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Current treatment of hepatitis C in HIV co-infected patients

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. Main points. Chronic HCV infection Candidates Pre therapeutic assessement

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Current treatment of hepatitis C in HIV co-infected patients

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  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 70 > 5,9 log 60 UI/ml < 5,9 log 50 UI/ml 40 30 20 10 0 geno 1 geno 2-3 Torriani et al NEJM 2004,

  7. Liver biopsy in HIV/HCV co-infected patients Not required for treatment decision Required for treatment decision • Genotype 2 and 3 • Genotype 1 and 4 , and low HCV load (≤800,000 IU/ml) • 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 Alberti et al, 1st ECC, J Hepatol 2005

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

  9. Doses of Peg IFN and ribavirin

  10. Doses of Peg-IFNa • Peg-IFNa 2a 180 mg/w • Peg-IFNa 2b 1.5 mg/kg/w 100 80 60 44 SVR (%) 40 40 27 27 20 0 APRICOT ACTG 5071 RIBAVIC LAGUNO Peg-IFN 2a Peg-IFN 2b

  11. SVR with PegIFN + RBV in HIV/HCV patients APRICOT ACTG5071 RIBAVIC LAGUNO Gobal 40% 27% 27% 44% Genotype 2-3 62% 44% 27% 53% Genotype 1 29% 17% (1 and 4) 14% 38% (1 and 4)

  12. Dose of ribavirin is critical Genotype 1 or 4 Genotype 2 or 3 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

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

  14. Increased ribavirine dose useful in genotype 1 with high viral load (WIN-R) Group A: PEG-IFNα-2b + ribavirin 800 mg/d vs. Group B: PEG-IFNα-2b. + ribavirin 13 + 2 mg/kg G1: 48 week G2-3 : 24 sem. vs. 48 week Genotype 1 Genotype 2, 3 p = 0.173 p = 0.047 39 68 40 65 34 60 32 58 27 70 30 SVR (%) 20 SVR (%) n= 10 n= 725 776 446 391 322 316 588 602 0 0 Viral load> 600 000 Ul/ml Viral load < 600 000 Ul/ml 24 weeks 48 weeks Jacobson et al. LB3, AASLD 2005

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

  16. APRICOT (800mg/d) vs PRESCO and FRIED (1000-1200 mg/d) : genotype 1 response 100 % 90 % 80 % 70 % 46% 60 % Percentage of patients Apricot 34% 36% 50 % Presco 31% 29% 40 % Fried 30 % 13% 20 % 10 % 0 % < 50 UI / ml W 4 SVR On-treatment analysis Soriano, ICAAC 2006, accepted

  17. Relation between RBV concentration and sustained virologic response in Co-infected patients 3,5 D4 W2 W3 3 Virologic failure Virologic succes 2,5 2 RBV Concentration (mg/L) 1,5 1 0,5 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time (hours) Breilh D., Abstract 928, CROI 2005

  18. Recommended treatment duration = 48 weeks

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

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

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

  22. Early viral Kinetics in RIBAVIC trial VPP VPN 99 100 94 82 80 71 60 40 20 0 W4 W12 Carrat et al. JAMA 2004

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

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

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

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

  27. Impact of adherence on SVR with PegIFNa 2a/ribavirinbitherapy SVR depends on RBV doses within the 12 first weeks 70 60 66 p=0.01 50 57 40 45 30 20 10 0 0 > 97 % 80 - 97 % 60 - 80 % < 60 % Reddy et al. EASL 2005

  28. Prevention and proactive management of adverse events Influenza-like syndrome paracetamol +/- NSAID Depression Manage depressive mood changes Anemia Hb < 8 g/dl : 3.8% Neutropenia avoid AZT Use EPO Use G-CSF Mitochondrial toxicity (1-3%) Liver decompensation No ddI (d4t) : RR X 2.3 Hyper or hyothyroidism betablockers levothyroxin 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) ddI d4T % with mitochondrial toxicity Yes Yes 24 % Yes No 7 % No Yes 0 % Non No 2 % 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 Hb decrease at W4 RBV dose decrease at W4 3,14 60 % 52 % 3 1,96 40 % 2 Patients with RBV dose decrease Hb (g/dl) 20 % 1 20 % 0 0 % AZT No AZT AZT No AZT Alvarez D et al. 12th Conference on Retroviruses and Opportunistic Infections (Abstract #: P-192). Boston, MA USA, February 22–25, 2005

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

  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 Partial response or relapse No response = true non responder Retreatment

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

  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% • 1.5mg/kg/wk PEG 2b for 12 weeks • Initiation from 1st positive RNA result either at : SVR (%) Time of Rx onset Intent to Rx Treated 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 Geno 1 Geno 2+3 Geno 4 • Kamal et al Gastroenterology 2006;130:632-8

  37. Comparison of the 2 largest studies of acute HCV infection Kamal et alWiegard et al N° patients 168 89 Rx duration 12 weeks 24 weeks SVR 95% (early Rx) 89% Main group Occ exposure: 56% IDU, sex: 44% +ve factors Geno non-1 ALT >500 • 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 • Kamal et al Gastroenterology 2006;130:632-8; Wiegand et al Hepatology 2006; 43: 250-6

  38. Treatment of acute HCV hepatitis in HIV infection Initiation from PCR/seroconversion at 12 weeks Vogel et al, J Viral Hepatitis, 2005; Gilleece et al, J AIDS 2005;Dominguez S et al, submitted

  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 IFNa ? • Slow responders : longer duration of therapy ? • True non responders: maintenance therapy ? • New molecules.

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