1. How to manage non responders Lawrence Serfaty Service d’Hépatologie, UMR S 893 Hôpital Saint-Antoine, UPMC, Paris Clinical case 1

2. Clinical Case oFemale, 58 yrs, african o80kg/162 cm (BMI 31) oHBP tt amlodipine, high cholesterol tt lovastatin oBlood transfusion in 1983 oHCV diagnosis in 2005 oGenotype 1b oHCV VL 3.6 M IU/ml, HIV and HBV - oLiver biopsy : A3F2

3. Clinical case D0W12W24 HCV VL IU/ml 3 600 000228 65944 843 PEG2b 120µg/d + ribavirin 1.2g/d

4. Question Type of response ? Breakthrough Partial response Nul response Relapse

5. Question Type of response ? Breakthrough Partial response Nul response Relapse

6. Patterns of treatment failure with SOC in HCV patients Log viral load Breakthrough PEG + Riba McHutchison JG et al. N Engl J Med 2009 Buti M et al. Hepatology 2010: 48: 1700-1712 2 log

7. Clinical Case: 5 yrs later oP=74kg oALT 67, AST 73, GGT 61 oPT 84%, bili 11 µm/l, albumin 36g/l oHb 14.3, PNN 1161, platelets 139 000 oHOMA=3.6 oHCV VL 2M IU/ml oFibroscan: 10±1.4 Kpa oUS: normal liver oLiver biopsy : A2F3

8. Question : Management of patient ? Correction of insulin resistance Retreatment with SOC PIs-based triple therapy Change of concomitant treatments

9. Question : Management of patient ? Correction of insulin resistance Retreatment with SOC PIs-based triple therapy Change of concomitant treatments

10. REALIZE: SVR in Prior Relapsers, Partial Responders and Null Responders SVR (%) Prior relapsers Prior partial responders Pbo/ PR48 4/27 T12/ PR48 29/49 LI T12/ PR48 26/48 n/N= Pbo/ PR48 2/37 T12/ PR48 21/72 LI T12/ PR48 25/75 Pbo/ PR48 16/68 T12/ PR48 121/145 LI T12/ PR48 124/141 Prior null responders * * * * * * *p<0.001 vs Pbo/PR48

11. HOMA and SVR in patients treated with SOC: Metaanalysis Deltenre et al. J Hepatol 2011

12. Serfaty L et al. Gut 2012 HOMA and VR in patients treated with telaprevir-based regimen 147 G1 naive patients treated with telaprevir-based triple therapy

14. Question Management of patient: triple therapy regimen ? Response guided therapy Fixed treatment duration Lead-in phase 48 weeks treatment

15. Question Management of patient: triple therapy regimen ? Response guided therapy Fixed treatment duration Lead-in phase 48 weeks treatment

16. Victrelis ® (Boceprevir) : treatment regimen (EMA) Naive patients (excepted F4) Treatment failure patients (excepted nul responder and F4 ) - F4 - Nul responder W0 W4W8W12*W24*W28W36W48 Undetectable HCV RNA at W8 Detectable HCV RNA at W8

17. Telaprevir + PegIFN + RBV Naive patients and relapsers (excepted F4) - F4 patients - non responders W0 W48 W12 W24 PegIFN + RBV Telaprevir + PegIFN + RBV Undetectable HCV RNA at W4 and W12 Incivo ® (Telaprevir) : treatment regimen (EMA) Detectable HCV RNA at W4 and/or W12

18. RelapsersPartial responders Nul responders %RVS Treatment failure patients: SVR according to HCV viral load decline at W4 of lead-in (Telaprevir) Poordad F et al. J Hepatol 2011; 54: S6

19. Balance : to treat or not to treat poor interferon responder ? - Resistant variants occurrence - New or higher rate of side effects - Cost of Pis (±EPO) Lead in phase Dosage adjustment (tolerance)

20. Resistant variant occurrence and sensitivity to interferon n patients 41% 6% * SPRINT-2 + RESPOND-2 pooled data

21. 4 weeks lead in phase, then 44 weeks boceprevir-based triple therapy Clinical Case: treatment decision + Stop lovastatin

22. D0W4 PNN 9001710 Hb 1410 Platelets 139 000174 000 HCV VL IU/ml 2 000 000143 700 PEG 2b 100µg + RBV 1.2g Clinical Case EPO 30 000 UI/w

23. D0W4W6W8 PNN 90017108801320 Hb 1410 9.8 Platelets 139 000174 000136 000118 000 HCV VL IU/ml 2 000 000143 70011816 PEG 2b 100µg + RBV 1.2g Clinical Case Boc 800mgx3 EPO 30 000 IU/w

24. Question : Management of patient ? Stop treatment because breakthrough Stop treatment because non response Looking for resistance mutations Continuing treatment

25. Question : Management of patient ? Stop treatment because breakthrough Stop treatment because non response Looking for resistance mutations Continuing treatment

26. Stopping rules with boceprevir - HCV RNA rebound > 1 log - HCV RNA ≥ 100 IU/ml at W12 - Detectable HCV RNA at W24 W0 W4W8W12*W24*W28W36W48

27. D0W4W6W8W12W16 PNN 9001710880132016301270 Hb 1410 98.69.3 Platelets 139 000174 000136 000118 000121 000130 000 HCV VL IU/ml 2 000 000143 70011816<12 PEG 2b 100µg + RBV 1.2g Clinical Case Boc 800mgx3 EPO 30 000 IU/w

28. Conclusion oTriple therapy is now the reference treatment in G1 non responders oFixed treatment duration 48 weeks oLead in phase in nul responders  VL decline > 1log: triple therapy  VL decline < 1log: discussion