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 Infections respiratoires VIH Diarrhées Tuberculose Malaria Rougeole Hépatite B Pertussis Tétanos néonatal Hépatite C Décès par an ~3,5 million ~3,0 million ~2,2 million ~2,0 million ~1-3 million ~888,000 ~750,000 ~355,000 ~300,000 ~ 250,000 Source : CDC, WHO, UNICEF, UNAIDS

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

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

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

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

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

9. Progression to cirrhosis influence of alcohol and immune status Benhamou et al. Hepatology 1999;30:1054-1058 Estimated duration of HCV infection Fibrosis (METAVIR) CD4<200/µL OH>50 g/j CD4 <200/µL OH <50 g/j CD4 >200/µL OH<50 g/j HIV- OH<50 g/j

11. Treatment of chronic hepatitis C Genotype 2/3 Genotype 1/4 < 800 000 UI/mL > 800 000 UI/ml PEG IFN2 (a:180 /b:1.5 µg) RBV 800 mg 48 w Fibrosis: > 2 HCV RNA Fibrosis: 0/1 PEG IFN2 (a:180 /b:1.5 µg) RBV 1000-1200 mg 48 w Rx differed Alberti et al. 1st ECCC. J Hepatol. 2005

12. PEG IFN/RBV Virological response GT 1 GT 4 GT 1/4 GT 2/3 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 GT2/3, Rx 48 w

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

14. Impact of HCV RNA on SVR Torriani F et al. NEJM. 2004. GT 1 GT 2/3 Cooper D. et al, XV AIDS Conference HCV RNA Liver evaluation for GT1, high HCV RNA 21 (43 %) 49 > 5000 cp/mL 23 (35 %) 66 50-5000 cp/mL 72 (42 %) 173 < 50 cp/mL HIV RNA 90 (47 %) 216 ≥ 350 /  L 26 (36 %) 72 < 350 /  L 8 (47 %) 17 < 200/  L CD4 SVR N

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

16. VR n (%) PPV (%) NPV (%) G1 G2/3 G1 G2/3 G1 G2/3 119 (68) 83 (87) 39 70 93 92 71 (40) 76 (80) 58 74 90 84 Week 4 22 (13) 35 (37) 82 94 79 57 148 (84) 89 (94) 34 66 96 100 110 (63) 84 (88) 45 70 98 100 60 (34) 68 (72) 70 82 92 89 log 10 drop Week 12 Torriani F, et al. 45th ICAAC 2005; Abstract 1024 APRICOT ≥ 1 log 10 drop ≥ 2 log 10 drop HCV RNA -ve ≥ 1 log 10 drop ≥ 2 HCV RNA -ve

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

23. Assessed by the METAVIR scoring system. HBsAg+ vs HBsAg+/HIV GHPS cohort Benhamou et al CROI 2005 <.0001 <.0001 N=54 2 (2-2) 29.6% 1 34.7 N=469 1 (1-2) 16 1 30.1 Liver biopsy* Fibrosis (median) - Cirrhosis (%) Inflammation (median) - A2/3 (%) <.0001 62.1% 37.8 HBVDNA> 6 log (%) <.0001 34.8% 17.1 LAM-R HBV (%) <.0001 78.8% 49.9 HBeAg + (%) NS 57 (47-74) 29.1 50 (45-56) 26.7 Median ALT ALT< 2xULN (%) P HIV positive N=164 HIV negative N=504

24. Liver Mortality Rate (per 1000 PY) MACS Thio et al. Lancet 2004

25. 0 0.25 0.50 0.75 1 0 75 150 225 300 Follow up (months) Proportion of patients free Of liver decompensation HIV – (n=504) HIV + (n=164) P=0.004 Liver decompensation in HBsAg+ Benhamou et al. CROI 2005

29. HIV/HBV FTC Log 10 HBV DNA 24 22 20 20 17 33 33 33 33 33 10 10 10 7 7 FTC HBV+HIV FTC HBV d4T HBV+HIV FTC is not licensed for the treatment of HBV. Raffi F. IAS Conference, July 13-16, 2003, Abstract # 215. FTC HBV+HIV d4T HBV+HIV FTC in Chronic HBV (FTCB-102)

30. HIV/HBV LAM-R: ETV ETV PBO 5.56 HBV DNA (log 10 copies/ml) 9.19 4.79 5.63 Weeks RDZ double binded phase All the patients: ETV 1.0 mg Pessoa et al. ICAAC 2005

31. HIV/HBV LAM-R ADV HBV DNA (log 10 copies/ml) - 6.2 log 10 c/ml p<0.001* † 27 patients remain on study * p<0.001 Wilcoxon Sign Rank Test Benhamou et al, Lancet, 2001 & J Hepatol in press HBV DNA (< 2.6 log 10 copies/ml) 8/35 HBeAg negativation 3/33* HBe seroconversion 2/33* ADV (weeks) - 5.9 log 10 c/ml p<0.001* - 4.7 log 10 c/ml P<0.001* - 5.5 log 10 c/ml p<0.001* 31 29 31 30 31 29 27 † 27 n = 35

33. Peters M et al. CROI 2005. HIV/HBV ADV vs TDF *Roche Cobas Amplicor, LLQ 200 copies/mL ADV TDF HBV DNA (log 10 c/mL)* ADV 25 24 23 20 18 17 TDF 27 26 23 18 17 18

34. HIV/HBV: anti-HBV therapy * Added to LMV in the majority of the cases. ** < 6log copies/ml Wong DK et al. Gastroenterology 1995. Di Martino V et al. Gastroenterology 2002. Dore GJ et al. J Infect Dis 1999 .Benhamou Y et al. Hepatology 1996. Pessoa W et al. CROI 2005. Raffi F et al. 2003 IAS. Peter M et al. CROI 2005.. Ristig MB et al. J Infect Dis. 2002. Benhamou Y et al. N Engl J Med. 2003 . Benhamou Y et al. Lancet 2001 and AASLD, 2003 No yes yes YES? Yes Poor Anti HIV activity ? 49% ? 3.6 wt, preC, LAM-R?? 24 51 ETV* wt, preC, LAM-R wt, preC LAM-R wt, preC wt, preC wt, preC Anti-HBV activity ADV* TDF* FTC LAM IFN 33-50% 35-66% 7% 4 - 5.4 48-144 35 ? 12-20% 9% 26%** 12-24 87 ? ? ? Histological improvement ? ? 30-50% ALT response 4% ? 11% HBe seroconv. 4.4 3 2.7 HBV DNA decline (log cp/ml) 24-48 48 48 Duration (weeks) 200 33 215 No. of patients

35. HBV resistance Lai C et al. N Engl J Med 1998 . Leung N et al. J Hepatol 1999 . Chang T et al. Antiv Ther 2000 . Benhamou Y et al. Hepatology 1999 . Benhamou Y et al. Lancet 2001 and AADSL 2003. Data on file. NV-02B-003. Idenix. HIV/HBV HBV Patients (%)

36. Treatment Algorithm Patients with Compensated Disease and No indication for HIV therapy

37. Treatment Algorithm Patients with Compensated Disease and indication for HIV therapy