12h
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q12h
Metformin alone Period
3
bull Anaacutelise retrospectiva de adultos HIV+ que mudaram o esquema para
outros contendo DTG e fazendo uso concomitante de metformina
(n=15)
bull DTG natildeo alterou a resposta ao uso da metformina nos pacientes
diabeacuteticos
ndash Natildeo houve diferenccedila significante nos niacuteveis de glicose em jejum nem
na concentraccedilatildeo de HbA1 observados antes e depois da troca para
DTG
Na vida real natildeo houve diferenccedila significativa na glicemia de jejum nem na Hb glicada antes e depois da troca para DTG
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
BHIVA 2016 April Manchester UKCB Jones1 J Tan1 J Robinson1 H Tate1 H Lamba1
1Merck Sharp ampDohme Limited Hertford Road Hoddesdon Hertfordshire
- Comorbidades satildeo frequentes
- 70 das pessoas fazem uso de outros medicamentos
- Supressatildeo viral alcanccedilada em cerca de 85 dos casos
independentemente da idade das comorbidades e do uso
de outros medicamentos
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
n=19215 RAL em 83 dos esquemas (n=1428)
Switching From a Boosted Protease Inhibitor (PIr) Based Regimen to a
Dolutegravir (DTG) Regimen in Virologically Suppressed Patients With
High Cardiovascular Risk (Framingham Score gt10 or Age gt 50 Years) Is
Non-Inferior and Decreases Lipids The NEAT 022 Study
JM Gatell1 L Assoumou2 G Moyle3 L Waters4 E Martinez5 H-J
Stellbrink6 G Guaraldi7 S de Wit8 F Raffi9 A Pozniak10 on behalf of
NEAT022 Study Group
1Hospital ClinicIDIBAPS University of Barcelona Infectious Diseases Barcelona Spain 2Sorbone Universites INSERM
UPMC Univ Paris 06 IPLESP UMRS 1136 Paris France 3Chelsea and Westminster Hospital London United Kingdom4Mortimer Market Center London United Kingdom 5Hospital ClinicIDIBAPS University of Barcelona Barcelona Spain6Infectiologisches Centrum Hamburg Germany 7University of Modena and Reggio Emilia Modena Italy 8Saint Pierre
University Hospital Universiteacute Libre de Bruxelles Brussels Belgium 9CHU
Hotel-Dieu Nantes Nantes France 10Chelsea amp Westminster Hospital London United Kingdom
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
HIV e Aterosclerose
HIV-1-Associated Atherosclerosis Unraveling the Missing LinkJ Am Coll Cardiol 2017 Jun 2769(25)3084-3098 doi 01016jjacc201705012Kearns A Gordon J Burdo TH Qin X
Doenccedila cardiovascular incluindo aterosclerose e outras complicaccedilotildees associadas eacute causa
crescente de morbidade e mortalidade nos pacientes infectados pelo HIV na era poacutes-
HAART
Terapia antirretroviral comorbidades associadas tais como dislipidemia abuso de drogas
infecccedilotildees oportunistas e outros fatores de risco relacionados a haacutebitos de vida satildeo
importantes tanto para precipitar como para piorar a aterosclerose
Tipo 1 resulta espontaneamente da instabilidade da placa ateroscleroacutetica
Tipo 2 ocorre por desequiliacutebrio entre consumooferta de oxigecircnio vasoespasmo (por exemplo infecccedilatildeo ou uso de cocaiacutena)
EVENTOS CARDIOVASCULARES
Infarto Agudo do Miocaacuterdio
FatoresAnos Perdidos de Vida Idade 35 a 80 anos (95 CI)
Risco de morte
HIV + que nunca fumaram
(HIV + nunca que fumaram vs controlesque nunca fumaram)
51 (44ndash58) 03
Controles fumantes
(controles fumantes vs controles quenunca fumaram)
36 (31ndash40) 344
HIV + fumantes
(HIV + fumantes vs HIV + que nuncafumaram)
123 (115ndash130) 615
Tabagismo Mortalidade e HIV Helleberg Clin Infect Dis 2013
Nuacutemero de Anos Perdidos e Risco de Morte Atribuiacutedo agrave Populaccedilatildeo de Fumantes e com HIV
Em um local onde o tratamento da infecccedilatildeo pelo HIV eacute organizado e gratuito pessoas portadoras do HIV e
fumantes perdem mais anos de vida para o tabagismo do que para o proacuteprio viacuterus Satildeo 123 anos de vida
perdidos para o cigarro O excesso de mortalidade de fumantes eacute triplicado e o risco de morte associado
ao tabagismo eacute duplicado entre HIV + em comparaccedilatildeo agrave populaccedilatildeo natildeo fumante mesmo com HIV
NA-ACCORD Fumo hipertensatildeo arterial e niacuteveis de colesterol aumentam
risco de IAM em portadores do HIV
bull Metanaacutelise retrospectivabull Eventos validados de 7 coortes cliacutenicas
NA-ACCORD 12000 -122013 bull N = 29515[1]
ndash Fraccedilatildeo atribuiacutevel agrave populaccedilatildeo proporccedilatildeo de IM evitaacuteveis pela prevenccedilatildeo de fatores de risco modificaacuteveis relacionados com o HIV e tradicionais
ndash 347 pacientes (12) apresentavam IM de tipo 1 devido agrave ruptura da placa
ndash A anaacutelise de sensibilidade foi feita para 16687 pacientes (57) com dados de IMC 227 apresentaram IM tipo 1
ndash ~ 40 de reduccedilatildeo IM possiacutevel atraveacutes da prevenccedilatildeo do tabagismo TC elevado ou hipertensatildeo independentemente do IMC
1 Althoff KN et al CROI 2017 Abstract 130 2 Shepherd L et al CROI
2017 Abstract 131 Slide credit
clinicaloptionscom
bull Em outra anaacutelise separada (DAD) a interrupccedilatildeo do fumo reduziu as taxas globaisde cacircncer apoacutes 1 ano (exceto pulmatildeo quepermaneceu alta mesmo apoacutes 5 anos)[2]
Ajuste para idade sexo raccedila e fatores de risco
listados daggerP lt 05
Adjusted Population Attributable Fractions for MI[1]
MI
BMI Subgrou
p
Traditional MI risk factors
Smoking 38dagger 36
Elevated TC 43dagger 39dagger
HTN 41dagger 39dagger
All 3 (smoking TC HTN) 86
HIV-related MI risk factors
DM 2 4
CKD 3 3
CD4+ cell count 10dagger 14dagger
VL 6 8
AIDS 2 -1
HCV coinfection 8dagger 14dagger
bull Uso recente de ABC associado com ~70 aumento risco de IM
ndash Uso recente definido como ainda em uso ou interrupccedilatildeo dentrodos uacuteltimos seis meses
bull Exposiccedilatildeo cumulativa
ndash ao ABC foi associada com pequeno aumento do risco de IM
ndash ao Lopinavirr foi associada com aumento do risco de IM
Estudo DAD
Risco Cardiovascular
Abacavir e Risco de Infarto Agudo do Miocaacuterdio e Doenccedila Cerebrovascularna era HAART
R Bedimo12 A Westfall3 H Drechsler12 P Tebas41VA North Texas Healthcare System Medicine Dallas United States 2University of Texas Southwestern MedicalCenter Medicine Dallas United States 3University of Alabama at Birmingham Medicine Birmingham United
States 4University of Pennsylvania Medicine Philadelphia United States
19424 pacientes acompanhados por cerca de 4 anos (75311 pessoas-ano) 278 IAM e 868 AVC entre pessoas com mais fatores de risco para DCV incluindo hepatite C e doenccedila renal
Taxa global IAM 369 por 1000 pessoas-ano AVC 1168 por 1000 pessoas-ano
Abacavir associado a maior risco de IAM (hazard ratio [HR] 127 ou 27 aumento do risco) e de AVC (HR 117)
Anaacutelise foi repetida apoacutes controle dos fatores de risco conhecidos paraDCV e condiccedilotildees coexistentes (idade hiperlipidemia hipertensatildeo diabetes tabagismo) e a associaccedilatildeo entre abacavir e IAM ou AVC deixou de ser forte e deixou de ser estatisticamente significante
Pacientes HIV+ com problemas renais satildeo mais medicados com abacavir comoalternativa ao tenofovir e jaacute tecircm maior risco de DCV e de AVC o que passoua ser considerado fator de confusatildeo na anaacutelise
DAD exposiccedilatildeo ao ATVRTV ou DRVRTV e risco
cardiovascular
bull Prospectivo Jan2009 (BL) ateacute o primeiro evento CV uacuteltima visita + 6 meses ou 01022016
bull (N = 35711)
ndash 1157 pts (32) apresentaram DCV (IM AVE morte suacutebita) ou se submeteram a um procedimento cardiacuteaco invasivo
bull Exposiccedilatildeo cumulativa a DRVRTV estaacute associada a risco CV - anaacutelisemultivariada 59 risco aumentadocom 5 anos de uso
ndash Associaccedilatildeo natildeo parece ser mediada pordislipidemia
bull Limitaccedilotildees Fatores de confusatildeo potencialmente natildeomensuraacuteveis num estudo observacional ndash Natildeo foipossiacutevel diferenciar entre DRVRTV 800100 QD vs DRVRTV 600100 BID
bull Natildeo avaliou uso de estatinas natildeo ajustou para supressatildeo viral Fumo atual apenas Exposiccedilatildeo aotabaco em maccedilosano natildeo foi avaliada exposiccedilatildeopreacutevia a IP de primeira geraccedilatildeo natildeo avaliada
Ryom L et al CROI 2017 Abstract 128LB
Incidence Rates of CVD andCumulative Exposure to ATV+RTV and DRV+RTV
ATV+RTV DRV+RTV
Cumulative years of drug exposure
200
150
100
50
40
30
20
0
Incid
en
ce r
ate
1000 P
YF
U (
95
CI)
Incidecircncia de Doenccedilas Crocircnicas
Aumenta Exponencialmente com a Idade
Idade
INC
IDEcirc
NC
IA
Idade eacute o maior fator de riscoSlide cortesia de Peter Reiss
Schouten J et al Clin Infect Dis 2014
Comorbidades relacionadas agrave idade
A IDADE Eacute FATOR DE RISCO INDEPENDENTE E NAtildeO MODIFICAacuteVEL PARA DCV
J GUNTER ET AL ACTA CLINICA BELGICA INTERNATIONAL JOURNAL OF CLINICAL AND LABORATORY MEDICINE
Prevalecircncia de Fatores Predisponentes
para Fragilidade
KKooij et al 8th Netherlands Conference on HIV Pathogenesis Epidemiology Prevention and Treatment Amsterdam November 2014
Causas de Morte 1999-2011
Continuous Increase of Cardiovascular Diseases Diabetes and Non-HIV Related Cancers
as Causes of Death in HIV-Infected Individuals in Brazil An Analysis of Nationwide Data
Paula AA Schechter M Tuboi SH Faulhaber JC Luz PM et al (2014) PLOS ONE 9(4)
e94636 httpsdoiorg101371journalpone0094636
bull 12366853 atestados
bull 151706 (123) HIVAIDS
ATVr DRVr EFV RPV DTG RAL ABC FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Antihypert
ensiv
eagents
Amlodipine
Atenolol
Bisoprolol
Enalapril
Felodipine
Indapamide
Lisinopril
Losartan
Nifedipine
Olmesartan
Perindopril
Valsartan
Interaccedilotildees com Antihipertensivos
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Potential interaction
no dose adjustment
required
ATVr DRVr EFV RPV DTG RAL
AB
C FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Lip
id-l
ow
ering a
gents
Atorvastatin
Fluvastatin
Lovastatin
Pravastatin
Rosuvastatin
Simvastatin
Antidia
betic a
gents
Glibenclamid
e (Glyburide)
Linagliptin
Metformin
Nateglinide
Saxagliptin
Sitagliptin
Interaccedilotildees Medicamentosas com Hipolipemiantes e Hipoglicemiantes
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Do not co-
administer
Potential interaction
no dose adjustment
required
Interaccedilotildees com Medicamentos que atuam no SNC
BOOSTED FREE AGENTS BOOSTED AGENTS
DTGII RAL EFV ETV RPV EVGc DRVr
Stim
ula
nts
amyl nitrate
cocaine
ecstasy (MDMA)
mephedrone
methamphetamine
Dep
ress
ants
alcohol
alprazolam
codeine
diazepam
GHB (gamma hydroxybutyrate)
heroin (diamorphone)
hydrocodone
hydromorphone
ketamine
pethidine (meperideine)
methadone
midazolam (oral)
morphine
oxycodone
temazepam
triazolam
Hal
luci
no
gen
s
cannabis
lysergic acid dietheylamide (LSD)
phencyclidine (PCP angle dust)
Further information (in vivo in vitro or from label) at wwwhiv-druginteractionsorg
These drugs should not be co-administered
Potential interaction-may require close monitoring alteration of drug dosage or timing of administration
No clinically significant expected
Dose do DTG interfere nos niacuteveis de Metformina
Haacute aumento da exposiccedilatildeo plasmaacutetica da metformina
quando coadministrada com DTG e o efeito produzido
(PK) no niacutevel de metformina eacute dose-dependente do DTG
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50 mgq24h
Metf
orm
in c
on
cen
trati
on
(microg
mL
)
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q24h
Metformin alone Period
3
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50mg q12h
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q12h
Metformin alone Period
3
bull Anaacutelise retrospectiva de adultos HIV+ que mudaram o esquema para
outros contendo DTG e fazendo uso concomitante de metformina
(n=15)
bull DTG natildeo alterou a resposta ao uso da metformina nos pacientes
diabeacuteticos
ndash Natildeo houve diferenccedila significante nos niacuteveis de glicose em jejum nem
na concentraccedilatildeo de HbA1 observados antes e depois da troca para
DTG
Na vida real natildeo houve diferenccedila significativa na glicemia de jejum nem na Hb glicada antes e depois da troca para DTG
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
BHIVA 2016 April Manchester UKCB Jones1 J Tan1 J Robinson1 H Tate1 H Lamba1
1Merck Sharp ampDohme Limited Hertford Road Hoddesdon Hertfordshire
- Comorbidades satildeo frequentes
- 70 das pessoas fazem uso de outros medicamentos
- Supressatildeo viral alcanccedilada em cerca de 85 dos casos
independentemente da idade das comorbidades e do uso
de outros medicamentos
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
n=19215 RAL em 83 dos esquemas (n=1428)
Switching From a Boosted Protease Inhibitor (PIr) Based Regimen to a
Dolutegravir (DTG) Regimen in Virologically Suppressed Patients With
High Cardiovascular Risk (Framingham Score gt10 or Age gt 50 Years) Is
Non-Inferior and Decreases Lipids The NEAT 022 Study
JM Gatell1 L Assoumou2 G Moyle3 L Waters4 E Martinez5 H-J
Stellbrink6 G Guaraldi7 S de Wit8 F Raffi9 A Pozniak10 on behalf of
NEAT022 Study Group
1Hospital ClinicIDIBAPS University of Barcelona Infectious Diseases Barcelona Spain 2Sorbone Universites INSERM
UPMC Univ Paris 06 IPLESP UMRS 1136 Paris France 3Chelsea and Westminster Hospital London United Kingdom4Mortimer Market Center London United Kingdom 5Hospital ClinicIDIBAPS University of Barcelona Barcelona Spain6Infectiologisches Centrum Hamburg Germany 7University of Modena and Reggio Emilia Modena Italy 8Saint Pierre
University Hospital Universiteacute Libre de Bruxelles Brussels Belgium 9CHU
Hotel-Dieu Nantes Nantes France 10Chelsea amp Westminster Hospital London United Kingdom
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
Tipo 1 resulta espontaneamente da instabilidade da placa ateroscleroacutetica
Tipo 2 ocorre por desequiliacutebrio entre consumooferta de oxigecircnio vasoespasmo (por exemplo infecccedilatildeo ou uso de cocaiacutena)
EVENTOS CARDIOVASCULARES
Infarto Agudo do Miocaacuterdio
FatoresAnos Perdidos de Vida Idade 35 a 80 anos (95 CI)
Risco de morte
HIV + que nunca fumaram
(HIV + nunca que fumaram vs controlesque nunca fumaram)
51 (44ndash58) 03
Controles fumantes
(controles fumantes vs controles quenunca fumaram)
36 (31ndash40) 344
HIV + fumantes
(HIV + fumantes vs HIV + que nuncafumaram)
123 (115ndash130) 615
Tabagismo Mortalidade e HIV Helleberg Clin Infect Dis 2013
Nuacutemero de Anos Perdidos e Risco de Morte Atribuiacutedo agrave Populaccedilatildeo de Fumantes e com HIV
Em um local onde o tratamento da infecccedilatildeo pelo HIV eacute organizado e gratuito pessoas portadoras do HIV e
fumantes perdem mais anos de vida para o tabagismo do que para o proacuteprio viacuterus Satildeo 123 anos de vida
perdidos para o cigarro O excesso de mortalidade de fumantes eacute triplicado e o risco de morte associado
ao tabagismo eacute duplicado entre HIV + em comparaccedilatildeo agrave populaccedilatildeo natildeo fumante mesmo com HIV
NA-ACCORD Fumo hipertensatildeo arterial e niacuteveis de colesterol aumentam
risco de IAM em portadores do HIV
bull Metanaacutelise retrospectivabull Eventos validados de 7 coortes cliacutenicas
NA-ACCORD 12000 -122013 bull N = 29515[1]
