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Bica et al. Clin Infect Dis 2001;32:492497
Puoti et al. JAIDS 2000;24:211217
Soriano et al. Eur J Epidemiol 1999;15:14
Soriano et al. PRN Notebook 2002;7:1015
Martin-Carbonero et al. AIDS Res Human Retrovirus 2001;17:14671471
Hepatitis in HIV (+) Patients
Hepatitis C Virus
Hepatitis B Virus
Hepatitis in HIV (+) Patients
Hepatitis C Virus
Hepatitis B Virus
HIVHCV co-infection
Prevalence
30% of patients with HIV infection are co-infected with HCV
among HIV-infected intravenous drug users, this figure rises to
5090%
HIV accelerates the clinical course of HCV-related liver
disease
time to cirrhosis is dramatically reduced
liver disease is now the leading cause of death among
hospitalised AIDS patients
HCV co-infection:
increases the risk of antiretroviral drugrelated hepatotoxicity
reduces the CD4 response to antiretroviral therapy
Sherman et al. Antiviral Ther 2000; 5 (Suppl. 1):6465
Lauer & Walker. N Engl J Med 2001; 345:4145
Soriano et al. XIII International AIDS Conference, 2000; Abstract ThOrB655
Braitstein et al. 2nd IAS Conference on HIV Pathogenesis and Treatment, 2003; Abstract 214
HIVHCV co-infection
25 23.2
16 14.9%
14 20
Time (years)
P < 0.001
Frequency (%)
12 P < 0.01
10 15
8
10 6.9
6
4 2.6% 5
2
0 0
HIV HIV + HIV HIV +
n= 431 116 n= 431 116
amphetamin (4,7 %)
barbiturat 1 (0,5 %)
Usage of substance : injection 167 (83,1 %)
non-injection 34 (16,9 %)
Mean Age (year) : 21,42 + 4,3
Mean Narcotics Usage (months) : 28,3 + 19
Mean age of begin (year) : 19
7.5%
15% 3a
2b
1a
2a
1b 57.5%
10%
10%
n = 40
Gani RA, Med J Indonesia 2000
Multivariate Analysis
Risk Factors :
Sexual relationship
Anti-HCV positivity :
Tattoo Tattoo (OR 1,39 (95%
Piercing CI 1,24 - 1,56)
Blood Transfusion Needle Sharing (5,47
Surgery (95% CI 2,38 - 12,6)
Family History
History of Hepatitis
Needle Sharing
40 44
35
36
30
31 32
25 29
28
20
1 2 3
15
10
5
8.8% 11.8% 13.8%
0
01 02 0
3 4 5 6 Anti-HIV +
Maret April Mei Juni Juli Agustus
77.9 %
HIV
60
(19,1 %)
253
(80,8 %)
HCV-HIV
253
(80,8 %)
HCV-HIV
140
120
100
80
60
68.8
40 44.4
20
HCV-HIV HIV
Data POKDISUS AIDS RSUPN-CM, 2004
Perbandingan Klinis HIV dengan HCV-HIV
Proporsi Hepatotoksisitas ART (n = 162)
100%
80%
60%
40%
50.0
20% 40.2
33.3
7.7
0%
HIV HBV-HIV HCV-HIV HBV-HCV-HIV
Data POKDISUS AIDS RSUPN-CM, 2004
Perbandingan Klinis HIV dengan HCV-HIV
Sreening : Anti-HCV
HCV-RNA and Genotype
Liver function study : Serum Albumin, Total
Bilirubin, Protrombin time
Hepatocellular Necrosis : ALT and AST
Begin : CD4 >200 /uL
Perbandingan Terapi HCV-HIV
Study N Treatment Schedule Discontinue End-of- Sustained
treatment treatment virological
due to AE response response
Perez 68 Peg-IFn2b 15 % 40 % 28 %
Olmeda et 1.5g/kg/wk + ribavirin
al (2003) 800 mg/d 48 wk (genos
1 & 4) & 24 wk genos
2,3)
Voight et 72 Peg-IFn2b 17 % 46 % 26 %
