1. Patrick MARCELLIN

2. THE CHALLENGE OF TREATING NON RESPONDERS Patrick Marcellin Service d’Hépatologie and INSERM CRB3 Hôpital Beaujon, Clichy University of Paris

3. WHO TO RETREAT? SIDE EFFECTS TOLERANCE COST FIBROSIS 0-1 PROSCONS SYMPTOMS GENOTYPE MOTIVATION FIBROSIS 2-4

4. HOW TO TREAT A NON RESPONDER? Two strategies - Viral eradication - Maintenance therapy

5. HOW TO TREAT A NON RESPONDER? Two strategies - Viral eradication - Maintenance therapy

6. The probability of viral eradication depends on: - Type of non response - Previous therapy - Cause(s) of non response

7. The probability of viral eradication depends on: - Type of non response - Previous therapy - Cause(s) of non response

8. 0123 1 2 3 4 5 6 7 7 142128 Limit of detection Days Serum HCV RNA 1 st phase 2 nd phase Partial non responder Slow responder Rapid responder Null non responder Neumann et al. 2000 Type of non response

9. 0123 1 2 3 4 5 6 7 7 142128 Limit of detection Days Serum HCV RNA 1 st phase 2 nd phase Partial non responder Slow responder Rapid responder Null non responder Neumann et al. 2000 Type of non response

10. The probability of viral eradication depends on: - Type of non response - Previous therapy - Cause(s) of non response

11. Previous therapy - Conventional interferon - Standard combination - Pegylated combination

12. HALT-C SVR according to previous therapy 28% 12% 0 10 20 30 40 50 % IFN (n=219) IFN + RBV (n=385) p<0.0001 Schiffman. Gastroenterology 2005

13. BEAUJON SVR according to previous therapy 35% 10% 0 10 20 30 40 50 % IFN (n=49) IFN + RBV (n=50) Ripault et al. DDW 2003

14. SVR to PEG IFN+RBV in NRs to IFN+RBV According to Genotype 0% 37% 0 10 20 30 40 50 SVR % Genotype 2-3 Genotype 1 Moucari et al. J Hepatol in press

15. SVR to PEG IFN+RBV in NRs to IFN+RBV According to Cirrhosis 0% 32% 0 10 20 30 40 50 SVR % No cirrhosis Cirrhosis Moucari et al. J Hepatol in press

16. HCV RNA (log 10 copies/ml) Treatment Week RETREATMENT BY PEGYLATED COMBINATION OF 154 NON RESPONDERS TO STANDARD COMBINATION Moucari et al. J Hepatol, in press

17. RETREATMENT FOR ERADICATION Partial response Non response Genotype 2-3 Genotype 1 No cirrhosisCirrhosis PROSCONS

18. PROBABILITY OF SVR TO RETREATMENT P = P2 - P1 P is the probability of response to retreatment according to the probability of response to the new treatment (P2) minus the probability of response to the prior treatment (P1)

19. The probability of viral eradication depends on: - Type of non response - Previous therapy - Cause(s) of non response

20. Cause(s) of non response related to the patient: To manage before retreatment - Alcool:stop - Overweight:weight loss - Insulin resistancetreatment? - Iron overload:phlebotomy - Psychologic:prepare

21. Cause(s) of non response related to reduced dosing: To manage during retreatment - Anemia: EPO - Neutropenia: GCSF - Depression: anti-depressive - Others …

22. PERSPECTIVES - Optimise current therapy - New drugs

23. PERSPECTIVES - Optimize current therapy - New drugs

24. OPTIMIZE CURRENT THERAPY - Increase dose of PEG IFN - Increase duration of therapy - Better adjust dose of RBV according to body weight - Improve PEG IFN pharmacokinetic (2 injections/week for PEG IFN a2b?)

25. REPEAT Background Initial retreatment studies have suggested a benefit of induction doses and/or prolonged duration of treatment in previous non- responders Jacobson. Hepatology 2005 Strader. Hepatology 2004 Diago. Hepatology 2003

26. REPEAT Patients Non-responders to ≥12 weeks’ treatment with standard-dose PEG IFN alfa-2b plus ribavirin

27. Follow-up Study Week 04824961236607284 Follow-up 360  g Peg-IFN alpha2a + RBV Follow-up 360  g Peg-IFN alpha2a + RBV 180  g Peg-IFN alpha2a + RBV Follow-up REPEAT study design 950 patients randomized 2:1:1:2 A B C D 180  g Peg-IFN alpha2a + RBV Marcellin et al. AASLD 2005

