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Coinfezione HIVCoinfezione HIV--HCV HCV e e
HIVHIV-- HBVHBVQuando trattare?Quando trattare?
Nicola BoffaNicola BoffaSalernoSalerno
11stst INFECTIVOLOGY TODAYINFECTIVOLOGY TODAYPAESTUM 13PAESTUM 13--1414--15 MAGGIO 200415 MAGGIO 2004
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P-2
ViralViralReplicationReplication
ImmuneImmuneResponseResponse
Necroinflammatory Necroinflammatory activityactivity
FibrosisFibrosis
1010--40 yrs40 yrs
ChronicChronicHepatitis B Hepatitis B
EXPOSURE TOEXPOSURE TOHBVHBV
AsymptAsympt. Cirrhosis. Cirrhosis
33 --6%
6%
x
yr.
x yr
.
InsertionalInsertional mutagenesismutagenesisepigenetic alterationsepigenetic alterations
↑↑Cell proliferationCell proliferation↓↓ApoptosisApoptosis
..2-
15 y
rs
HCCHCC
ESLDESLD
DeathDeath
ALTALT
HBeAg/HBeAbHBeAg/HBeAbHBcAbIgMHBcAbIgM
HBVHBVDNADNA
Histology:Histology:NecoinflammatoryNecoinflammatory activityactivityFibrosisFibrosis
HBcAbOccultHBcAbHBcAbOccultOccult
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P-3
HCV and HIV InfectionHCV and HIV Infection
HCV and HIV have emerged as important and HCV and HIV have emerged as important and prevalent viral infections worldwideprevalent viral infections worldwide
Estimated prevalence of HCV in HIV infected Estimated prevalence of HCV in HIV infected patientspatients
30 30 -- 40% of all HIV40% of all HIV--infectedinfected60 60 -- 85% of hemophiliac patients85% of hemophiliac patients52 52 -- 90% of IDU90% of IDU4 4 -- 8% of MSM8% of MSM
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P-4
HCV/HIV CoHCV/HIV Co--infection:infection:Geographical VariationGeographical Variation
Prevalence of HCV Among Populations of Prevalence of HCV Among Populations of HIVHIV--infected Patients, Published or Presented 1990infected Patients, Published or Presented 1990--20012001
*All or a high proportion of the patients were intravenous drug *All or a high proportion of the patients were intravenous drug users (users (IDUsIDUs))
Switzerland: 49.8%*
EuroSIDA study: 33.5%
Greece: 13.8%Thailand: 13%
Singapore: 2.7%
India: 92%*
South Africa: 1%
Brazil: 14.8-54.7%
Argentina: 58.5%*
USA: 11.7-33%
Canada: 69% Germany: 13.8-52%
Spain: 95%*
France: 29.3%
Martinique: 18%Italy: 69%
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P-5
Prevalence of HCV and HBV coPrevalence of HCV and HBV co--infection in Italian HIV+infection in Italian HIV+from cohort and observational databasesfrom cohort and observational databases
4652
3,2 4 3,3 4,8
0
10
20
30
40
50
60
HCVAb+ HBsAg+ HBsAg+/HCVAb+
I.Co. N.A. 3917 pz. MASTER DBASE 8183 pz. I C O
N A
ItalianCohort
NaiveAntiretroviral
BergamoBergamoBrescia1Brescia1--22BustoBustoCremonaCremonaFerraraFerraraFirenzeFirenzeLeccoLeccoPaviaPaviaP. P. LigureLigureVerbaniaVerbania
In In ItalyItaly::60.000 HIV/HCV 60.000 HIV/HCV coco--infectedinfected9600 HIV9600 HIV--HBV HBV coco--infectedinfected9000 HIV9000 HIV--HBVHBV--HCV coHCV co--infectedinfected
% o
f pat
ient
s
ICONA, Bari 12-13 giugno 2002
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P-6
PrevalencePrevalence of of HepatitisHepatitis VVirusesiruses infectioninfectionin 1238 HIV+ and in 1870 HIVin 1238 HIV+ and in 1870 HIV--
Infectious Diseases Department .Infectious Diseases Department .-- University of University of BresciaBrescia
68
11 1212
96
1612 10 4
HIVAll (1238)IDU (837)Sexual Exposure (401)
General Population (1870)
100
80
Prev
alen
ce, %
60
3 1,5 0,15
40
20
0HCVAb+ HBsAg+ HDVAb+
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P-7
MASTER observational DBASE:MASTER observational DBASE:% HIV+ with % HIV+ with hypertransaminasemiahypertransaminasemia stratified stratified
according to according to etiologyetiology
54,549,1
65,2
% with elevated ALTHCVAb+HBsAgHCVAb+/HBsAg+ 86
3,8 10
31
69ALT> VN ALT < VN
BergamoBergamoBrescia1Brescia1--22BustoBustoCremonaCremonaFerraraFerraraFirenzeFirenzeLeccoLeccoPaviaPaviaP. P. LigureLigureVerbaniaVerbania
8103 HIV+8103 HIV+
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P-8
HIV/HCV CoHIV/HCV Co--infectioninfection
HIV infected patients have prolonged life HIV infected patients have prolonged life expectancy due to availability of highly active expectancy due to availability of highly active antiretroviral therapyantiretroviral therapy
Hepatitis C is a leading cause of morbidity Hepatitis C is a leading cause of morbidity and mortalityand mortality
Compared with HCV monoCompared with HCV mono--infectioninfectionHigher HCV RNA titersHigher HCV RNA titersMore rapid progression to cirrhosis and end stage More rapid progression to cirrhosis and end stage liver diseaseliver disease∴∴ more urgency to treatmore urgency to treat
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P-9
Impact of HIV Coinfection Impact of HIV Coinfection HCVHCV--Related Clinical OutcomesRelated Clinical Outcomes
0
5
10
15
20
25
30
HIV/HCV HCVPL
D (%
)
Montreal hemophilia cohortMontreal hemophilia cohort154 patients (81 HIV+)154 patients (81 HIV+)
Risk PLDRisk PLDOdds ratio 7.4 Odds ratio 7.4 Mean duration between Mean duration between HCV and PLD: 17.2 yearsHCV and PLD: 17.2 years
Survival after PLD Survival after PLD Mean: 3.2 years Mean: 3.2 years 73% developed AIDS73% developed AIDS
HCV = hepatitis C virus; HIV = human immunodeficiency virus; PLD = progressive liver disease. Lesens et al. J Infect Dis. 1999;179:1254-1258.
