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Ko-infeksi Hepatitis C dan HIV

Menjadi Tantangan Epidemi


yang Akan Datang
Bagaimana Pencegahan dan
Penanggulangannya
Rino A Gani*, Evy Yunihastuti**, Sjamsuridjal Djauzi**

*Divisi Hepatologi Departemen Ilmu Penyakit Dalam


FKUI/RSUPN Cipto Mangunkusumo, Jakarta
**POKDISUS AIDS RSUPN Cipto Mangunkusumo, Jakarta
Liver disease has become a major cause of
death in the era of potent antiretroviral therapy

Mortality from end-stage liver disease as a


percentage of all deaths among HIV patients
60
Pre-therapy era 50%
50 45%
Therapy era
Mortality (%)

40 35%
30

20
13% 12%
10 5%
0
Italy (Brescia) Spain (Madrid) USA (Boston)
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

HCV viral load higher in HIVHCV co-infection versus


HCV only
Greater risk of sexual HCV transmission in HIVHCV
co-infection versus HCV only
HIV has helper role
Effect of HIV on progression to cirrhosis
in HCV-infected people
Ten-year incidence Mean time to cirrhosis
of cirrhosis (%) (years)

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

Soto et al. J Hepatol 1997;26:15


Subject Characteristics
Sex : Male 181 (90,6 %)
Female 19 (9,4 %)
Adictive Substance : heroin 190 (94,8 %)

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

Gani RA, Med J Indonesia 2000


Risk Factors of Hepatitis Transmission in Drug
Addicts
Yes
n %
Sex 77 38,3
Tattoo 40 19,8
Body Piercing 77 38,3
Surgery 22 11,1
Blood Transfusion 4 1,9
History of Hepatitis 21 10,5
Family History 14 6,8

Gani RA, Med J Indonesia 2000


Jakarta :
I.V drug users 80.1 % Anti HCV +
8.8 % HBsAg +
Gani RA, et al. Med J Indonesia; 2002
Genotype of Hepatitis C in IDU

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

Gani RA, Med J Indonesia 2000


HCV HIV Co-infection in IDU
Person
45

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

Gani RA, Med J Indonesia 2000


Proportion of Hepatitis Among HIV Patients
n = 68
10,6 % Occult HBsAg +ve
Hepatitis B
Anti-HCV +-ve
HBsAg and Anti-HCV +-ve
7.3 % 2.9 %
All - ve
11.7 %

77.9 %

Indah G, Cipto Mangunkusumo Hospital, 2008


Joice B, Cipto Mengunkusumo Hospital 2009
Proporsi HIV : HCV-HIV
(n = 313)

HIV
60
(19,1 %)

253
(80,8 %)

HCV-HIV

Data POKDISUS AIDS RSUPN-CM, 2004


Perbandingan Klinis HIV dengan HCV-HIV
Proporsi HIV vs HCV-HIV (n = 313)
518 pasien HIV +
313 pasien diperiksa Anti-HCV
HIV
60
(19,1 %)

253
(80,8 %)

HCV-HIV

Data POKDISUS AIDS RSUPN-CM, 2004


Perbandingan Klinis HIV dengan HCV-HIV
Perbandingan ALT (n = 313)
U/L 200
180
p < 0.004
160

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

Prevelensi ko-infeksi HCV-HIV tinggi di kalangan


pasien HIV positif
Terdapat perbedaan klinis antara pasien HIV
dengan ko-infeksi HCV-HIV :
Kerusakan hati lebih tinggi pada pasien ko-infeksi HCV-
HIV
Beratnya penyakit HIV lebih besar pada ko-infeksi
HCV-HIV
Hepatotoksisitas ART lebih banyak terjadi pada ko-
infeksi HCV-HIV
Diagnosis HCV in HCV-HIV Co-Infection

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)

