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 COST FIBROSIS 0-1 PROSCONS SYMPTOMS GENOTYPE MOTIVATION FIBROSIS 2-4

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

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

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

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

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 Type of non response

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 Type of non response

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

Previous therapy - Conventional interferon - Standard combination - Pegylated combination

HALT-C SVR according to previous therapy 28% 12% % IFN (n=219) IFN + RBV (n=385) p< Schiffman. Gastroenterology 2005

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

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

SVR to PEG IFN+RBV in NRs to IFN+RBV According to Cirrhosis 0% 32% SVR % No cirrhosis Cirrhosis Moucari et al. J Hepatol in press

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

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

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)

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

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

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

PERSPECTIVES - Optimise current therapy - New drugs

PERSPECTIVES - Optimize current therapy - New drugs

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?)

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

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

Follow-up Study Week 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

Virological Response at Week 12 Patients (%) <600 IU/mL<50 IU/mL≥2-log 10 drop * * * p<  g (n=469) 360  g (n=473) HCV RNA p< p= Marcellin et al. AASLD 2005

PERSPECTIVES - Optimise current therapy - New drugs

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

Merimepodib (VX 497) in non responders (IFN+RBV) Weeks 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

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%

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

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

Valopicitabine (NM283) HCV RNA 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 mg Doses croissantes mg + anti-émetique Traitement 24 (Godofsky et al., DDW 2004)

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 HCV RNA HCV RNA ,6 log 10 -3,7 log 10 -1,2 log 10

HCV 796 (Wyeth) (Chandra et al, DDW 2006) Placebo 50 mg 100 mg 250 mg 500 mg 1000 mg 1500 mg Days HCV RNA HCV RNA Treatment F-U

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

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

MAINTENANCE THERAPY

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

- 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

- 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

IN PRACTICAL

Non Responder

False non Responder

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

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

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

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

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