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P-10
Increasing Mortality From Increasing Mortality From ESLD in Patients With HIVESLD in Patients With HIV
One third of 1998 cohort One third of 1998 cohort had recent history of had recent history of discontinuing HAART discontinuing HAART secondary to secondary to hepatotoxicityhepatotoxicity
More than 1/2 who died More than 1/2 who died with ESLD had either with ESLD had either NDVL or CD4 >200/mmNDVL or CD4 >200/mm33 6 6 months prior to deathmonths prior to death
ESLD = end stage liver disease; NDVL = no detectable viral load.Bica et al. Clin Infect Dis. 2001;32:492-497.
ESLD
-Rel
ated
Dea
ths
(%)
1991
1996
1998
1114
5050
40
30
20
10
0
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P-11
MortalitMortalitàà per AIDS ed insufficienza epatica (ESLD) per AIDS ed insufficienza epatica (ESLD) in una coorte di pazienti di Torino e Verona, 1987in una coorte di pazienti di Torino e Verona, 1987--20012001
0
20
40
60
80
100
120
87 88 89 90 91 92 93 94 95 96 97 98 99 00 01
Dead from AidsDead from liver failure
Di Perri G. et al., 2001
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P-12
Trend dei tassi di mortalitTrend dei tassi di mortalitàà per ESLDper ESLD
2.352.35--6.636.633.93.926.626.6828828222220012001
1.931.93--5.985.983.43.422.822.8744744171720002000
1.391.39--5.055.052.72.717.817.8672672121219991999
1.611.61--5.275.272.92.919.619.6764764151519981998
1.091.09--3.983.982.12.114.114.1853853121219971997
1.161.16--4.044.042.12.114.614.6893893131319961996
--116.76.760946094414119871987--9595
95% CI95% CIRate Rate ratioratio
ESLD per ESLD per 1000 P1000 P--YYPP--YYESLDESLDAnnoAnno
Poisson regression analysis: p = 0.002 Di Perri G. et al., 2001
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P-13
Update 2002Update 2002Morbidity/Mortality in HIV/HCVMorbidity/Mortality in HIV/HCV
80 -
70 -
60 -
50 -
40 -
30 -
20 -
10 -
0 -0 5 10 15 20 25 30
Per
cent
age
of C
irrho
sis
HIV Negative
HIV Positive
HCV Duration (years)P=.04.HCV = hepatitis C; HIV = human immunodeficiency virus.Di Martino et al. Hepatology. 2001;34:1193-1199.
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P-14
Outcomes After HAART According to Outcomes After HAART According to HCV Status and IVDUHCV Status and IVDU
Aliv
e W
ithou
t Pro
gres
sion
(%)
Time Since HAART (months)
Swiss HIV CohortHCV+, IVDU+HCV+, IVDU-HCV-, IVDU-
1009590858075706560
0 7 14 21 28 35 42
HAART= highly active antiretroviral therapy; HCV = hepatitis C virus; IVDU = intravenous drug use. Greub et al. Lancet. 2000;356:1800-1805.
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P-15
EffectEffect of HAART on of HAART on HepatitisHepatitis CC
HaartHaart isis associatedassociated withwith a a substanzialsubstanzialimprovementimprovement in in survivalsurvival and and thisthis inclutedincluted a a significantsignificant improvementimprovement in in liverliver--relatedrelated deathsdeathsattibuitedattibuited toto HCV HCV
QurishiQurishi N, N, KreuzbergKreuzberg C, C, LuchtersLuchters G, G, etet al.al. EffectEffect of of antiretroviralantiretroviral therapytherapy on on liverliver--relatedrelated mortalitymortality in in patientspatients withwith HIV and HIV and hepatitishepatitis C virus C virus coinfectioncoinfection. . LancetLancet. 2003;362:1708. 2003;362:1708--17131713
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P-16
Why treat HCV infection in patients with HIV?Why treat HCV infection in patients with HIV?
In patients infected with HIV, HCV clearly has In patients infected with HIV, HCV clearly has a worse prognosis a worse prognosis
Evidence is mounting that HCV worsens the Evidence is mounting that HCV worsens the prognosis of HIV (Swiss cohort study)prognosis of HIV (Swiss cohort study)
In patients infected with HIV, HCV may soon In patients infected with HIV, HCV may soon be the leading cause of death be the leading cause of death
HAART HAART hepatotoxicityhepatotoxicity may necessitate HCV may necessitate HCV treatment in order for patients to tolerate HIV treatment in order for patients to tolerate HIV medicationsmedications
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P-17
Obstacles in the Treatment Obstacles in the Treatment of HIV/HCV Patientsof HIV/HCV Patients
Higher degrees of fibrosis at baselineHigher degrees of fibrosis at baseline
Higher baseline levels of HCV RNAHigher baseline levels of HCV RNA
PrePre--existing existing cytopeniascytopenias
Mental health and substance abuse issuesMental health and substance abuse issues
Drug interactionsDrug interactionsPotentiationPotentiation of drugof drug--induced toxicitiesinduced toxicitiesPotential negative impact on HIV controlPotential negative impact on HIV control
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P-18
RIBAVIRINARIBAVIRINA
inibizione della fosforilazionedi timidina
in vitro
ZDV ddIddC3TCd4T
in vivo
• nessuna interazione con HAART• acidosi lattica (ddI ?)
