1. Management of non naïve patients with hepatitis C "Non-Responders" 3rd Paris Hepatitis Conference, Paris, 19.01.2009 Christoph Sarrazin J. W. Goethe-University Hospital, Frankfurt Medizinische Klinik I Germany

2. Definition of virologic non-response Currently used definitions of non-response Less than 2 log decline of HCV RNA concentration at week 12 of therapy Detectable HCV RNA at week 24 of therapy Problems: -PEG-IFN dose, ribavirin dose -Compliance, dose reductions, interruptions -Discont. due to and management of side effects -HCV assays - inter-assay variability - detection limits (5 - 10 - 50 IU/ml)

3. Quantification of HCV RNA by diff. assays CobasTaqMan (CAP) / RealTimeHCV / Versant bDNA clinical samples (n=65) Differences between HCV RNA assays: may be up to 0,7 log steps (factor 3 - 4) Differences between HCV RNA assays: may be up to 0,7 log steps (factor 3 - 4) Vermehren et al., J Clin Microbiol 2008

4. Detection limits of old and new assays Stopping rule at week 24 for pts. with detectable HCV RNA with negative predictive values of 98- 100% Based on assays with detection limits 30-50 IU/ml Based on 48 weeks max. treatment duration Problems: -Currently used assays have detection limits of 5-10 IU/ml -Extension of treatment duration to 72 weeks -Negative predictive values for detectable HCV RNA at week 24 for pts treated for 72 wks only 90% Davis et al., Hepatology 2003, Berg et al., Gastroenterology 2007

5. Definition of virologic non-response Differentiation between partial non-response and null-response Partial non-response: - HCV RNA detectable at week 24 Null-response: - decline of less than 1 log at week 4 - decline of less than 2 log at week 12

6. Your approach for discontinuation What is your personal approach for treatment discontinuation? 1.Strict application to the 2 log decline and HCV RNA detectable at week 24 rules 2.Strict application to the 2 log decline rule but discontinuation at week 24 only in patients with HCV RNA >50 IU/ml 3.Continuation of therapy as long as HCV RNA declines and becomes undetectable at week 24 by a highly sensitive assay (<5-10 IU/ml) 4.Continuation of therapy as long as HCV RNA declines, is at least below 15 IU/ml at week 24 and becomes undetectable at week 30

7. Options for re-treatment 1.PEG-Interferon and Ribavirin 2.PEG-Interferon and Ribavirin and STAT-C

8. EPIC 3 Study design and baseline characteristics Patients with chronic hepatitis C and compensated liver disease (METAVIR- F2 - F4) Nonresponse or Relapse to - standard interferon plus ribavirin or - PEG-interferon plus ribavirin n=1336 Treatment duration 48 weeks if 2 log decline at week 12 80% genotype 1 77% IFN + riba versus 22% PEG-IFN + riba 42% F4 fibrosis (cirrhosis) Poynard et al., AASLD 2006

9. EPIC3 sustained virologic response rates IFN/RibavirinPegIFN/Ribavirin SVR (%) (n)95% CISVR (%) (n)95% CI All patients 24.7% (254/1030)21.2, 28.1 16.1% (48/299)10.6, 21.5 Previous tx. response Relapse 44.6% (95/213)35.8, 53.4 35.7% (40/112)24.1, 47.4 Nonresponse 17.2% (116/673)13.5, 21.0 4.1% (7/172)0.2, 8.0 Genotype 1 16.7% (138/825)13.4, 20.1 11.5% (28/243)6.3, 16.8 2/3 61.5% (102/166)51.7, 71.2 43.6% (17/39)23.1, 64 4 31.3% (10/32)10.1, 52.4 20.0% (3/15)--- METAVIR Fibrosis F2 31.8% (92/289)24.9, 38.9 22.7% (15/66)9.4, 36.0 F3 26.3% (85/323)20.0, 32.6 17.4% (16/92)7.2, 27.6 F4 18.5% (77/416)13.6, 23.4 12.1% (17/141)5.0, 19.1 Baseline viral load HVL (>600,000 IU/mL) 20.5% (116/566)16.1, 24.9 10.7% (18/169)4.5, 16.8 LVL (<600,000 IU/mL) 29.7% (138/464) 24.3, 35.2 23.3% (30/129) 13.7, 32.8 (Rel.+NR)