ndash Fraccedilatildeo atribuiacutevel agrave populaccedilatildeo proporccedilatildeo de IM evitaacuteveis pela prevenccedilatildeo de fatores de risco modificaacuteveis relacionados com o HIV e tradicionais
ndash 347 pacientes (12) apresentavam IM de tipo 1 devido agrave ruptura da placa
ndash A anaacutelise de sensibilidade foi feita para 16687 pacientes (57) com dados de IMC 227 apresentaram IM tipo 1
ndash ~ 40 de reduccedilatildeo IM possiacutevel atraveacutes da prevenccedilatildeo do tabagismo TC elevado ou hipertensatildeo independentemente do IMC
1 Althoff KN et al CROI 2017 Abstract 130 2 Shepherd L et al CROI
2017 Abstract 131 Slide credit
clinicaloptionscom
bull Em outra anaacutelise separada (DAD) a interrupccedilatildeo do fumo reduziu as taxas globaisde cacircncer apoacutes 1 ano (exceto pulmatildeo quepermaneceu alta mesmo apoacutes 5 anos)[2]
Ajuste para idade sexo raccedila e fatores de risco
listados daggerP lt 05
Adjusted Population Attributable Fractions for MI[1]
MI
BMI Subgrou
p
Traditional MI risk factors
Smoking 38dagger 36
Elevated TC 43dagger 39dagger
HTN 41dagger 39dagger
All 3 (smoking TC HTN) 86
HIV-related MI risk factors
DM 2 4
CKD 3 3
CD4+ cell count 10dagger 14dagger
VL 6 8
AIDS 2 -1
HCV coinfection 8dagger 14dagger
bull Uso recente de ABC associado com ~70 aumento risco de IM
ndash Uso recente definido como ainda em uso ou interrupccedilatildeo dentrodos uacuteltimos seis meses
bull Exposiccedilatildeo cumulativa
ndash ao ABC foi associada com pequeno aumento do risco de IM
ndash ao Lopinavirr foi associada com aumento do risco de IM
Estudo DAD
Risco Cardiovascular
Abacavir e Risco de Infarto Agudo do Miocaacuterdio e Doenccedila Cerebrovascularna era HAART
R Bedimo12 A Westfall3 H Drechsler12 P Tebas41VA North Texas Healthcare System Medicine Dallas United States 2University of Texas Southwestern MedicalCenter Medicine Dallas United States 3University of Alabama at Birmingham Medicine Birmingham United
States 4University of Pennsylvania Medicine Philadelphia United States
19424 pacientes acompanhados por cerca de 4 anos (75311 pessoas-ano) 278 IAM e 868 AVC entre pessoas com mais fatores de risco para DCV incluindo hepatite C e doenccedila renal
Taxa global IAM 369 por 1000 pessoas-ano AVC 1168 por 1000 pessoas-ano
Abacavir associado a maior risco de IAM (hazard ratio [HR] 127 ou 27 aumento do risco) e de AVC (HR 117)
Anaacutelise foi repetida apoacutes controle dos fatores de risco conhecidos paraDCV e condiccedilotildees coexistentes (idade hiperlipidemia hipertensatildeo diabetes tabagismo) e a associaccedilatildeo entre abacavir e IAM ou AVC deixou de ser forte e deixou de ser estatisticamente significante
Pacientes HIV+ com problemas renais satildeo mais medicados com abacavir comoalternativa ao tenofovir e jaacute tecircm maior risco de DCV e de AVC o que passoua ser considerado fator de confusatildeo na anaacutelise
DAD exposiccedilatildeo ao ATVRTV ou DRVRTV e risco
cardiovascular
bull Prospectivo Jan2009 (BL) ateacute o primeiro evento CV uacuteltima visita + 6 meses ou 01022016
bull (N = 35711)
ndash 1157 pts (32) apresentaram DCV (IM AVE morte suacutebita) ou se submeteram a um procedimento cardiacuteaco invasivo
bull Exposiccedilatildeo cumulativa a DRVRTV estaacute associada a risco CV - anaacutelisemultivariada 59 risco aumentadocom 5 anos de uso
ndash Associaccedilatildeo natildeo parece ser mediada pordislipidemia
bull Limitaccedilotildees Fatores de confusatildeo potencialmente natildeomensuraacuteveis num estudo observacional ndash Natildeo foipossiacutevel diferenciar entre DRVRTV 800100 QD vs DRVRTV 600100 BID
bull Natildeo avaliou uso de estatinas natildeo ajustou para supressatildeo viral Fumo atual apenas Exposiccedilatildeo aotabaco em maccedilosano natildeo foi avaliada exposiccedilatildeopreacutevia a IP de primeira geraccedilatildeo natildeo avaliada
Ryom L et al CROI 2017 Abstract 128LB
Incidence Rates of CVD andCumulative Exposure to ATV+RTV and DRV+RTV
ATV+RTV DRV+RTV
Cumulative years of drug exposure
200
150
100
50
40
30
20
0
Incid
en
ce r
ate
1000 P
YF
U (
95
CI)
Incidecircncia de Doenccedilas Crocircnicas
Aumenta Exponencialmente com a Idade
Idade
INC
IDEcirc
NC
IA
Idade eacute o maior fator de riscoSlide cortesia de Peter Reiss
Schouten J et al Clin Infect Dis 2014
Comorbidades relacionadas agrave idade
A IDADE Eacute FATOR DE RISCO INDEPENDENTE E NAtildeO MODIFICAacuteVEL PARA DCV
J GUNTER ET AL ACTA CLINICA BELGICA INTERNATIONAL JOURNAL OF CLINICAL AND LABORATORY MEDICINE
Prevalecircncia de Fatores Predisponentes
para Fragilidade
KKooij et al 8th Netherlands Conference on HIV Pathogenesis Epidemiology Prevention and Treatment Amsterdam November 2014
Causas de Morte 1999-2011
Continuous Increase of Cardiovascular Diseases Diabetes and Non-HIV Related Cancers
as Causes of Death in HIV-Infected Individuals in Brazil An Analysis of Nationwide Data
Paula AA Schechter M Tuboi SH Faulhaber JC Luz PM et al (2014) PLOS ONE 9(4)
e94636 httpsdoiorg101371journalpone0094636
bull 12366853 atestados
bull 151706 (123) HIVAIDS
ATVr DRVr EFV RPV DTG RAL ABC FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Antihypert
ensiv
eagents
Amlodipine
Atenolol
Bisoprolol
Enalapril
Felodipine
Indapamide
Lisinopril
Losartan
Nifedipine
Olmesartan
Perindopril
Valsartan
Interaccedilotildees com Antihipertensivos
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Potential interaction
no dose adjustment
required
ATVr DRVr EFV RPV DTG RAL
AB
C FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Lip
id-l
ow
ering a
gents
Atorvastatin
Fluvastatin
Lovastatin
Pravastatin
Rosuvastatin
Simvastatin
Antidia
betic a
gents
Glibenclamid
e (Glyburide)
Linagliptin
Metformin
Nateglinide
Saxagliptin
Sitagliptin
Interaccedilotildees Medicamentosas com Hipolipemiantes e Hipoglicemiantes
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Do not co-
administer
Potential interaction
no dose adjustment
required
Interaccedilotildees com Medicamentos que atuam no SNC
BOOSTED FREE AGENTS BOOSTED AGENTS
DTGII RAL EFV ETV RPV EVGc DRVr
Stim
ula
nts
amyl nitrate
cocaine
ecstasy (MDMA)
mephedrone
methamphetamine
Dep
ress
ants
alcohol
alprazolam
codeine
diazepam
GHB (gamma hydroxybutyrate)
heroin (diamorphone)
hydrocodone
hydromorphone
ketamine
pethidine (meperideine)
methadone
midazolam (oral)
morphine
oxycodone
temazepam
triazolam
Hal
luci
no
gen
s
cannabis
lysergic acid dietheylamide (LSD)
phencyclidine (PCP angle dust)
Further information (in vivo in vitro or from label) at wwwhiv-druginteractionsorg
These drugs should not be co-administered
Potential interaction-may require close monitoring alteration of drug dosage or timing of administration
No clinically significant expected
Dose do DTG interfere nos niacuteveis de Metformina
Haacute aumento da exposiccedilatildeo plasmaacutetica da metformina
quando coadministrada com DTG e o efeito produzido
(PK) no niacutevel de metformina eacute dose-dependente do DTG
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50 mgq24h
Metf
orm
in c
on
cen
trati
on
(microg
mL
)
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q24h
Metformin alone Period
3
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50mg q12h
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q12h
Metformin alone Period
3
bull Anaacutelise retrospectiva de adultos HIV+ que mudaram o esquema para
outros contendo DTG e fazendo uso concomitante de metformina
(n=15)
bull DTG natildeo alterou a resposta ao uso da metformina nos pacientes
diabeacuteticos
ndash Natildeo houve diferenccedila significante nos niacuteveis de glicose em jejum nem
na concentraccedilatildeo de HbA1 observados antes e depois da troca para
DTG
Na vida real natildeo houve diferenccedila significativa na glicemia de jejum nem na Hb glicada antes e depois da troca para DTG
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
BHIVA 2016 April Manchester UKCB Jones1 J Tan1 J Robinson1 H Tate1 H Lamba1
1Merck Sharp ampDohme Limited Hertford Road Hoddesdon Hertfordshire
- Comorbidades satildeo frequentes
- 70 das pessoas fazem uso de outros medicamentos
- Supressatildeo viral alcanccedilada em cerca de 85 dos casos
independentemente da idade das comorbidades e do uso
de outros medicamentos
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
n=19215 RAL em 83 dos esquemas (n=1428)
Switching From a Boosted Protease Inhibitor (PIr) Based Regimen to a
Dolutegravir (DTG) Regimen in Virologically Suppressed Patients With
High Cardiovascular Risk (Framingham Score gt10 or Age gt 50 Years) Is
Non-Inferior and Decreases Lipids The NEAT 022 Study
JM Gatell1 L Assoumou2 G Moyle3 L Waters4 E Martinez5 H-J
Stellbrink6 G Guaraldi7 S de Wit8 F Raffi9 A Pozniak10 on behalf of
NEAT022 Study Group
1Hospital ClinicIDIBAPS University of Barcelona Infectious Diseases Barcelona Spain 2Sorbone Universites INSERM
UPMC Univ Paris 06 IPLESP UMRS 1136 Paris France 3Chelsea and Westminster Hospital London United Kingdom4Mortimer Market Center London United Kingdom 5Hospital ClinicIDIBAPS University of Barcelona Barcelona Spain6Infectiologisches Centrum Hamburg Germany 7University of Modena and Reggio Emilia Modena Italy 8Saint Pierre
University Hospital Universiteacute Libre de Bruxelles Brussels Belgium 9CHU
Hotel-Dieu Nantes Nantes France 10Chelsea amp Westminster Hospital London United Kingdom
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
FatoresAnos Perdidos de Vida Idade 35 a 80 anos (95 CI)
Risco de morte
HIV + que nunca fumaram
(HIV + nunca que fumaram vs controlesque nunca fumaram)
51 (44ndash58) 03
Controles fumantes
(controles fumantes vs controles quenunca fumaram)
36 (31ndash40) 344
HIV + fumantes
(HIV + fumantes vs HIV + que nuncafumaram)
123 (115ndash130) 615
Tabagismo Mortalidade e HIV Helleberg Clin Infect Dis 2013
Nuacutemero de Anos Perdidos e Risco de Morte Atribuiacutedo agrave Populaccedilatildeo de Fumantes e com HIV
Em um local onde o tratamento da infecccedilatildeo pelo HIV eacute organizado e gratuito pessoas portadoras do HIV e
fumantes perdem mais anos de vida para o tabagismo do que para o proacuteprio viacuterus Satildeo 123 anos de vida
perdidos para o cigarro O excesso de mortalidade de fumantes eacute triplicado e o risco de morte associado
ao tabagismo eacute duplicado entre HIV + em comparaccedilatildeo agrave populaccedilatildeo natildeo fumante mesmo com HIV
NA-ACCORD Fumo hipertensatildeo arterial e niacuteveis de colesterol aumentam
risco de IAM em portadores do HIV
bull Metanaacutelise retrospectivabull Eventos validados de 7 coortes cliacutenicas
NA-ACCORD 12000 -122013 bull N = 29515[1]
ndash Fraccedilatildeo atribuiacutevel agrave populaccedilatildeo proporccedilatildeo de IM evitaacuteveis pela prevenccedilatildeo de fatores de risco modificaacuteveis relacionados com o HIV e tradicionais
ndash 347 pacientes (12) apresentavam IM de tipo 1 devido agrave ruptura da placa
ndash A anaacutelise de sensibilidade foi feita para 16687 pacientes (57) com dados de IMC 227 apresentaram IM tipo 1
ndash ~ 40 de reduccedilatildeo IM possiacutevel atraveacutes da prevenccedilatildeo do tabagismo TC elevado ou hipertensatildeo independentemente do IMC
1 Althoff KN et al CROI 2017 Abstract 130 2 Shepherd L et al CROI
2017 Abstract 131 Slide credit
clinicaloptionscom
bull Em outra anaacutelise separada (DAD) a interrupccedilatildeo do fumo reduziu as taxas globaisde cacircncer apoacutes 1 ano (exceto pulmatildeo quepermaneceu alta mesmo apoacutes 5 anos)[2]
Ajuste para idade sexo raccedila e fatores de risco
listados daggerP lt 05
Adjusted Population Attributable Fractions for MI[1]
MI
BMI Subgrou
p
Traditional MI risk factors
Smoking 38dagger 36
Elevated TC 43dagger 39dagger
HTN 41dagger 39dagger
All 3 (smoking TC HTN) 86
HIV-related MI risk factors
DM 2 4
CKD 3 3
CD4+ cell count 10dagger 14dagger
VL 6 8
AIDS 2 -1
HCV coinfection 8dagger 14dagger
bull Uso recente de ABC associado com ~70 aumento risco de IM
ndash Uso recente definido como ainda em uso ou interrupccedilatildeo dentrodos uacuteltimos seis meses
bull Exposiccedilatildeo cumulativa
ndash ao ABC foi associada com pequeno aumento do risco de IM
ndash ao Lopinavirr foi associada com aumento do risco de IM
Estudo DAD
Risco Cardiovascular
Abacavir e Risco de Infarto Agudo do Miocaacuterdio e Doenccedila Cerebrovascularna era HAART
R Bedimo12 A Westfall3 H Drechsler12 P Tebas41VA North Texas Healthcare System Medicine Dallas United States 2University of Texas Southwestern MedicalCenter Medicine Dallas United States 3University of Alabama at Birmingham Medicine Birmingham United
States 4University of Pennsylvania Medicine Philadelphia United States
19424 pacientes acompanhados por cerca de 4 anos (75311 pessoas-ano) 278 IAM e 868 AVC entre pessoas com mais fatores de risco para DCV incluindo hepatite C e doenccedila renal
Taxa global IAM 369 por 1000 pessoas-ano AVC 1168 por 1000 pessoas-ano
Abacavir associado a maior risco de IAM (hazard ratio [HR] 127 ou 27 aumento do risco) e de AVC (HR 117)
Anaacutelise foi repetida apoacutes controle dos fatores de risco conhecidos paraDCV e condiccedilotildees coexistentes (idade hiperlipidemia hipertensatildeo diabetes tabagismo) e a associaccedilatildeo entre abacavir e IAM ou AVC deixou de ser forte e deixou de ser estatisticamente significante
Pacientes HIV+ com problemas renais satildeo mais medicados com abacavir comoalternativa ao tenofovir e jaacute tecircm maior risco de DCV e de AVC o que passoua ser considerado fator de confusatildeo na anaacutelise
DAD exposiccedilatildeo ao ATVRTV ou DRVRTV e risco
cardiovascular
bull Prospectivo Jan2009 (BL) ateacute o primeiro evento CV uacuteltima visita + 6 meses ou 01022016
bull (N = 35711)
ndash 1157 pts (32) apresentaram DCV (IM AVE morte suacutebita) ou se submeteram a um procedimento cardiacuteaco invasivo
bull Exposiccedilatildeo cumulativa a DRVRTV estaacute associada a risco CV - anaacutelisemultivariada 59 risco aumentadocom 5 anos de uso
ndash Associaccedilatildeo natildeo parece ser mediada pordislipidemia
bull Limitaccedilotildees Fatores de confusatildeo potencialmente natildeomensuraacuteveis num estudo observacional ndash Natildeo foipossiacutevel diferenciar entre DRVRTV 800100 QD vs DRVRTV 600100 BID
bull Natildeo avaliou uso de estatinas natildeo ajustou para supressatildeo viral Fumo atual apenas Exposiccedilatildeo aotabaco em maccedilosano natildeo foi avaliada exposiccedilatildeopreacutevia a IP de primeira geraccedilatildeo natildeo avaliada
Ryom L et al CROI 2017 Abstract 128LB
Incidence Rates of CVD andCumulative Exposure to ATV+RTV and DRV+RTV
ATV+RTV DRV+RTV
Cumulative years of drug exposure
200
150
100
50
40
30
20
0
Incid
en
ce r
ate
1000 P
YF
U (
95
CI)
Incidecircncia de Doenccedilas Crocircnicas
Aumenta Exponencialmente com a Idade
Idade
INC
IDEcirc
NC
IA
Idade eacute o maior fator de riscoSlide cortesia de Peter Reiss
Schouten J et al Clin Infect Dis 2014
Comorbidades relacionadas agrave idade
A IDADE Eacute FATOR DE RISCO INDEPENDENTE E NAtildeO MODIFICAacuteVEL PARA DCV
J GUNTER ET AL ACTA CLINICA BELGICA INTERNATIONAL JOURNAL OF CLINICAL AND LABORATORY MEDICINE
Prevalecircncia de Fatores Predisponentes
para Fragilidade
KKooij et al 8th Netherlands Conference on HIV Pathogenesis Epidemiology Prevention and Treatment Amsterdam November 2014
