el futuro del tratamiento antirretroviral · 2018-12-10 · el futuro del tratamiento...
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Dr. José M. Miró Servicio de Enfermedades Infecciosas
Hospital Clínic - IDIBAPSUniversidad de Barcelona
Barcelona
Dr. José M. Miró Servicio de Enfermedades Infecciosas
Hospital Clínic - IDIBAPSUniversidad de Barcelona
BarcelonaCorreo electrónico: [email protected] electrónico: [email protected]
El Futuro del Tratamiento Antirretroviral
XXII Jornadas Internacionales sobre TB - 2018Mesa Redonda: Guías de Práctica Clínica en TB/VIH
26 de Noviembre del 2018
XXII Jornadas Internacionales sobre TB - 2018Mesa Redonda: Guías de Práctica Clínica en TB/VIH
26 de Noviembre del 2018
Potential conflict of interestPotential conflict of interestDr. José M Miró has received honoraria for speaking or
participating in Advisory Boards and/or research grants from the following Pharmaceutical Companies:
Dr. José M Miró has received honoraria for speaking or participating in Advisory Boards and/or research grants from
the following Pharmaceutical Companies:
MerckNovartisPfizerRoche TheravanceViiV Healthcare
MerckNovartisPfizerRoche TheravanceViiV Healthcare
Abbvie Contrafect CubistGenentechGilead Sciences Jansen-Cilag
Abbvie Contrafect CubistGenentechGilead Sciences Jansen-Cilag
The Future of Antiretroviral Treatment
The Future of Antiretroviral Treatment
Where we come from: 1 - 2 - 3Where we are now: TT regimens New regimens: 2D oral New regimens: 2D long-acting Monotherapy Take home messages
Where we come from: 1 - 2 - 3Where we are now: TT regimens New regimens: 2D oral New regimens: 2D long-acting Monotherapy Take home messages
THE EVOLUTION OF HIV THERAPY >30 ARTS
FDA. Antiretroviral drugs used in the treatment of HIV infection http://www.fda.gov/ForPatients/Illness/HIVAIDS/Treatment/ucm118915.htm Accessed August 2015FDA news release November 2015 http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm471300.htm Accessed November 2015
1984 2018
Retrovir 100 mg capsule
<50 cop./mLInSTI
STR
Hosp. Clinic-IDIBAPS-Univ. of Barcelona, Barcelona, SpainHosp. Clinic-IDIBAPS-Univ. of Barcelona, Barcelona, Spain
Hospital Clinic of BarcelonaHIV cohort (1983-2018)8,500 patients (historical cohort)
5,300 active patients5,100 (95%) on ART (>95% VL BDL)
Number of new and accumulated HIV-infected patients and patients on ART at the H. Clinic of Barcelona (1986-2017)
5267 patients98% on
ART
PrEP !!!
Percentage of patients with undetectable HIV RNA viral load (<400 c/mL) on ART at the H. Clinic of Barcelona (1995-2017)
50%
97%
0%
80-90%
Lee FJ et al PLoS One 2014;9:e97482; Carr A et al. Glasgow 2018 P#51
Annual mortality rates in the cohort of HIV-infected patients of the H. Clinic of Barcelona (1986-2017)
20%
<1%
The Constant Evolution of Initial ART at the Hospital Clinic of Barcelona, Spain (1990-2017)
InSTI = 60%
/r/c
Where we come from: 1 - 2 - 3Where we are now: TT regimens New regimens: 2D oral New regimens: 2D long-acting Monotherapy Take home messages
Where we come from: 1 - 2 - 3Where we are now: TT regimens New regimens: 2D oral New regimens: 2D long-acting Monotherapy Take home messages
The Future of Antiretroviral Treatment
The Future of Antiretroviral Treatment
Fast Track Targets by 2020
73%of all people living
with HIV
VIRALLY SUPPRESSED
=
Target 1 Target 2 Target 3 Overall target
diagnosed with HIV
ON ART
living with HIV
DIAGNOSED
on ART
VIRALLY SUPPRESSED
75% 79% 81%= 49%UNAIDS 2018
Progress toward achieving the 1st 9090% of all PLHIV who know their status (n=39)
Source: ECDC. Dublin Declaration monitoring 2018; validated unpublished data.Latest available data reported, ranging from 2014‐2017.
Target reached Above regional average Below regional average
Global target 90%
Europe and Central Asia 80%80%
Global target 90%
Europe and Central Asia 64%
Source: ECDC. Dublin Declaration monitoring 2018; validated unpublished data.Latest available data reported, ranging from 2014‐2017.