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P-19
PathwayPathway metabolico che conduce al potenziamentometabolico che conduce al potenziamentodi di didanosinadidanosina ((ddIddI) da parte di ) da parte di ribavirinaribavirina (RBV)(RBV)
RBV
Ribavirina-MP
IMP-DH IMP
Inositolo
Nucleosidi naturali
ddI
ddIMP
ddAMP
- +
ddIADP
ddIATP- -
DNA γ-polimerasiRT-HIV
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P-20
Question about use of IFN/RBVQuestion about use of IFN/RBVin HIVin HIV--Infected PatientsInfected Patients
Will HIV control wane?Will HIV control wane?
Will CD4 counts decline?Will CD4 counts decline?
Will preWill pre--existing anemia be exacerbated by existing anemia be exacerbated by use of RBV?use of RBV?
Will DDIWill DDI--associated toxicities increase with associated toxicities increase with the use of RBV?the use of RBV?
Will treatment be safe and effective?Will treatment be safe and effective?
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P-21
Treatment of HIV/HCV With PEGTreatment of HIV/HCV With PEG--IFN IFN αα--2b 2b + RBV+ RBV
68 patients na68 patients naïïve to IFNve to IFN
73% on ART; CD4 >30073% on ART; CD4 >300
HIV RNA <5,000 copies/mlHIV RNA <5,000 copies/ml
50% with high HCV RNA; 35% with genotype 350% with high HCV RNA; 35% with genotype 3
Only 17% with liver biopsyOnly 17% with liver biopsy
Duration of treatment dependent on genotypeDuration of treatment dependent on genotype
Perez-Olmeda, M. AIDS 2003;17(7):1023-28.
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P-22
Treatment of HIV/HCV With PEGTreatment of HIV/HCV With PEG--IFN IFN αα--2b + RBV2b + RBV
ETR: 40%ETR: 40%
SVR: 28% (intention to treat)SVR: 28% (intention to treat)
30% relapsed off therapy30% relapsed off therapy
No adverse effect on HIV controlNo adverse effect on HIV control
Perez-Olmeda M. AIDS. 2003;17(7):1023-28.
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P-23
Treatment of HIV/HCV With PEGTreatment of HIV/HCV With PEG--IFN IFN αα--2b + RBV2b + RBV
Predictors of Virological Response to HCV Therapy—Multivariate Analysis of SVR
Parameter OR P
HCV genotype 3 3.5 0.052HCV RNA <800,000 IU/mL 5.5 0.009
Perez-Olmeda M. AIDS 2003;17(7):1023-28
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P-24
ACTG A5071: Study DesignACTG A5071: Study Design
21 centers:134 patients randomized
IFN α-2a + RBV 600 mg → 1 g/d
PEG-IFN α-2a 180 µg qw+ RBV 600 mg → 1 g/d
Biopsy Biopsy for virologic response
67
67
Follow-up
6 MIU tiw 3 MIU tiw
Biopsy for virologic nonresponse:Histologic response → continueHistologic nonresponse → D/C
0 12 24 48 72
Weeks
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P-25
ACTGACTG--A5071A5071
BaselineIFN-RBV (n =
67)PEG-RBV (n =
66)CD4+ cell count, median
cells/mcL444 492
Genotype 1 78% 77%
Fibrosis (median) 2.0 2.0
Results SVR -- 72 weeks
All patients 8 (12%) 18 (27%)*
Genotype 1 3/52 (6%) 7/51 (14%)
Other genotypes 5/15 (33%) 11/15 (73%)
Premature discontinuation
For adverse reactions 8 (12%) 8 (12%)
*
PP </= </= .05.05
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P-26
ACTG A5071: ACTG A5071: HistologicHistologic Response (HR) in Response (HR) in VirologicVirologic NonNon--responders (NR) (24 responders (NR) (24 settsett))
IFN + R PEG-IFN + Rn=67 n=66
NR 57 (85%) 37 (56%)
Wk 24 bx obtained 37 23
Histologic response 15 (40%) 6 (26%)
VR + HR 25 (37%) 35 (53%)
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P-27
48 Wk
Screening
IFN α-2b 3 MIU TIW + RBV 800 mg/d
PEG-IFN α-2b 1.5 mcg/kg/wk +RBV 800 mg/d
n = 158
n = 157
RIBAVIC (ANRS HCO2): RIBAVIC (ANRS HCO2): PEGPEG--IFN IFN αα--2b/RBV2b/RBV
(N = 416) n = 206
n = 210
Pol et al. J Hepatology 2003;38:92A
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P-28
RIBAVIC:RIBAVIC:Patient DemographicsPatient Demographics
80% on HAART80% on HAART
Mean CD4 = 515Mean CD4 = 515
60% HIV <200, Mean HIV RNA = 3.48 log60% HIV <200, Mean HIV RNA = 3.48 log1010
F3F3--4 = 39%, normal ALT = 16%4 = 39%, normal ALT = 16%
Pol et al. J Hepatology 2003;38:92A
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P-29
RIBAVIC: SVR RIBAVIC: SVR (412 Patients) (412 Patients) –– ITT analysisITT analysis
27
15
0
20
40
60
ITT
% U
ndet
ecta
ble
PEG-IFN α-2b/RBV
IFN α-2b/RBV
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P-30
RIBAVIC: SVR RIBAVIC: SVR for those who completed therapyfor those who completed therapy
38
26
0
20
40
60
on treatment
% U
ndet
ecta
ble
PEG-IFN α-2b/RBV
IFN α-2b/RBV