Causas de Morte 1999-2011
Continuous Increase of Cardiovascular Diseases Diabetes and Non-HIV Related Cancers
as Causes of Death in HIV-Infected Individuals in Brazil An Analysis of Nationwide Data
Paula AA Schechter M Tuboi SH Faulhaber JC Luz PM et al (2014) PLOS ONE 9(4)
e94636 httpsdoiorg101371journalpone0094636
bull 12366853 atestados
bull 151706 (123) HIVAIDS
ATVr DRVr EFV RPV DTG RAL ABC FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Antihypert
ensiv
eagents
Amlodipine
Atenolol
Bisoprolol
Enalapril
Felodipine
Indapamide
Lisinopril
Losartan
Nifedipine
Olmesartan
Perindopril
Valsartan
Interaccedilotildees com Antihipertensivos
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Potential interaction
no dose adjustment
required
ATVr DRVr EFV RPV DTG RAL
AB
C FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Lip
id-l
ow
ering a
gents
Atorvastatin
Fluvastatin
Lovastatin
Pravastatin
Rosuvastatin
Simvastatin
Antidia
betic a
gents
Glibenclamid
e (Glyburide)
Linagliptin
Metformin
Nateglinide
Saxagliptin
Sitagliptin
Interaccedilotildees Medicamentosas com Hipolipemiantes e Hipoglicemiantes
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Do not co-
administer
Potential interaction
no dose adjustment
required
Interaccedilotildees com Medicamentos que atuam no SNC
BOOSTED FREE AGENTS BOOSTED AGENTS
DTGII RAL EFV ETV RPV EVGc DRVr
Stim
ula
nts
amyl nitrate
cocaine
ecstasy (MDMA)
mephedrone
methamphetamine
Dep
ress
ants
alcohol
alprazolam
codeine
diazepam
GHB (gamma hydroxybutyrate)
heroin (diamorphone)
hydrocodone
hydromorphone
ketamine
pethidine (meperideine)
methadone
midazolam (oral)
morphine
oxycodone
temazepam
triazolam
Hal
luci
no
gen
s
cannabis
lysergic acid dietheylamide (LSD)
phencyclidine (PCP angle dust)
Further information (in vivo in vitro or from label) at wwwhiv-druginteractionsorg
These drugs should not be co-administered
Potential interaction-may require close monitoring alteration of drug dosage or timing of administration
No clinically significant expected
Dose do DTG interfere nos niacuteveis de Metformina
Haacute aumento da exposiccedilatildeo plasmaacutetica da metformina
quando coadministrada com DTG e o efeito produzido
(PK) no niacutevel de metformina eacute dose-dependente do DTG
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50 mgq24h
Metf
orm
in c
on
cen
trati
on
(microg
mL
)
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q24h
Metformin alone Period
3
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50mg q12h
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q12h
Metformin alone Period
3
bull Anaacutelise retrospectiva de adultos HIV+ que mudaram o esquema para
outros contendo DTG e fazendo uso concomitante de metformina
(n=15)
bull DTG natildeo alterou a resposta ao uso da metformina nos pacientes
diabeacuteticos
ndash Natildeo houve diferenccedila significante nos niacuteveis de glicose em jejum nem
na concentraccedilatildeo de HbA1 observados antes e depois da troca para
DTG
Na vida real natildeo houve diferenccedila significativa na glicemia de jejum nem na Hb glicada antes e depois da troca para DTG
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
BHIVA 2016 April Manchester UKCB Jones1 J Tan1 J Robinson1 H Tate1 H Lamba1
1Merck Sharp ampDohme Limited Hertford Road Hoddesdon Hertfordshire
- Comorbidades satildeo frequentes
- 70 das pessoas fazem uso de outros medicamentos
- Supressatildeo viral alcanccedilada em cerca de 85 dos casos
independentemente da idade das comorbidades e do uso
de outros medicamentos
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
n=19215 RAL em 83 dos esquemas (n=1428)
Switching From a Boosted Protease Inhibitor (PIr) Based Regimen to a
Dolutegravir (DTG) Regimen in Virologically Suppressed Patients With
High Cardiovascular Risk (Framingham Score gt10 or Age gt 50 Years) Is
Non-Inferior and Decreases Lipids The NEAT 022 Study
JM Gatell1 L Assoumou2 G Moyle3 L Waters4 E Martinez5 H-J
Stellbrink6 G Guaraldi7 S de Wit8 F Raffi9 A Pozniak10 on behalf of
NEAT022 Study Group
1Hospital ClinicIDIBAPS University of Barcelona Infectious Diseases Barcelona Spain 2Sorbone Universites INSERM
UPMC Univ Paris 06 IPLESP UMRS 1136 Paris France 3Chelsea and Westminster Hospital London United Kingdom4Mortimer Market Center London United Kingdom 5Hospital ClinicIDIBAPS University of Barcelona Barcelona Spain6Infectiologisches Centrum Hamburg Germany 7University of Modena and Reggio Emilia Modena Italy 8Saint Pierre
University Hospital Universiteacute Libre de Bruxelles Brussels Belgium 9CHU
Hotel-Dieu Nantes Nantes France 10Chelsea amp Westminster Hospital London United Kingdom
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
NA-ACCORD Fumo hipertensatildeo arterial e niacuteveis de colesterol aumentam
risco de IAM em portadores do HIV
bull Metanaacutelise retrospectivabull Eventos validados de 7 coortes cliacutenicas
NA-ACCORD 12000 -122013 bull N = 29515[1]
ndash Fraccedilatildeo atribuiacutevel agrave populaccedilatildeo proporccedilatildeo de IM evitaacuteveis pela prevenccedilatildeo de fatores de risco modificaacuteveis relacionados com o HIV e tradicionais
ndash 347 pacientes (12) apresentavam IM de tipo 1 devido agrave ruptura da placa
ndash A anaacutelise de sensibilidade foi feita para 16687 pacientes (57) com dados de IMC 227 apresentaram IM tipo 1
ndash ~ 40 de reduccedilatildeo IM possiacutevel atraveacutes da prevenccedilatildeo do tabagismo TC elevado ou hipertensatildeo independentemente do IMC
1 Althoff KN et al CROI 2017 Abstract 130 2 Shepherd L et al CROI
2017 Abstract 131 Slide credit
clinicaloptionscom
bull Em outra anaacutelise separada (DAD) a interrupccedilatildeo do fumo reduziu as taxas globaisde cacircncer apoacutes 1 ano (exceto pulmatildeo quepermaneceu alta mesmo apoacutes 5 anos)[2]
Ajuste para idade sexo raccedila e fatores de risco
listados daggerP lt 05
Adjusted Population Attributable Fractions for MI[1]
MI
BMI Subgrou
p
Traditional MI risk factors
Smoking 38dagger 36
Elevated TC 43dagger 39dagger
HTN 41dagger 39dagger
All 3 (smoking TC HTN) 86
HIV-related MI risk factors
DM 2 4
CKD 3 3
CD4+ cell count 10dagger 14dagger
VL 6 8
AIDS 2 -1
HCV coinfection 8dagger 14dagger
bull Uso recente de ABC associado com ~70 aumento risco de IM
ndash Uso recente definido como ainda em uso ou interrupccedilatildeo dentrodos uacuteltimos seis meses
bull Exposiccedilatildeo cumulativa
ndash ao ABC foi associada com pequeno aumento do risco de IM
ndash ao Lopinavirr foi associada com aumento do risco de IM
Estudo DAD
Risco Cardiovascular
Abacavir e Risco de Infarto Agudo do Miocaacuterdio e Doenccedila Cerebrovascularna era HAART
R Bedimo12 A Westfall3 H Drechsler12 P Tebas41VA North Texas Healthcare System Medicine Dallas United States 2University of Texas Southwestern MedicalCenter Medicine Dallas United States 3University of Alabama at Birmingham Medicine Birmingham United
States 4University of Pennsylvania Medicine Philadelphia United States
19424 pacientes acompanhados por cerca de 4 anos (75311 pessoas-ano) 278 IAM e 868 AVC entre pessoas com mais fatores de risco para DCV incluindo hepatite C e doenccedila renal
Taxa global IAM 369 por 1000 pessoas-ano AVC 1168 por 1000 pessoas-ano
Abacavir associado a maior risco de IAM (hazard ratio [HR] 127 ou 27 aumento do risco) e de AVC (HR 117)
Anaacutelise foi repetida apoacutes controle dos fatores de risco conhecidos paraDCV e condiccedilotildees coexistentes (idade hiperlipidemia hipertensatildeo diabetes tabagismo) e a associaccedilatildeo entre abacavir e IAM ou AVC deixou de ser forte e deixou de ser estatisticamente significante
Pacientes HIV+ com problemas renais satildeo mais medicados com abacavir comoalternativa ao tenofovir e jaacute tecircm maior risco de DCV e de AVC o que passoua ser considerado fator de confusatildeo na anaacutelise
DAD exposiccedilatildeo ao ATVRTV ou DRVRTV e risco
cardiovascular
bull Prospectivo Jan2009 (BL) ateacute o primeiro evento CV uacuteltima visita + 6 meses ou 01022016
bull (N = 35711)
ndash 1157 pts (32) apresentaram DCV (IM AVE morte suacutebita) ou se submeteram a um procedimento cardiacuteaco invasivo
bull Exposiccedilatildeo cumulativa a DRVRTV estaacute associada a risco CV - anaacutelisemultivariada 59 risco aumentadocom 5 anos de uso
ndash Associaccedilatildeo natildeo parece ser mediada pordislipidemia
bull Limitaccedilotildees Fatores de confusatildeo potencialmente natildeomensuraacuteveis num estudo observacional ndash Natildeo foipossiacutevel diferenciar entre DRVRTV 800100 QD vs DRVRTV 600100 BID
bull Natildeo avaliou uso de estatinas natildeo ajustou para supressatildeo viral Fumo atual apenas Exposiccedilatildeo aotabaco em maccedilosano natildeo foi avaliada exposiccedilatildeopreacutevia a IP de primeira geraccedilatildeo natildeo avaliada
Ryom L et al CROI 2017 Abstract 128LB
Incidence Rates of CVD andCumulative Exposure to ATV+RTV and DRV+RTV
ATV+RTV DRV+RTV
Cumulative years of drug exposure
200
150
100
50
40
30
20
0
Incid
en
ce r
ate
1000 P
YF
U (
95
CI)
Incidecircncia de Doenccedilas Crocircnicas
Aumenta Exponencialmente com a Idade
Idade
INC
IDEcirc
NC
IA
Idade eacute o maior fator de riscoSlide cortesia de Peter Reiss
Schouten J et al Clin Infect Dis 2014
Comorbidades relacionadas agrave idade
A IDADE Eacute FATOR DE RISCO INDEPENDENTE E NAtildeO MODIFICAacuteVEL PARA DCV
J GUNTER ET AL ACTA CLINICA BELGICA INTERNATIONAL JOURNAL OF CLINICAL AND LABORATORY MEDICINE
Prevalecircncia de Fatores Predisponentes
para Fragilidade
KKooij et al 8th Netherlands Conference on HIV Pathogenesis Epidemiology Prevention and Treatment Amsterdam November 2014
Causas de Morte 1999-2011
Continuous Increase of Cardiovascular Diseases Diabetes and Non-HIV Related Cancers
as Causes of Death in HIV-Infected Individuals in Brazil An Analysis of Nationwide Data
Paula AA Schechter M Tuboi SH Faulhaber JC Luz PM et al (2014) PLOS ONE 9(4)
e94636 httpsdoiorg101371journalpone0094636
bull 12366853 atestados
bull 151706 (123) HIVAIDS
ATVr DRVr EFV RPV DTG RAL ABC FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Antihypert
ensiv
eagents
Amlodipine
Atenolol
Bisoprolol
Enalapril
Felodipine
Indapamide
Lisinopril
Losartan
Nifedipine
Olmesartan
Perindopril
Valsartan
Interaccedilotildees com Antihipertensivos
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Potential interaction
no dose adjustment
required
ATVr DRVr EFV RPV DTG RAL
AB
C FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Lip
id-l
ow
ering a
gents
Atorvastatin
Fluvastatin
Lovastatin
Pravastatin
Rosuvastatin
Simvastatin
Antidia
betic a
gents
Glibenclamid
e (Glyburide)
Linagliptin
Metformin
Nateglinide
Saxagliptin
Sitagliptin
Interaccedilotildees Medicamentosas com Hipolipemiantes e Hipoglicemiantes
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Do not co-
administer
Potential interaction
no dose adjustment
required
Interaccedilotildees com Medicamentos que atuam no SNC
BOOSTED FREE AGENTS BOOSTED AGENTS
DTGII RAL EFV ETV RPV EVGc DRVr
Stim
ula
nts
amyl nitrate
cocaine
ecstasy (MDMA)
mephedrone
methamphetamine
Dep
ress
ants
alcohol
alprazolam
codeine
diazepam
GHB (gamma hydroxybutyrate)
heroin (diamorphone)
hydrocodone
hydromorphone
ketamine
pethidine (meperideine)
methadone
midazolam (oral)
morphine
oxycodone
temazepam
triazolam
Hal
luci
no
gen
s
cannabis
lysergic acid dietheylamide (LSD)
phencyclidine (PCP angle dust)
Further information (in vivo in vitro or from label) at wwwhiv-druginteractionsorg
These drugs should not be co-administered
Potential interaction-may require close monitoring alteration of drug dosage or timing of administration
No clinically significant expected
Dose do DTG interfere nos niacuteveis de Metformina
Haacute aumento da exposiccedilatildeo plasmaacutetica da metformina
quando coadministrada com DTG e o efeito produzido
(PK) no niacutevel de metformina eacute dose-dependente do DTG
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50 mgq24h
Metf
orm
in c
on
cen
trati
on
(microg
mL
)
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q24h
Metformin alone Period
3
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50mg q12h
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q12h
Metformin alone Period
3
bull Anaacutelise retrospectiva de adultos HIV+ que mudaram o esquema para
outros contendo DTG e fazendo uso concomitante de metformina
(n=15)
bull DTG natildeo alterou a resposta ao uso da metformina nos pacientes
diabeacuteticos
ndash Natildeo houve diferenccedila significante nos niacuteveis de glicose em jejum nem
na concentraccedilatildeo de HbA1 observados antes e depois da troca para
DTG
Na vida real natildeo houve diferenccedila significativa na glicemia de jejum nem na Hb glicada antes e depois da troca para DTG
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
BHIVA 2016 April Manchester UKCB Jones1 J Tan1 J Robinson1 H Tate1 H Lamba1
1Merck Sharp ampDohme Limited Hertford Road Hoddesdon Hertfordshire
- Comorbidades satildeo frequentes
- 70 das pessoas fazem uso de outros medicamentos
- Supressatildeo viral alcanccedilada em cerca de 85 dos casos
independentemente da idade das comorbidades e do uso
de outros medicamentos
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
n=19215 RAL em 83 dos esquemas (n=1428)
Switching From a Boosted Protease Inhibitor (PIr) Based Regimen to a
Dolutegravir (DTG) Regimen in Virologically Suppressed Patients With
High Cardiovascular Risk (Framingham Score gt10 or Age gt 50 Years) Is
Non-Inferior and Decreases Lipids The NEAT 022 Study
JM Gatell1 L Assoumou2 G Moyle3 L Waters4 E Martinez5 H-J
Stellbrink6 G Guaraldi7 S de Wit8 F Raffi9 A Pozniak10 on behalf of
NEAT022 Study Group
1Hospital ClinicIDIBAPS University of Barcelona Infectious Diseases Barcelona Spain 2Sorbone Universites INSERM
UPMC Univ Paris 06 IPLESP UMRS 1136 Paris France 3Chelsea and Westminster Hospital London United Kingdom4Mortimer Market Center London United Kingdom 5Hospital ClinicIDIBAPS University of Barcelona Barcelona Spain6Infectiologisches Centrum Hamburg Germany 7University of Modena and Reggio Emilia Modena Italy 8Saint Pierre
University Hospital Universiteacute Libre de Bruxelles Brussels Belgium 9CHU
Hotel-Dieu Nantes Nantes France 10Chelsea amp Westminster Hospital London United Kingdom
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
bull Uso recente de ABC associado com ~70 aumento risco de IM
ndash Uso recente definido como ainda em uso ou interrupccedilatildeo dentrodos uacuteltimos seis meses
bull Exposiccedilatildeo cumulativa
ndash ao ABC foi associada com pequeno aumento do risco de IM
ndash ao Lopinavirr foi associada com aumento do risco de IM
Estudo DAD
Risco Cardiovascular
Abacavir e Risco de Infarto Agudo do Miocaacuterdio e Doenccedila Cerebrovascularna era HAART
R Bedimo12 A Westfall3 H Drechsler12 P Tebas41VA North Texas Healthcare System Medicine Dallas United States 2University of Texas Southwestern MedicalCenter Medicine Dallas United States 3University of Alabama at Birmingham Medicine Birmingham United
States 4University of Pennsylvania Medicine Philadelphia United States
19424 pacientes acompanhados por cerca de 4 anos (75311 pessoas-ano) 278 IAM e 868 AVC entre pessoas com mais fatores de risco para DCV incluindo hepatite C e doenccedila renal