10. REPEAT study design and baseline characteristics Randomization (105 centers, 2:1:1:2, n=950) R Study weeks 0 48241236607284 96 Follow-up 360 µg plus RBV 1000/1200 mg Peg-IFN alfa-2a (40KD) 180 µg Follow-up 360 µg plus RBV 1000/1200 mg 180 µg Follow-up plus RBV 1000/1200 mg Follow-up plus RBV 1000/1200 mg A B D Peg-IFN alfa-2a (40KD) 180 µg Peg-IFN alfa-2a (40KD) 180 µg C R Jensen et al., AASLD 2007  Patients with non-response to PEG-2b + riba  91% genotype 1  25-30% F3-4 fibrosis

11. REPEAT sustained virologic response rates p=0.006, Odds ratio 2.0 (95% CI 1.21, 3.31) 7% 14% 9% 16% 0% 20% SVR 360/180 µg 72 weeks (A) 360/180 µg 48 weeks (B) 180 µg 72 weeks (C) 180 µg 48 weeks (D) 52/31711/15622/15627/313 10%

12. REPEAT Impact of cirrhosis in genotype 1 26/304 9% 3% 6/116 54/312 5% 17% 72 weeks (360/180 µg and 180 µg) (A+C) 48 weeks (360/180 µg and 180 µg) (B+D) CirrhoticNon-cirrhoticCirrhoticNon-cirrhotic 4/120 0% 20% 10% SVR SVR rates in GT-1 patients: - 11% (72 wks.) - 6% (48 wks.)

13. REPEAT Predictive value HCV RNA <50 IU/mL at week 12 All patients treated (n=942) 0% 20% 40% 60% 80% 100% 57/10020/57 57% 35% 15/373 17/412 4% 72 weeks (360/180 µg and 180 µg) (A+C) 48 weeks (360/180 µg and 180 µg) (B+D) SVR <50 IU/mL at week 12: YES 17% (157 / 942) <50 IU/mL at week 12: NO 83% (785 / 942) SVR 0% 20% 40% 60% 80% 100%

14. Boceprevir (SCH503034) Triple-Therapy for PEG/R NR, GT 1, 48 Wks., n=357 BocPEG2bRibaChange Wk 12-17EOTSVR 100 yesnoRiba + B 8006%2% 200 yesnoRiba + B 80016%12% 400 yesyesB 80020%14% 400yesnoRiba + B 80013%5% 800yesnoRiba21%4% PlacyesyesB 800 TW12 pos.32%7% Schiff et al., EASL 2008 - SVR prediction: response at wk 8, >24-36 wks HCV RNA neg. - AE: anemia +1,5g/dl, nausea, fatigue, 8% discont. - Resistance in patients with break-through / withouth SVR

15. Results PROVE 3 Study (USA/EU) HCV Genotyp 1, Telaprevir, Nonresponder McHutchison et al. AASLD 2008 HCV RNA negative [%] 83 8% 12 + 12 TVR+PEG2a+Riba →PEG2a+Riba ETR 65 Standard PEG2a+Riba 41 ? SVR12 ETR SVR12 24 + 24 TVR+PEG2a+Riba →PEG2a+Riba 73 ? 30% n=66 n=68 Relapser Non-Responder n=40 Wk 12 Non-Responder 88 71 55 n=64 Wk 12 ETR SVR12 Wk 12 Wk36 SVR12 Wk 12 Relapser and Non-Responder ?

16. German HCV Guideline 2009 Recommendation for Non-responders  Non-response to (PEG)-interferon-alfa-monotherapie: re-treatment with PEG-interferon-alfa / ribavirin combination therapy [B].  Non-response to (PEG)-interferon-alfa/ ribavirin combination therapy: check initial treatment for improvement (dose of PEG-interferon, dose of ribavirin, dose reductions, tx interruptions, tx duration, HCV RNA kinetics, managment of side effects, compliance …) [C].  If HCV-RNA is detectable at week 12 [A] or at week 24 [C] in patients with slow response in the initial therapy, re-treatment should be discontinued.  In patients with virologic response treatment should be performed for 72 weeks [A].  No general recommendation for low-dose PEG-interferon monotherapy for prevention of fibrosis progression or complications of liver disease [A]. Consensus: 98% Sarrazin et al., German HCV Consensus Conference 2008

17. Your approach for selection of non- responders for re-treatment What is your personal approach for selection of non-responders for re-treatment? 1.Re-treatment of all non-responders who whish to receive a second course of therapy 2.Re-treatment only if a patient achieved at least a partial-response during the first course of therapy 3.Re-treatment only if dose of peg-interferon, and ribavirin as well as the management of side effects can be optimized 4.General recommendation to wait for future treatment options

18. Management of non naïve patients with hepatitis C "Non-Responders" 3rd Paris Hepatitis Conference, Paris, 19.01.2009 Christoph Sarrazin J. W. Goethe-University Hospital, Frankfurt Medizinische Klinik I Germany