1. Current treatment of hepatitis C in HIV co-infected patients Dominique SALMON Internal Medicine Department, COCHIN Hospital Paris, FRANCE 12th ISVHLD - ANRS Co-infection day, July 5, 2006

2. Main points Chronic HCV infection Candidates Pre therapeutic assessement Peg IFN and RBV doses Treatment duration Management of adverse events Acute HCV infection

3. Candidates and Pretherapeutic assessement

4. Candidates to therapy All HCV chronically infected patients should be offered treatment if the benefits outweigh the risks CD4 < 200/mm3 : treat HIV first Alcoholics : - same efficacy of PegIFN + RBV - Pb of adherence to treatment Active drug users: - opiate substitution priority - case by case evaluation Alberti et al, 1st ECC, J Hepatol 2005

5. Pretherapeutic liver evaluation HCV genotype HCV viral load Liver biopsy: useful, but not mandatory when a decision to treat has been taken New markers of fibrosis

6. Impact of genotype and HCV-RNA on SVR % pts with SVR in APRICOT Torriani et al NEJM 2004, 0 10 20 30 40 50 60 70 geno 1geno 2-3 > 5,9 log UI/ml < 5,9 log UI/ml

7. Liver biopsy in HIV/HCV co- infected patients  Genotype 1 and 4, and high HCV load (>800,000 IU/ml)  Presence of co-morbidities : - Excessive alcohol consumption - HBV and/or delta co-infection - Medication hepatotoxicity  Genotype 2 and 3  Genotype 1 and 4, and low HCV load (≤800,000 IU/ml) Required for treatment decision Not required for treatment decision Alberti et al, 1st ECC, J Hepatol 2005

8. New tests of fibrosis FibroScan + seric markers Discordance Concordance Liver biopsy Treatment or follow-up Follow-up Minimal fibrosis < F2 Moderate or severe fibrosis F >2 Treatment Castera et al. Gastroenterology 2005; 128: 343-50.

9. Doses of Peg IFN and ribavirin

10. Doses of Peg-IFN  ACTG 5071 RIBAVICLAGUNOAPRICOT Peg-IFN 2aPeg-IFN 2b Peg-IFN  2a 180  g/w Peg-IFN  2b 1.5  g/kg/w 40 27 44 0 20 40 60 80 100 SVR (%)

11. SVR with PegIFN + RBV in HIV/HCV patients 38% (1 and 4) 14%17% (1 and 4) 29% Genotype 1 53%27%44%62% Genotype 2-3 44%27% 40%Gobal LAGUNORIBAVICACTG 5071 APRICOT

12. Genotype 2 or 3 Genotype 1 or 4 Low ARN HCV < 800 000 UI/ml High ARN HCV > 800 000 UI/ml Ribavirin 800 mg Ribavirin 1000-1200 mg Alberti et al, 1st ECC, J Hepatol 2005 Dose of ribavirin is critical

13. Genotype 2 or 3 Genotype 1 or 4 WhateverHIV-RNA Ribavirin 800 mg Ribavirin 1000-1200 mg Alberti et al, 1st ECC, J Hepatol 2005 Dose of ribavirinin 2006

14. Increased ribavirine dose useful in genotype 1 with high viral load (WIN-R) Jacobson et al. LB3, AASLD 2005 Genotype 2, 3 65 58 68 60 0 70 24 weeks48 weeks SVR (%) 27 34 32 39 0 10 20 30 40 Viral load > 600 000 Ul/ml Viral load < 600 000 Ul/ml SVR (%) Genotype 1 p = 0.173 Group A: PEG-IFNα-2b + ribavirin 800 mg/d vs. Group B: PEG-IFNα-2b. + ribavirin 13 + 2 mg/kg G1: 48 weekG2-3 : 24 sem. vs. 48 week p = 0.047 725776446391322 316588602 n=

