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Patrick MARCELLIN

Patrick MARCELLIN. THE CHALLENGE OF TREATING NON RESPONDERS Patrick Marcellin Service d’Hépatologie and INSERM CRB3 Hôpital Beaujon, Clichy University of Paris. WHO TO RETREAT?. SIDE EFFECTS TOLERANCE CO ST FIBROSIS 0-1. SYMPTOMS GENOTYPE MOTIVATION FIBROSIS 2-4. PROS. CONS.

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Patrick MARCELLIN

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  1. Patrick MARCELLIN

  2. THE CHALLENGE OF TREATING NON RESPONDERSPatrick MarcellinService d’Hépatologie and INSERM CRB3Hôpital Beaujon, ClichyUniversity of Paris

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

  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. Type of non response 7 Null non responder 6 1st phase Partial non responder 5 Slow responder 4 Serum HCV RNA 2nd phase 3 Limit of detection 2 Rapid responder 1 14 21 28 0 1 2 3 7 Days Neumann et al. 2000

  9. Type of non response 7 Null non responder 6 1st phase Partial non responder 5 Slow responder 4 Serum HCV RNA 2nd phase 3 Limit of detection 2 Rapid responder 1 14 21 28 0 1 2 3 7 Days Neumann et al. 2000

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

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

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

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

  16. RETREATMENT BY PEGYLATED COMBINATION OF 154 NON RESPONDERS TO STANDARD COMBINATION HCV RNA (log10 copies/ml) Treatment Week Moucari et al. J Hepatol, in press

  17. RETREATMENT FOR ERADICATION Partial response Non response Genotype 2-3 Genotype 1 No cirrhosis Cirrhosis PROS CONS

  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 resistance treatment? • - 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. REPEATBackground • 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. REPEATPatients • Non-responders to ≥12 weeks’ treatment with standard-dose PEG IFN alfa-2b plus ribavirin

  27. REPEAT study design950 patients randomized 2:1:1:2 360 g Peg-IFN alpha2a + RBV Follow-up A Peg-IFN alpha2a + RBV 360 g Follow-up B 180 g Peg-IFN alpha2a + RBV Follow-up C 180 g Peg-IFN alpha2a + RBV Follow-up D 0 12 24 36 48 60 72 84 96 Study Week Marcellin et al. AASLD 2005

  28. Virological Response at Week 12 p<0.0001 180 g (n=469) 70 360 g (n=473) 62* 60 p<0.0001 50 45 42* 40 Patients (%) p=0.0031 30 25 20* 20 13 10 0 ≥2-log10 drop <600 IU/mL <50 IU/mL Marcellin et al. AASLD 2005 HCV RNA

  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. 8 7 6 PEG IFN + Riba Median HCV RNA (log 10) 5 PEG IFN + Riba + 25 mg VX 497 PEG IFN + Riba + 50 mg VX 497 4 3 2 0 4 8 12 16 20 24 Merimepodib (VX 497) in non responders (IFN+RBV) Weeks Marcellin et al. EASL 2004

  32. ViramidineAnemia Hemoglobine <10 g/dL 30% 27% 25% 20% 15% 11% 10% % 5% 2% 0% 0% 400 mg 600 mg 800 mg 1000/1200 mg Ribavirin Viramidine

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

  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 0.2 0 Placebo 50 mg x 1/j -0.2 100 mg x 1/j -0.4 200 mg x 1/j 400 mg x 1/j -0.6 200 mg x 2/j -0.8 Doses croissantes 100-800 mg -1 Doses croissantes 400-800 mg + anti-émetique Traitement -1.2 1 2 3 4 5 8 11 15 16 17 22 JDays (Godofsky et al., DDW 2004)

  36. R1626 (Roche) Treatment F-U 1 0 Placebo -1 500 mg x 2/j 1500 mg x 2/j -2 HCV RNA -1,2 log10 3000 mg x 2/j -3 4500 mg x 2/j -2,6 log10 -4 -3,7 log10 -5 0 5 10 15 20 25 30 Days (Roberts et al, AASLD 2006)

  37. HCV 796 (Wyeth) 1 F-U Treatment 0 P l a c e b o - 1 5 0 m g 1 0 0 m g HCV RNA 2 5 0 m g - 2 5 0 0 m g 1 0 0 0 m g 1 5 0 0 m g - 3 - 1 2 5 8 1 1 1 4 1 7 2 0 2 3 2 6 2 9 Days (Chandra et al, DDW 2006)

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

  39. 0 -0,5 -1 PEG IFN HCV RNA Levels Change PEG IFN +200 mg SCH -1,5 PEG IFN + 400 mg SCH -2 ) -2,5 -3 0 1 2 3 5 7 8 9 10 12 13 Days SCH 503034 ± IFN PEG a2b 1.5g/kg HCV 1, IFN Non-Responders

  40. MAINTENANCE THERAPY

  41. MAINTENANCE THERAPY Reduce necro-inflam. Tolerability Reduce HCC? Cost Improve survival? Not proven F3-F4 F1-F2 ALT decrease No ALT decrease PROS CONS

  42. TREATMENT OF NON RESPONDERS • - 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)

  43. TREATMENT OF NON RESPONDERS - 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

  44. IN PRACTICAL

  45. Non Responder

  46. Non Responder False non Responder

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

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

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

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