Progress toward achieving the 2nd 9090% of those diagnosed on ART (n=39)
Target reached Above regional average Below regional average95%
Progress toward achieving the 3rd 9090% of those on ART virally suppressed (n=33)
Global target 90%
Europe and Central Asia 84%
Source: ECDC. Dublin Declaration monitoring 2018; validated unpublished data.Latest available data reported, ranging from 2014‐2017.
Target reached Above regional average Below regional average
@ECDC_HIVAIDS
88%
NRTIZidovudine (AZT)Didanosine (ddI)Zalcitabine (ddC)Lamivudine (3TC)*Stavudine (d4T)Abacavir (ABV)*Emtricitavine (FTC)*
NRTIZidovudine (AZT)Didanosine (ddI)Zalcitabine (ddC)Lamivudine (3TC)*Stavudine (d4T)Abacavir (ABV)*Emtricitavine (FTC)*
PROTEASA INHIBITORS (PI)Saquinavir / Indinavir / Nelfinavir Ritonavir (rtv) Fosamprenavir/rtvLopinavir/rtv*Atazanavir/r/c*Tipranavir/rDarunavir/r/c*
PROTEASA INHIBITORS (PI)Saquinavir / Indinavir / Nelfinavir Ritonavir (rtv) Fosamprenavir/rtvLopinavir/rtv*Atazanavir/r/c*Tipranavir/rDarunavir/r/c*
NNRTIEfavirenz* NevirapineEtravirineRilpivirine*Doravirine*
NNRTIEfavirenz* NevirapineEtravirineRilpivirine*Doravirine*
NtRTITenofovir (TDF/TAF)*NtRTITenofovir (TDF/TAF)*
ENTRY INHIBITORS- Fusion inhibitor: Enfuvirtide (T-20)- CCR5 inhibitor: Maraviroc
ENTRY INHIBITORS- Fusion inhibitor: Enfuvirtide (T-20)- CCR5 inhibitor: Maraviroc
Antiretroviral Drugs Marketed in Spain (2018)Antiretroviral Drugs Marketed in Spain (2018)
INTEGRASE INHIBITORSRaltegravirElvitegravir/cobicistat*Dolutegravir*Cabotegravir*
INTEGRASE INHIBITORSRaltegravirElvitegravir/cobicistat*Dolutegravir*Cabotegravir* *STRs
http://www.biology.arizona.edu/immunology/tutorials/AIDS/treatment.html
Targets of antiretroviral drugs
NRTINNRTINtTI
Protease inhibitors
Entryinhibitors
IntegraseInhibitors
Maturationinhibitors
Saag MS et al. JAMA. 2018; 320:379-396
Recommended Initial ART Regimens for Treating HIV Infection in 2018Saag MS et al. JAMA. 2018;320:379-396.
Alternative ART Regimens for Treating HIV Infection in 2018
Saag MS et al. JAMA. 2018;320:379-396.
B/F/TAF vs. DTG/3TC/ABC
B/F/TAF vs. DTG plus TAF/FTC
96 wk. Results Presented at the IDWeek and HIV Glasgow Meetings in 2018
B/F/TAF vs. DTG/3TC/ABC
Gallant J, et al. Lancet. 2017;390:2063-2072 & Wohl D et al. IDWeek. October 3-7, 2018
No R mutationsAE D/C = 0/5
92% vs. 93% at W48
B/F/TAF vs. DTG/3TC/ABC
Gallant J, et al. Lancet. 2017;390:2063-2072 & Wohl D et al. IDWeek. October 3-7, 2018
GS-US-380-1490 Study Design
Phase 3, randomized, double-blind, active-controlled study – Stratified by HIV-1 RNA, CD4 cell count, geographic region (USA vs non-USA)– North America, Europe, Australia, and Latin America– Chronic hepatitis B and/or C virus (HBV/HCV) infection allowed
Primary endpoint: proportion with HIV-1 RNA <50 copies/mL at Week 48– B/F/TAF 89.4% vs DTG + F/TAF 92.9% with HIV-1 RNA <50 c/mL (p=0.12)1
Secondary endpoint: proportion with HIV-1 RNA <50 copies/mL at Week 96– Noninferiority margin of 12% based on FDA Snapshot algorithm
23
ClinicalTrials.gov NCT02607956. c, copies; eGFRCG, estimated glomerular filtration rate by Cockcroft-Gault equation.1. Sax et al. Lancet 2017; 390:2073-82.