Chung et 66 Peg-IFn2a 180g/wk 12 % 41 % 27 %


al (2004) + ribavirin 600 mg/d (geno 1: 29%) (geno 1: 14%)
(incr. to 1 gr/d at wk (geno 3: 80%) (geno 3:73%)
12)
48 wk (all genos)
Perronne 205 Peg-IFn2b 38 % 36 % 27 %
et al 1.5g/kg/wk + ribavirin (geno 1-4:29%)
(2004) 800 mg/d 48 wk (all (geno 2-3:62%)
genos)
Torriani et 289 Peg-IFn2a 180g/wk 12 % 49 % 40%
al (2004) + ribavirin 600 mg/d (geno 1:38%) (geno 1:29%)
48 wk (all genos) (geno 2-3:64%) (geno 2-3:62%)
Virologic Response* End of Treatment
vs End of Follow-up (Genotype 1)

End of treatment End of follow-up


60%

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)

End of treatment End of follow-up


70%
64% 62%
60% 57%

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

HIV negative HIV positive

Hadler et al1 9/134 (7%) 3/14 (21%)


N = 148

Bodsworth et al2 2/46 (4%) 7/31 (23%)


N = 77

1. Hadler SC, et al. J Infect Dis. 1991;163:454.


2. Bodsworth NJ, et al. J Infect Dis. 1991;163:1138.
HIV Infection Lowers the Rate of HBeAg
Seroconversion

Follow-up, Mean HBeAg SC HBeAg SC


(years) HIV- HIV+ RR
Krogsgaard1 3.1 11% 4%
N = 33
Gilson2 2.8 49%* 12%* 0.4
n = 124

*5-year estimate
SC = seroconversion; RR = relative risk

1. Krogsgaard K, et al. Hepatology. 1987;7:37. 2. Gilson RJ, et al. AIDS. 1997;11:597.


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
Level of HBV Replication

HIV+ HIV-
(n = 61) (n = 43) P-value
HBeAg positive 79% 54% .01
Mean serum
HBV DNA 2380 1470 1610 1170 .06
(pg/mL)

Gilson RJ, et al. AIDS. 1997;11:597.


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 Increases Cirrhosis But Not ALT Levels
in Patients with Chronic HBV

HIV- HIV+
(n = 67) (n = 65) P-value

ALT (IU/L) 188 127 103 76 .04

Cirrhosis 13% 28% .0001

Colin JF, et al. Hepatology. 1999;29:1306.


Progression to Cirrhosis Is More Rapid in
HIV/HBV-Coinfected Patients
100
90
HIV -
80
70 HIV+ (CD4 <200/mm3)
% Cirrhosis

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

Thio CL, et al. Lancet. 2002;360:1921.


Multicenter Cohort Study (MACS)
Liver-Related Mortality
Coinfected men were >8 times more likely to
die from liver disease than those infected with
Mortality Rate/1000 Person Years

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-

*All P-values are in relation to HIV-/HBV-


Thio CL, et al. Lancet. 2002;360:1921.
Multicenter Cohort Study (MACS)
Liver-Related Mortality
Coinfected men were nearly 19 times more
likely to die from liver disease than those
Mortality Rate/1000 Person Years

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-

*All P-values are in relation to HIV-/HBV-


Thio CL, et al. Lancet. 2002;360:1921.
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
Reactivation of HBV in
HIV-Infected Patients
Reported in patients who were HBsAg-/anti-HBs+1,2
Mechanisms include
Accelerated loss of anti-HBs3
Low-level replication despite anti-HBs4
Reinfection in setting of immunosuppression
Emergence from latent reservoir in immunosuppression
Development of HBsAg escape mutants not shown5

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

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
Occult Hepatitis B

Defined as HBV DNA without HBsAg


Clinical significance unknown
Deletions in pre-S2/S regions1
Serologic patterns varied2
22%

78%
HBcAb and/or HBsAb+ HBcAb and HBsAb-

1. Chaudhuri V, et al. Gastroenterology. 2004;127:1356.


2. Torbenson M, et al. Lancet Infect Dis. 2002;2:479.
Conclusion: 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
Treatment Option in HBV-HCV Co-infection

