1. 36 year old HCV+ woman, Risk factor: occasional IVDU 15 years ago First treatment with PEG-IFN/RBV in 2002 –only qualitative PCR available : positive at W12 and W24 –Treatment stopped after 24 weeks Weight: 65 kg, BMI: 23 No comorbidity, no medications Genotype 1a, viral load 6.1 log 10 Fibroscan: 7.5 KPa Fibrotest: 0.47 (Fibrosis  F1-F2) Case study

2. She complains about fatigue She wants to be treated because of this fatigue. No biological or clinical contraindication for the treatment

3. Would you treat this patient ? No, –because of no significant fibrosis –Would wait 2d wave PI Yes, –because she is really motivated

4. Would you perform an IL28B genotyping in this patient ? Yes, –because the IL28B polymorphism can influence the treatment strategy No

5. % SVR 6 13 22 28 17 22 5 29 38 62 48 66 5 10 6 11 13 18 Boceprevir in treatment experienced patients : SVR rates by IL28B genotype Poordad F, et al. J Hepatol 2011;54(Suppl.):S6

6. Telaprevir in treatment experienced patients: SVR Rates by IL28B Genotype and Prior Response Prior relapsers Patients achieving SVR (%) Prior partial responders Prior null responders CCCT TT CCCT TT CCCT TT Pooled T12/PR48 (n=209) Pbo/PR48 (n=52) Pooled T12/PR48 (n=79) Pbo/PR48 (n=20) Pooled T12/PR48 (n=134) Pbo/PR48 (n=33) 51/58 4/12100/117 6/3029/34 3/105/81/5 33/57 2/1010/14 0/5 4/1027/92 1/1810/32 1/15 n/N= n/a Younossi Z et al. Gastroenterology 2011;

7. Impact of IL28B polymorphisms on SVR in naïve patients RVS (%) PR48 50/64 n/N= CCTT BOC44/ PR48 44/55 CT BOC RGT 63/77 PR48 33/116 BOC44/ PR48 82/115 BOC RGT 67/103 PR48 10/37 BOC RGT 23/42 78 82 80 28 65 71 27 55 59 0 20 40 60 80 100 BOC44/ PR48 26/44 RVS (%) PR48 35/55 n/N= CCTT T12PR 45/50 PR48 6/26 T12PR 16/22 PR48 20/80 T12PR 48/68 CT 64 90 25 71 23 73 0 20 40 60 80 100 Poordad F, et al. J Hepatol 2011;54(Suppl.):S6 Jacobson IM, et al. J Hepatol 2011;54(Suppl.):S542

8. RVS (%) PR48 50/64 n/N= CCTT BOC44/ PR48 44/55 CT BOC RGT 63/77 PR48 33/116 BOC44/ PR48 82/115 BOC RGT 67/103 PR48 10/37 BOC RGT 23/42 78 82 80 28 65 71 27 55 59 0 20 40 60 80 100 BOC44/ PR48 26/44 RVS (%) PR48 35/55 n/N= CCTT T12PR 45/50 PR48 6/26 T12PR 16/22 PR48 20/80 T12PR 48/68 CT 64 90 25 71 23 73 0 20 40 60 80 100 Poordad F, et al. J Hepatol 2011;54(Suppl.):S6 Jacobson IM, et al. J Hepatol 2011;54(Suppl.):S542 89 % of CC patients treated with BOC/PR were eligible for shorter therapy Impact of IL28B polymorphisms on SVR in naïve patient 80 % of CC patients treated with BOC/PR were eligible for shorter therapy

9. SVR in patients with a favorable IL28B polymorphism and a RVR (rs8099917) 0 20 40 60 80 100 IL28B rs 8099917 TT VL < 600,000 IU/mL 24 week. 48 week. 95 99 70 97 SVR in patients with RVR (%) IL28B rs 8099917 TT VL ≥ 600,000 IU/mL Liu CH, AASLD 2011, # 414 NSp <0.001