48Week 0 144
Treatment-Naïve Adults HIV-1 RNA ≥500 c/mL eGFRCG ≥30 mL/min
n=320
n=325
1° Endpoint
96
DTG + F/TAF Placebo QDB/F/TAF QD
B/F/TAF Placebo QD
DTG + F/TAF QD
1:1
2º Endpoint
B/F/TAF vs. DTG plus TAF/FTC
Stellbrink HJ et al. HIV Glasgow. October 28-31, 2018
Virologic Outcome at Week 96Snapshot analysis
At Week 96, B/F/TAF was noninferior to DTG + F/TAF by FDA Snapshot analysis– Per protocol analysis: B/F/TAF 100% vs DTG + F/TAF 98%
Mean CD4 increase from baseline at Week 96: – B/F/TAF +237 cells/µL vs DTG + F/TAF +281 cells/µL (p=0.008)– Mean CD4 % change B/F/TAF 11% vs DTG + F/TAF 11% (p=0.37)– Mean absolute CD4 B/F/TAF 693 vs DTG + F/TAF 733 (p=0.13)
24
P-value was from analysis of variance (ANOVA) model adjusted by the baseline HIV-1 RNA and region stratum.
% Treatment Difference (95% CI)
-7.9 3.2-2.3
-12 120-6 6
FavorsDTG + F/TAF
FavorsB/F/TAF
84
412
86
311
0
20
40
60
80
100
HIV-1 RNA <50 copies/mL
HIV-1 RNA ≥50 copies/mL
No VirologicData
DTG + F/TAF (n=325)
B/F/TAF (n=320)
Prop
ortio
n of
par
ticip
ants
, %
Virologic Outcome
269320
281325
14320
9325
35325
37320
No R mutationsAE D/C = 6/5
89% vs. 93% at W48B/F/TAF vs. DTG plus TAF/FTC
Sax PE, et al. Lancet. 2017;390:2073-2082 & Stellbrink HJ et al. HIV Glasgow. October 28-31, 2018
B/F/TAF vs. DTG/3TC/ABCvs. DTG
plus TAF/FTCPros- Same day T&T w/STR- HBV
Cons- Acute infection- Advanced Infection- Avoid in TB/HIV- Less long-term data
Pros- More long-term data- TB/HIV
Cons- HLA-B*5701 testing- Same day T&T w/TAF/FTC- HBV w/TAF/FTC- Advanced Infection- NRC (DTG) and CVD (ABC) issues- Teratogenicity (e.g. NTD)
Evolution of ART regimens over time1984-2018 Future of ART
/r/c
Where we come from: 1 - 2 - 3Where we are now: TT regimens New regimens: 2D oral New regimens: 2D long-acting Monotherapy Take home messages
Where we come from: 1 - 2 - 3Where we are now: TT regimens New regimens: 2D oral New regimens: 2D long-acting Monotherapy Take home messages
The Future of Antiretroviral Treatment
The Future of Antiretroviral Treatment
What are the reasons to start/switch to 2DC• To avoid potential NRTI-related toxicity
- Bone- Kidney- Cardiovascular- Other
• Less exposure to ART drugs throughout life• Economic cost• Naïve or virologically suppressed patients • No antiretroviral-resistance mutations• Never do it in HBV/HIV coinfected patients
2D vs. TT RCT
Naïve- GARDEL (LPV/r + 3TC)- KALEA (LPV/r + TDF)- NEAT001/ANRS143 (DRV/r + RAL)*- ANDES (DRV/r + 3TC)Switching- OLE (LPV/r + 3TC)- ATLAS-M (ATV/r + 3TC)- SALT (ATV/r + 3TC)- DUAL-GESIDA (DRV/r + 3TC)
r/PI-based 2DC
*Not recommended if plasma HIV RNA VL >100.000 copies/mL and CD4 < 200/mm3
bPI-based 2DC: Trial Designs
Study Follow Up Week Dual Triple Treatment History
GARDEL (n=306) 96 LPV/r + 3TC LPV/r + 2 NRTI Naïve
KALEAD (n=152) 24 LPV/r + TDF LPV/r + 2 NRTI Naïve
ANDES (n=145) 48 DRV/r + 3TC DRV/r + 3TC/TDF Naïve
OLE (n=250) 48 LPV/r + 3TC LPV/r + 2 NRTI Switch
ATLAS‐M (n=266) 96 ATV/r + 3TC ATV/r + 2 NRTI Switch
SALT (n=267) 96 ATV/r + 3TC ATV/r + 2 NRTI Switch
DUAL‐GESIDA (n=249) 48 DRV/r + 3TC DRV/r + 2 NRTI Switch
Total (n=1635)
Liev Z et al. HIV Glasgow. October 28-31, 2018
0
20
40
60
80
100
<50cp/ml PDVF Resistance D/AE
bPI-based 2DC: Summary Findings
HIV‐RNA <50 copies/mL
Protocol Defined Virological Failure
Resistance Mutations
Discontinuations due to adverse
events
Dual
DualDual
Dual
Triple
TripleTriple
Triple
83.6% 80.6%
5.0% 4.5%0.7% 0.7%
2.7% 3.9%
Percen
tage of p
atients w
ho achieved
endp
oint ( %)
Only few NRTI mutations in 2D and TT arms (M184V). No major PI mutations.