Lamivudine (along with anti-retroviral therapy)


Adevovir 10 mg
Entecavir not recommended
Telbivudine 600 mg
Tenofovir
Lamivudine

InhibitsHBV DNA synthesis and HIV reverse


transcriptase
Dose for HIV-positive patients: 300 mg QD
Do not use without other anti-HIV drugs
HBV and HIV resistance mutations
Duration

HBeAg+: indefinite or 6 months after


anti-HBe
HBeAg-: prolonged
Lamivudine Treatment of CHB
in 122 HIV/HBV-Coinfected Patients
AZT-containing ART +/- Lamivudine at Week 52

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

CHB = chronic hepatitis B; ART = antiretroviral therapy; LAM = lamivudine.


Dore GJ, et al. J Infect Dis. 1999;180:607.
Lamivudine (LAM) Treatment of CHB
in 122 HIV/HBV-Coinfected Patients
LAM/LAM + Loviride vs Placebo Added to AZT-Containing ART at Week 52

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

Lai C-L, et al. Clin Infect Dis. 2003;36:687.


Predictors of
Lamivudine-Resistant HBV
Associated factors
High body mass index (BMI)1
CD4 decline1
Higher pretreatment HBV DNA, ALT2
>1000 copies/mL HBV DNA 33 and 62 months after treatment
Indicators of emergence
HBV DNA increase 0.5 log
Increasing ALT4
Clinical deterioration/hepatitis flares5-7

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

651 patients randomized 2:1


HBV DNA+; HBsAg+ >6 months
Ishak fibrosis score 4

Up to 5 years of therapy

Placebo QD Lamivudine 100 mg QD


(n = 215) (n = 436)
Study terminated early
Average exposure 32.4 months

CHB = chronic hepatitis B


Liaw YF, et al. N Engl J Med. 2004;351:1567.
Lamivudine in HBeAg+/ CHB
Time to Disease Progression by YMDD Status

25 Placebo (n = 215)
YMDDm (n = 209)
% Patients with Disease

Wild Type (n = 221) 21%


20
Placebo
Progression

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

CHB = chronic hepatitis B; HCC = hepatocellular carcinoma


Reprinted with permission, from Liaw YF, et al. N Engl J Med. 2004;351:1521.
Copyright 2004 Massachusetts Medical Society. All rights reserved.
Emtricitabine

Active against HIV and HBV


Dose: 200 mg QD
Not effective in lamivudine-resistant HBV
Do not use without full anti-HIV treatment
Duration
HBeAg+: indefinite or 6 months after
anti-HBe
HBeAg-: prolonged
Emtricitabine in HIV/HBV Coinfection
Proportion of Patients with HBV DNA 4700 copies/mL

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

Harris J, et al. 11th CROI. February 8-11, 2004. Abstract 836.


Reprinted with permission from Gilead Sciences Inc.
Adefovir Dipivoxil

Nucleotide analog of adenosine monophosphate


Dose: 10 mg QD
Not active against HIV at this dose
Useful if only HBV treatment needed
Theoretic potential to produce HIV resistance
to tenofovir
HBV resistance: 8% at 3 years1
Duration: same as lamivudine
1. Hadziyannis S, et al. N Engl J Med. 2003;348:800.
Adefovir for Lamivudine-Resistant HBV in HIV-Infected
Patients
Median Change in HBV DNA
- 0.0
HBV DNA (log1 0copies/mL)

-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

Locarnini S, et al. 40th EASL. April 13-17, 2005. Abstract 36.


