1. Hépatites Virales C et B et Infection par le
VIH

2. Causes de décès d’origine infectieuse
dans le monde (2000)
HIV – HBV – HCV : TOP 10
Maladies Décès par an
Infections respiratoires ~3,5 million
VIH ~3,0 million
Diarrhées ~2,2 million
Tuberculose ~2,0 million
Malaria ~1-3 million
Rougeole ~888,000
Hépatite B ~750,000
Pertussis ~355,000
Tétanos néonatal ~300,000
Hépatite C ~ 250,000
Source : CDC, WHO, UNICEF, UNAIDS

3. Viral hepatitis in HIV-infected
patients
HCV HBV
Prevalence 20%-35% 7%-10%
Mortality Major cause of death Higher compare to
HBV mono-infected
Progression to Accelerated ?
Cirrhosis
Hepatotoxicity Controversies ?
of anti-retroviral
therapies
Active consideration for
treatment of hepatitis

4. Hépatite Chronique C
Chez les Patients
Co-infectés par le VIH

5. Influence of HIV on HCV
• Major cause of mortality
• More severe liver lesions vs HCV
mono-infected
• Higher HCV RNA

6. No influence of HCV/HBV on response to
HAART : EuroSIDA cohort
HIV RNA <400 copies/ml 50% rise in CD4
70
70
50
50
HCV 30
30
10 10
0 3 6 9 12
Konopnicki D et al. AIDS. 2005;19:593-601.

7. Influence du VIH sur le VHC
Mortalité liée à l’atteinte hépatique
Mortalité chez les patients VIH en France
Étude du groupe GERMIVIC
100 91,6
90 84,5
80
70
60
50 48,7 47
%
40,4
40 36,7
30
20 14,3 12,6
10 8 6,9
2
6,6 8,8
1,5 1 1
0
1995 1997 2001 2003
Mortalité Globale Mortalité liée au Sida Mortalité liée au foie CHC
Caboub et al, CID 2001; Rosenthal et al, AIDS 2003.

8. Impact of HAART on liver related
mortality
1.1 Global Mortality
Global Mortality 1.1
Liver Mortality
Liver Mortality
HAART
0.9 HAART
0.9
Survival
ARV
Survival
p < 0,0001 Untreated
0.7 0.7
0.5 ARV 0.5
p < 0,018
Untreated
0.3 0.3
0 1000 2000 3000 4000 5000 6000 0 1000 2000 3000 4000 5000 6000
Days of observation Days of observation
Qurishi N et al, Lancet 2003

9. Progression to cirrhosis
influence of alcohol and immune
status
CD4 <200/µL
CD4 >200/ L
OH <50 g/j
OH<50 g/j
4 CD4<200/ L
OH>50 g/j HIV-
OH<50 g/j
Fibrosis 3
(METAVIR)
2
1
0
5 10 15 20 25 30 35 40
Estimated duration of HCV infection
Benhamou et al. Hepatology 1999;30:1054-1058

10. Timing for Anti-HCV and ARV
initiation
HIV mono-infected HIV/HCV
< 200 CD4 cells/µL ARV recommended
> 200 CD4 cells/µL and ARV possible : - ARV recommended
< 350 CD4 cells/µL - High HIV RNA and - ARV before anti-HCV
- Rapid CD4 decline
> 350 CD4 cells/µL and Monitor - Monitor HIV
< 500 CD4 cells/µL - Anti-HCV recommended
(if indicated)
CD4>350 :
• Fibrosis progression rate is reduced
• CD4 decline to « dangerous » level if anti-VHC is initiated
Alberti et al. 1st ECCC. J Hepatol. 2005 Adapted from IAS–USA panel guidelines. Yeni P. at al. JAMA, 2004

11. Treatment of chronic hepatitis C
Genotype 2/3 Genotype 1/4
HCV RNA
< 800 000 UI/mL > 800 000 UI/ml
Fibrosis: 0/1 Fibrosis: >2
TREAT
Rx differed TREAT
Alberti et al. 1st ECCC. J Hepatol. 2005

12. w
R
x
48 PEG IFN/RBV
,
/3
G
T2 Virological response
GT 1/4 GT 2/3
90%
90%
80% 80%
80% 73%
70% 68%
70% 64%62%
60%
60% 53%
50%
50%
38%
40%
GT 4 40%
29% 29% 31%
30% GT 1
21% 30%
20% 14% 15% 20%
10% 10%
0% 0%
ACTG APRICOT RIBAVIC ACTG APRICOT Laguno RIBAVIC
EOT SVR EOT SVR
RBV 800 mg 24 weeks
Torriani F et al. NEJM 2004. Carrat F et al. JAMA 2004. Laguno C ett al. AIDS 2004. Chung R. NEJM. 2004