2D vs. TT RCT
Naïve- GARDEL (LPV/r + 3TC)- KALEA (LPV/r + TDF)- NEAT001/ANRS143 (DRV/r + RAL)- ANDES (DRV/r + 3TC)Switching- OLE (LPV/r + 3TC)- ATLAS-M (ATV/r + 3TC)- SALT (ATV/r + 3TC)- DUAL-GESIDA (DRV/r + 3TC)
r/PI-based 2DC DTG-based 2DCNaïve (+ 3TC)- PADDLE (single arm)- ACTG A5353 (single arm)- GEMINI 1+2 (DTG + 3TC)
Switching- SWORD 1+2 (DTG + RPV)- ASPIRE (DTG + 3TC)- ANRS 167 LAMIDOL (single arm DTG + 3TC)
22nd International AIDS Conference; July 23-27, 2018; Amsterdam, the Netherlands
a−10% noninferiority margin for individual studies.
GEMINI-1 and -2 Phase III Study Design
Cahn P et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.
DTG + 3TC (N=716)
Day 1
Screening (28 d)
Identically designed, randomized, double-blind, parallel-group, multicenter, noninferiority studies
DTG + TDF/FTC (N=717)
DTG + 3TC
Week48
Primary endpoint at Week 48:
participants withHIV-1 RNA <50 c/mL
(ITT-E snapshot)a
Double-blind phase
Open-labelphase
Continuation phase
CountriesArgentina Australia BelgiumCanada France GermanyItaly Republic of Korea Mexico Netherlands Peru PolandPortugal Romania Russian Federation South Africa Spain Switzerland Taiwan United Kingdom United States
Week144
Week 24
Week96
• ART-naive adults• VL 1000-500,000 c/mL
1:1
Eligibility criteria•≤10 days of prior ART•No evidence of pre-existing viral resistance based on presence of any major resistance-associated mutation•No HBV infection or need for HCV therapy
Baseline stratification factors: plasma HIV-1 RNA (≤100,000 c/mL vs >100,000 c/mL) CD4+ cell count (≤200 cells/mm3 vs >200 cells/mm3).
22nd International AIDS Conference; July 23-27, 2018; Amsterdam, the Netherlands
Pooled Snapshot Outcomes at Week 48: ITT-E and Per Protocol Populations
Cahn P et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.
aBased on Cochran-Mantel-Haenszel stratified analysis adjusting for the following baseline stratification factors: plasma HIV-1 RNA (≤100,000 c/mL vs >100,000 c/mL), CD4+ cell count (≤200 cells/mm3 vs >200 cells/mm3), and study (GEMINI-1 vs GEMINI-2). bPP, per protocol: population consisted of participants in the ITT-E population except for significant protocol violators, which could potentially affect efficacy outcomes as determined by the medical monitor prior to database lock.
Virologic outcome Adjusted treatment difference (95% CI)a
DTG + TDF/FTC DTG + 3TC
-4.4 1.1
-1.7
Percentage-point difference• DTG + 3TC is non-inferior to DTG + TDF/FTC
with respect to proportion <50 c/mL at Week 48 (snapshot, ITT-E population) in both studies
• No treatment-emergent INSTI mutations or NRTI mutations
-1.3
-3.9 1.2
ITT-E
PP
ITT-E DTG + 3TC (N=716) DTG + TDF/FTC (N=717)PPb DTG + 3TC (N=694) DTG + TDF/FTC (N=693)
22nd International AIDS Conference; July 23-27, 2018; Amsterdam, the Netherlands
TRDF Analysis
566576
>100,000≤100,000 >200 ≤200Baseline HIV-1
RNA, c/mLBaseline CD4+
cell count, cell/mm3
Pooled Outcomes at Week 48 Stratified by Baseline HIV-1 RNA and CD4+ Cell Count: Snapshot and TRDF Analysis
Snapshot Analysis
• 2% of participants in each arm had baseline HIV-1 RNA >500,000 c/mL. Treatment related discontinuation = failure (TRDF) population accounts for confirmed virologic withdrawal (CVW), withdrawal due to lack of efficacy, withdrawal due to treatment-related AE, and participants who met protocol-defined stopping criteria. DTG + 3TC CD4 <200 Snapshot non-response (n=13): 1 CVW, 3 with VL >50 in window (2 of 3 re-suppressed), 2 discontinued due to AE (TB, Chagas disease), 2 protocol violations, 2 lost to follow-up, 1 withdrew consent, 1 withdrew to start HCV treatment, 1 change in ART (incarcerated). DTG + TDF/FTC < 200 Snapshot non-response (n=4):1 investigator discretion, 1 withdrew consent, 1 lost to follow-up, 1 VL >50 (re-suppressed).