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P-31
RIBAVIC: RIBAVIC: ETR in Genotype 1/4ETR in Genotype 1/4
9
26
0
5
10
15
20
25
30
Genotype
IFN + RBVPEG - IFN +RBV
Patie
nts
With
EVR
(%)
Pol et al. J Hepatology 2003;38:92A
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P-32
RIBAVIC: RIBAVIC: Safety and TolerabilitySafety and Tolerability
High rate of High rate of SAEsSAEs, resulting in therapy , resulting in therapy discontinuations (34% PEG; 36% std IFN)discontinuations (34% PEG; 36% std IFN)
Psychiatric, 21 eventsPsychiatric, 21 eventsInfections, 12Infections, 12HematologicHematologic, 9, 9Liver failure, 10Liver failure, 10HyperlactatemiaHyperlactatemia, 8, 8
•• Association with Association with ddIddI (OR ~ 23)(OR ~ 23)
Pol et al. J Hepatology 2003;38:92A
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P-33
APRICOT Study DesignAPRICOT Study Design
FollowFollow--upupIFN alfa-2a (3 MIU, tiw) plus RBV (800 mg daily)
FollowFollow--upupPEG-IFN alfa-2a (180 µg, qw) plus RBV placebo
FollowFollow--upupPEG-IFN alfa-2a (180 µg, qw) plus RBV (800 mg daily)
Study WeeksStudy Weeks00 48482424 7272
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P-34
Key Inclusion CriteriaKey Inclusion CriteriaHCV criteriaHCV criteria
1.1. Liver biopsy (Liver biopsy (≤≤15 months) consistent with 15 months) consistent with 2.HCV infection, If cirrhotic Child2.HCV infection, If cirrhotic Child--Pugh GradePugh Grade AA
HIV criteria HIV criteria 1.HIV antibody or quantifiable HIV RNA1.HIV antibody or quantifiable HIV RNA2.CD42.CD4++ cell count cell count
•• ≥≥200/200/µµL L oror•• ≥≥100/100/µµL to L to <<200/200/µµL with L with <<5000 copies/5000 copies/mmLL
HIV RNAHIV RNA3.HIV disease stable with or without anti3.HIV disease stable with or without anti--retroviral retroviral treatmenttreatment
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P-35
Baseline Characteristics: HCVBaseline Characteristics: HCVIFN alfaIFN alfa--2a 2a PEGPEG--IFN alfaIFN alfa--2a2a PEGPEG--IFN alfaIFN alfa--2a2a
+ RBV+ RBV + Placebo+ Placebo + RBV+ RBV(N = 285)(N = 285) (N = 286)(N = 286) (N = 289)(N = 289)
HCV RNA (IU/HCV RNA (IU/mLmL x 10x 106 6 ))MeanMean 5.25.2 6.36.3 5.65.6MedianMedian 3.63.6 4.64.6 3.53.5RangeRange 0.006 0.006 -- 4444 0.006 0.006 -- 3030 0.006 0.006 -- 4444
HCV Genotype (%)HCV Genotype (%)Type 1Type 1 6060 6161 6161Type nonType non--11 4040 3838 383822 55 66 4433 2626 2626 282844 88 77 66OtherOther <<11 <1<1 <1<1
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P-36
Baseline Characteristics: HIVBaseline Characteristics: HIVIFN alfaIFN alfa--2a 2a PEGPEG--IFN alfaIFN alfa--2a2a PEGPEG--IFN alfaIFN alfa--2a2a
+ RBV+ RBV + Placebo+ Placebo + RBV+ RBV(N = 285)(N = 285) (N = 286)(N = 286) (N = 289)(N = 289)
ART* (%)ART* (%) 8484 8585 8484
HIV RNAHIV RNAMedianMedian <<5050 <<5050 <<5050RangeRange <<50 50 -- 640,622640,622 <<50 50 -- 490,625490,625 <<50 50 -- 580,679580,679
CD4CD4++ CountsCounts(cells/(cells/µµL)L)
MeanMean 542542 530530 520520<<200 (%)200 (%) 77 55 66
*Any treatment used as antiretroviral therapy*Any treatment used as antiretroviral therapy
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P-37
12%
20%
40%
0%
10%
20%
30%
40%
50%
60%
IFN alfa-2a + RBV PEG-IFN alfa-2a +Placebo
PEG-IFN alfa-2a +RBV
Sustained Sustained VirologicVirologic ResponseResponse%
of P
atie
nts
% o
f Pat
ient
s
N = 285 N = 286 N = 289
P = 0.0078P = 0.0078
P = P = <<0.00010.0001P = P = <<0.00010.0001
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P-38
7%
20%14%
36%29%
62%
0%
10%
20%
30%
40%
50%
60%
70%
Genotype 1 Genotype 2, 3
IFN alfa-2a + RBV PEG-IFN alfa-2a + Placebo PEG-IFN alfa-2a + RBV
Sustained Sustained VirologicVirologic ResponseResponseby Genotypeby Genotype
N = 171 N = 175 N = 176 N = 89 N = 90 N = 95
% o
f Pat
ient
s%
of P
atie
nts
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P-39
Withdrawal from TreatmentWithdrawal from Treatment
5%3%
14%12% 12%
24%
15%
10%
<.1%0%
5%
10%
15%
20%
25%
30%
IFN alfa-2a + RBV PEG-IFN alfa-2a +Placebo
PEG-IFN alfa-2a +RBV
Laboratory abnormality Adverse event Non-safety
% o
f Pat
ient
s%
of P
atie
nts
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P-40
Adverse Events Adverse Events ≥≥20%20%
IFN alfaIFN alfa--2a 2a PEGPEG--IFN alfaIFN alfa--2a2a PEGPEG--IFN alfaIFN alfa--2a2a+ RBV+ RBV + Placebo+ Placebo + RBV+ RBV
(N = 285)(N = 285) (N = 286)(N = 286) (N = 288)(N = 288)