13. PRESCO APRICOT
(overall SVR 50%) (overall SVR 40%)
72%
62%
50
Patients (%)
40
36%
30 29%
20
10
0
Geno 1 Geno 3 Geno 1 Geno 3
n=191 n=152 n=176 n=95
24, 48 or 72 weeks therapy all 48 weeks therapy
HIV-pos; weight-based RBV HIV-pos; low RBV dose
Ramos et al. J Viral Hepat (in press)

14. r
fo A
a
n
tio RN
l u CV
Impact of HCV RNA on
a
ev h H
r
ve , hi
i 1
L T
g SVR
G
HCV RNA
100
N SVR
CD4
80 GT 1 GT 2/3 < 200/µL 17 8 (47 %)
P ro p o rtio n o f p a tie n ts
61
61 63
60 < 350 /µL 72 26 (36 %)
≥ 350 /µL 216 90 (47 %)
40
18 HIV RNA
20 < 50 cp/mL 173 72 (42 %)
50-5000 cp/mL 66 23 (35 %)
0
> 5000 cp/mL 49 21 (43 %)
≤800,000 >800,000 ≤800,000 >800,000
n=46 n=130 n=28 n=67
Torriani F et al. NEJM. 2004. Cooper D. et al, XV AIDS Conference

15. APRICOT
SVR according to Rx exposure
GT1 GT2/3
50
100
39%
40
SVR rate (%)
SVR rate (%)
80 69%
29%
30 59%
60
20
40
11% 26%
10 20
n= 176 62 114 n= 111 27 84
0 0
All <80/80/80 ≥80/80/80 All <70/70/70 ≥70/70/70
patients exposure* exposure patients exposure* exposure
*Patients violated the rule if ≥1 of the three targets
were not achieved Opravil M. et al. 45th ICAAC 2005; Abstract 2038

16. APRICOT
VR n (%) PPV (%) NPV (%)
Week 4 G1 G2/3 G1 G2/3 G1 G2/3
≥1 log10 drop 119 (68) 83 (87) 39 70 93 92
≥2 log10 drop 71 (40) 76 (80) 58 74 90 84
HCV RNA -ve 22 (13) 35 (37) 82 94 79 57
Week 12
≥1 log10 drop 148 (84) 89 (94) 34 66 96 100
≥2 log10 drop 110 (63) 84 (88) 45 70 98 100
HCV RNA -ve 60 (34) 68 (72) 70 82 92 89
Torriani F, et al. 45th ICAAC 2005; Abstract 1024

17. PEG IFN2 (a:180 /b:1.5 µg) - RBV 1000 - 1200 mg

18. PEG IFN/RBV : Specific AE
• Liver decompensation : 10% of cirrhotic pts
• Pl., Bilirubin, P alc, Hb and ddI
• Compensated cirrhosis: No ddI, Monitoring +++
• Mitochondiral toxicity (1%-3%)
• ddI (d4T) (RR x23)
• No ddI – (d4T ?)
• Monitor : Amylase, lipase, lactic acid
• Anemia : Hb <8 g/dL : 3.8%
• AZT (RR x2)
• Use EPO
• Neutropenia : Neutrophils <750: 2-11%
• Use GCSF
Alberti A et al. 1st ECCC. J Hepatol. 2005 .Torriani F et al. NEJM 2004. Carrat F et al. JAMA 2004. Chung R et al. NEJM. 2004

19. CONCLUSION
• HCV coinfection: X30 in HIV vs general population
• HCV coinfection major cause of mortality and
morbidity in HIV population
• Less than 20% of the Patients have received anti-
HCV therapy in Europe
• Coinfected patients should be actively considered for
HCV therapy

20. Hépatite Chronique B
Chez les Patients
Co-infectés par le VIH

21. Prevalence of HBsAg+ in HIV Infected
Patients
• EuroSIDA Cohort (n= 9802) :
Patients screened for HBsAg: 5883 (60%)
HBsAg+: 530 (9%)
- South: 9.1%
- Central: 9.2%
- North: 9.7%
- East: 6%
Konopnicki D, et al. AIDS. 2005.