Taxa global IAM 369 por 1000 pessoas-ano AVC 1168 por 1000 pessoas-ano
Abacavir associado a maior risco de IAM (hazard ratio [HR] 127 ou 27 aumento do risco) e de AVC (HR 117)
Anaacutelise foi repetida apoacutes controle dos fatores de risco conhecidos paraDCV e condiccedilotildees coexistentes (idade hiperlipidemia hipertensatildeo diabetes tabagismo) e a associaccedilatildeo entre abacavir e IAM ou AVC deixou de ser forte e deixou de ser estatisticamente significante
Pacientes HIV+ com problemas renais satildeo mais medicados com abacavir comoalternativa ao tenofovir e jaacute tecircm maior risco de DCV e de AVC o que passoua ser considerado fator de confusatildeo na anaacutelise
DAD exposiccedilatildeo ao ATVRTV ou DRVRTV e risco
cardiovascular
bull Prospectivo Jan2009 (BL) ateacute o primeiro evento CV uacuteltima visita + 6 meses ou 01022016
bull (N = 35711)
ndash 1157 pts (32) apresentaram DCV (IM AVE morte suacutebita) ou se submeteram a um procedimento cardiacuteaco invasivo
bull Exposiccedilatildeo cumulativa a DRVRTV estaacute associada a risco CV - anaacutelisemultivariada 59 risco aumentadocom 5 anos de uso
ndash Associaccedilatildeo natildeo parece ser mediada pordislipidemia
bull Limitaccedilotildees Fatores de confusatildeo potencialmente natildeomensuraacuteveis num estudo observacional ndash Natildeo foipossiacutevel diferenciar entre DRVRTV 800100 QD vs DRVRTV 600100 BID
bull Natildeo avaliou uso de estatinas natildeo ajustou para supressatildeo viral Fumo atual apenas Exposiccedilatildeo aotabaco em maccedilosano natildeo foi avaliada exposiccedilatildeopreacutevia a IP de primeira geraccedilatildeo natildeo avaliada
Ryom L et al CROI 2017 Abstract 128LB
Incidence Rates of CVD andCumulative Exposure to ATV+RTV and DRV+RTV
ATV+RTV DRV+RTV
Cumulative years of drug exposure
200
150
100
50
40
30
20
0
Incid
en
ce r
ate
1000 P
YF
U (
95
CI)
Incidecircncia de Doenccedilas Crocircnicas
Aumenta Exponencialmente com a Idade
Idade
INC
IDEcirc
NC
IA
Idade eacute o maior fator de riscoSlide cortesia de Peter Reiss
Schouten J et al Clin Infect Dis 2014
Comorbidades relacionadas agrave idade
A IDADE Eacute FATOR DE RISCO INDEPENDENTE E NAtildeO MODIFICAacuteVEL PARA DCV
J GUNTER ET AL ACTA CLINICA BELGICA INTERNATIONAL JOURNAL OF CLINICAL AND LABORATORY MEDICINE
Prevalecircncia de Fatores Predisponentes
para Fragilidade
KKooij et al 8th Netherlands Conference on HIV Pathogenesis Epidemiology Prevention and Treatment Amsterdam November 2014
Causas de Morte 1999-2011
Continuous Increase of Cardiovascular Diseases Diabetes and Non-HIV Related Cancers
as Causes of Death in HIV-Infected Individuals in Brazil An Analysis of Nationwide Data
Paula AA Schechter M Tuboi SH Faulhaber JC Luz PM et al (2014) PLOS ONE 9(4)
e94636 httpsdoiorg101371journalpone0094636
bull 12366853 atestados
bull 151706 (123) HIVAIDS
ATVr DRVr EFV RPV DTG RAL ABC FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Antihypert
ensiv
eagents
Amlodipine
Atenolol
Bisoprolol
Enalapril
Felodipine
Indapamide
Lisinopril
Losartan
Nifedipine
Olmesartan
Perindopril
Valsartan
Interaccedilotildees com Antihipertensivos
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Potential interaction
no dose adjustment
required
ATVr DRVr EFV RPV DTG RAL
AB
C FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Lip
id-l
ow
ering a
gents
Atorvastatin
Fluvastatin
Lovastatin
Pravastatin
Rosuvastatin
Simvastatin
Antidia
betic a
gents
Glibenclamid
e (Glyburide)
Linagliptin
Metformin
Nateglinide
Saxagliptin
Sitagliptin
Interaccedilotildees Medicamentosas com Hipolipemiantes e Hipoglicemiantes
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Do not co-
administer
Potential interaction
no dose adjustment
required
Interaccedilotildees com Medicamentos que atuam no SNC
BOOSTED FREE AGENTS BOOSTED AGENTS
DTGII RAL EFV ETV RPV EVGc DRVr
Stim
ula
nts
amyl nitrate
cocaine
ecstasy (MDMA)
mephedrone
methamphetamine
Dep
ress
ants
alcohol
alprazolam
codeine
diazepam
GHB (gamma hydroxybutyrate)
heroin (diamorphone)
hydrocodone
hydromorphone
ketamine
pethidine (meperideine)
methadone
midazolam (oral)
morphine
oxycodone
temazepam
triazolam
Hal
luci
no
gen
s
cannabis
lysergic acid dietheylamide (LSD)
phencyclidine (PCP angle dust)
Further information (in vivo in vitro or from label) at wwwhiv-druginteractionsorg
These drugs should not be co-administered
Potential interaction-may require close monitoring alteration of drug dosage or timing of administration
No clinically significant expected
Dose do DTG interfere nos niacuteveis de Metformina
Haacute aumento da exposiccedilatildeo plasmaacutetica da metformina
quando coadministrada com DTG e o efeito produzido
(PK) no niacutevel de metformina eacute dose-dependente do DTG
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50 mgq24h
Metf
orm
in c
on
cen
trati
on
(microg
mL
)
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q24h
Metformin alone Period
3
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50mg q12h
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q12h
Metformin alone Period
3
bull Anaacutelise retrospectiva de adultos HIV+ que mudaram o esquema para
outros contendo DTG e fazendo uso concomitante de metformina
(n=15)
bull DTG natildeo alterou a resposta ao uso da metformina nos pacientes
diabeacuteticos
ndash Natildeo houve diferenccedila significante nos niacuteveis de glicose em jejum nem
na concentraccedilatildeo de HbA1 observados antes e depois da troca para
DTG
Na vida real natildeo houve diferenccedila significativa na glicemia de jejum nem na Hb glicada antes e depois da troca para DTG
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
BHIVA 2016 April Manchester UKCB Jones1 J Tan1 J Robinson1 H Tate1 H Lamba1
1Merck Sharp ampDohme Limited Hertford Road Hoddesdon Hertfordshire
- Comorbidades satildeo frequentes
- 70 das pessoas fazem uso de outros medicamentos
- Supressatildeo viral alcanccedilada em cerca de 85 dos casos
independentemente da idade das comorbidades e do uso
de outros medicamentos
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
n=19215 RAL em 83 dos esquemas (n=1428)
Switching From a Boosted Protease Inhibitor (PIr) Based Regimen to a
Dolutegravir (DTG) Regimen in Virologically Suppressed Patients With
High Cardiovascular Risk (Framingham Score gt10 or Age gt 50 Years) Is
Non-Inferior and Decreases Lipids The NEAT 022 Study
JM Gatell1 L Assoumou2 G Moyle3 L Waters4 E Martinez5 H-J
Stellbrink6 G Guaraldi7 S de Wit8 F Raffi9 A Pozniak10 on behalf of
NEAT022 Study Group
1Hospital ClinicIDIBAPS University of Barcelona Infectious Diseases Barcelona Spain 2Sorbone Universites INSERM
UPMC Univ Paris 06 IPLESP UMRS 1136 Paris France 3Chelsea and Westminster Hospital London United Kingdom4Mortimer Market Center London United Kingdom 5Hospital ClinicIDIBAPS University of Barcelona Barcelona Spain6Infectiologisches Centrum Hamburg Germany 7University of Modena and Reggio Emilia Modena Italy 8Saint Pierre
University Hospital Universiteacute Libre de Bruxelles Brussels Belgium 9CHU
Hotel-Dieu Nantes Nantes France 10Chelsea amp Westminster Hospital London United Kingdom
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
Abacavir e Risco de Infarto Agudo do Miocaacuterdio e Doenccedila Cerebrovascularna era HAART
R Bedimo12 A Westfall3 H Drechsler12 P Tebas41VA North Texas Healthcare System Medicine Dallas United States 2University of Texas Southwestern MedicalCenter Medicine Dallas United States 3University of Alabama at Birmingham Medicine Birmingham United
States 4University of Pennsylvania Medicine Philadelphia United States
19424 pacientes acompanhados por cerca de 4 anos (75311 pessoas-ano) 278 IAM e 868 AVC entre pessoas com mais fatores de risco para DCV incluindo hepatite C e doenccedila renal
Taxa global IAM 369 por 1000 pessoas-ano AVC 1168 por 1000 pessoas-ano
Abacavir associado a maior risco de IAM (hazard ratio [HR] 127 ou 27 aumento do risco) e de AVC (HR 117)
Anaacutelise foi repetida apoacutes controle dos fatores de risco conhecidos paraDCV e condiccedilotildees coexistentes (idade hiperlipidemia hipertensatildeo diabetes tabagismo) e a associaccedilatildeo entre abacavir e IAM ou AVC deixou de ser forte e deixou de ser estatisticamente significante
Pacientes HIV+ com problemas renais satildeo mais medicados com abacavir comoalternativa ao tenofovir e jaacute tecircm maior risco de DCV e de AVC o que passoua ser considerado fator de confusatildeo na anaacutelise
DAD exposiccedilatildeo ao ATVRTV ou DRVRTV e risco
cardiovascular
bull Prospectivo Jan2009 (BL) ateacute o primeiro evento CV uacuteltima visita + 6 meses ou 01022016
bull (N = 35711)
ndash 1157 pts (32) apresentaram DCV (IM AVE morte suacutebita) ou se submeteram a um procedimento cardiacuteaco invasivo
bull Exposiccedilatildeo cumulativa a DRVRTV estaacute associada a risco CV - anaacutelisemultivariada 59 risco aumentadocom 5 anos de uso
ndash Associaccedilatildeo natildeo parece ser mediada pordislipidemia
bull Limitaccedilotildees Fatores de confusatildeo potencialmente natildeomensuraacuteveis num estudo observacional ndash Natildeo foipossiacutevel diferenciar entre DRVRTV 800100 QD vs DRVRTV 600100 BID
bull Natildeo avaliou uso de estatinas natildeo ajustou para supressatildeo viral Fumo atual apenas Exposiccedilatildeo aotabaco em maccedilosano natildeo foi avaliada exposiccedilatildeopreacutevia a IP de primeira geraccedilatildeo natildeo avaliada
Ryom L et al CROI 2017 Abstract 128LB
Incidence Rates of CVD andCumulative Exposure to ATV+RTV and DRV+RTV
ATV+RTV DRV+RTV
Cumulative years of drug exposure
200
150
100
50
40
30
20
0
Incid
en
ce r
ate
1000 P
YF
U (
95
CI)
Incidecircncia de Doenccedilas Crocircnicas
Aumenta Exponencialmente com a Idade
Idade
INC
IDEcirc
NC
IA
Idade eacute o maior fator de riscoSlide cortesia de Peter Reiss
Schouten J et al Clin Infect Dis 2014
Comorbidades relacionadas agrave idade
A IDADE Eacute FATOR DE RISCO INDEPENDENTE E NAtildeO MODIFICAacuteVEL PARA DCV
J GUNTER ET AL ACTA CLINICA BELGICA INTERNATIONAL JOURNAL OF CLINICAL AND LABORATORY MEDICINE
Prevalecircncia de Fatores Predisponentes
para Fragilidade
KKooij et al 8th Netherlands Conference on HIV Pathogenesis Epidemiology Prevention and Treatment Amsterdam November 2014
Causas de Morte 1999-2011
Continuous Increase of Cardiovascular Diseases Diabetes and Non-HIV Related Cancers
as Causes of Death in HIV-Infected Individuals in Brazil An Analysis of Nationwide Data
Paula AA Schechter M Tuboi SH Faulhaber JC Luz PM et al (2014) PLOS ONE 9(4)
e94636 httpsdoiorg101371journalpone0094636
bull 12366853 atestados
bull 151706 (123) HIVAIDS
ATVr DRVr EFV RPV DTG RAL ABC FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Antihypert
ensiv
eagents
Amlodipine
Atenolol
Bisoprolol
Enalapril
Felodipine
Indapamide
Lisinopril
Losartan
Nifedipine
Olmesartan
Perindopril
Valsartan
Interaccedilotildees com Antihipertensivos
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Potential interaction
no dose adjustment
required
ATVr DRVr EFV RPV DTG RAL
AB
C FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Lip
id-l
ow
ering a
gents
Atorvastatin
Fluvastatin
Lovastatin
Pravastatin
Rosuvastatin
Simvastatin
Antidia
betic a
gents
Glibenclamid
e (Glyburide)
Linagliptin
Metformin
Nateglinide
Saxagliptin
Sitagliptin
Interaccedilotildees Medicamentosas com Hipolipemiantes e Hipoglicemiantes
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Do not co-
administer
Potential interaction
no dose adjustment
required
Interaccedilotildees com Medicamentos que atuam no SNC
BOOSTED FREE AGENTS BOOSTED AGENTS
DTGII RAL EFV ETV RPV EVGc DRVr
Stim
ula
nts
amyl nitrate
cocaine
ecstasy (MDMA)
mephedrone
methamphetamine
Dep
ress
ants
alcohol
alprazolam
codeine
diazepam
GHB (gamma hydroxybutyrate)
heroin (diamorphone)
hydrocodone
hydromorphone
ketamine
pethidine (meperideine)
methadone
midazolam (oral)
morphine
oxycodone
temazepam
triazolam
Hal
luci
no
gen
s
cannabis
lysergic acid dietheylamide (LSD)
phencyclidine (PCP angle dust)
Further information (in vivo in vitro or from label) at wwwhiv-druginteractionsorg
These drugs should not be co-administered
Potential interaction-may require close monitoring alteration of drug dosage or timing of administration
No clinically significant expected
Dose do DTG interfere nos niacuteveis de Metformina
Haacute aumento da exposiccedilatildeo plasmaacutetica da metformina
quando coadministrada com DTG e o efeito produzido
(PK) no niacutevel de metformina eacute dose-dependente do DTG
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50 mgq24h
Metf
orm
in c
on
cen
trati
on
(microg
mL
)
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q24h
Metformin alone Period
3
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50mg q12h
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q12h
Metformin alone Period
3
bull Anaacutelise retrospectiva de adultos HIV+ que mudaram o esquema para
outros contendo DTG e fazendo uso concomitante de metformina
(n=15)
bull DTG natildeo alterou a resposta ao uso da metformina nos pacientes
diabeacuteticos
ndash Natildeo houve diferenccedila significante nos niacuteveis de glicose em jejum nem
na concentraccedilatildeo de HbA1 observados antes e depois da troca para
DTG
Na vida real natildeo houve diferenccedila significativa na glicemia de jejum nem na Hb glicada antes e depois da troca para DTG
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
BHIVA 2016 April Manchester UKCB Jones1 J Tan1 J Robinson1 H Tate1 H Lamba1
1Merck Sharp ampDohme Limited Hertford Road Hoddesdon Hertfordshire
- Comorbidades satildeo frequentes
- 70 das pessoas fazem uso de outros medicamentos
- Supressatildeo viral alcanccedilada em cerca de 85 dos casos
independentemente da idade das comorbidades e do uso
de outros medicamentos
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
n=19215 RAL em 83 dos esquemas (n=1428)
Switching From a Boosted Protease Inhibitor (PIr) Based Regimen to a
Dolutegravir (DTG) Regimen in Virologically Suppressed Patients With
High Cardiovascular Risk (Framingham Score gt10 or Age gt 50 Years) Is
Non-Inferior and Decreases Lipids The NEAT 022 Study
JM Gatell1 L Assoumou2 G Moyle3 L Waters4 E Martinez5 H-J
Stellbrink6 G Guaraldi7 S de Wit8 F Raffi9 A Pozniak10 on behalf of
NEAT022 Study Group
1Hospital ClinicIDIBAPS University of Barcelona Infectious Diseases Barcelona Spain 2Sorbone Universites INSERM
UPMC Univ Paris 06 IPLESP UMRS 1136 Paris France 3Chelsea and Westminster Hospital London United Kingdom4Mortimer Market Center London United Kingdom 5Hospital ClinicIDIBAPS University of Barcelona Barcelona Spain6Infectiologisches Centrum Hamburg Germany 7University of Modena and Reggio Emilia Modena Italy 8Saint Pierre
University Hospital Universiteacute Libre de Bruxelles Brussels Belgium 9CHU
Hotel-Dieu Nantes Nantes France 10Chelsea amp Westminster Hospital London United Kingdom
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
DAD exposiccedilatildeo ao ATVRTV ou DRVRTV e risco
cardiovascular
bull Prospectivo Jan2009 (BL) ateacute o primeiro evento CV uacuteltima visita + 6 meses ou 01022016
bull (N = 35711)