FatigueFatigue 40%40% 41%41% 44%44%PyrexiaPyrexia 35%35% 43%43% 44%44%HeadacheHeadache 41%41% 38%38% 39%39%MyalgiaMyalgia 29%29% 33%33% 36%36%NauseaNausea 25%25% 27%27% 30%30%DiarrheaDiarrhea 24%24% 26%26% 28%28%InsomniaInsomnia 29%29% 21%21% 26%26%AstheniaAsthenia 24%24% 22%22% 28%28%DepressionDepression 22%22% 20%20% 26%26%ArthralgiaArthralgia 18%18% 20%20% 20%20%Weight decreasedWeight decreased 14%14% 18%18% 20%20%
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P-41
Incidence of Laboratory and Clinical Incidence of Laboratory and Clinical Events Associated with HCV TreatmentEvents Associated with HCV Treatment
IFN alfaIFN alfa--2a 2a PEGPEG--IFN alfaIFN alfa--2a2a PEGPEG--IFN alfaIFN alfa--2a2a+ RBV+ RBV + Placebo+ Placebo + RBV+ RBV
(N = 285)(N = 285) (N = 286)(N = 286) (N = 289)(N = 289)N (%)N (%) N (%)N (%) N (%)N (%)
ANC <0.5 x10ANC <0.5 x1099/L/L 11 ((<<1)1) 3737 (13)(13) 3131 (11)(11)
Platelets <20 x10Platelets <20 x1099/L/L 00 (0)(0) 11 ((<<1)1) 11 ((<<1)1)
Hemoglobin Hemoglobin 44 (1)(1) 1010 (3)(3) 1111 (4)(4)<8.5 <8.5 g/dLg/dL
Triglycerides Triglycerides 1010 (4)(4) 1616 (6)(6) 1616 (6)(6)>1200 mg/>1200 mg/dLdL
Weight decrease Weight decrease 7575 (26)(26) 7070 (25)(25) 7272 (25)(25)of >10%of >10%
Serious depressionSerious depression 22 ((<<1)1) 44 ((<<1)1) 33 ((<<1)1)
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P-42
Impact of HCV Treatment on Absolute Impact of HCV Treatment on Absolute CD4CD4++ Count and CD4Count and CD4++%*%*
IFN alfaIFN alfa--2a 2a PEGPEG--IFN alfaIFN alfa--2a2a PEGPEG--IFN alfaIFN alfa--2a2a+ RBV+ RBV + Placebo+ Placebo + RBV+ RBV
Baseline**Baseline**CD4CD4++ cells/cells/µµLL 512512 481481 476476CDCD44++%% 2626 2525 2525
Change fromChange frombaseline at baseline at week 48**week 48**
CD4CD4++ cells/cells/µµLL --9999 --115115 --140140CD4CD4++%% +2.3+2.3 +2.1+2.1 +3.9+3.9
** Patients who completed 48 weeks of treatment Patients who completed 48 weeks of treatment **** MedianMedian
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P-43
Impact of HCV Treatment on HIVImpact of HCV Treatment on HIV--1 RNA1 RNAMedian LogMedian Log1010 HIV RNA (copies/HIV RNA (copies/mLmL))
∆∆ from Baselinefrom Baseline ∆∆ from Baselinefrom Baselineat Endat End 4 Weeks after4 Weeks after
BaselineBaseline of Treatmentof Treatment End of TreatmentEnd of Treatment
Patients receiving ARTPatients receiving ARTat baselineat baseline
IFNIFN alfaalfa--2a + RBV2a + RBV 1.6991.699 0.0000.000 0.0000.000PEGPEG--IFNIFN alfaalfa--2a + Placebo2a + Placebo 1.6991.699 0.0000.000 0.0000.000PEGPEG--IFNIFN alfaalfa--2a + RBV2a + RBV 1.6991.699 0.0000.000 0.0000.000
Patients Patients notnot receiving ARTreceiving ARTat baselineat baseline
IFNIFN alfaalfa--2a + RBV2a + RBV 3.8523.852 0.0000.000 0.4140.414PEGPEG--IFNIFN alfaalfa--2a + Placebo2a + Placebo 4.0614.061 --0.9830.983 0.0550.055PEGPEG--IFNIFN alfaalfa--2a + RBV2a + RBV 3.9473.947 --0.8940.894 0.0560.056
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P-44
PEGPEG--IFN SVR: All Genotypes and Genotype 1IFN SVR: All Genotypes and Genotype 1(ACTG 5071 vs RIBAVIC vs APRICOT)(ACTG 5071 vs RIBAVIC vs APRICOT)
27% 27%
40%
14% 14%
29%
0%
10%
20%
30%
40%
50%
ACTG 5071 RIBAVIC APRICOT
All Genotypes Genotype 1
% S
VR%
SVR
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Comparison of MonoComparison of Mono--infection infection Results (NV15942 and NR16071) Results (NV15942 and NR16071)
with Key Cowith Key Co--infection Results infection Results (NR15961)(NR15961)
PegPeg--ifnifn alfa2a alfa2a 180 180 µµg + g + RBV 800 mg, 48 weeksRBV 800 mg, 48 weeks
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P-46
52% 52%
40%
0%
10%
20%
30%
40%
50%
60%NV15942 NR16071 NR15961
Sustained Sustained VirologicalVirological Response Response –– All All GenotypesGenotypes
((PegPeg--ifnifn alfaalfa--2a 2a 180 180 µµg + RBV 800 mg)g + RBV 800 mg)%
SVR
% S
VR
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P-47
41%
76%
40%
78%
29%
62%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
Genotype 1 Genotype 2, 3
NV15942 NR16071 NR15961
Sustained Sustained VirologicalVirological Response Response –– By GenotypeBy Genotype((PegPeg--ifnifn alfaalfa--2a 2a 180 180 µµg + RBV 800 mg)g + RBV 800 mg)
% S
VR%
SVR
N = 250 N = 141 N = 176 N = 99 N = 58 N = 95
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P-48
ACTG-A5071,RIBAVIC, APRICOTpermit the following conclusions for HIV/HCV coinfection
1. The combination of PEG and ribavirin x 48 weeks in patients with virologic response at week 12 appears to be the standard.