22. Influence of HIV on CHB
In the Pre HAART era, HIV in HBsAg positive patients (compared to
HBV mono-infected):
• Increased the risk of chronic infection after contamination
• Reduced the seroconversion rates to anti-HBe and anti- HBs
• Increased HBV replication
• Frequent reactivation related to CD4 decline
• Accelerated fibrosis progression
• Increased risk of liver decompensation, HCC and liver death
Bodsworth, JID 1989 ; Hadler, JID 1991 ; Krogsgaard, Hepatology 1987 ; Bodsworth, JID 1989 ; Gilson, AIDS 1997. Piroth, J
Hepatol 2002; Vogel Cancer Res 1991; Corallini Cncer Res 1993 ; Altavilla Am J Pathol 2000 ; Bodsworth, JID 1989 ; Mills,
Gastroenterol 1990 ; Goldin, J Clin Pathol 1990 ; Gilson, AIDS 1997 ; Thio, Lancet 2002 ; Di Martino, Gastroenterol 2002; Colin
Hepatol 1999; Perillo, Ann Int Med 1986 ; McDonald, J Hepatol 1987

23. Mortality
Liver-related mortality in 5293 patients (MACS), 1984 /1987–2000
Viral status
Liver-related Liver death
N HIV HBsAg mortality (n) (1000 pers/yr) P
3093 – – 0 0.0
139 – + 1 0.8 0.04
2346 + – 35 1.7 <0.0001
213 + + 26 14.2 <0.0001
5293 62 1.1
Liver related mortality
X 19 HBV/HIV vs HBV (RR:18; 73,1-766,1; P<0,001)
Thio CL, et al. Lancet. 2002;360:1921-1926.

24. Impact of HIV Infection on Progression
to HBV-Related Cirrhosis
100
90
80
% of cirrhosis
70
HIV positive
60
50
40 p=0.005
30
20
HIV negative
10
0
0 1 2 3 4 5 6 7 8 9 10
Follow-up (years)
Di Martino V et al. Gastroenterology. 2002.

25. Influence of HAART
• Increases duration of HBV
by improving survival
• Inhibition of HBV replication
• Increases the risk of ALT (LAM – FTC – ADV)
flares related to – Histological improvement
– Immune restoration
?
– Hepatotoxicity
– Reactivation
• ARV discontinuation
• HBV resistance
Proia et al. Am J Med 2000. Wit et al. JID 2002. Benhamou et al. J Hepatol 2005. Bruno et al. Gastroenerol 2002.
Bonacini et al. Gastroenterol 2002. Puoti et al. Antiviral Ther 2004. Gouskos AIDS 2004

26. HIV/HBV Co-infection Mortality
Liver-related mortality (1995-2003 - GERMIVIC Cohort)
ESLD related death % of total death ESLD related death: % of HBsAg+
16 45 42
14.3 38
40
14 12.6
35
12
30
10
25
21
8 6.6 20
6 15
7
4 10
1.5 5
2
0 0
1995 1997 2001 2003 1995 1997 2001 2003
Rosenthal E, et al. J Viral Hep. 2007.

27. Impact of Anti-HBV Therapy on Liver Fibrosis
ADV TDF
Median METAVIR F at Baseline = 2 Median time F. up : 29.5 months
70% Week 48 Week 192
50% F0-F1 F2 F3-F4
30%
50%
Improved * F0-F1 8 0 0
33% (n=8)
10%
8%
F2 7 6 4
-10% 20%
(n=17)
Worsened **
-30% N= 15 12 F3-F4 1 1 11
* Improvement defined as ≥1 point reduction
(n=13)
** Worsening defined as ≥ 1 point increase
Benhamou Y et al. J Hepatol 2005. Lacombe, et al. CROI 2009, Abstract 815.

28. Treatment of HBV in HIV Co-infected Patients
Licensed for
HIV HBV
Interferon (IFN)
Lamivudine (LAM)
Emtricitabine (FTC)
Entecavir (ETV)
Telbivudine (LDT)
Adefovir dipivoxil (ADV)
Tenofovir disoproxil fumarate
(TDF)

29. Interferon
Months of HBV DNA HBeAg
Pts α-IFN therapy CD4 <6 log clearance
McDonald 87 14 2.5-10 6 – – 0
Marcellin 93 10 3-5 4-6 20-858 2 2
Wong 95 12 10 6 No AIDS 1 1
Zylberberg 96 25 6 6 480 ± 234 9 2
Di Martino 02 26 5 6 331 ± 207 7 3
Total 87 19 (26%) 8 (9%)
McDonald. Hepatology. 1987; Marcellin. Gut. 1993; Wong. Gastroenterology. 1995; Zylberberg. Gastroenterol Clin Biol. 1996;
Di Martino. Gastroenterology. 2002.