ndash 1157 pts (32) apresentaram DCV (IM AVE morte suacutebita) ou se submeteram a um procedimento cardiacuteaco invasivo
bull Exposiccedilatildeo cumulativa a DRVRTV estaacute associada a risco CV - anaacutelisemultivariada 59 risco aumentadocom 5 anos de uso
ndash Associaccedilatildeo natildeo parece ser mediada pordislipidemia
bull Limitaccedilotildees Fatores de confusatildeo potencialmente natildeomensuraacuteveis num estudo observacional ndash Natildeo foipossiacutevel diferenciar entre DRVRTV 800100 QD vs DRVRTV 600100 BID
bull Natildeo avaliou uso de estatinas natildeo ajustou para supressatildeo viral Fumo atual apenas Exposiccedilatildeo aotabaco em maccedilosano natildeo foi avaliada exposiccedilatildeopreacutevia a IP de primeira geraccedilatildeo natildeo avaliada
Ryom L et al CROI 2017 Abstract 128LB
Incidence Rates of CVD andCumulative Exposure to ATV+RTV and DRV+RTV
ATV+RTV DRV+RTV
Cumulative years of drug exposure
200
150
100
50
40
30
20
0
Incid
en
ce r
ate
1000 P
YF
U (
95
CI)
Incidecircncia de Doenccedilas Crocircnicas
Aumenta Exponencialmente com a Idade
Idade
INC
IDEcirc
NC
IA
Idade eacute o maior fator de riscoSlide cortesia de Peter Reiss
Schouten J et al Clin Infect Dis 2014
Comorbidades relacionadas agrave idade
A IDADE Eacute FATOR DE RISCO INDEPENDENTE E NAtildeO MODIFICAacuteVEL PARA DCV
J GUNTER ET AL ACTA CLINICA BELGICA INTERNATIONAL JOURNAL OF CLINICAL AND LABORATORY MEDICINE
Prevalecircncia de Fatores Predisponentes
para Fragilidade
KKooij et al 8th Netherlands Conference on HIV Pathogenesis Epidemiology Prevention and Treatment Amsterdam November 2014
Causas de Morte 1999-2011
Continuous Increase of Cardiovascular Diseases Diabetes and Non-HIV Related Cancers
as Causes of Death in HIV-Infected Individuals in Brazil An Analysis of Nationwide Data
Paula AA Schechter M Tuboi SH Faulhaber JC Luz PM et al (2014) PLOS ONE 9(4)
e94636 httpsdoiorg101371journalpone0094636
bull 12366853 atestados
bull 151706 (123) HIVAIDS
ATVr DRVr EFV RPV DTG RAL ABC FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Antihypert
ensiv
eagents
Amlodipine
Atenolol
Bisoprolol
Enalapril
Felodipine
Indapamide
Lisinopril
Losartan
Nifedipine
Olmesartan
Perindopril
Valsartan
Interaccedilotildees com Antihipertensivos
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Potential interaction
no dose adjustment
required
ATVr DRVr EFV RPV DTG RAL
AB
C FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Lip
id-l
ow
ering a
gents
Atorvastatin
Fluvastatin
Lovastatin
Pravastatin
Rosuvastatin
Simvastatin
Antidia
betic a
gents
Glibenclamid
e (Glyburide)
Linagliptin
Metformin
Nateglinide
Saxagliptin
Sitagliptin
Interaccedilotildees Medicamentosas com Hipolipemiantes e Hipoglicemiantes
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Do not co-
administer
Potential interaction
no dose adjustment
required
Interaccedilotildees com Medicamentos que atuam no SNC
BOOSTED FREE AGENTS BOOSTED AGENTS
DTGII RAL EFV ETV RPV EVGc DRVr
Stim
ula
nts
amyl nitrate
cocaine
ecstasy (MDMA)
mephedrone
methamphetamine
Dep
ress
ants
alcohol
alprazolam
codeine
diazepam
GHB (gamma hydroxybutyrate)
heroin (diamorphone)
hydrocodone
hydromorphone
ketamine
pethidine (meperideine)
methadone
midazolam (oral)
morphine
oxycodone
temazepam
triazolam
Hal
luci
no
gen
s
cannabis
lysergic acid dietheylamide (LSD)
phencyclidine (PCP angle dust)
Further information (in vivo in vitro or from label) at wwwhiv-druginteractionsorg
These drugs should not be co-administered
Potential interaction-may require close monitoring alteration of drug dosage or timing of administration
No clinically significant expected
Dose do DTG interfere nos niacuteveis de Metformina
Haacute aumento da exposiccedilatildeo plasmaacutetica da metformina
quando coadministrada com DTG e o efeito produzido
(PK) no niacutevel de metformina eacute dose-dependente do DTG
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50 mgq24h
Metf
orm
in c
on
cen
trati
on
(microg
mL
)
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q24h
Metformin alone Period
3
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50mg q12h
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q12h
Metformin alone Period
3
bull Anaacutelise retrospectiva de adultos HIV+ que mudaram o esquema para
outros contendo DTG e fazendo uso concomitante de metformina
(n=15)
bull DTG natildeo alterou a resposta ao uso da metformina nos pacientes
diabeacuteticos
ndash Natildeo houve diferenccedila significante nos niacuteveis de glicose em jejum nem
na concentraccedilatildeo de HbA1 observados antes e depois da troca para
DTG
Na vida real natildeo houve diferenccedila significativa na glicemia de jejum nem na Hb glicada antes e depois da troca para DTG
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
BHIVA 2016 April Manchester UKCB Jones1 J Tan1 J Robinson1 H Tate1 H Lamba1
1Merck Sharp ampDohme Limited Hertford Road Hoddesdon Hertfordshire
- Comorbidades satildeo frequentes
- 70 das pessoas fazem uso de outros medicamentos
- Supressatildeo viral alcanccedilada em cerca de 85 dos casos
independentemente da idade das comorbidades e do uso
de outros medicamentos
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
n=19215 RAL em 83 dos esquemas (n=1428)
Switching From a Boosted Protease Inhibitor (PIr) Based Regimen to a
Dolutegravir (DTG) Regimen in Virologically Suppressed Patients With
High Cardiovascular Risk (Framingham Score gt10 or Age gt 50 Years) Is
Non-Inferior and Decreases Lipids The NEAT 022 Study
JM Gatell1 L Assoumou2 G Moyle3 L Waters4 E Martinez5 H-J
Stellbrink6 G Guaraldi7 S de Wit8 F Raffi9 A Pozniak10 on behalf of
NEAT022 Study Group
1Hospital ClinicIDIBAPS University of Barcelona Infectious Diseases Barcelona Spain 2Sorbone Universites INSERM
UPMC Univ Paris 06 IPLESP UMRS 1136 Paris France 3Chelsea and Westminster Hospital London United Kingdom4Mortimer Market Center London United Kingdom 5Hospital ClinicIDIBAPS University of Barcelona Barcelona Spain6Infectiologisches Centrum Hamburg Germany 7University of Modena and Reggio Emilia Modena Italy 8Saint Pierre
University Hospital Universiteacute Libre de Bruxelles Brussels Belgium 9CHU
Hotel-Dieu Nantes Nantes France 10Chelsea amp Westminster Hospital London United Kingdom
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
Incidecircncia de Doenccedilas Crocircnicas
Aumenta Exponencialmente com a Idade
Idade
INC
IDEcirc
NC
IA
Idade eacute o maior fator de riscoSlide cortesia de Peter Reiss
Schouten J et al Clin Infect Dis 2014
Comorbidades relacionadas agrave idade
A IDADE Eacute FATOR DE RISCO INDEPENDENTE E NAtildeO MODIFICAacuteVEL PARA DCV
J GUNTER ET AL ACTA CLINICA BELGICA INTERNATIONAL JOURNAL OF CLINICAL AND LABORATORY MEDICINE
Prevalecircncia de Fatores Predisponentes
para Fragilidade
KKooij et al 8th Netherlands Conference on HIV Pathogenesis Epidemiology Prevention and Treatment Amsterdam November 2014
Causas de Morte 1999-2011
Continuous Increase of Cardiovascular Diseases Diabetes and Non-HIV Related Cancers
as Causes of Death in HIV-Infected Individuals in Brazil An Analysis of Nationwide Data
Paula AA Schechter M Tuboi SH Faulhaber JC Luz PM et al (2014) PLOS ONE 9(4)
e94636 httpsdoiorg101371journalpone0094636
bull 12366853 atestados
bull 151706 (123) HIVAIDS
ATVr DRVr EFV RPV DTG RAL ABC FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Antihypert
ensiv
eagents
Amlodipine
Atenolol
Bisoprolol
Enalapril
Felodipine
Indapamide
Lisinopril
Losartan
Nifedipine
Olmesartan
Perindopril
Valsartan
Interaccedilotildees com Antihipertensivos
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Potential interaction
no dose adjustment
required
ATVr DRVr EFV RPV DTG RAL
AB
C FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Lip
id-l
ow
ering a
gents
Atorvastatin
Fluvastatin
Lovastatin
Pravastatin
Rosuvastatin
Simvastatin
Antidia
betic a
gents
Glibenclamid
e (Glyburide)
Linagliptin
Metformin
Nateglinide
Saxagliptin
Sitagliptin
Interaccedilotildees Medicamentosas com Hipolipemiantes e Hipoglicemiantes
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Do not co-
administer
Potential interaction
no dose adjustment
required
Interaccedilotildees com Medicamentos que atuam no SNC
BOOSTED FREE AGENTS BOOSTED AGENTS
DTGII RAL EFV ETV RPV EVGc DRVr
Stim
ula
nts
amyl nitrate
cocaine
ecstasy (MDMA)
mephedrone
methamphetamine
Dep
ress
ants
alcohol
alprazolam
codeine
diazepam
GHB (gamma hydroxybutyrate)
heroin (diamorphone)
hydrocodone
hydromorphone
ketamine
pethidine (meperideine)
methadone
midazolam (oral)
morphine
oxycodone
temazepam
triazolam
Hal
luci
no
gen
s
cannabis
lysergic acid dietheylamide (LSD)
phencyclidine (PCP angle dust)
Further information (in vivo in vitro or from label) at wwwhiv-druginteractionsorg
These drugs should not be co-administered
Potential interaction-may require close monitoring alteration of drug dosage or timing of administration
No clinically significant expected
Dose do DTG interfere nos niacuteveis de Metformina
Haacute aumento da exposiccedilatildeo plasmaacutetica da metformina
quando coadministrada com DTG e o efeito produzido
(PK) no niacutevel de metformina eacute dose-dependente do DTG
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50 mgq24h
Metf
orm
in c
on
cen
trati
on
(microg
mL
)
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q24h
Metformin alone Period
3
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50mg q12h
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q12h
Metformin alone Period
3
bull Anaacutelise retrospectiva de adultos HIV+ que mudaram o esquema para
outros contendo DTG e fazendo uso concomitante de metformina
(n=15)
bull DTG natildeo alterou a resposta ao uso da metformina nos pacientes
diabeacuteticos
ndash Natildeo houve diferenccedila significante nos niacuteveis de glicose em jejum nem
na concentraccedilatildeo de HbA1 observados antes e depois da troca para
DTG
Na vida real natildeo houve diferenccedila significativa na glicemia de jejum nem na Hb glicada antes e depois da troca para DTG
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
BHIVA 2016 April Manchester UKCB Jones1 J Tan1 J Robinson1 H Tate1 H Lamba1
1Merck Sharp ampDohme Limited Hertford Road Hoddesdon Hertfordshire
- Comorbidades satildeo frequentes
- 70 das pessoas fazem uso de outros medicamentos
- Supressatildeo viral alcanccedilada em cerca de 85 dos casos
independentemente da idade das comorbidades e do uso
de outros medicamentos
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
n=19215 RAL em 83 dos esquemas (n=1428)
Switching From a Boosted Protease Inhibitor (PIr) Based Regimen to a
Dolutegravir (DTG) Regimen in Virologically Suppressed Patients With
High Cardiovascular Risk (Framingham Score gt10 or Age gt 50 Years) Is
Non-Inferior and Decreases Lipids The NEAT 022 Study
JM Gatell1 L Assoumou2 G Moyle3 L Waters4 E Martinez5 H-J
Stellbrink6 G Guaraldi7 S de Wit8 F Raffi9 A Pozniak10 on behalf of
NEAT022 Study Group
1Hospital ClinicIDIBAPS University of Barcelona Infectious Diseases Barcelona Spain 2Sorbone Universites INSERM
UPMC Univ Paris 06 IPLESP UMRS 1136 Paris France 3Chelsea and Westminster Hospital London United Kingdom4Mortimer Market Center London United Kingdom 5Hospital ClinicIDIBAPS University of Barcelona Barcelona Spain6Infectiologisches Centrum Hamburg Germany 7University of Modena and Reggio Emilia Modena Italy 8Saint Pierre
University Hospital Universiteacute Libre de Bruxelles Brussels Belgium 9CHU
Hotel-Dieu Nantes Nantes France 10Chelsea amp Westminster Hospital London United Kingdom
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
Schouten J et al Clin Infect Dis 2014
Comorbidades relacionadas agrave idade
A IDADE Eacute FATOR DE RISCO INDEPENDENTE E NAtildeO MODIFICAacuteVEL PARA DCV
J GUNTER ET AL ACTA CLINICA BELGICA INTERNATIONAL JOURNAL OF CLINICAL AND LABORATORY MEDICINE
Prevalecircncia de Fatores Predisponentes
para Fragilidade
KKooij et al 8th Netherlands Conference on HIV Pathogenesis Epidemiology Prevention and Treatment Amsterdam November 2014
Causas de Morte 1999-2011
Continuous Increase of Cardiovascular Diseases Diabetes and Non-HIV Related Cancers
as Causes of Death in HIV-Infected Individuals in Brazil An Analysis of Nationwide Data
Paula AA Schechter M Tuboi SH Faulhaber JC Luz PM et al (2014) PLOS ONE 9(4)
e94636 httpsdoiorg101371journalpone0094636
bull 12366853 atestados
bull 151706 (123) HIVAIDS
ATVr DRVr EFV RPV DTG RAL ABC FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Antihypert
ensiv
eagents
Amlodipine
Atenolol
Bisoprolol
Enalapril
Felodipine
Indapamide
Lisinopril
Losartan
Nifedipine
Olmesartan
Perindopril
Valsartan
Interaccedilotildees com Antihipertensivos
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Potential interaction
no dose adjustment
required
ATVr DRVr EFV RPV DTG RAL
AB
C FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Lip
id-l
ow
ering a
gents
Atorvastatin
Fluvastatin
Lovastatin
Pravastatin
Rosuvastatin
Simvastatin
Antidia
betic a
gents
Glibenclamid
e (Glyburide)
Linagliptin
Metformin
Nateglinide
Saxagliptin
Sitagliptin
Interaccedilotildees Medicamentosas com Hipolipemiantes e Hipoglicemiantes
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Do not co-
administer
Potential interaction
no dose adjustment
required
Interaccedilotildees com Medicamentos que atuam no SNC
BOOSTED FREE AGENTS BOOSTED AGENTS
DTGII RAL EFV ETV RPV EVGc DRVr
Stim
ula
nts
amyl nitrate
cocaine
ecstasy (MDMA)
mephedrone
methamphetamine
Dep
ress
ants
alcohol
alprazolam
codeine
diazepam
GHB (gamma hydroxybutyrate)
heroin (diamorphone)
hydrocodone
hydromorphone
ketamine
pethidine (meperideine)
methadone
midazolam (oral)
morphine
oxycodone
temazepam
triazolam
Hal
luci
no
gen
s
cannabis
lysergic acid dietheylamide (LSD)
phencyclidine (PCP angle dust)
Further information (in vivo in vitro or from label) at wwwhiv-druginteractionsorg
These drugs should not be co-administered
Potential interaction-may require close monitoring alteration of drug dosage or timing of administration
No clinically significant expected
Dose do DTG interfere nos niacuteveis de Metformina
Haacute aumento da exposiccedilatildeo plasmaacutetica da metformina
quando coadministrada com DTG e o efeito produzido
(PK) no niacutevel de metformina eacute dose-dependente do DTG
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50 mgq24h
Metf
orm
in c
on
cen
trati
on
(microg
mL
)
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q24h
Metformin alone Period
3
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50mg q12h
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q12h
Metformin alone Period
3
bull Anaacutelise retrospectiva de adultos HIV+ que mudaram o esquema para
outros contendo DTG e fazendo uso concomitante de metformina
(n=15)
bull DTG natildeo alterou a resposta ao uso da metformina nos pacientes
diabeacuteticos
ndash Natildeo houve diferenccedila significante nos niacuteveis de glicose em jejum nem
na concentraccedilatildeo de HbA1 observados antes e depois da troca para
DTG
Na vida real natildeo houve diferenccedila significativa na glicemia de jejum nem na Hb glicada antes e depois da troca para DTG
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
BHIVA 2016 April Manchester UKCB Jones1 J Tan1 J Robinson1 H Tate1 H Lamba1