Adefovir Monotherapy and Risk of Selection
of HIV-Resistant Strains

Adefovir at higher doses selects for reverse transcriptase


mutations similar to tenofovir
Lysine 65 to arginine (K65R)
Lysine 70 to glutamic acid (K70E)
Data on adefovir at HBV dose (10 mg QD)
are scarce
Gelinck et al1 raise concerns for the use of adefovir
monotherapy for HBV in persons with uncontrolled
HIV replication

1. Gelinck LB, et al. J Hepatol. 2005;43:360.


Tenofovir DF

Acyclic nucleotide analog


Competitive inhibitor of HIV-1 reverse transcriptase
Chain terminator of HBV DNA
HIV dose 300 mg QD
Do not use without other anti-HIV treatment
Unknown HBV resistance rate
Increases didanosine levels
Duration
HBeAg+: indefinite or 6 months after anti-HBe
HBeAg-: prolonged
Tenofovir in HIV/HBV Coinfection
Observational Cohort
Median HBV DNA Change in
N = 107
Patients with Detectable
96% patients receiving lamivudine at start of HBV DNA at Baseline

Median HBV DNA (log10 copies/mL)


tenofovir 9
At baseline, 84% patients had detectable HBV 8
n = 90
DNA 7 8.0
Median follow-up period 10 months 6
P < .0001
Median change from baseline 5
of serum HBV DNA was 4
-3.8 log10 copies/mL 3
4.2
After median period of 2
10 months, 34% of patients
1
had undetectable HBV DNA
0
Baseline End of
Follow-Up

Trimoulet P, et al. 43rd ICAAC. September 13-17, 2003. Abstract V-783.


Tenofovir vs Adefovir for HIV/HBV-Coinfected Patients
on Stable ART
AACTG 5127 Study Design

Tenofovir 300 mg QD 96 weeks


Adefovir placebo
N = 52
Stratified by
HIV/HBV coinfection Compensated and decompensated
+/-lamivudine-resistant HBV liver function (CPT Score or <7)
HBV DNA 100,000
copies/mL CD4 count or <200 cells/mm3
HIV-1 RNA 1000 copies/mL
Randomized 1:1
Adefovir 10 mg QD

Tenofovir placebo 96 weeks


ART = antiretroviral therapy
Peters M, et al. 12th CROI. February 22-25, 2005. Abstract 124.
Tenofovir vs Adefovir for HIV/HBV-Coinfected Patients
on Stable ART
Serum HBV DNA DAVG48 (log10 copies/mL)*

(n) ADV TDF Diff Lower CI

ITT1 52 -3.12 -4.03 0.91 -0.498


Modified ITT2 47 -3.35 -4.46 1.11 -0.090
As treated3 41 -3.48 -4.76 1.28 0.180

*Roche Cobas Amplicor, LLQ 200 copies/mL


ART = antiretroviral therapy; ITT = intent-to-treat; ADV = adefovir; TDF = tenofovir;
DAVG48 = mean log10 time-weighted average HBV DNA change from baseline to week 48

1 ITT includes DAVG48 for all 52 subjects


2 Modified ITT includes all subjects with 2 postbaseline tests
3 As treated: includes as above with at least 36 weeks follow-up

Peters M, et al. 12th CROI. February 22-25, 2005. Abstract 124.


Similar anti-HBV Activity of Tenofovir and Adefovir
in HIV/HBV-Coinfected Patients

10
Adefovir
HBV DNA (log10)

Tenofovir
8

0
0 20 40 48 60 80 90
Weeks

Peters M, et al. 12th CROI. February 22-25, 2005. Abstract 124.


Entecavir

Cyclopentyl guanosine analog


Potent selective inhibitor of HBV replication
No significant activity against HIV
Poor substrate for human polymerases
No inhibition of human mitochondrial (gamma) polymerase
Inhibits all 3 HBV polymerase functions: priming, DNA-dependent
synthesis, reverse transcription
Phosphorylation: intracellular ETV-TP T1/2~15 hr
Entecavir (ETV) in Chronic HBV Monoinfection
Phase 3 Study Design

ETV 0.5 mg (n = 354) Responders


Naive HBeAg+
(ETV 022)1 Lamivudine (LAM)
100 mg (n = 355)

Naive HBeAg- ETV 0.5 mg (n = 325)


Partial
(ETV 027)2 LAM 100 mg (n = 313) responders

ETV 1.0 mg (n = 141)