30. HIV/HBeAg+ LAM-R
PEG-IFN α2a + ADV
HBV DNA ALT
N=17
PEG-IFN2a + ADV PEG-IFN2a + ADV
9
S e ru m H B V D N A (lo g
8 100
7
S e r u m A L T (IU /L )
80
c o p ie s /m L )
6
5 60
4
3 40
2 20
1
0 0
Baseline 12 24 48 72
4
8
12
24
36
40
48
60
72
e
lin
Weeks
se
Ba
Weeks
Ingliz P. et al, Antiviral Therapy 2008

31. Lamivudine
Median change in serum HBV DNA
HBV resistance to LAM
HIV/HBeAg+ Naïve Pts
Week 52
Median Change in Log HBV DNA
1
0
Proportion of patients LAM-R
0.75
-1 N= 57
0.50
-2
0.25
-3 -2.7
-4 0 350 700 1050 1400
Days ofamivudine therapy
l
-5 Number of patients 57 32 13 6 3
under observation
(LAM 150 mg bid)
Dore GJ, et al. J Infect Dis. 1999;180:607-613. Benhamou Y, et al. Hepatology 1999; 30:1302-06

32. Entecavir
ETV 1mg qd 48w = 4.3 log DNA decline in HIV/HBeAg+ LAM-R patients
Pessoa et al. AIDS 2008
• 17 HIV/HBV Pts who received ETV for HBV • Switch from a TDF to ETV for HBV
- Significant reduction in HIV RNA in the suppression
majority of pts
- 6 pts switched to ETV because of
Selection of M184V (HIV RT) TDF renal tox
following ETV treatment
ART naïve - HBeAg+ and HBV DNA <LOD: 6
ART experienced - L180M and M204V: 5
70
3/5 Total
60 • Outcome results:
% with M184V
6/12
50 3/7 - HBV rebound on ETV: 6
40
- Median time to rebound: 3 months
30
- All pts maintained HIV suppression
20
10
0
Median time M184V 148 days 98 days
Hull M, et al. 9th Intl. Congress on Drug Therapy in HIV
Audsley J, et al. 15th CROI, Boston 2008, #63. Infection. Glasgow 2008.

33. Telbivudine
• No in vitro anti HIV activity of LdT
HIV Isolate
NNRTI Multi drug resistant
ETV LdT
Drug ETV LdT
IC50 µM 11.67 >600
Fold change 0.93 >Max
HIV Isolate
Subtype A
Drug ETV LdT
IC50 µM 13.21 >600
Fold change 1.05 >Max
• One doubtful case of LdT anti-HIV activity ?
Low et al., CROI 2009. Abstract 813a Avila et al. CROI 2009, Abstract 1002.

34. Tenofovir Disoproxil Fumarate
TDF vs. TDF+LAM (48 weeks) TDF + LAM (48 weeks)
TDF TDF+LAM
100
LAM LAM
42/ 50
Naive Experienced
80 19 / 2 5
(n=9) (n=47)
29/ 50
14 / 2 5
Patients (%)
60
HBV DNA <15 9 41
40 9/ 25
UI/mL
12 / 5 0
20 Mean time to 49 67
3/ 50
1/ 2 5 DNA < LOD
0 (weeks)
DNA<3 AST<45 HBeAg HBsAg
log U/L loss loss
Schmutz G, et al. AIDS. 2006. Tuma R, et al. AASLD 2008, Abstract 967.

35. Tenofovir Disoproxil Fumarate
TDF- vs LAM- containing HAART in ARV-naïve HIV/HBeAg+ Co-infected Patients (TICO Study):
Randomized Thai trial (1:1:1) of LAM vs TDF vs LAM/TDF within an EFV-based HAART regimen
LAM TDF TDF+LAM
W48 outcomes p
N=12 N=12 N=12
Median DNA Reduction 4.07 4.57 4.73 .7
DNA <3 log 46% 92% 91% .01
HBeAg loss 3 1 3
Anti-HBe Seroconversion 1 1 3
HBsAg loss 1 1 1
Matthews G et al. Hepatology 2008

36. Treatment Algorithm
Patients with Compensated Liver Disease and
No Indication for HIV Therapy (CD4 count >350/µL)
HBV DNA
HBV DNA HBV DNA
<2000 IU/mL ≥2000 IU/mL
ALT Elevated
ALT Normal
• No treatment • Monitor ALT every • PEG IFN
3-12 months • LdT (if HBV DNA>LOD at w24 add ADV)
• Monitor every
6–12 months • Consider biopsy • ADV+LdT
and treat if disease
present • Early HAART initiation –TDF+LAM/FTC
ECC Statement. J Hepatol. 2005.
Rockstroh et al. HIV Medicine 2008.

37. Treatment Algorithm
Patients with Compensated Liver Disease and
Indication for HIV Therapy (CD4 count <350/µL)
HBV DNA Patients with
cirrhosis
HBV DNA HBV DNA
≥2000 IU/ml <2000 IU/ml
HAART including
TDF+LAM/FTC
Patients without Patients with
HBV-associated HBV-associated
HAART regimen
LAM resistance LAM resistance
of choice
Refer patient for liver
HAART including transplantation
Substitute one NRTI by
TDF+3T/FTC evaluation if
TDF or add TDF*
decompensation
*If feasible and appropriate from the perspective
ECC Statement. J Hepatol. 2005.
of maintaining HIV suppression. Rockstroh et al. HIV Medicine 2008.