10. Would you propose a lead-in in this patient ? Yes, regardless the PI –because it will help to define the responsiveness to interferon of this patient Yes but only in case of BOC prescription

11. Case study Day 1: start of antiviral therapy –Peginterferon  -2b 1.5 ug/kg/week –Ribavirin: 300 mg BID Week 4: –Side effect: fatigue –Viral load: 5.2 log10 (vs 6.1 log10 at D1)

12. Will you add a protease inhibitor ? No, because of <1 log 10 decline. –Probability of SVR is very low. –Probability of resistance very high. Yes, despite <1 log 10 decline. –Probability of SVR remains significant

13. 17 67 _ 80 110 _ 90 114 _ PR48BOC/PR48BOC RGT 25 73 79 0 20 40 60 80 100 SVR (%) 0 12 _ 15 46 _ 15 44 _ PR48 BOC/PR48 BOC RGT 0 33 34 0 20 40 60 80 100 SVR (%) <1 log 10 HCV RNA reduction at Week 4 ≥1 log 10 HCV RNA reduction at Week 4 Bacon BR., et al. N Engl J Med 2011; 364:1207-1217. SVR according to the response during the lead –in: boceprevir

14. Predictive Value of Week 4 Response in Prior Relapsers, Partial and Null Responders Patients achieving SVR (%) <1 log 10 HCV RNA reduction at Week 4 ≥1 log 10 HCV RNA reduction at Week 4 Prior relapsers Prior partial responders Prior null responders Prior treatment response provides a more granular prediction of SVR than < or ≥ 1 log response after 4 weeks of Peg/RBV lead-in phase Lawitz EJ et al. Gastroenterology 2011

15. Lead-in Predicts SVR and Resistance 15 Poordad F. N Engl J Med. 2011; 364:1195-1206. Boceprevir resistance-associated variants: - ≥1 log 10 decline: BOC RGT: 4% (10/232) BOC/PR48: 6% (13/231) - <1 log 10 decline: BOC RGT: 52% (49/95) BOC/PR48: 40% (38/94)

16. ↓ viral load 0.9 log in this patient Variability of Taqman Roche: 0.3-0.5 log

17. Case study Start boceprevir 800 mg/8h (12 pills/day) at Week 4. Week 8. – Side effects:  fatigue, dysgeusia, no rash. – Hb: 10.5 g/dL (vs 13 g/dL at Day 1). – HCV RNA: 3.4 log IU/ml (6.1 log at baseline) 17

18. What will be your attitude ? Stop all treatment – Because the probability of SVR = 0 Continue the triple therapy and check again the viral response at W12 (W12 stopping rule) Stop BOC and continue PEG-IFN/RBV

19. Boceprevir : SVR according to viral response at week 8 in patient poorly responsive to PEG-IFN Bacon BR, AASLD 2011, 33 actualisé RESPOND 2SPRINT 2Combined studies SVR (%) 30 38 33 49 21 48 83 50 79 0 20 40 80 100 < 3 0 91 3-44-5> 5 Undetectable 16 0 16 0 0 28 < 33-44-5> 5 Undetectable < 33-44-5> 5 Undetectable 9 0 44 60 3838 6 28 10 20 10 11 2 23 23 70 15 31 23 29 5 31 29 98 25 51 33 40 0 17

20. Impact of TW12 stopping rules in naive patients Jacobson, AASLD 2011, #954

21. Impact of TW12 stopping rules in treatment experienced patients Jacobson, AASLD 2011, #954

22. Stop rules 0 4 8 12 24 28 36 48 RNA ≥100 UI/ml ↕ 3 B and PR Weeks RNA detectable ↕ B and PR Stop rules for boceprevir 0 4 8 12 24 36 48 RNA > 1000 UI/ml ↕ T and PR RNA detectable ↕ PR Stop rules for telaprevir Weeks

23. Case study All the drugs stopped at this point….