DTG + 3TC DTG + TDF/FTC
>100,000≤100,000 >200 ≤200Baseline HIV-1
RNA, c/mLBaseline CD4+
cell count, cell/mm3
553564
138140
149153
642653
647662
6263
5555
526576
531564
129140
138153
605653
618662
5063
5155
Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.
SWORD-1 and -2: Phase III Study Design
*8% non-inferiority margin for pooled data. -10% non-inferiority margin for individual studiesHBV, hepatitis B virus; ITT(-E), intent to treat (- exposed); NRTI, nucleoside reverse transcriptase inhibitor
Inclusion criteria• On stable CAR 6 months before
screening• 1st or 2nd ART with no change in prior
regimen due to VF• Confirmed HIV-1 RNA <50 c/mL during
the 12 months before screening• HBV-negative
DTG + RPV (N=513)
Day 1
Screening
Week 148
Identically designed, randomised, multicentre, open-label, parallel-group, non-inferiority studies
CAR (N=511) DTG + RPV
VL <50 c/mL on INI, NNRTI,or PI + 2 NRTIs
1:1
DTG + RPV
Week 52Primary endpoint
at 48 weeks: subjects withVL <50 c/mL
(ITT-E snapshot)*
Early-switch phase Late-switch phase Continuation phase
Countries:Argentina Australia Belgium CanadaFrance Germany Italy NetherlandsRussia Spain Taiwan United KingdomUnited States
Llibre JM, et al. CROI 2017. Oral Presentation 44LB
SWORD-1 and -2: Snapshot Outcomes at Week 48
Llibre JM, et al. CROI 2017. Oral Presentation 44LB
*Adjusted for age and baseline third agent
CAR DTG + RPV
–4.3 3.0
SWORD-1
SWORD-2
–3.9 4.2
SWORD-1
SWORD-2
95 96 94 94
<1 <1 <1 2 4 4 5 4
0.2
–0.6
Percentage-point difference
DTG + RPV is non-inferior to CAR with respect to snapshot in the ITT-E population (<50 c/mL) at Week 48 in both studies
0
Virologic outcomes Adjusted treatment difference (95% CI)*
• No INI resistance-associated mutations were identified
Evolution of ART regimens over time
2D or not 2Dthat is the question
Hamlet, Act III, Scene I. Sir William Shakespeare, 1564 - 1616.
Pros- Excellent efficacy & safety data- More long-term data- No bPI mutations- bPI can be used in CKD
Cons- DDIs- No STRs- “b/PI-side effects”
Pros- Excellent efficacy & safety data- STRs (DTG+RPV, DTG+3TC soon)- No DDIs- No DTG mutations- DTG + RPV can be used in CKD
Cons- Limited data in acute/recent infection- Limited data in advanced patients- “DTG-side effects”- RPV must be taken with food, avoid
PPIs and separated from antiacids.