1Merck Sharp ampDohme Limited Hertford Road Hoddesdon Hertfordshire
- Comorbidades satildeo frequentes
- 70 das pessoas fazem uso de outros medicamentos
- Supressatildeo viral alcanccedilada em cerca de 85 dos casos
independentemente da idade das comorbidades e do uso
de outros medicamentos
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
n=19215 RAL em 83 dos esquemas (n=1428)
Switching From a Boosted Protease Inhibitor (PIr) Based Regimen to a
Dolutegravir (DTG) Regimen in Virologically Suppressed Patients With
High Cardiovascular Risk (Framingham Score gt10 or Age gt 50 Years) Is
Non-Inferior and Decreases Lipids The NEAT 022 Study
JM Gatell1 L Assoumou2 G Moyle3 L Waters4 E Martinez5 H-J
Stellbrink6 G Guaraldi7 S de Wit8 F Raffi9 A Pozniak10 on behalf of
NEAT022 Study Group
1Hospital ClinicIDIBAPS University of Barcelona Infectious Diseases Barcelona Spain 2Sorbone Universites INSERM
UPMC Univ Paris 06 IPLESP UMRS 1136 Paris France 3Chelsea and Westminster Hospital London United Kingdom4Mortimer Market Center London United Kingdom 5Hospital ClinicIDIBAPS University of Barcelona Barcelona Spain6Infectiologisches Centrum Hamburg Germany 7University of Modena and Reggio Emilia Modena Italy 8Saint Pierre
University Hospital Universiteacute Libre de Bruxelles Brussels Belgium 9CHU
Hotel-Dieu Nantes Nantes France 10Chelsea amp Westminster Hospital London United Kingdom
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
A IDADE Eacute FATOR DE RISCO INDEPENDENTE E NAtildeO MODIFICAacuteVEL PARA DCV
J GUNTER ET AL ACTA CLINICA BELGICA INTERNATIONAL JOURNAL OF CLINICAL AND LABORATORY MEDICINE
Prevalecircncia de Fatores Predisponentes
para Fragilidade
KKooij et al 8th Netherlands Conference on HIV Pathogenesis Epidemiology Prevention and Treatment Amsterdam November 2014
Causas de Morte 1999-2011
Continuous Increase of Cardiovascular Diseases Diabetes and Non-HIV Related Cancers
as Causes of Death in HIV-Infected Individuals in Brazil An Analysis of Nationwide Data
Paula AA Schechter M Tuboi SH Faulhaber JC Luz PM et al (2014) PLOS ONE 9(4)
e94636 httpsdoiorg101371journalpone0094636
bull 12366853 atestados
bull 151706 (123) HIVAIDS
ATVr DRVr EFV RPV DTG RAL ABC FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Antihypert
ensiv
eagents
Amlodipine
Atenolol
Bisoprolol
Enalapril
Felodipine
Indapamide
Lisinopril
Losartan
Nifedipine
Olmesartan
Perindopril
Valsartan
Interaccedilotildees com Antihipertensivos
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Potential interaction
no dose adjustment
required
ATVr DRVr EFV RPV DTG RAL
AB
C FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Lip
id-l
ow
ering a
gents
Atorvastatin
Fluvastatin
Lovastatin
Pravastatin
Rosuvastatin
Simvastatin
Antidia
betic a
gents
Glibenclamid
e (Glyburide)
Linagliptin
Metformin
Nateglinide
Saxagliptin
Sitagliptin
Interaccedilotildees Medicamentosas com Hipolipemiantes e Hipoglicemiantes
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Do not co-
administer
Potential interaction
no dose adjustment
required
Interaccedilotildees com Medicamentos que atuam no SNC
BOOSTED FREE AGENTS BOOSTED AGENTS
DTGII RAL EFV ETV RPV EVGc DRVr
Stim
ula
nts
amyl nitrate
cocaine
ecstasy (MDMA)
mephedrone
methamphetamine
Dep
ress
ants
alcohol
alprazolam
codeine
diazepam
GHB (gamma hydroxybutyrate)
heroin (diamorphone)
hydrocodone
hydromorphone
ketamine
pethidine (meperideine)
methadone
midazolam (oral)
morphine
oxycodone
temazepam
triazolam
Hal
luci
no
gen
s
cannabis
lysergic acid dietheylamide (LSD)
phencyclidine (PCP angle dust)
Further information (in vivo in vitro or from label) at wwwhiv-druginteractionsorg
These drugs should not be co-administered
Potential interaction-may require close monitoring alteration of drug dosage or timing of administration
No clinically significant expected
Dose do DTG interfere nos niacuteveis de Metformina
Haacute aumento da exposiccedilatildeo plasmaacutetica da metformina
quando coadministrada com DTG e o efeito produzido
(PK) no niacutevel de metformina eacute dose-dependente do DTG
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50 mgq24h
Metf
orm
in c
on
cen
trati
on
(microg
mL
)
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q24h
Metformin alone Period
3
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50mg q12h
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q12h
Metformin alone Period
3
bull Anaacutelise retrospectiva de adultos HIV+ que mudaram o esquema para
outros contendo DTG e fazendo uso concomitante de metformina
(n=15)
bull DTG natildeo alterou a resposta ao uso da metformina nos pacientes
diabeacuteticos
ndash Natildeo houve diferenccedila significante nos niacuteveis de glicose em jejum nem
na concentraccedilatildeo de HbA1 observados antes e depois da troca para
DTG
Na vida real natildeo houve diferenccedila significativa na glicemia de jejum nem na Hb glicada antes e depois da troca para DTG
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
BHIVA 2016 April Manchester UKCB Jones1 J Tan1 J Robinson1 H Tate1 H Lamba1
1Merck Sharp ampDohme Limited Hertford Road Hoddesdon Hertfordshire
- Comorbidades satildeo frequentes
- 70 das pessoas fazem uso de outros medicamentos
- Supressatildeo viral alcanccedilada em cerca de 85 dos casos
independentemente da idade das comorbidades e do uso
de outros medicamentos
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
n=19215 RAL em 83 dos esquemas (n=1428)
Switching From a Boosted Protease Inhibitor (PIr) Based Regimen to a
Dolutegravir (DTG) Regimen in Virologically Suppressed Patients With
High Cardiovascular Risk (Framingham Score gt10 or Age gt 50 Years) Is
Non-Inferior and Decreases Lipids The NEAT 022 Study
JM Gatell1 L Assoumou2 G Moyle3 L Waters4 E Martinez5 H-J
Stellbrink6 G Guaraldi7 S de Wit8 F Raffi9 A Pozniak10 on behalf of
NEAT022 Study Group
1Hospital ClinicIDIBAPS University of Barcelona Infectious Diseases Barcelona Spain 2Sorbone Universites INSERM
UPMC Univ Paris 06 IPLESP UMRS 1136 Paris France 3Chelsea and Westminster Hospital London United Kingdom4Mortimer Market Center London United Kingdom 5Hospital ClinicIDIBAPS University of Barcelona Barcelona Spain6Infectiologisches Centrum Hamburg Germany 7University of Modena and Reggio Emilia Modena Italy 8Saint Pierre
University Hospital Universiteacute Libre de Bruxelles Brussels Belgium 9CHU
Hotel-Dieu Nantes Nantes France 10Chelsea amp Westminster Hospital London United Kingdom
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
Prevalecircncia de Fatores Predisponentes
para Fragilidade
KKooij et al 8th Netherlands Conference on HIV Pathogenesis Epidemiology Prevention and Treatment Amsterdam November 2014
Causas de Morte 1999-2011
Continuous Increase of Cardiovascular Diseases Diabetes and Non-HIV Related Cancers
as Causes of Death in HIV-Infected Individuals in Brazil An Analysis of Nationwide Data
Paula AA Schechter M Tuboi SH Faulhaber JC Luz PM et al (2014) PLOS ONE 9(4)
e94636 httpsdoiorg101371journalpone0094636
bull 12366853 atestados
bull 151706 (123) HIVAIDS
ATVr DRVr EFV RPV DTG RAL ABC FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Antihypert
ensiv
eagents
Amlodipine
Atenolol
Bisoprolol
Enalapril
Felodipine
Indapamide
Lisinopril
Losartan
Nifedipine
Olmesartan
Perindopril
Valsartan
Interaccedilotildees com Antihipertensivos
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Potential interaction
no dose adjustment
required
ATVr DRVr EFV RPV DTG RAL
AB
C FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Lip
id-l
ow
ering a
gents
Atorvastatin
Fluvastatin
Lovastatin
Pravastatin
Rosuvastatin
Simvastatin
Antidia
betic a
gents
Glibenclamid
e (Glyburide)
Linagliptin
Metformin
Nateglinide
Saxagliptin
Sitagliptin
Interaccedilotildees Medicamentosas com Hipolipemiantes e Hipoglicemiantes
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Do not co-
administer
Potential interaction
no dose adjustment
required
Interaccedilotildees com Medicamentos que atuam no SNC
BOOSTED FREE AGENTS BOOSTED AGENTS
DTGII RAL EFV ETV RPV EVGc DRVr
Stim
ula
nts
amyl nitrate
cocaine
ecstasy (MDMA)
mephedrone
methamphetamine
Dep
ress
ants
alcohol
alprazolam
codeine
diazepam
GHB (gamma hydroxybutyrate)
heroin (diamorphone)
hydrocodone
hydromorphone
ketamine
pethidine (meperideine)
methadone
midazolam (oral)
morphine
oxycodone
temazepam
triazolam
Hal
luci
no
gen
s
cannabis
lysergic acid dietheylamide (LSD)
phencyclidine (PCP angle dust)
Further information (in vivo in vitro or from label) at wwwhiv-druginteractionsorg
These drugs should not be co-administered
Potential interaction-may require close monitoring alteration of drug dosage or timing of administration
No clinically significant expected
Dose do DTG interfere nos niacuteveis de Metformina
Haacute aumento da exposiccedilatildeo plasmaacutetica da metformina
quando coadministrada com DTG e o efeito produzido
(PK) no niacutevel de metformina eacute dose-dependente do DTG
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50 mgq24h
Metf
orm
in c
on
cen
trati
on
(microg
mL
)
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q24h
Metformin alone Period
3
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50mg q12h
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q12h
Metformin alone Period
3
bull Anaacutelise retrospectiva de adultos HIV+ que mudaram o esquema para
outros contendo DTG e fazendo uso concomitante de metformina
(n=15)
bull DTG natildeo alterou a resposta ao uso da metformina nos pacientes
diabeacuteticos
ndash Natildeo houve diferenccedila significante nos niacuteveis de glicose em jejum nem
na concentraccedilatildeo de HbA1 observados antes e depois da troca para
DTG
Na vida real natildeo houve diferenccedila significativa na glicemia de jejum nem na Hb glicada antes e depois da troca para DTG
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
BHIVA 2016 April Manchester UKCB Jones1 J Tan1 J Robinson1 H Tate1 H Lamba1
1Merck Sharp ampDohme Limited Hertford Road Hoddesdon Hertfordshire
- Comorbidades satildeo frequentes
- 70 das pessoas fazem uso de outros medicamentos
- Supressatildeo viral alcanccedilada em cerca de 85 dos casos
independentemente da idade das comorbidades e do uso
de outros medicamentos
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
n=19215 RAL em 83 dos esquemas (n=1428)
Switching From a Boosted Protease Inhibitor (PIr) Based Regimen to a
Dolutegravir (DTG) Regimen in Virologically Suppressed Patients With
High Cardiovascular Risk (Framingham Score gt10 or Age gt 50 Years) Is
Non-Inferior and Decreases Lipids The NEAT 022 Study
JM Gatell1 L Assoumou2 G Moyle3 L Waters4 E Martinez5 H-J
Stellbrink6 G Guaraldi7 S de Wit8 F Raffi9 A Pozniak10 on behalf of
NEAT022 Study Group
1Hospital ClinicIDIBAPS University of Barcelona Infectious Diseases Barcelona Spain 2Sorbone Universites INSERM
UPMC Univ Paris 06 IPLESP UMRS 1136 Paris France 3Chelsea and Westminster Hospital London United Kingdom4Mortimer Market Center London United Kingdom 5Hospital ClinicIDIBAPS University of Barcelona Barcelona Spain6Infectiologisches Centrum Hamburg Germany 7University of Modena and Reggio Emilia Modena Italy 8Saint Pierre
University Hospital Universiteacute Libre de Bruxelles Brussels Belgium 9CHU
Hotel-Dieu Nantes Nantes France 10Chelsea amp Westminster Hospital London United Kingdom
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
Causas de Morte 1999-2011
Continuous Increase of Cardiovascular Diseases Diabetes and Non-HIV Related Cancers
as Causes of Death in HIV-Infected Individuals in Brazil An Analysis of Nationwide Data
Paula AA Schechter M Tuboi SH Faulhaber JC Luz PM et al (2014) PLOS ONE 9(4)
e94636 httpsdoiorg101371journalpone0094636
bull 12366853 atestados
bull 151706 (123) HIVAIDS
ATVr DRVr EFV RPV DTG RAL ABC FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Antihypert
ensiv
eagents
Amlodipine
Atenolol
Bisoprolol
Enalapril
Felodipine
Indapamide
Lisinopril
Losartan
Nifedipine
Olmesartan
Perindopril
Valsartan
Interaccedilotildees com Antihipertensivos
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Potential interaction
no dose adjustment
required
ATVr DRVr EFV RPV DTG RAL
AB
C FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Lip
id-l
ow
ering a
gents
Atorvastatin
Fluvastatin
Lovastatin
Pravastatin
Rosuvastatin
Simvastatin
Antidia
betic a
gents
Glibenclamid
e (Glyburide)
Linagliptin
Metformin
Nateglinide
Saxagliptin
Sitagliptin
Interaccedilotildees Medicamentosas com Hipolipemiantes e Hipoglicemiantes
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Do not co-
administer
Potential interaction
no dose adjustment
required
Interaccedilotildees com Medicamentos que atuam no SNC
BOOSTED FREE AGENTS BOOSTED AGENTS
DTGII RAL EFV ETV RPV EVGc DRVr
Stim
ula
nts
amyl nitrate
cocaine
ecstasy (MDMA)
mephedrone
methamphetamine
Dep
ress
ants
alcohol
alprazolam
codeine
diazepam
GHB (gamma hydroxybutyrate)
heroin (diamorphone)
hydrocodone
hydromorphone
ketamine
pethidine (meperideine)
methadone
midazolam (oral)
morphine
oxycodone
temazepam
triazolam
Hal
luci
no
gen
s
cannabis
lysergic acid dietheylamide (LSD)
phencyclidine (PCP angle dust)
Further information (in vivo in vitro or from label) at wwwhiv-druginteractionsorg
These drugs should not be co-administered
Potential interaction-may require close monitoring alteration of drug dosage or timing of administration
No clinically significant expected
Dose do DTG interfere nos niacuteveis de Metformina
Haacute aumento da exposiccedilatildeo plasmaacutetica da metformina
quando coadministrada com DTG e o efeito produzido
(PK) no niacutevel de metformina eacute dose-dependente do DTG
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50 mgq24h
Metf
orm
in c
on
cen
trati
on
(microg
mL
)
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q24h
Metformin alone Period
3
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50mg q12h
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q12h
Metformin alone Period
3
bull Anaacutelise retrospectiva de adultos HIV+ que mudaram o esquema para
outros contendo DTG e fazendo uso concomitante de metformina
(n=15)
bull DTG natildeo alterou a resposta ao uso da metformina nos pacientes
diabeacuteticos
ndash Natildeo houve diferenccedila significante nos niacuteveis de glicose em jejum nem
na concentraccedilatildeo de HbA1 observados antes e depois da troca para
DTG
Na vida real natildeo houve diferenccedila significativa na glicemia de jejum nem na Hb glicada antes e depois da troca para DTG
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
BHIVA 2016 April Manchester UKCB Jones1 J Tan1 J Robinson1 H Tate1 H Lamba1
1Merck Sharp ampDohme Limited Hertford Road Hoddesdon Hertfordshire
- Comorbidades satildeo frequentes
- 70 das pessoas fazem uso de outros medicamentos
- Supressatildeo viral alcanccedilada em cerca de 85 dos casos
independentemente da idade das comorbidades e do uso
de outros medicamentos
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
n=19215 RAL em 83 dos esquemas (n=1428)
Switching From a Boosted Protease Inhibitor (PIr) Based Regimen to a
Dolutegravir (DTG) Regimen in Virologically Suppressed Patients With
High Cardiovascular Risk (Framingham Score gt10 or Age gt 50 Years) Is
Non-Inferior and Decreases Lipids The NEAT 022 Study