2. The rates of SVR reported were 27% to 40% for all patients and 14% to 29% for genotype 1.
3. These rates are significantly lower than those reported for patients with HCV monoinfection.
4. HCV RNA virologic response with < 2 log10 IU/mL at 12 weeks predicts SVR but not necessarily histologic response.
5. The treatment is generally well tolerated and has no significant impact on HIV, although CD4+ cell counts decrease temporarily during therapy with PEG.
6. PEG may have significant anti-HIV activity in those with HIV viremia at baseline
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P-49
Chronic hepatitis B in patients co-infectedwith HIV
HBsAg seropositivityHBsAg seropositivity : 10%: 10%
Higher prevalence of cirrhosis than HIV negative Higher prevalence of cirrhosis than HIV negative HBVHBV--infected patientsinfected patients
Decrease survival of HIVDecrease survival of HIV--HBV coHBV co--infected infected individualsindividuals compared compared to HIV monoto HIV mono--infectedinfected
Rustgi VK et al. Ann Intern Med. 1984;101:795-7.Colin JF et al. Hepatology. 1999;29:1306-10.
Gilson RJC et al. AIDS. 1997;11:597-606.
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P-50
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9 10 years
% o
fcirr
hosi
s
VIH negative
VIH positive
p=0.005
HIV/HBV co-infection: Natural history
Adapted from Di Martino V et al. Gastroenterology 2002; 123: 1812-1822
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P-51
HIV/HBV coHIV/HBV co--infection: infection: Natural history Natural history (MACS)(MACS)
LiverLiver--related mortalityrelated mortality, in a , in a cohort cohort of 5293 patients, 1984 /1987 of 5293 patients, 1984 /1987 -- 20002000
N Viral N Viral status status LiverLiver--related related Liver Liver death death ppHIV HIV HBsAg mortalityHBsAg mortality (n) (1000 pers/(n) (1000 pers/yryr))
30933093 -- -- 0 0.0 0 0.0 139 139 -- + 1 0.8 + 1 0.8 0.040.042346 + 2346 + -- 35 1.7 <035 1.7 <0.0001.0001213 + + 26 213 + + 26 14.2 <0.0001 14.2 <0.0001 5293 62 5293 62 1.1 1.1
Liver related mortalityX 19 HBV/HIV vs HBV (RR18; 73,1-766,1 - p<0,001)
Thio CL et al. Lancet 2002; 360: 1921-1926.
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P-52
Treatment of HBV in HIV co-infected patients
• Interferon
• Lamivudine
• Adefovir dipivoxil
• Tenofovir fumarate disoproxil
• FTC (Emtriva)
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P-53
Treatment of HBV in HIV coTreatment of HBV in HIV co--infected patients: infected patients: IFN IFN αα2a2a
HBeAg and HBV DNA negativation (<5 pg/mL) inpatients treated with IFN α2a
MIU/TIWMIU/TIW HIV+HIV+ HIVHIV--
2.52.5 0/ 50/ 5 1/ 41/ 4
55 0/ 40/ 4 1/ 51/ 5
1010 0/ 50/ 5 4/ 94/ 9
ControlControl 0/ 30/ 3 0/ 60/ 6
Mac Donald et al. Hepatology. 1987;7:719-23.
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P-54
Treatment of HBV in HIV coTreatment of HBV in HIV co--infected patients: infected patients: IFN IFN αα22
HBeAg and HBV DNA negativation (<5 pg/mL) in homosexualmen treated with IFN α2a
HIV+HIV+
(n=25)(n=25)
HIVHIV--
(n=25)(n=25)
10 MIU/TIW10 MIU/TIW
12 12 weeksweeks
1/12 (8.3%)1/12 (8.3%) 5/13 (38.5%)5/13 (38.5%)
ControlControl 0/13 (0%)0/13 (0%) 1/12 (8.3%)1/12 (8.3%)
Wong DK et al. Gastroenterology. 1995;108:165-71.
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P-55
Treatment of HBV in HIV co-infected patients
• Interferon
• Lamivudine
• Adefovir dipivoxil
• Tenofovir fumarate disoproxil
• FTC (Emtriva)
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P-56
Treatment of HBV in HIV co-infected patients: Lamivudine
One year of lam on HBV serological markers in HIV co-infected patients
HBV DNA >5 pg/mLn=27
HBV DNA <5 pg/mLn=10
0 (0%)
5 (18.5%)
0 (0%)
3 (11%)
26 (96.3%)
Loss of HBsAg
Loss of HBeAg
Seroconversion to anti-HBs
Seroconversion to anti-HBe
Loss of serum HBV DNA(MH- 1 000 000 copies/mL)Loss of serum HBV DNA(PCR – 1000 copies/mL)
23 (88.5%)
3 (30%)
⎯
2 (20%)
⎯
⎯
6 (100%)
Y Benhamou et al. Ann Intern Med. 1996;125:705-712.
