Benhamou Hcv Hiv Du 2010
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Benhamou Hcv Hiv Du 2010 Presentation Transcript

  • 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.