JM Gatell1 L Assoumou2 G Moyle3 L Waters4 E Martinez5 H-J
Stellbrink6 G Guaraldi7 S de Wit8 F Raffi9 A Pozniak10 on behalf of
NEAT022 Study Group
1Hospital ClinicIDIBAPS University of Barcelona Infectious Diseases Barcelona Spain 2Sorbone Universites INSERM
UPMC Univ Paris 06 IPLESP UMRS 1136 Paris France 3Chelsea and Westminster Hospital London United Kingdom4Mortimer Market Center London United Kingdom 5Hospital ClinicIDIBAPS University of Barcelona Barcelona Spain6Infectiologisches Centrum Hamburg Germany 7University of Modena and Reggio Emilia Modena Italy 8Saint Pierre
University Hospital Universiteacute Libre de Bruxelles Brussels Belgium 9CHU
Hotel-Dieu Nantes Nantes France 10Chelsea amp Westminster Hospital London United Kingdom
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
ATVr DRVr EFV RPV DTG RAL ABC FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Antihypert
ensiv
eagents
Amlodipine
Atenolol
Bisoprolol
Enalapril
Felodipine
Indapamide
Lisinopril
Losartan
Nifedipine
Olmesartan
Perindopril
Valsartan
Interaccedilotildees com Antihipertensivos
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Potential interaction
no dose adjustment
required
ATVr DRVr EFV RPV DTG RAL
AB
C FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Lip
id-l
ow
ering a
gents
Atorvastatin
Fluvastatin
Lovastatin
Pravastatin
Rosuvastatin
Simvastatin
Antidia
betic a
gents
Glibenclamid
e (Glyburide)
Linagliptin
Metformin
Nateglinide
Saxagliptin
Sitagliptin
Interaccedilotildees Medicamentosas com Hipolipemiantes e Hipoglicemiantes
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Do not co-
administer
Potential interaction
no dose adjustment
required
Interaccedilotildees com Medicamentos que atuam no SNC
BOOSTED FREE AGENTS BOOSTED AGENTS
DTGII RAL EFV ETV RPV EVGc DRVr
Stim
ula
nts
amyl nitrate
cocaine
ecstasy (MDMA)
mephedrone
methamphetamine
Dep
ress
ants
alcohol
alprazolam
codeine
diazepam
GHB (gamma hydroxybutyrate)
heroin (diamorphone)
hydrocodone
hydromorphone
ketamine
pethidine (meperideine)
methadone
midazolam (oral)
morphine
oxycodone
temazepam
triazolam
Hal
luci
no
gen
s
cannabis
lysergic acid dietheylamide (LSD)
phencyclidine (PCP angle dust)
Further information (in vivo in vitro or from label) at wwwhiv-druginteractionsorg
These drugs should not be co-administered
Potential interaction-may require close monitoring alteration of drug dosage or timing of administration
No clinically significant expected
Dose do DTG interfere nos niacuteveis de Metformina
Haacute aumento da exposiccedilatildeo plasmaacutetica da metformina
quando coadministrada com DTG e o efeito produzido
(PK) no niacutevel de metformina eacute dose-dependente do DTG
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50 mgq24h
Metf
orm
in c
on
cen
trati
on
(microg
mL
)
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q24h
Metformin alone Period
3
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50mg q12h
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q12h
Metformin alone Period
3
bull Anaacutelise retrospectiva de adultos HIV+ que mudaram o esquema para
outros contendo DTG e fazendo uso concomitante de metformina
(n=15)
bull DTG natildeo alterou a resposta ao uso da metformina nos pacientes
diabeacuteticos
ndash Natildeo houve diferenccedila significante nos niacuteveis de glicose em jejum nem
na concentraccedilatildeo de HbA1 observados antes e depois da troca para
DTG
Na vida real natildeo houve diferenccedila significativa na glicemia de jejum nem na Hb glicada antes e depois da troca para DTG
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
BHIVA 2016 April Manchester UKCB Jones1 J Tan1 J Robinson1 H Tate1 H Lamba1
1Merck Sharp ampDohme Limited Hertford Road Hoddesdon Hertfordshire
- Comorbidades satildeo frequentes
- 70 das pessoas fazem uso de outros medicamentos
- Supressatildeo viral alcanccedilada em cerca de 85 dos casos
independentemente da idade das comorbidades e do uso
de outros medicamentos
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
n=19215 RAL em 83 dos esquemas (n=1428)
Switching From a Boosted Protease Inhibitor (PIr) Based Regimen to a
Dolutegravir (DTG) Regimen in Virologically Suppressed Patients With
High Cardiovascular Risk (Framingham Score gt10 or Age gt 50 Years) Is
Non-Inferior and Decreases Lipids The NEAT 022 Study
JM Gatell1 L Assoumou2 G Moyle3 L Waters4 E Martinez5 H-J
Stellbrink6 G Guaraldi7 S de Wit8 F Raffi9 A Pozniak10 on behalf of
NEAT022 Study Group
1Hospital ClinicIDIBAPS University of Barcelona Infectious Diseases Barcelona Spain 2Sorbone Universites INSERM
UPMC Univ Paris 06 IPLESP UMRS 1136 Paris France 3Chelsea and Westminster Hospital London United Kingdom4Mortimer Market Center London United Kingdom 5Hospital ClinicIDIBAPS University of Barcelona Barcelona Spain6Infectiologisches Centrum Hamburg Germany 7University of Modena and Reggio Emilia Modena Italy 8Saint Pierre
University Hospital Universiteacute Libre de Bruxelles Brussels Belgium 9CHU
Hotel-Dieu Nantes Nantes France 10Chelsea amp Westminster Hospital London United Kingdom
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
ATVr DRVr EFV RPV DTG RAL
AB
C FTC 3TC TDF
EVGc
FTCTA
F
EVGc
FTCTD
F
Lip
id-l
ow
ering a
gents
Atorvastatin
Fluvastatin
Lovastatin
Pravastatin
Rosuvastatin
Simvastatin
Antidia
betic a
gents
Glibenclamid
e (Glyburide)
Linagliptin
Metformin
Nateglinide
Saxagliptin
Sitagliptin
Interaccedilotildees Medicamentosas com Hipolipemiantes e Hipoglicemiantes
No clinically
significant
interaction
expected
Potential interaction may
require
dose adjustment or
monitoring
Do not co-
administer
Potential interaction
no dose adjustment
required
Interaccedilotildees com Medicamentos que atuam no SNC
BOOSTED FREE AGENTS BOOSTED AGENTS
DTGII RAL EFV ETV RPV EVGc DRVr
Stim
ula
nts
amyl nitrate
cocaine
ecstasy (MDMA)
mephedrone
methamphetamine
Dep
ress
ants
alcohol
alprazolam
codeine
diazepam
GHB (gamma hydroxybutyrate)
heroin (diamorphone)
hydrocodone
hydromorphone
ketamine
pethidine (meperideine)
methadone
midazolam (oral)
morphine
oxycodone
temazepam
triazolam
Hal
luci
no
gen
s
cannabis
lysergic acid dietheylamide (LSD)
phencyclidine (PCP angle dust)
Further information (in vivo in vitro or from label) at wwwhiv-druginteractionsorg
These drugs should not be co-administered
Potential interaction-may require close monitoring alteration of drug dosage or timing of administration
No clinically significant expected
Dose do DTG interfere nos niacuteveis de Metformina
Haacute aumento da exposiccedilatildeo plasmaacutetica da metformina
quando coadministrada com DTG e o efeito produzido
(PK) no niacutevel de metformina eacute dose-dependente do DTG
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50 mgq24h
Metf
orm
in c
on
cen
trati
on
(microg
mL
)
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q24h
Metformin alone Period
3
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50mg q12h
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q12h
Metformin alone Period
3
bull Anaacutelise retrospectiva de adultos HIV+ que mudaram o esquema para
outros contendo DTG e fazendo uso concomitante de metformina
(n=15)
bull DTG natildeo alterou a resposta ao uso da metformina nos pacientes
diabeacuteticos
ndash Natildeo houve diferenccedila significante nos niacuteveis de glicose em jejum nem
na concentraccedilatildeo de HbA1 observados antes e depois da troca para
DTG
Na vida real natildeo houve diferenccedila significativa na glicemia de jejum nem na Hb glicada antes e depois da troca para DTG
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
BHIVA 2016 April Manchester UKCB Jones1 J Tan1 J Robinson1 H Tate1 H Lamba1
1Merck Sharp ampDohme Limited Hertford Road Hoddesdon Hertfordshire
- Comorbidades satildeo frequentes
- 70 das pessoas fazem uso de outros medicamentos
- Supressatildeo viral alcanccedilada em cerca de 85 dos casos
independentemente da idade das comorbidades e do uso
de outros medicamentos
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
n=19215 RAL em 83 dos esquemas (n=1428)
Switching From a Boosted Protease Inhibitor (PIr) Based Regimen to a
Dolutegravir (DTG) Regimen in Virologically Suppressed Patients With
High Cardiovascular Risk (Framingham Score gt10 or Age gt 50 Years) Is
Non-Inferior and Decreases Lipids The NEAT 022 Study
JM Gatell1 L Assoumou2 G Moyle3 L Waters4 E Martinez5 H-J
Stellbrink6 G Guaraldi7 S de Wit8 F Raffi9 A Pozniak10 on behalf of
NEAT022 Study Group
1Hospital ClinicIDIBAPS University of Barcelona Infectious Diseases Barcelona Spain 2Sorbone Universites INSERM
UPMC Univ Paris 06 IPLESP UMRS 1136 Paris France 3Chelsea and Westminster Hospital London United Kingdom4Mortimer Market Center London United Kingdom 5Hospital ClinicIDIBAPS University of Barcelona Barcelona Spain6Infectiologisches Centrum Hamburg Germany 7University of Modena and Reggio Emilia Modena Italy 8Saint Pierre
University Hospital Universiteacute Libre de Bruxelles Brussels Belgium 9CHU
Hotel-Dieu Nantes Nantes France 10Chelsea amp Westminster Hospital London United Kingdom
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
Interaccedilotildees com Medicamentos que atuam no SNC
BOOSTED FREE AGENTS BOOSTED AGENTS
DTGII RAL EFV ETV RPV EVGc DRVr
Stim
ula
nts
amyl nitrate
cocaine
ecstasy (MDMA)
mephedrone
methamphetamine
Dep
ress
ants
alcohol
alprazolam
codeine
diazepam
GHB (gamma hydroxybutyrate)
heroin (diamorphone)
hydrocodone
hydromorphone
ketamine
pethidine (meperideine)
methadone
midazolam (oral)
morphine
oxycodone
temazepam
triazolam
Hal
luci
no
gen
s
cannabis
lysergic acid dietheylamide (LSD)
phencyclidine (PCP angle dust)
Further information (in vivo in vitro or from label) at wwwhiv-druginteractionsorg
These drugs should not be co-administered
Potential interaction-may require close monitoring alteration of drug dosage or timing of administration
No clinically significant expected
Dose do DTG interfere nos niacuteveis de Metformina
Haacute aumento da exposiccedilatildeo plasmaacutetica da metformina
quando coadministrada com DTG e o efeito produzido
(PK) no niacutevel de metformina eacute dose-dependente do DTG
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50 mgq24h
Metf
orm
in c
on
cen
trati
on
(microg
mL
)
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q24h
Metformin alone Period
3
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50mg q12h
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q12h
Metformin alone Period
3
bull Anaacutelise retrospectiva de adultos HIV+ que mudaram o esquema para
outros contendo DTG e fazendo uso concomitante de metformina
(n=15)
bull DTG natildeo alterou a resposta ao uso da metformina nos pacientes
diabeacuteticos
ndash Natildeo houve diferenccedila significante nos niacuteveis de glicose em jejum nem
na concentraccedilatildeo de HbA1 observados antes e depois da troca para
DTG
Na vida real natildeo houve diferenccedila significativa na glicemia de jejum nem na Hb glicada antes e depois da troca para DTG
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
BHIVA 2016 April Manchester UKCB Jones1 J Tan1 J Robinson1 H Tate1 H Lamba1
1Merck Sharp ampDohme Limited Hertford Road Hoddesdon Hertfordshire
- Comorbidades satildeo frequentes
- 70 das pessoas fazem uso de outros medicamentos
- Supressatildeo viral alcanccedilada em cerca de 85 dos casos
independentemente da idade das comorbidades e do uso
de outros medicamentos
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
n=19215 RAL em 83 dos esquemas (n=1428)
Switching From a Boosted Protease Inhibitor (PIr) Based Regimen to a
Dolutegravir (DTG) Regimen in Virologically Suppressed Patients With
High Cardiovascular Risk (Framingham Score gt10 or Age gt 50 Years) Is
Non-Inferior and Decreases Lipids The NEAT 022 Study
JM Gatell1 L Assoumou2 G Moyle3 L Waters4 E Martinez5 H-J
Stellbrink6 G Guaraldi7 S de Wit8 F Raffi9 A Pozniak10 on behalf of
NEAT022 Study Group
1Hospital ClinicIDIBAPS University of Barcelona Infectious Diseases Barcelona Spain 2Sorbone Universites INSERM
UPMC Univ Paris 06 IPLESP UMRS 1136 Paris France 3Chelsea and Westminster Hospital London United Kingdom4Mortimer Market Center London United Kingdom 5Hospital ClinicIDIBAPS University of Barcelona Barcelona Spain6Infectiologisches Centrum Hamburg Germany 7University of Modena and Reggio Emilia Modena Italy 8Saint Pierre
University Hospital Universiteacute Libre de Bruxelles Brussels Belgium 9CHU
Hotel-Dieu Nantes Nantes France 10Chelsea amp Westminster Hospital London United Kingdom
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
Dose do DTG interfere nos niacuteveis de Metformina
Haacute aumento da exposiccedilatildeo plasmaacutetica da metformina
quando coadministrada com DTG e o efeito produzido
(PK) no niacutevel de metformina eacute dose-dependente do DTG
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50 mgq24h
Metf
orm
in c
on
cen
trati
on
(microg
mL
)
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q24h
Metformin alone Period
3
01
10
100
0 4 8 12
Metformin AlonePeriod 1Metformin + DTG 50mg q12h
Nominal time (hours)
Metformin alone Period
1
Metformin + DTG 50 mg
q12h
Metformin alone Period
3
bull Anaacutelise retrospectiva de adultos HIV+ que mudaram o esquema para
outros contendo DTG e fazendo uso concomitante de metformina
(n=15)
bull DTG natildeo alterou a resposta ao uso da metformina nos pacientes
diabeacuteticos
ndash Natildeo houve diferenccedila significante nos niacuteveis de glicose em jejum nem
na concentraccedilatildeo de HbA1 observados antes e depois da troca para
DTG
Na vida real natildeo houve diferenccedila significativa na glicemia de jejum nem na Hb glicada antes e depois da troca para DTG
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
BHIVA 2016 April Manchester UKCB Jones1 J Tan1 J Robinson1 H Tate1 H Lamba1
1Merck Sharp ampDohme Limited Hertford Road Hoddesdon Hertfordshire
- Comorbidades satildeo frequentes
- 70 das pessoas fazem uso de outros medicamentos
- Supressatildeo viral alcanccedilada em cerca de 85 dos casos
independentemente da idade das comorbidades e do uso
de outros medicamentos
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
n=19215 RAL em 83 dos esquemas (n=1428)
Switching From a Boosted Protease Inhibitor (PIr) Based Regimen to a
Dolutegravir (DTG) Regimen in Virologically Suppressed Patients With
High Cardiovascular Risk (Framingham Score gt10 or Age gt 50 Years) Is
Non-Inferior and Decreases Lipids The NEAT 022 Study
JM Gatell1 L Assoumou2 G Moyle3 L Waters4 E Martinez5 H-J
Stellbrink6 G Guaraldi7 S de Wit8 F Raffi9 A Pozniak10 on behalf of
NEAT022 Study Group
1Hospital ClinicIDIBAPS University of Barcelona Infectious Diseases Barcelona Spain 2Sorbone Universites INSERM
UPMC Univ Paris 06 IPLESP UMRS 1136 Paris France 3Chelsea and Westminster Hospital London United Kingdom4Mortimer Market Center London United Kingdom 5Hospital ClinicIDIBAPS University of Barcelona Barcelona Spain6Infectiologisches Centrum Hamburg Germany 7University of Modena and Reggio Emilia Modena Italy 8Saint Pierre
University Hospital Universiteacute Libre de Bruxelles Brussels Belgium 9CHU
Hotel-Dieu Nantes Nantes France 10Chelsea amp Westminster Hospital London United Kingdom