15. PRESCO trial Study weeks 0 96 72 48 24 60 84 Peg-IFN + RBV 1000-1200 mg/day 12 36 Follow-up G2,3 G1,4 G2,3 Follow-up Only patients who achieved EVR (>2 log drop in HCV-RNA at week 12) continued treatment. n=389

16. APRICOT (800mg/d) vs PRESCO and FRIED (1000-1200 mg/d) : genotype 1 response Soriano, ICAAC 2006, accepted On-treatment analysis 31% Percentage of patients 34% 29% 36% 46% 13% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% <50UI/ml W4SVR Apricot Presco Fried

17. Breilh D., Abstract 928, CROI 2005 RBV Concentration (mg/L) 0 0 0,5 1 1,5 2 2,5 3 3,5 1234567891011121314 Time (hours) D4W2W3 Virologic failure Virologic failure Virologic succes Virologic succes Relation between RBV concentration and sustained virologic response in Co-infected patients

18. Recommended treatment duration = 48 weeks

19. Positive predictive value of early virological response (EVR) on SVR 74 % 94% 58 % 82% 66 % 83% EVR at W4 > 2 log drop HCV RNA undetectable HCV-RNA 70 %45 %56 % EVR at W12 > 2 log drop HCV RNA Genotype 2/3 Genotype 1 All genotypes Torriani, NEJM, 2004, 292;

20. Probability of success is evaluable as early as W4 >2 log HCV-RNA decrease HCV-RNA undetectable SVR probability 60% geno 1 58% SVR probability 83% geno 2/3 74%

21. Negative predictive value of early virological response (EVR) 84 %90 %88 % No EVR at W4 < 2 log drop HCV RNA 100 %98 %- No EVR at W12 < 2 log drop HCV RNA Genotype 2/3 Genotype 1 All genotypes Torriani, NEJM, 2004, 292;

22. Early viral Kinetics in RIBAVIC trial 82 94 71 99 0 20 40 60 80 100 W4W12 VPPVPN Carrat et al. JAMA 2004

23. Duration of treatment Evaluate at week 12 early virological response HCV-RNA  > 2 log Treatment for 48 weeks If HCV-RNA neg at W24 TTT should be stopped HCV-RNA  < 2 log Alberti et al, 1st ECC, J Hepatol 2005

24. Optimal duration for genotype 2,3 in HIV co-infected patients ?

26. Keep patients on the optimal dose of peg-IFN and ribavirin Proactive management of adverse events and antiretroviral treatment 23%31%39%25%Tx interruption 31% pegIFN RBV 10% 25% 34% 18% 16% 20% 25% 18%  dose AE Lab abnormality LagunoACTG 5071 RibavicApricot Torriani NEJM 2004;Carrat Jama 2004; Chung,NEJM 2004; Laguno AIDS 2004

27. Impact of adherence on SVR with PegIFN  a  /ribavirin bitherapy SVR depends on RBV doses within the 12 first weeks Reddy et al. EASL 2005 p=0.01 66 57 45 0 0 10 20 30 40 50 60 70 >97%80-97%60-80%<60%

28. Prevention and proactive management of adverse events betablockers levothyroxin Hyper or hyothyroidism No ddI (d4t) : RR X 2.3 Mitochondrial toxicity (1-3%) Liver decompensation avoid AZT Use EPO Use G-CSF Anemia Hb < 8 g/dl : 3.8% Neutropenia Manage depressive mood changes Depression paracetamol +/- NSAID Influenza-like syndrome keep > 95% of the dose mainly for the first 3 months

29. RIBAVIC – Mitochondrial toxicity (pancreatitis –hyperlactatemia) Incidence –27,5 / 1000 pat./year (all) –34,1 / 1000 pat./year (with ARV) –0 / 1000 pat./year (without ARV) 2 %NoNon 0 %YesNo 7 %NoYes 24 %Yes % with mitochondrial toxicity d4TddI Multivariate analysis : odds-ratio for ddI = 23 [95 % CI : 5-105] Carrat et al. JAMA 2004; 292: 2839-2848