al (2003) 1.5g/kg/wk + ribavirin
800 mg/d 48 wk (genos
1 & 4) & 24 wk genos
2,3)
Ballesteros 28 Peg-IFn2b 29 % 25 % 29 %
et al 1.5g/kg/wk + ribavirin
(2004) 800 mg/d 48 wk (genos
1 & 4) & 24 wk genos
2,3)
Moreno et
35 Peg-IFn2b 17 % 40 % 31 %
al (2004)
1.5g/kg/wk + ribavirin
800 mg/d 48 wk (genos
1 & 4) & 24 wk genos
2,3)
50%
40% 38%
% Response
29%
30%
21%
20%
14%
10% 8% 7%
0%
IFN alfa-2a + RBV PEG-IFN alfa-2a PEG-IFN alfa-2a
(40 kDa) + Placebo (40 kDa) + RBV
* Defined as <50 IU/mL HCV RNA
Virologic Response* End of Treatment
vs End of Follow-up (Genotype 2 and 3)
50%
% Response
40% 36%
30% 27%
20%
20%
10%
0%
IFN alfa-2a + RBV PEG-IFN alfa-2a PEG-IFN alfa-2a
(40 kDa) + Placebo (40 kDa) + RBV
* Defined as <50 IU/mL HCV RNA
Hepatitis in HIV (+) Patients
Hepatitis C Virus
Hepatitis B Virus
Effects of HIV on the Natural History of
Chronic Hepatitis B
Lower rate of HBeAg seroconversion following acute
HBV infection
Higher levels of HBV DNA
Higher incidence of cirrhosis and
liver-related mortality
Higher risk of reactivation
Occult hepatitis B reported
HIV Infection Increases the Risk of Chronic
HBV After Acute Infection
Progression to Chronic HBV
*5-year estimate
SC = seroconversion; RR = relative risk
HIV+ HIV-
(n = 61) (n = 43) P-value
HBeAg positive 79% 54% .01
Mean serum
HBV DNA 2380 1470 1610 1170 .06
(pg/mL)
HIV- HIV+
(n = 67) (n = 65) P-value
60
50
40 P = .005
30
20
10
0
0 1 2 3 4 5 6 7 8 9 10
Years
Adapted from Di Martino V, et al. Gastroenterology. 2002;123:1812. Copyright 2002 American
Gastroenterological Association. Reprinted with permission.
HIV/HBV Coinfection
Multicenter Cohort Study (MACS)
5293 men, who had been tested for HIV
and HBV, between 1984 and 1991
HBsAg prevalence higher in HIV+
compared with HIV-
HIV+, 8.3% of 2559 patients
HIV-, 4.3% of 3232 patients
30
HIV alone
25
Liver-Related
20
P <.0001
15 14.2
10
P <.0001
5 P = .04
1.7 0.75 0.00
0
HIV+/HBV+ HIV+/HBV- HIV-/HBV+ HIV-/HBV-
30
infected with HBV alone
25
Liver-Related
20
P <.0001
15 14.2
10
P <.0001
5 P = .04
1.7
0.75 0.00
0
HIV+/HBV+ HIV+/HBV- HIV-/HBV+ HIV-/HBV-
1. Lazizi Y, et al. J Infect Dis. 1988;158:666. 2. Vento S, et al. Lancet. 1989;2:108. 3. Biggar RJ, et al.
N Engl J Med. 1987;316:630. 4. Rehermann B, et al. Nat Med. 1996;2:1104. 5. Wagner AA, et al. AIDS.
2004;18:569.
Effects of HIV on the Natural History of
Chronic Hepatitis B
78%
HBcAb and/or HBsAb+ HBcAb and HBsAb-
60
52%
50
40%
LAM 150 mg BID
Patients (%)
40
(n = 97)
30 P = .018 Placebo (n = 25)
22%
19%
20
10%
10
0%
0
HBV DNA <400 HBeAg ALT
copies/mL Loss Normalization
Time in Weeks
0 4 8 12 20 28 36 44 52
Median Change in Log HBV DNA
0
-0.5 -0.0 log10 copies/mL
-1
(P < .001)
-1.5
-2
-2.7 log10 copies/mL
-2.5
-3 LAM 150 mg BID (n = 97)
-3.5 Placebo (n = 25)
Reprinted with permission, from Dore GJ, et al. J Infect Dis. 1999;180:607. Copyright The University
of Chicago Press.