2D vs. TT RCTr/PI-based 2DC DTG-based 2DC
Potential 2DC RCTs in naïve patients• DTG+3TC vs. bDRV+3TC• BIC+3TC vs. DTG+3TC or bDRV+3TC• DTG+3TC in Acute-Recent/Advanced Patients
Where we come from: 1 - 2 - 3Where we are now: TT regimens New regimens: 2D oral New regimens: 2D long-acting Monotherapy Take home messages
Where we come from: 1 - 2 - 3Where we are now: TT regimens New regimens: 2D oral New regimens: 2D long-acting Monotherapy Take home messages
The Future of Antiretroviral Treatment
The Future of Antiretroviral Treatment
What are the reasons to use long-acting (LA) antiretrovirals for treating HIV-infection
Adherence to oral antiretrovirals can be variable Special populations
- Drug and alcohol abuse- Psychiatric illness
Antiretroviral stigma Patients´ preference
Monroe M et al. Bioengineering & Translational Medicine 2018;3:102–123
Requirements Infrequent dosing (~ 2-3 months) Practical injection volume (≤ 4mL) Minimal PK tail High genetic barrier to resistance Minimal injection associated
adverse events Stable formulation ideally without
cold chain requirements
LA ARV drugs LA Rilpivirine LA Cabotegravir MK-8591 (EFdA)* GS-CA1 (Capsid inhibitor)** Broadly Neutralizing
Monoclonal antibodies (PRO140; UB-421; VRC01; VRC01-LS; 3BNC117; 10-1074)
Main Characteristics of LA ARV drugs
*Nucleoside reverse transcriptase translocation inhibitor” – inhibits reverse transcriptase by two different mechanisms. Implant Formulations Release Effective Drug Levels for >180 days; ** Capsid inhibitor. It is the most potent antiretroviral agent.
4343Spreen W et al. JAIDS 2014;67:487-92.
Cabotegravir (CAB) LA Single Injection Provides Detectable Drugin Plasma for 48 Weeks
T im e (weeks)0 4 8 12 16 20 24 28 32 36 40 44 48
Plas
ma
CAB
(g/
mL)
0 .1
1
100m g IM200m g IM400m g IM800m g IM (split)100m g SC200m g SC400m g SC (split)
4*PA‐IC90
PA‐IC90
Mean Concentration-Time Profile (n=6/cohort)
CAB 5mg/day p.o.Ctau = 0.6 ug/mL
(0.67 ug/mL)
CAB LA apparent half-life ~40days versus CAB oral ~40hr half-life
Very very long PK tail !
23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA
• CAB is an HIV-1 integrase inhibitor– Oral 30 mg tablet (t½, ~40 hours) – LA nanosuspension 200 mg/mL (t½, ~20-40 days)
• RPV is an HIV-1 NNRTI– Oral 25 mg tablet (t½, ~50 hours)– LA nanosuspension 300 mg/mL (t½, ~30-90 days)
• Oral 2-drug CAB + RPV proof of efficacy through Week 96 in LATTE-1
Parenteral Cabotegravir + Rilpivirine as Long-Acting Maintenance Therapy: LATTE-1 RCT
Margolis et al. Lancet ID. 2015; 15:1145-55.
BL, baseline; CAB, cabotegravir; CI, confidence interval; EFV, efavirenz; LA, long-acting; NNRTI, non-nucleoside reverse transcriptase inhibitor; RPV, rilpivirine; t1/2, half-life.
0
20
40
60
80
100
CAB 10 mg (n=60) CAB 30 mg (n=60)CAB 60 mg (n=61) EFV 600 mg (n=62)
12 1684BL 2 242628 32 36 40 48 60 72 84 96
Prop
ortio
n, %
(95%
CI)
21st International AIDS Conference; July 18-22, 2016; Durban, South Africa
Induction period
LATTE-2 Study Design (Phase 2)
Week 32 Primary analysis Dosing regimen
selection
Day 1 Randomization
2:2:1
Week 48 Analysis
Dosing regimen confirmation
CAB 400 mg IM + RPV 600 mg IM Q4W (n=115)
CAB 600 mg IM + RPV 900 mg IM Q8W (n=115)
Week 96b
CAB loading dose at Day 1
CAB loading doses at Day 1 and Week 4
CAB 30 mg + ABC/3TC for
20 weeks
CAB 30 mg + ABC/3TC PO QD (n=56)
CAB 30 mg + ABC/3TC PO QD for 20 weeks
(N=309)
Maintenance perioda
Add RPV PO QD
4 weeks
Inclusion criteria
• >18 years old• Naive to antiretroviral therapy• CD4+ >200 cells/mm3
Exclusion criteria
• Positive for hepatitis B• ALT ≥5 × ULN• Creatinine clearance <50
mL/min
Qualification for maintenance
• HIV-1 RNA <50 c/mL between Week -4 and Day 1
Margolis et al. AIDS 2016; Durban, South Africa. Abstract THAB0206LB.
ABC/3TC, abacavir/lamivudine; ALT, alanine aminotransferase; IM, intramuscular; PO, orally; QD, once daily; Q4W, every 4 weeks; Q8W, every 8 weeks; ULN, upper limit of normal. aSubjects who withdrew after at least 1 IM dose entered the long-term follow-up period. bSubjects can elect to enter Q4W and Q8W LA Extension Phase beyond Week 96.