30. AZT: impact on anemia and RBV doses 52 % 20 % 0 % 20 % 40 % 60 % AZTNo AZT Patients with RBV dose decrease Hb decrease at W4 3,14 1,96 0 1 2 3 AZTNo AZT Hb (g/dl) RBV dose decrease at W4 Alvarez D et al. 12th Conference on Retroviruses and Opportunistic Infections (Abstract #: P-192). Boston, MA USA, February 22–25, 2005

31. *p = 0,009 ; † p < 0,001 ; ‡ p < 0,03 ; § p = 0,003 ; Epoetin alfa vs. Placebo. PhysicalMentalVitality † ‡ * § Afdhal et al. Gastroenterology 2004 Impact of Epoetin alfa 9% 5% 12% 14% 11% -1% 8% 9% 22% 6% 23% 25% -5 0 5 10 15 20 25 30 35 40 % Change from Study Entry Week9 17Week9 17Week9 17 Epoetin alfa / Placebo /Epoetin alfa

32. Management of non responders Was the treatment adequate ? No Adherence Pb, side effects, low doses Yes 100% of the dose during the first 12 W Retreatment Partial response or relapse No response = true non responder

33. Approach dependent on histology : Minimal disease => wait new drugs Significant disease (F3-F4) => –Monitor ESLD and HCC –Consider alternative strategies Maintenance therapy HAART Retreatment High dose peg-IFN? New drugs ?

34. Acute HCV treatment

35. Treatment of acute HCV hepatitis 168 HCV monoinfected:  ALT (5-10x), PCR and/or sero-conversion Egypt, USA, Germany Geno 1, 4: 60% 1.5  g/kg/wk PEG  2b for 12 weeks Initiation from 1 st positive RNA result either at : SVR (%) Time of Rx onsetIntent to RxTreated 8 weeks (n=43)95%95% 12 weeks (n=43)93%91% 20 weeks (n=82)77%70% Kamal et al Gastroenterology 2006;130:632-8

36. Treatment of acute HCV Kamal et al Gastroenterology 2006;130:632-8 Geno 1 Geno 2+3 Geno 4

37. Comparison of the 2 largest studies of acute HCV infection Kamal et alWiegard et al N° patients16889 Rx duration12 weeks24 weeks SVR95% (early Rx)89% Main groupOcc exposure: 56%IDU, sex: 44% +ve factorsGeno non-1ALT >500 Kamal et al Gastroenterology 2006;130:632-8; Wiegand et al Hepatology 2006; 43: 250-6 PEG alone 12 weeks as good as 24 weeks Delay up to 12 weeks max from diagnosis Max chance of SVR for geno 2 or 3

38. Treatment of acute HCV hepatitis in HIV infection N°RegimenDuration (weeks) genotype% SVR Vogel M et al 11Variable23-48GT 1/4 : 10 Other: 1 91% Gilleece YC et al 27PegIFN +RBV24GT 1: 20 Other : 4 55% 100% Dominguez S et al 14PegIFN + RBV24GT 1/4 : 8 Other: 3 71.4% Vogel et al, J Viral Hepatitis, 2005; Gilleece et al, J AIDS 2005;Dominguez S et al, submitted Initiation from PCR/seroconversion at 12 weeks

39. Conclusion (1) As eradication is possible, hepatitis C treatment discussed for all patients, except if minimal liver disease Histological evaluation crucial: liver biopsy should not be an obstacle new tools available. Improved success rates with HCV therapy due to: –proactive management side effects –increased ribavirine dose (1000-1200mg genotype 1)

40. Conclusion (2) Duration of treatment (48 weeks) depends on EVR: –at 12 weeks : stop if no significant response –at 24 weeks : stop if viral load remains positive. Fields of research : –Geno1, high VL : higher doses RBV and/or Peg IFN  ? –Slow responders : longer duration of therapy ? –True non responders: maintenance therapy ? –New molecules.