Lamivudine-refractory
HBeAg+ (ETV 026)3 LAM 100 mg (n = 145) Nonresponders

Baseline Week 48 Week 52


(Liver Biopsy) (Liver Biopsy) (Patient Management Decision)

1. Chang TT, et al. Hepatology. 2004;40:193A. 2. Shouval D, et al. Hepatology. 2004;40:728A.


3. Sherman M, et al. Hepatology. 2004;40:664A.
Entecavir in Naive Chronic HBV Monoinfection
HBV DNA <400 c/mL Through Week 48

Naive HBeAg+1 Naive HBeAg-2


Patients Achieving Response (%)

ETV (n = 354) ETV (n = 325)


100 LAM (n = 355) 100 LAM (n = 313) 91

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

Histologic Naive HBeAg+1


Improvement Naive HBeAg-2
Lamivudine-
HBV DNA < 400 Refractory
copies/mL HBeAg+3
ALT 1 ULN

HBe
Seroconversion

-20 -10 0 10 20 30 40 50 60
LVD Better ETV Better

1. Chang TT, et al. Hepatology. 2004;40:193A. 2. Shouval D, et al. Hepatology. 2004;40:728A.


3. Sherman M, et al. Hepatology. 2004;40:664A.
Entecavir in HBV/HBV Coinfection
Phase 2 Study Design (ETV 038)

Entecavir (1.0 mg QD) + continued


lamivudine (150 mg BID or 300 mg Open-Label
QD) (n = 51) Entecavir (1.0 mg QD)
Double-blind

Placebo (QD) + continued


lamivudine (150 mg BID or 300 mg
QD) (n = 17)

Screening Week 2 Week 12 Week 24 Week 48*


HBV DNA levels HBV DNA HBV DNA levels HBV DNA levels
by PCR assay levels by PCR by PCR assay by PCR assay
assay
Randomization

*Open label rollover protocol for eligible participants


Pessoa W, et al. 12th CROI. February 22-25, 2005. Abstract 123.
Entecavir in HBV/HBV Coinfection
Mean Change in HBV DNA Through Week 24
HBV DNA by PCR (log10 copies/mL)

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

Pessoa W, et al. 12th CROI. February 22-25, 2005. Abstract 123.


Entecavir Efficacy and Resistance in
Nucleoside-Naive CHB Monoinfection at Year 2
Study 022 HBeAg+
Percent of Subjects* Study
022 027
HBeAg+ HBeAg-
HBV DNA (Copies/mL)

Y 1 Treated 354 325


1011
1010 Y 2 Treated 258 52
109
Y 1 Rebounds 6 (1.7%) 5 (1.5%)
108
107 Y 2 Rebounds 6 (2.3%) 1 (1.9%)
106
105 Genotypic Resistance Y1 & Y2 0 (0%) 0 (0%)
104
103
300999
<300 45% 69% 81% 28% 40% 49%

* Circle size corresponds to percentage of patients.


Wk 0 24 48 96 0 2448 96 Each column of circles adds up to 100%.
ETV LAM
n = 352 331 341 226 354 322 324 101

CHB = chronic hepatitis B; ETV = entecavir; LAM = lamivudine

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

HBV DNA (Copies/mL)


Study 026, phase 3 1010
109
HBV DNA <300 c/mL at year 2 with entecavir,
108
30%
107
18 entecavir patients with HBV 106
rebound at year 2 105
12 attributable to emergent 104
entecavir resistance 103
T184 or S202 300999
Entecavir resistance mutations in <300
6% 22% 30% <1% 2%
6% of lamivudine-refractory patients
at baseline Wk 0 24 48 96 0 24 48
Entecavir Lamivudine
n = 183 181 171 100 190 178 157
* Circle size corresponds to percentage of patients.
Each column of circles adds up to 100%.