Lamivudine in HBV Monoinfection
Incidence of YMDD Mutants Over TimeIntegrated Phase 3 Data
100
80 70%
60 53%
42%
40
24%
20
n = 426 n = 74 n = 58 n = 58
0
Year 1 Year 2 Year 3 Year 4
1. Wolters LM, et al. J Clin Virol. 2002;24:173. 2. Yuen M-F, et al. Hepatology. 2001;34:785. 3. Buti M,
et al. J Infect Dis. 2001;183:1277. 4. Liaw Y-F, et al. Gastroenterology. 2000;119:172. 5. Liaw YF, et al.
Hepatology. 1999;30:567. 6. Hadziyannis SJ, et al. Hepatology. 2000;32:847. 7. De Man RA, et al. J
Hepatol. 1998;29:669.
Lamivudine in HBeAg+/- CHB
Study Design
Prospective, double-blind trial
HBeAg- and HBeAg+ patients; All HIV negative
Up to 5 years of therapy
25 Placebo (n = 215)
YMDDm (n = 209)
% Patients with Disease
15
13%
YMDDm
10
5%
5
Wild Type
0
0 6 12 18 24 30 36
Time After Randomization (months)
CHB = chronic hepatitis B
Liaw YF, et al. N Engl J Med. 2004;351:1567.
Lamivudine in HBeAg+/ CHB
Progression to HCC
Diagnosis of HCC (%)
P = .047
10
7.4%
Placebo
5 3.9%
Lamivudine
0
0 6 12 18 24 30 36
Months
70
60
% HBV DNA 4700
copies/mL (LOD)
50
40
30 FTC HBV + HIV (W48 = 59%)
20 FTC in Chronic HBV (W48 = 55%)
10
0
0 12 24 36 48
Week
HIV/HBV n = 24 22 20 20 17
HBV n = 33 33 32 31 32
-2.0 Week 48
-4.68 log10
-3.0 copies/m Week 96
L -5.24 log10
Week 144
P < .0001 copies/m
-4.0 -5.90 log10
L
copies/mL
P < .0001
-5.0 P < .0001
-6.0
-7.0
0 12 24 36 48 60 72 84 96 108 120 132 144
n= 35 35 31 25 31 30 31 30 30 24 28 28 28
Weeks on ADV
Benhamou Y, et al. 11th CROI; Feb. 8-11, 2004. Abstract 835.
Reprinted with permission from Gilead Sciences Inc.
Adefovir for Lamivudine-Resistant HBV in HIV-Infected
Patients
Median Change in Serum ALT
120
100 Week 48
53 IU/L
P < .001
Serum ALT (IU/L)
Week 96
80 46 IU/L
P < .001
60 Week 144
31 IU/L
P < .001
40 ULN
20
0 4 8 12 16 20 24 28 32 36 40 44 48 60 72 84 96 108 120 132 144
n= 2
3 3 34 3 3 3 3 3 2 3 3 3 3 3 3 3 2 2 2 2
5 5 2 1 2 3 1 8 0 1 1 1 1 1 7 0 6 9 9 8
Weeks on ADV
Benhamou Y, et al. 11th CROI; Feb. 8-11, 2004. Abstract 835.
Reprinted with permission from Gilead Sciences Inc.