28. Virological Response at Week 12 Patients (%) <600 IU/mL<50 IU/mL≥2-log 10 drop 25 42 * 13 20 * 45 62 * p<0.0001 180  g (n=469) 360  g (n=473) HCV RNA 0 10 20 30 40 50 60 70 p<0.0001 p=0.0031 Marcellin et al. AASLD 2005

29. PERSPECTIVES - Optimise current therapy - New drugs

30. NEW DRUGS New “IFN”: Albuferon Gene shuffled interferon New “ribavirins”: Levovirine Merimepodib Viramidine Enzyme inhibitors: Anti-polymerase Anti-protease

31. Merimepodib (VX 497) in non responders (IFN+RBV) Weeks 2 3 4 5 6 7 8 04812162024 Median HCV RNA (log 10) PEG IFN + Riba PEG IFN + Riba + 25 mg VX 497 PEG IFN + Riba + 50 mg VX 497 Marcellin et al. EASL 2004

32. Viramidine Anemia Viramidine Hemoglobine <10 g/dL % 30% 25% 20% 15% 10% 5% 0% 400 mg600 mg800 mg Ribavirin 1000/1200 mg 0% 2% 11% 27%

33. Viramidine Phase 3 VISER 1 SVR Viramidine 800mg Ribavirin 1000/1200 mg 52% 38%. 100% 75% 50% 25% 0% %

34. ENZYME INHIBITORS Anti-polymerase NM 283 (Idenix/Novartis) R1626 (Roche) HCV 796 (Wyeth)… Anti-protease VX 950 (Vertex) Schering 503034 Others...

35. Valopicitabine (NM283) HCV RNA -1.2 -0.8 -0.6 -0.4 -0.2 0 0.2 13581116151722 JDays Placebo 50 mg x 1/j 100 mg x 1/j 200 mg x 1/j 400 mg x 1/j 200 mg x 2/j Doses croissantes 100-800 mg Doses croissantes 400-800 mg + anti-émetique Traitement 24 (Godofsky et al., DDW 2004)

36. R1626 (Roche) (Roberts et al, AASLD 2006) Placebo 500 mg x 2/j 1500 mg x 2/j 3000 mg x 2/j 4500 mg x 2/j Treatment F-U Days 051015202530 HCV RNA HCV RNA -5 -4 -3 -2 0 1 -2,6 log 10 -3,7 log 10 -1,2 log 10

37. HCV 796 (Wyeth) (Chandra et al, DDW 2006) -125811141720232629 -3 -2 -1 0 1 Placebo 50 mg 100 mg 250 mg 500 mg 1000 mg 1500 mg Days HCV RNA HCV RNA Treatment F-U

39. PegIFN-Ribavirine-VX 950 Study Time (in Days) media n Limit of Quantitation Limit of Detection Lawitz et al., DDW 2006

40. SCH 503034 ± IFN PEG a2b 1.5  g/kg HCV 1, IFN Non-Responders

41. MAINTENANCE THERAPY

42. Reduce necro-inflam. Tolerability Reduce HCC?Cost Improve survival? Not proven F3-F4F1-F2 ALT decreaseNo ALT decrease PROSCONS

43. - The probability of SVR to ReTX depends on type of non response, previous therapy and characteristics of patients (genotype, cirrhosis) -Viral eradication is rarely obtained (10%) with pegylated combination in NRs to optimal standard combination - Viral eradication may be obtained in NRs to sub-optimal combination (correct causes of NR) TREATMENT OF NON RESPONDERS

44. - The efficacy of new drugs (anti-protease, anti-polymerase…) remains to be demonstrated. Triple or double TX? - Maintenance therapy is justified In patients with severe liver disease, if it induces a biochemical response (ALT<2N) - Its modalities and the patients who benefit need to be precised TREATMENT OF NON RESPONDERS

45. IN PRACTICAL

46. Non Responder

47. False non Responder

48. Non Responder False non Responder Cause of non response? Treat the cause

49. Non Responder False non Responder Cause of non response? Treat the cause ReTX Response Eradication

50. Non Responder False non Responder Cause of non response? Treat the cause ReTX Response Maintenance therapy - if F3 or F4 - if biochemical response - if tolerance OK Eradication Non response

51. Non Responder False non Responder True non Responder Cause of non response? Treat the cause ReTX Response Maintenance therapy - if F3 or F4 - if biochemical response - if tolerance OK Eradication Non response

52. Non Responder False non Responder True non Responder Cause of non response? Treat the cause ReTX Response Maintenance therapy - if F3 or F4 - if biochemical response - if tolerance OK Eradication Non response Trial