Reprinted with permission, from Colonno RJ, et al. J Hepatology. 2005;42(suppl 2):173.
Copyright 2005 EASL.
Combination Therapy

May be more potent


May prevent or delay development
of drug resistance
Ideal combination needs to
be determined
Viral Replication and Mutational Frequency

High virion production


101213 virions per day
High mutational rate
Lack of proofreading capacity of HBV RT
10-5 substitution/ base/cycle
101011 point mutations produced per day
All possible single base changes can be
produced per day
Single and double mutations pre-exist in
patients
Adefovir Lamivudine for Lamivudine-Resistant
HBeAg-Negative CHB Monoinfection
Study Design

Patients on lamivudine added adefovir or switched to adefovir monotherapy

Randomization Week 0 Week 48

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)

Koskinas J, et al. 40th EASL. April 13-17, 2005. Abstract 501.


Adefovir Lamivudine for Lamivudine-Resistant
HBeAg-Negative CHB Monoinfection
HBV DNA Response
Mean Change in HBV DNA from

Week 24 Week 48
Baseline (log10 copies/mL)

-1
Adefovir

Adefovir + Lamivudine
-2 -1.85

-2.31
-2.44
-3 -2.80

P > .0001 for all


comparisons

Koskinas J, et al. 40th EASL. April 13-17, 2005. Abstract 501.


Tenofovir Lamivudine
in ART-Naive HIV/HBV Coinfection
Study Design (Study 903)

Interim Analysis
Week 48 Week 144

Tenofovir QD, Lamivudine BID


ART-naive Stavudine placebo BID, efavirenz QD
HIV/HBV-coinfected (n = 5)
patients
Lamivudine BID, Tenofovir Placebo QD
Randomized 1:1 Stavudine BID, efavirenz QD
(n = 6)

Cooper D, et al. 10th CROI. February 10-14, 2003. Abstract 825.


Tenofovir Lamivudine
in ART-Naive HIV/HBV Coinfection
Interim Results

Tenofovir +
Lamivudine Lamivudine
Week 48 n=5 n=6

Mean change HBV DNA -4.70 -2.95


(log10 copies/mL)

HBV DNA <1000 4 1


copies/mL
YMDD 0/1 4/5
Anti-HBe+ 1 1
Mean change ALT level -55 -22
(IU/L)

P > .05 for all comparisons


Cooper D, et al. 10th CROI. February 10-14, 2003. Abstract 825.
Prevention of HBV Resistance in HIV/HBV-
Coinfected Patients

Potent suppression of HBV replication


Entecavir > lamivudine, adefovir
Decreased anti-HBV activity against
lamivudine-resistant HBV
Avoid sequential monotherapy
Combination therapy may increase potency
and decrease resistance
Tenofovir + emtricitabine or lamivudine
Entecavir + tenofovir
Peginterferon
Take-Home Messages

Antiretroviral therapy (ART) indicated


Include 2 drugs active against HBV
Tenofovir, emtricitabine, lamivudine
If YMDD mutant (ie, lamivudine-resistant), consider
adding entecavir
ART not indicated
PEG IFNhigh ALT, no cirrhosis
Entecavir
0.5 mg/d, lamivudine naive
1.0 mg/d lamivudine resistant
Adefovir 10 mg/d
Durationuntil anti-HBe seroconversion
HIVHCV co-infection:
management issues

Treatment of HIVHCV co-infection is very challenging


Adherence is a major issue
Therefore, treatment needs of HIVHCV co-infected
patients differ from those of mono-infected patients
Key Exclusion Criteria

Decompensated liver disease


Other chronic liver disease
Active HIV-related opportunistic infections
Significant medical conditions
Psychiatric/neurological
Pulmonary
Cardiac
Thyroid/immunologically-mediated disease
Retinopathy

Pregnancy/male partners of pregnant women


Serum HBV DNA Levels Correlate with
CDC Stage

HBV DNA Correlated with CDC stage (N = 232)

CDC stage I II III

HBV DNA (pg/mL) 30 28 94 157 219 278

Ockenga J, et al. J Hepatol. 1997;27:18.


Multicenter Cohort Study (MACS)
Multivariate Factors, HIV+/HBV+

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

Thio CL, et al. Lancet. 2002;360:1921.