Analysis of Adefovir (ADV) Resistance
in Chronic HBV
Pooled data from 5 studies 2 resistance mutations
Development of resistance N236T
22 patients over 4 years Lamivudine (LAM) susceptibility 2-
Only with ADV monotherapy fold in vitro
Higher HBV DNA predictive of
ADV resistance
Undetectable HBV DNA in 5 of 8
patients adding/switching to LAM
within 1 year
Week 48 HBV DNA Week 144 A181V
(log10 copies/mL) ADV Resistance, % LAM susceptibility 14-fold
<3 4 in vitro
36 26
>6 67
23 log10 HBV DNA reduction after
>6 months of LAM + ADV
10
Adefovir
HBV DNA (log10)
Tenofovir
8
0
0 20 40 48 60 80 90
Weeks
80 69 80 73
60 60
38
40 40
20 20
P < .0001 P < .0001
0 0
0 12 24 36 48 0 12 24 36 48
Weeks
ETV = entecavir; LAM = lamivudine.
1. Chang TT, et al. Hepatology. 2004;40:193A. 2. Shouval D, et al. Hepatology. 2004;40:728A.
Entecavir in Lamivudine-Refractory
HBeAg+ Chronic HBV Monoinfection
HBV DNA <400 c/mL Through Week 48
40
ETV (n = 141)
LAM (n = 145)
Patients Achieving
30
Response (%)
21
20
10 P < .0001
1
0
B/L 12 24 36 48
Weeks
ETV = entecavir; LAM = lamivudine
Sherman M, et al. Hepatology. 2004;40:664A.
Entecavir in Chronic HBV Monoinfection
HBV DNA Mean Reduction at Week 48
Lamivudine-Refractory
Naive HBeAg+ Naive HBeAg- HBeAg+
0
-0.48
-1
-2
log10 copies/mL
-3
-4
P < .0001
-4.5
-5
-5.0 P < .0001 -5.1
-5.4
-6
P < .0001 Entecavir
-7 Lamivudine
-6.9
-8
Baraclude (entecavir). Product Information. Princeton, NJ: Bristol-Myers Squibb Company; 2005.
Entecavir in HBeAg+ Chronic HBV Monoinfection
Hbe Seroconversion at Week 48
25
Patients Achieving Response (%)
21 P = .33
20
18 Entecavir
Lamivudine
15
10
8
P = .06
5
3
0
Naive HBeAg+ Lamivudine-Refractory
HBeAg+
Baraclude (entecavir). Product Information. Princeton, NJ: Bristol-Myers Squibb Company; 2005.
Studies 022 and 026
Entecavir in HBeAg+ Chronic HBV Monoinfection
Summary of Week 48 Efficacy
Entecavir minus Lamivudine: Difference Estimate and CI
HBe
Seroconversion
-20 -10 0 10 20 30 40 50 60
LVD Better ETV Better
1
+0.11 log10 Placebo
0 Entecavir
-1
*P <.0001
for each comparison
-2 * on-treatment
-3 -3.66 log10
*
-4 *
-5 Weeks
0 2 12 24
Entecavir n = 51 49 46 48
Placebo n = 17 16 16 16
Reprinted with permission, from Colonno RJ, et al. J Hepatology. 2005;42(suppl 2):173.
Copyright 2005 EASL.
Entecavir Efficacy and Resistance in
Lamivudine Refractory CHB Monoinfection at Year 2
Pooled data of studies comparing entecavir Study 014 and 026
and lamivudine Percent of Subjects *
Study 014, phase 2 1011
Reprinted with permission, from Colonno RJ, et al. J Hepatology. 2005;42(suppl 2):173.
Copyright 2005 EASL.
Combination Therapy
Adefovir dipivoxil 10 mg QD
(n = 28)
HBeAg- patients with 24 weeks
lamivudine follow-up
resistance Adefovir dipivoxil 10 mg QD
+ lamivudine 100 mg QD
(N = 50)
(n = 22)
Week 24 Week 48
Baseline (log10 copies/mL)
-1
Adefovir
Adefovir + Lamivudine
-2 -1.85
-2.31
-2.44
-3 -2.80
Interim Analysis
Week 48 Week 144
Tenofovir +
Lamivudine Lamivudine
Week 48 n=5 n=6
In HIV+/HBV+ men,
higher liver-related mortality was observed for each
risk factor, alcohol 210 g/wk and CD4 cell count
<100 cells/L, but none was significantly associated
with liver death