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P-57
Treatment of HBV in HIV co-infected patients: Lamivudine
Changes in ALT (UI/mL) during lamivudine therapy
0
50
100
150
200
250
300
Baseline 2 4 6 8 10 12
ALT
(UI/L
)
HBV DNA >5x105 copies/mL at baseline
HBV DNA <5x105 copies/mL at baseline
P<0.05
Lamivudine therapy duration (months)
Y Benhamou et al. Ann Intern Med. 1996;125:705-712.
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P-58
Treatment of HBV in HIV coTreatment of HBV in HIV co--infected patients: infected patients: LamivudineLamivudine
-3,5
-3
-2,5
-2
-1,5
-1
-0,5
00 4 8 12 20 28 36 44 52
Time in Weeks
Med
ian
Cha
nge
in L
og H
BV
DN
A
Lamivudine Placebo
Median change in serum HBV DNA over 52 weeks
-2.7 log10 copies/mL
Dore GJ et al. J Infect Dis. 1999;180:607-13
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P-59
Treatment of HBV in HIV co-infected patients: Lamivudine resistance
Cumulative risk for the development of HBV resistance to lamivudine
0.25
0.50
0.75
1
0 350 700 1050 1400
Days of lamivudine therapy
Prop
ortio
nof
pat
ient
s w
ith re
laps
e
N= 57
YMDD mutations were documented in all patients with resistance
of H
BV
repl
icat
ion
Number of patients 57 32 13 6 3under observation
Benhamou Y, et al. Hepatology 1999; 30:1302-06.
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P-60
Treatment of HBV in HIV co-infected patients
Interferon
Lamivudine
Adefovir dipivoxil
Tenofovir fumarate disoproxil
FTC (Emtriva)
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P-61
Treatment of Treatment of LAMLAM--R R HBV in HIV coHBV in HIV co--infected patients: infected patients: AdefovirAdefovir
Baseline HBV characteristics Baseline HBV characteristics
Median HBV DNA (log10 copies/mL)
Median ALT (IU/L)
HBeAg positive
n=35
8.75
81
33
Liver Histology (METAVIR)
- Mean (±SEM) Activity
- Mean (±SEM) Fibrosis
- Cirrhosis
n=23
1.52 ± 0.15
2.04 ± 0.24
22%
HIV RNA (log10 copies/mL) Mean (±SEM) CD4 cell count (cells/mm3) Mean (±SEM)
2.88 ± 0.13
422 ± 34
Benhamou Y et al. Lancet. 2001. 358:718-23
Benhamou Y et al. AASLD 2003
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P-62
Treatment of Treatment of LAMLAM--R R HBV in HIV coHBV in HIV co--infected patients: infected patients: AdefovirAdefovir
Week 144 -5.5 log10 copies/mL
p<0.001
0.50
-0.50
-6.50
-5.50
-4.50
-3.50
-2.50
-1.50
0 4 8 12 16 20 24 28 32 36 40 44 48 60 72
Week 96 -4.8 log10 copies/mL
p<0.001
Week 48 -4 log10 copies/mL
P<0.001
N = 31 30 30 30 25 26 28 2884 96 108 120 132 144
Weeks on ADV
HB
V D
NA
(cop
ies/
mL)
35 35 33 32 33 33 31 30 30 30 31 31 31
Median change in serum HBV DNA
Benhamou Y et al. AASLD 2003Benhamou Y et al. Lancet. 2001. 358:718-23
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P-63
Treatment of LAM-R HBV in HIV co-infected patients: Adefovir
Median Median cchangehange in in sserumerum ALTALT
200
N =
Week 14431 IU/L p<0.001
*: ULN of serum ALT levels is 37 IU/L
20
40
60
80
100
120
140
160
180
0 4 8 12 16 20 24 28 32 36 40 44 48 60 72 84 96 108 120 132 144
Weeks on ADV
Seru
m A
LT (I
U/L
)
* ULN
Week 9646 IU/L p<0.001
Week 4853 IU/L p<0.001
35 35 34 32 31 32 33 31 28 30 31 31 31 31 31 27 30 26 29 29 28
Benhamou Y et al. AASLD 2003Benhamou Y et al. Lancet. 2001. 358:718-23
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P-64
Treatment of Treatment of LAMLAM--R R HBV in HIV coHBV in HIV co--infected patients: infected patients: AdefovirAdefovir
0%3%
10%
19% 20%
37% 39%
64%
0%
10%
20%
30%
40%
50%
60%
70%
Baseline Week 48 Week 96 Week 144
Weeks on ADV
HBV DNA < 2.6 log10 copies/mL
ALT Normalization
Patie
nts
(%)
Benhamou et al. AASLD 2003
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P-65
Treatment of HBV in HIV co-infected patients
• Interferon
• Lamivudine
• Adefovir dipivoxil
• Tenofovir fumarate disoproxil
• FTC (Emtriva)
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P-66
TDFTDF in HIV/HBVin HIV/HBV ccoo--iinfectednfected ppatientsatients
N Wild type/ LAM-R
Duration of TDF (weeks)
Change in HBV DNA (log10 copies/mL)
Cooper D 12 5/7 24 -5±0.7*
Nelson M 20 9/11 52 4**
Ristig MB 6 0/6 24 4.3**
Benhamou Y 12 0/12 24 -3.83±0.38* * Mean. ** Median