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
bull Anaacutelise retrospectiva de adultos HIV+ que mudaram o esquema para
outros contendo DTG e fazendo uso concomitante de metformina
(n=15)
bull DTG natildeo alterou a resposta ao uso da metformina nos pacientes
diabeacuteticos
ndash Natildeo houve diferenccedila significante nos niacuteveis de glicose em jejum nem
na concentraccedilatildeo de HbA1 observados antes e depois da troca para
DTG
Na vida real natildeo houve diferenccedila significativa na glicemia de jejum nem na Hb glicada antes e depois da troca para DTG
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
BHIVA 2016 April Manchester UKCB Jones1 J Tan1 J Robinson1 H Tate1 H Lamba1
1Merck Sharp ampDohme Limited Hertford Road Hoddesdon Hertfordshire
- Comorbidades satildeo frequentes
- 70 das pessoas fazem uso de outros medicamentos
- Supressatildeo viral alcanccedilada em cerca de 85 dos casos
independentemente da idade das comorbidades e do uso
de outros medicamentos
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
n=19215 RAL em 83 dos esquemas (n=1428)
Switching From a Boosted Protease Inhibitor (PIr) Based Regimen to a
Dolutegravir (DTG) Regimen in Virologically Suppressed Patients With
High Cardiovascular Risk (Framingham Score gt10 or Age gt 50 Years) Is
Non-Inferior and Decreases Lipids The NEAT 022 Study
JM Gatell1 L Assoumou2 G Moyle3 L Waters4 E Martinez5 H-J
Stellbrink6 G Guaraldi7 S de Wit8 F Raffi9 A Pozniak10 on behalf of
NEAT022 Study Group
1Hospital ClinicIDIBAPS University of Barcelona Infectious Diseases Barcelona Spain 2Sorbone Universites INSERM
UPMC Univ Paris 06 IPLESP UMRS 1136 Paris France 3Chelsea and Westminster Hospital London United Kingdom4Mortimer Market Center London United Kingdom 5Hospital ClinicIDIBAPS University of Barcelona Barcelona Spain6Infectiologisches Centrum Hamburg Germany 7University of Modena and Reggio Emilia Modena Italy 8Saint Pierre
University Hospital Universiteacute Libre de Bruxelles Brussels Belgium 9CHU
Hotel-Dieu Nantes Nantes France 10Chelsea amp Westminster Hospital London United Kingdom
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
BHIVA 2016 April Manchester UKCB Jones1 J Tan1 J Robinson1 H Tate1 H Lamba1
1Merck Sharp ampDohme Limited Hertford Road Hoddesdon Hertfordshire
- Comorbidades satildeo frequentes
- 70 das pessoas fazem uso de outros medicamentos
- Supressatildeo viral alcanccedilada em cerca de 85 dos casos
independentemente da idade das comorbidades e do uso
de outros medicamentos
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
n=19215 RAL em 83 dos esquemas (n=1428)
Switching From a Boosted Protease Inhibitor (PIr) Based Regimen to a
Dolutegravir (DTG) Regimen in Virologically Suppressed Patients With
High Cardiovascular Risk (Framingham Score gt10 or Age gt 50 Years) Is
Non-Inferior and Decreases Lipids The NEAT 022 Study
JM Gatell1 L Assoumou2 G Moyle3 L Waters4 E Martinez5 H-J
Stellbrink6 G Guaraldi7 S de Wit8 F Raffi9 A Pozniak10 on behalf of
NEAT022 Study Group
1Hospital ClinicIDIBAPS University of Barcelona Infectious Diseases Barcelona Spain 2Sorbone Universites INSERM
UPMC Univ Paris 06 IPLESP UMRS 1136 Paris France 3Chelsea and Westminster Hospital London United Kingdom4Mortimer Market Center London United Kingdom 5Hospital ClinicIDIBAPS University of Barcelona Barcelona Spain6Infectiologisches Centrum Hamburg Germany 7University of Modena and Reggio Emilia Modena Italy 8Saint Pierre
University Hospital Universiteacute Libre de Bruxelles Brussels Belgium 9CHU
Hotel-Dieu Nantes Nantes France 10Chelsea amp Westminster Hospital London United Kingdom
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
Raltegravir treatment outcomes among older patients and those with comorbidities A sub-analysis of the CRICKET study
n=19215 RAL em 83 dos esquemas (n=1428)
Switching From a Boosted Protease Inhibitor (PIr) Based Regimen to a
Dolutegravir (DTG) Regimen in Virologically Suppressed Patients With
High Cardiovascular Risk (Framingham Score gt10 or Age gt 50 Years) Is
Non-Inferior and Decreases Lipids The NEAT 022 Study
JM Gatell1 L Assoumou2 G Moyle3 L Waters4 E Martinez5 H-J
Stellbrink6 G Guaraldi7 S de Wit8 F Raffi9 A Pozniak10 on behalf of
NEAT022 Study Group
1Hospital ClinicIDIBAPS University of Barcelona Infectious Diseases Barcelona Spain 2Sorbone Universites INSERM
UPMC Univ Paris 06 IPLESP UMRS 1136 Paris France 3Chelsea and Westminster Hospital London United Kingdom4Mortimer Market Center London United Kingdom 5Hospital ClinicIDIBAPS University of Barcelona Barcelona Spain6Infectiologisches Centrum Hamburg Germany 7University of Modena and Reggio Emilia Modena Italy 8Saint Pierre
University Hospital Universiteacute Libre de Bruxelles Brussels Belgium 9CHU
Hotel-Dieu Nantes Nantes France 10Chelsea amp Westminster Hospital London United Kingdom
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
Switching From a Boosted Protease Inhibitor (PIr) Based Regimen to a
Dolutegravir (DTG) Regimen in Virologically Suppressed Patients With
High Cardiovascular Risk (Framingham Score gt10 or Age gt 50 Years) Is
Non-Inferior and Decreases Lipids The NEAT 022 Study
JM Gatell1 L Assoumou2 G Moyle3 L Waters4 E Martinez5 H-J
Stellbrink6 G Guaraldi7 S de Wit8 F Raffi9 A Pozniak10 on behalf of
NEAT022 Study Group
1Hospital ClinicIDIBAPS University of Barcelona Infectious Diseases Barcelona Spain 2Sorbone Universites INSERM
UPMC Univ Paris 06 IPLESP UMRS 1136 Paris France 3Chelsea and Westminster Hospital London United Kingdom4Mortimer Market Center London United Kingdom 5Hospital ClinicIDIBAPS University of Barcelona Barcelona Spain6Infectiologisches Centrum Hamburg Germany 7University of Modena and Reggio Emilia Modena Italy 8Saint Pierre
University Hospital Universiteacute Libre de Bruxelles Brussels Belgium 9CHU
Hotel-Dieu Nantes Nantes France 10Chelsea amp Westminster Hospital London United Kingdom
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
bull Multicecircntrico (32 siacutetios) 96 semanas (Europeu seis paiacuteses)
prospectivo randomizado aberto (open-label) ensaio de natildeo-
inferioridade (~10)
bull Criteacuterio de elegibilidade
ndash HIV-1 RNA lt 50 cpml por ge 6 meses em terapia tripla com 2 ITRN + IPr
ndash Idade gt50 anos eou score de risco de Framingham gt10 em 10 anos
ndash Sem mutaccedilotildees de resistecircncia documentadas e sem falha viral preacutevia
confirmada durante uso de terapia antirretroviral
Desenho do Estudo
Randomization
11
stratified by
country
PIr + 2NRTs (PIr)
DTG + 2NRTIs (DTG)
Week 0 48
96
DTG + 2NRTIs (DTG)
Immediate switching Deferred switching
Primary endpoint
Adapted from
reference 62
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
Resultado Impacto nos lipiacutedeos
No changes in the utilization of lipid lowering agents
Around 30 in each arm and both at baseline and week 48
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
bull Mais de 48 semanas pacientes virologicamente suprimidos alto risco
cardiovascular idade acima de 50 anos score de Framingham gt10
terapia tripla (2 anaacutelogos e IPr)
ndash Troca para DTG natildeo foi inferior
ndash Houve melhora do colesterol total e das fraccedilotildees em todos os
subgrupos
ndash Poucas falhas viroloacutegicas e nenhuma mutaccedilatildeo de resistecircncia
selecionada
bull Toleracircncia boa e similar em ambos os braccedilos
bull Subestudos em andamento para avaliar marcadores bioloacutegicos (ECG
e outros)
bull Trocar por DTG mostrou benefiacutecio potencial e reduziu o risco
cardiovascular
Conclusotildees
Gatell et al IAS 2017 Paris France Slides TUAB0102
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
ElvitegravirCobicistatEmtricitabineTenofovirDF Demonstrates Comparable Efficacy
and FavorableTolerability to EfavirenzEmtricitabineTenofovir DF and to Ritonavir-
boosted Atazanavir Plus EmtricitabineTenofovir
DF in Patients ge50 Years at Week 96
Studies 102 and 103 ndash Age Sub-analysis
J Gallant1 D Hardy2 F Bredeek3 K Workowski4 W Towner5 L Dau6 H Liu6 J Curley6 M Rhee6 D Piontkowsky6 J
Szwarcberg6
1Southwest CARE Center Santa Fe NM 2David Geffen School of Medicine-UCLA Los Angeles CA
3Metropolis Med Group San Francisco CA 4Emory Univ Atlanta GA 5Kaiser Permanente Los Angeles CA 6Gilead
Sciences Foster City CA
- Taxas de supressatildeo similares aos pacientes com lt 50 anos
- Baixa taxa de resistecircncia (n=1)
- Menor taxa de tonteira e alteraccedilotildees do sono em relaccedilatildeo a ATVr
- Menor alteraccedilatildeo da funccedilatildeo renal em comparaccedilatildeo ao ATVr
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
Caracteriacutesticas dos Antirretrovirais
In the presence of confirmed or suspected integrase resistance DTG should be taken twice daily preferably
with food
Once dailyNo food
requirementsNo time-of-day requirements Booster-free Notes
DTG Yes Yes Yes YesCan be taken with orwithout food
EVGc Yes No Yes NoTake with food (recommended)
RAL No Yes Yes Yes Twice-daily dosing
EFV Yes No No YesBedtime dosing on empty stomach (recommended)
RPV Yes No Yes Yes Take with food (mandatory)
ATVbooster Yes No Yes NoTake with food (recommended)
DRVbooster Yes No Yes NoTake with food (recommended)
Yes
No
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
Efeitos adversos relacionados ao SNC em pessoas virgens de terapia
SPRING-2 FLAMINGO SINGLE ARIA
Cases n ()
DTG
N=411
RAL
(n=411)
DTG
(n=242)
DRVr
(n=242)
DTG
(n=414)
EFV
(n=419)
DTG
(n=248)
ATVr
(n=247)
Insomnia
Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)
Drug-relateddagger 6 (14) 3 (07) 4 (17) 5 (21) 43 (104) 28 (67) 5 (20) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 4 (10) 1 (04) 0
Anxiety
Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)
Drug-relateddagger 1 (02) 2 (05) 1 (04) 0 4 (10) 11 (26) 0 1 (04)
Led to withdrawaldagger 0 0 0 0 0 4 (10) 0 0
Depression
Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11sect (4)
Drug-relateddagger 1 (02) 2 (05) 0 0 13 (31) 19 (45) 1(04) 1 (04)
Led to withdrawaldagger 0 0 0 0 1 (02) 6 (14) 0 0
Suicidality
Overall 4 (lt1) 6 (1) 4 (2) 1 (lt1) 3 (lt1) 7 (2) 3 (1) 4 (2)
Drug-relateddagger 0 0 1 (04) 0 0 4 (10) 1 (04) 0
Led to withdrawaldagger 0 2 (05) 1 (04) 0 0 1 (02) 0 0
All third agents were part of a three-drug regimen containing two NRTIs
Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with
EFV daggerProportion of population
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
Coorte OPERA Incidecircncia de alteraccedilotildees no SNC
Prospectively-captured routine clinical data (electronic medical records) from 79 outpatient clinics
across 15 states in the United States daggerAll agents listed were given with other ARVs Daggeranxiety
depression insomnia or suicidality
ARV antiretroviral RPV rilpivirine
39 40
3134
28
24
0
10
20
30
40
50
18
2119 18
1718
0
10
20
30
40
50
1314 14
12 1314
0
10
20
30
40
50
Subjects with history of
CNS disordersDagger
CNS disordersDagger
(all subjects)
lsquoNewrsquo CNS disordersDagger
occurring in subjects
with no prior history
of that disorder
CNS disordersDagger
during treatment
more common with
RAL than DTG
bull OPERA database analysis 11539 subjects in routine US practice who received regimensdagger containing
DTG (19) EFV (14) RAL (8) DRV (15) RPV (15) or EVG (29)
DTG prescriptions include
a high proportion of
subjects with CNS
disorders at baseline
Frequency of lsquonewrsquo
CNS AEs similar
across regimens
Su
bje
cts
(
)
Baseline On-study
DTG n=2180 EFV n=1622 RAL n=917 DRV n=1759 RPV n=1758 EVG n=3303
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
Eficaacutecia Superior do Dolutegravir
In SINGLE 414 patients received DTG + ABC3TCdaggerDTG 50 mg + ABC 600 mg3TC 300 mg were used Bioequivalence has been
demonstrated26
DaggerIn FLAMINGO on Day 1 in the DTG arm 163 and 79 patients received TDFFTC
or ABC3TC respectively in the DRVr arm 162 and 80 patients received
TDFFTC or ABC3TC respectivelysectIn SPRING-2 on Day 1 in the DTG arm 242 and 169 patients received TDFFTC
or ABC3TC respectively in the RAL arm 247 and 164 patients received TDFFTC
or ABC3TC respectively In SAILING DTG and raltegravir were combined with a background regimenparaIn STRIIVING 551 virologically suppressed patients were randomised
274 received TRIUMEQ (DTGABC3TC) and 277 continued their current ART
regimens (42 PIs 27 INIs and 31 NNRTIs)In VIKING-3 patients received DTG + current failing regimen on Days 1ndash7 From
Day 8 on patients received DTG in combination with an optimised background
regimen
ART = antiretroviral therapy BID = twice daily
BR = background regimen cART = combination antiretroviral therapy DRVr =
darunavirritonavir DTG = dolutegravir FTC = emtricitabine
OBR = optimised background regimen PI = protease inhibitor
QD = once daily RAL = raltegravir TDF = tenofovir disoproxil fumarate
AltamenteexperimentadosExperimentadosVirgens de terapia
Superior
efficacy
Non-inferior
Non-
comparative
Superior efficacy vs DRVr
at Weeks 48 and 96
FLAMINGO
DTG 50 mg + 2 NRTIs QD vs DRVr 800
mg100 mg + 2 NRTIs QD (N=484)
Superior efficacy vs EFVTDFFTC
at Weeks 48 96 and 144
SINGLE
DTG + ABC3TCdagger QD vs EFVTDFFTC
QD (N=833)
Comparable efficacy vs RAL
at Weeks 48 and 96
SPRING-2
DTG 50 mg QD + 2 NRTIs vs RAL 400
mg BID + 2 NRTIs (N=822)
Superior efficacy vs RAL
up to Week 48
SAILING
DTG 50 mg QD + BR vs RAL 400 mg BID
+ BR (N=715)
Maintained efficacy following treatment
switch vs continuation of current ARV
regimen
up to Week 24
STRIIVING
DTGABC3TC QD vs cART (N=551)
Sustained efficacy
up to Week 48
VIKING-3
DTG 50 mg BID + OBR
(N=183)
Superior efficacy vs ATVr
at Week 48 in women
ARIA
DTGABC3TC vs ATVr
300 mg100 mg + TDFFTC QD (N=495)
Comparando a ITRNN IPr e INI
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
Farmacovigilacircncia DTG ndash Brasil
Janeiro a Junho 2017
bull Total de 39990 pacientes em uso de DTG
bull 22683 iniciaram com DTG
bull 17307 trocaram de RAL para DTG
bull Ateacute 30 Junho 2017 3086 questionaacuterios preenchidos
para avaliar efeitos adversos
Nenhum 93 (n=2879)
Algum 7 (n=207)
Adele Benzaken Ministry of Health of Brazil Enhanced ARV Monitoring in
Countries Brazil IAS 2017
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034
Fatos e Desafios
- A expectativa de vida das pessoas vivendo com HIV (PVHIV) vem aumentando e eacute similar a da populaccedilatildeo em geral especialmente em paiacuteses desenvolvidos- Quanto maior o tempo de evoluccedilatildeo maior o risco de comorbidades infecciosas e natildeo infecciosas incluindo doenccedilas metaboacutelicas endoacutecrinas e cardiovasculares - Fatores de risco aleacutem do proacuteprio HIV precisam ser controlados dieta tabagismo sedentarismo alcoolismo dislipidemia alteraccedilotildees da glicose hipertensatildeo arterial e outros- Interaccedilotildees medicamentosas satildeo comuns pelo acuacutemulo de novos medicamentos para diferentes comorbidades
Smit M Brinkman K Geerlings S et al Future challenges for clinical care of an ageing population infected with HIV a modelling study Lancet Infect Dis 201515(7)810ndash818Dyslipidemia Atherosclerosis and Cardiovascular DiseaseAn Increasingly Important Triad in an Aging Population Living With HIVJane A OHalloran Claudette S Satchell Patrick WG MallonFuture Virology 20138(10)1021-1034