286/309 (92,5%)
21st International AIDS Conference; July 18-22, 2016; Durban, South Africa
LATTE 2. HIV-1 RNA <50 c/mL at 48 wk. ITT-ME (Snapshot)
Abstract THAB0206LB.
Oral IM
Virologic outcomes Treatment differences (95% CI)
-6.6 12.4
Q8W IM (CAB 600 + RPV 900 mg)
-7.6 11.6
Q4W IM (CAB 400 + RPV 600 mg)
ITT-e (286 out of 309)
Margolis et al. Lancet ID 2015; 15:1145-55.
9th IAS Conference on HIV Science; July 23-26, 2017; Paris, France
Virologic outcomes Treatment differences (95% CI)
Oral IMQ8W IM
−8.4% 14.4%
Q4W IM
− 0.6% 20.5%
Eron et al. IAS 2017; Paris, France. MOAX0205LB; * Margolis DA et al. HIV Glasgow, UK, October 28-31, 2018
ITT-ME, intent-to-treat maintenance exposed; LA, long acting; Q4W, every 4 weeks; Q8W, every 8 weeks.
LATTE 2. HIV-1 RNA <50 c/mL at 96 wk. ITT-ME (Snapshot)90% Q8W vs. 83% Q4W
at W160*
Evolution of ART regimens over time
LA or not LAthat is the question
Hamlet, Act III, Scene I. Sir William Shakespeare, 1564 - 1616.
Pros- Innovative approach- Excellent efficacy data- Safety (except ISR)- Useful for non-adherent target
populations- Also useful for PrEP
Cons- No data in VS patients with
CD4<200/mm3- Lead-in oral phase duration not
well defined- Best schedule not defined yet- Drug toxicity management- Resistance concern- Limited PK data in sanctuaries- Stopping rules not defined (long
PK tail)- Logistics outside RCT- Avoid TB-HIV
Long-Acting (LA) ART
Where we come from: 1 - 2 - 3Where we are now: TT regimens New regimens: 2D oral New regimens: 2D long-acting Monotherapy Take home messages
Where we come from: 1 - 2 - 3Where we are now: TT regimens New regimens: 2D oral New regimens: 2D long-acting Monotherapy Take home messages
The Future of Antiretroviral Treatment
The Future of Antiretroviral Treatment
Monotherapy
Naïve- MONARK (LPV/r)*- IMANI I, II (LPV/r)*
Switching- OK / OK04 (LPV/r)- KALMO / IMANI III (LPV/r)- ACTG5201 (ATV/r)*- ATARIMO / OREY (ATV/r)*- MONET / MONOI / MONARCH (DRV/r)
PI/r-Monotherapy
*Hight rates of treatment failures
PI/r monotherapy• Not recommended in naïve patients• LPV/r and DRV/r demonstrated the
non-inferiority in switching trials• Strict adherence is necessary• VF not associated with PI R mutations• Most patients resupressed with TT• EACS Guidelines considered this
option for selected patients
SEMINARIO VIH: ACTUALIZACIÓN EN TRATAMIENTO ANTIRRETROVIRAL TRIPLE Y DUAL
MOBIDIP/ANRS286 RCT in sub-Saharan Africa
The patients came from a prospective cohort generated after
the 2LADY study
PI/r* monotherapy (n=133)Randomization
1:1
Basal Week 24 Week 96
- HIV-1 VL <200 c/mL ≥ 6 mo.- CD4> 100 cels / mm3- Adherence ≥ 90% last control- No ART changes in last 3 mo.
2 NRTI + 1 boosted PI PI/r* + 3TC (n=132)
PI/r Mono PI/r + 3TC Total
Ciaffi L, et al. Lancet HIV 2017;4:e384-e392
SEMINARIO VIH: ACTUALIZACIÓN EN TRATAMIENTO ANTIRRETROVIRAL TRIPLE Y DUAL
Ciaffi L, et al. Lancet HIV 2017;4:e384-e392
The monotherapy arm was stopped by recommendation
of the DSMB
Treatment Failure (ITT análisis)
Efficacy of the PI/r + 3TC arm at W96 was 92%7/8 VF were genotyped: without R to PIs or NRTI
MOBIDIP/ANRS286 RCT in sub-Saharan Africa
2%
21%
Monotherapy
Naïve- MONARK (LPV/r)- IMANI I, II (LPV/r)
Switching- OK / OK04 (LPV/r)- KALMO / IMANI III (LPV/r)- ACTG5201 (ATV/r)- ATARIMO / OREY (ATV/r)- MONET / MONOI / MONARCH (DRV/r)
PI/r-Monotherapy DTG-MonotherapyNaïve- No studies
Switching- DOLAM (TT vs. 2D vs. M)- DOMONO (TT vs. M)- Several cohort studies- Recent HIV Infection (TT vs. M)*
*Only study without any case of VF. Braun DL et al. IAS Amsterdam, July 2018.