Cooper D et al. CID. 2003: 124Nelson M et al. AIDS. 2003;17:F7-F10
Ristig MB et al. J Infect Dis. 2002;186:1844-7Benhamou Y et al. N Engl J Med. 2003;348:177-8
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P-67
TDFTDF in HIV/HBVin HIV/HBV ccoo--iinfectednfected ppatientsatientsChange in HBV DNA during TDF therapy in HIV/HBV co-infected
HBV DNA (median; SD) (log10 copies/mL)
P
N
Median (range) of follow-up (months)
Baseline
End of follow up
Change from baseline
- Total
- HBeAg+
- HBeAg-
88
66
19
8.8 (1.0 – 21.0)
8.0 (1.0 – 21.0)
6.0 (1.0 – 17.0)
8.02 (1.97)
8.17 (1.55)
4.84 (2.15)
2.95 (1.54)
3.05 (1.67)
2.30 (2.15)
-3.82 (2.04)
-3.68 (2.00)
-2.54 (1.82)
< 0.001
< 0.001
< 0.001
Benhamou et al. For the TECOVIR Study Group. AASLD 2003
76% of the patients were receiving LAM at TDF initiation (presumed
LAM-R)
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P-68
TDFTDF in HIV/HBVin HIV/HBV ccoo--iinfectednfected ppatientsatients
Time to DNA negativation (<2.3 copies/mL)
Benhamou et al. For the TECOVIR Study Group. AASLD 2003
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P-69
TDFTDF in HIV/HBVin HIV/HBV ccoo--iinfectednfected ppatientsatients
26.1
57.9
8.24.8
0
10
20
30
40
50
60
70
Patients with HBeAg+ at baseline (n=65) Patients with HBeAg- at baseline (n=19)
Prop
ortio
n of
pat
ient
s (%
)
HBV DNA negativation (<2.3 log10 copies/mL)
HBeAg negativation
HBeAg serconversion
Benhamou et al. For the TECOVIR Study Group. AASLD 2003
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P-70
Treatment of HBV in HIV co-infected patients
• Interferon
• Lamivudine
• Adefovir dipivoxil
• Tenofovir fumarate disoproxil
• FTC (Emtricitabina)
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P-71
FTCFTC in HIV/HBVin HIV/HBV ccoo--iinfectednfected ppatientsatients
-4
-3
-2
-1
0
0 12 24 36 48
FTC HBV+HIV d4T HBV+HIV FTC in Chronic HBV (FTCB-102)
Log 1
0H
BV
DN
A
24 22 20 20 1733 33 33 33 3310 10 10 7 7
FTC HBV+HIVFTC HBVd4T HBV+HIV
Median HBV DNA change from baseline
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P-72
FTCFTC in HIV/HBVin HIV/HBV ccoo--iinfectednfected ppatientsatients
Resistance mutations in non HIV/HBV infected patientsResistance mutations in non HIV/HBV infected patients
1612
9
19
0
10
20
30
40
50
25 mg 100 mg 200 mg 200 mg
% 4848 WeeksWeeks 9696 WeeksWeeks
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P-73
Cross Resistance Cross Resistance in vivoin vivo
M204VM204V
V173LV173L
A181VA181V
M250VM250V
L180ML180M
A184GA184G
S202IS202I
N236TN236T
M204IM204I
LAMLAM
ETVETV
LdTLdT
FTCFTC
ADV/ ADV/ TDFTDF
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P-74
Treatment of Treatment of CCHB in HIV coHB in HIV co--infected patientsinfected patients
If ARV is indicated for HIVIf ARV is indicated for HIVHBV treatment has to be considered : TDF HBV treatment has to be considered : TDF –– FTC FTC –– LAM in LAM in ARV regimentARV regimentLAMLAM--R R patients : patients :
•• TDF or ADVTDF or ADV
If ARV is not indicated for HIVIf ARV is not indicated for HIVADVADV
PerspectivesPerspectives:: combinationscombinationsNRTsNRTs : Nucleotides (TDF : Nucleotides (TDF –– ADV) + Nucleosides (FTC ADV) + Nucleosides (FTC –– LAM)LAM)NRTIsNRTIs/PEG IFN/PEG IFN??
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P-75
HAART Related HAART Related HepatotoxicityHepatotoxicity in HIV/HBV Coin HIV/HBV Co--infected Patientsinfected Patients
No.No. HAARTHAART HCV/HBVHCV/HBV IncidenceIncidence PredictorsPredictors
Sulkowski Sulkowski M.M. 211211 PIPI 51%51% 11%11% HCV, HCV, HBVHBV,, ↑↑CD4, CD4, RTVRTV
SavesSaves M.M. 748748 PIPI 41%41% 9%9% HCV, HCV, HBVHBV previous previous cytolysiscytolysis
NunezNunez M.M. 222222 PI, PI, NNRTINNRTI 40%40% 9%9% HCV, age, HCV, age, alcoholalcohol
Sulkowski Sulkowski M.M. 8787 2 NRTI2 NRTI 61%61% 6%6% HCV, HCV, HBVHBV, , ↑↑ CD4CD4
Saves Saves M.M. 12491249 2 NRTI2 NRTI 44%44% 6%6% HCV, HCV, HBVHBV previous previous cytolysiscytolysis
Sulkowski M et al. JAMA 283:74-80. Saves M et al. AIDS 1999;13:F115-F121.
Nunez M et al. JAIDS 2001;27:426-31.
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P-76
Tomba del tuffatoreTomba del tuffatore