Study (n) 24 weeksProportion (95% CI)
48 weeksProportion (95% CI)
Gubavu et al. (21) 0.00% (0.00‐16.1) –
Katlama et al. (28) 10.7% (2.27‐28.2) –
Lecompte et al. (8) 0.00% (0.00‐36.9) –
Oldenbüttel et al. (31) 3.23% (0.08‐16.7) –
Rojas et al. (31) 3.23% (0.08‐16.7) –
Rokx et al. (5) 0.00% (0.00‐52.2) 20.0% (0.51‐71.6)
Wijting et al. (96) 2.08% (0.25‐7.32) 8.33% (3.67‐15.8)
Borghetti et al. (36) 0.00% (0.00‐9.74) –
Gantner et al. (116) 0.86% (0.02‐4.71) –
Joly et al. (104) 0.96% (0.02‐5.24) 0.96% (0.02‐5.24)
Llibre et al. (513) 0.19% (0.00‐1.08) 0.39% (0.05‐1.40)
Maggiolo et al. (94) 0.00% (0.00‐3.85) 0.00% (0.00‐3.85)
Reynes et al. (27) 0.00% (0.00‐12.8) 0.00% (0.00‐12.8)
Riva et al. (61) 0.00% (0.00‐5.87) –
SUMMARY 0.8% (0.29‐2.19) 1.14% (0.22‐5.61)
DTG-Mono
DTG-Dual
Virological failure0% 5% 10% 15% 20% 25%
24 weeks 48 weeks
Meta-analysis DTG+3TC and DTG monotherapyProportion of virologic failures
Buzzi et al. EACS 2017; Milan, Italy. Oral PS1/2.
Mono
Dual
Virological failure0% 5% 10% 15% 20% 25%
3.18% (1.52‐6.52) 8.91% (4.70‐16.2)
0.32% (0.10‐0.97) 0.41% (0.13‐1.25)
→ On DTG monotherapy, 50% of virological failures develop a new resistance to integrase inhibitors
Evolution of ART regimens over time1984-2018 Future of ART
/r/c
Where we come from: 1 - 2 - 3Where we are now: TT regimens New regimens: 2D oral New regimens: 2D long-acting Monotherapy Take home messages
Where we come from: 1 - 2 - 3Where we are now: TT regimens New regimens: 2D oral New regimens: 2D long-acting Monotherapy Take home messages
The Future of Antiretroviral Treatment
The Future of Antiretroviral Treatment
Take Home MessagesTake Home Messages Current IAS ART guidelines recommend for initial therapy an integrase strand
transfer inhibitor (InSTI) (bictegravir or dolutegravir) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs).
Dual-therapy regimens that include boosted darunavir or dolutegravir plus lamivudine might be considered for initial therapy in selected non-advanced chronic HIV-infected patients.
Dual-therapy regimens that include a boosted protease inhibitor (lopinavir/darunavir) plus lamivudine or dolutegravir plus rilpivirine can be considered for switching therapy in selected virologically suppressed chronic HIV-infected patients.
Monotherapy with PIs or dolutegravir as a maintenance strategy is not recommended because of higher rates of treatment failure, often with resistant virus in patients taken dolutegravir monotherapy.
Current IAS ART guidelines recommend for initial therapy an integrase strand transfer inhibitor (InSTI) (bictegravir or dolutegravir) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs).
Dual-therapy regimens that include boosted darunavir or dolutegravir plus lamivudine might be considered for initial therapy in selected non-advanced chronic HIV-infected patients.
Dual-therapy regimens that include a boosted protease inhibitor (lopinavir/darunavir) plus lamivudine or dolutegravir plus rilpivirine can be considered for switching therapy in selected virologically suppressed chronic HIV-infected patients.
Monotherapy with PIs or dolutegravir as a maintenance strategy is not recommended because of higher rates of treatment failure, often with resistant virus in patients taken dolutegravir monotherapy.
J.R. ArribasA. CalmyE. LazzariJ.M. LlibreE. Martinez
G. MoraJ. Perez-Molina
Acknowledgements
A. Pharris
JansenGilead
ViiV Healthcare