1. Clinical case Laurent CASTERA 5th PHC, Paris, January 31 2012 Service d’Hépatologie Hôpital Beaujon, Université Paris-7, Clichy, France

2. Patient Case: 43-year-old male u Previous intravenous drug user u Alcohol intake > 50 g/day u HCV RNA 6 log10 copies/ml u Genotype 1 u HBV and HIV negative u Weight 90 Kg; height 170 cm

3. Patient Case: past history u In 1997: liver biopsy indicates chronic “active” hepatitis (i.e. METAVIR A2F2) u Treatment with IFN 3M IU thrice a week u Treatment stopped after 3 months because of poor tolerance and depression u Normalisation of ALT but no information on HCV RNA u Lost to follow-up until 2002

4. HB (g/dl) WBC (/mm 3 ) Platelet count (/mm3) AST (IU/L) ALT (IU/L) GGT (IU/L) AP (IU/L) Total bilirubin (µmol/L) PT 2002: Laboratory & morphologic results Liver US: steatosis, heterogenous parenchyma 14 6000 100 000 120 70 500 150 15 80%

5. Patient Case: liver biopsy u Metavir F3 with steatosis and NASH

6. 0 10 2 10 4 10 6 HCV-RNA (log 10 ) IU/mL ALT (UI/L) 50 100 200 250 10 8 0 150 Pegylated interferon alfa-2b 135 µg/w Ribavirin 1200mg/day ULN Time (Weeks) Patient Case: 1st retreatment

7. 0 10 2 10 4 10 6 HCV-RNA (log 10 ) IU/mL ALT (UI/L) 50 100 200 250 10 8 0 4 150 Pegylated interferon alfa-2b 135 µg/w Ribavirin 1200mg/day RBV 600 mg ULN Time (Weeks) Patient Case: 1st retreatment

8. 0 10 2 10 4 10 6 HCV-RNA (log 10 ) IU/mL ALT (UI/L) 50 100 200 250 10 8 0 4 150 Pegylated interferon alfa-2b 135 µg/w Ribavirin 1200mg/day RBV 600 mg 10 3 PEG-IFN 100 µg 12 ULN Time (Weeks) Patient Case: 1st retreatment

9. 0 10 2 10 4 10 6 HCV-RNA (log 10 ) IU/mL ALT (UI/L) 50 100 200 250 10 8 0 41224 150 Pegylated interferon alfa-2b 135 µg/w Ribavirin 1200mg/day RBV 600 mg 10 3 PEG-IFN 100 µg 10 3 Patient Case: 1st retreatment ULN Time (Weeks)

10. Factors associated with treatment failure Failure TREATMENT IFN dosage RBV dosage Ttt duration HOST Ethnicity Insulin-resistance Poor adherence Alcohol VIRUS Genotype 1 High viral load Viral kinetics Quasispecies DISEASE Cirrhosis HIV coinfection HBV coinfection

11. Factors associated with treatment failure Failure HOST Insulin-resistance Poor adherence Alcohol TREATMENT IFN dosage RBV dosage Ttt duration VIRUS Genotype 1 High viral load Viral kinetics Quasispecies DISEASE Cirrhosis HIV coinfection HBV coinfection Can be modified HOST Ethnicity Cannot be modified Diet Education Withdrawal EPO

12. Patient Case u Lost to follow-up until 2007. u New evaluation

13. Patient Case: ultrasound Splenomegaly, heterogenous parenchyma

14. Patient Case: FibroScan 20.0

15. Patient Case: upper GI endoscopy

16. Patient Case u Not keen to start new antiviral treatment because of side effects. u What would you do ?

17. Options u Retreatment with PegIFN+ RBV with optimization u Follow-up without treatment u Maintenance therapy with PegIFN monotherapy

18. Patient Case u Alcohol withdrawal for 6 months u Strict Diet with weight loss: 90 -> 75 kg u Psychiatric care

19. 0 10 2 10 4 10 6 HCV-RNA (log 10 ) IU/mL 10 8 Pegylated interferon alfa-2a 180 µg/w Ribavirin 1400mg/day Patient Case: 2nd retreatment EPO 30 000 IU/w ALT (UI/L) 50 100 200 250 0 150 Paroxetine 20 mg/d ULN Time (Weeks)

20. 0 10 2 10 4 10 6 HCV-RNA (log 10 ) IU/mL 10 8 4 Pegylated interferon alfa-2a 180 µg/w Ribavirin 1400mg/day 10 5 EPO 30 000 IU/w ALT (UI/L) 50 100 200 250 0 150 Paroxetine 20 mg/d ULN Time (Weeks) Patient Case: 2nd retreatment

21. 0 10 2 10 4 10 6 HCV-RNA (log 10 ) IU/mL 10 8 4 Pegylated interferon alfa-2a 180 µg/w Ribavirin 1400mg/day 10 5 EPO 30 000 IU/w ALT (UI/L) 50 100 200 250 0 150 Paroxetine 20 mg/d ULN Time (Weeks) 12 10 3 Patient Case: 2nd retreatment

22. 0 10 2 10 4 10 6 HCV-RNA (log 10 ) IU/mL 10 8 4 Pegylated interferon alfa-2a 180 µg/w Ribavirin 1400mg/day 10 5 EPO 30 000 IU/w ALT (UI/L) 50 100 200 250 0 150 Paroxetine 20 mg/d ULN Time (Weeks) 12 10 3 24 Patient Case: 2nd retreatment

23. 0 10 2 10 4 10 6 HCV-RNA (log 10 ) IU/mL 10 8 4 Pegylated interferon alfa-2a 180 µg/w Ribavirin 1400mg/day 10 5 EPO 30 000 IU/w ALT (UI/L) 50 100 200 250 0 150 Paroxetine 20 mg/d ULN Time (Weeks) 12 10 3 24 48 Patient Case: 2nd retreatment

24. 0 10 2 10 4 10 6 HCV-RNA (log 10 ) IU/mL 10 8 4 Pegylated interferon alfa-2a 180 µg/w Ribavirin 1400mg/day 10 5 EPO 30 000 IU/w ALT (UI/L) 50 100 200 250 0 150 Paroxetine 20 mg/d ULN Time (Weeks) 12 10 3 24 48 72 Patient Case: 2nd retreatment

25. Patient Case u What would you do ?

26. Boceprevir Relapsers Partial responders Telaprevir Relapsers Partial responders Null responders + 60% + 40% + 25% + 50% + 45% Triple therapy in genotype 1 non SVR

27. 36 0 2412 48 TLR in treatment-experienced patients REALIZE study: design 6072 TVR 750 mg q8h + Peg-IFN  2a + RBV Follow-up Peg-IFN  2a + RBV Peg- IFN  2 a + RBV Peg-IFN  2a + RBV Follow-up 284 Peg-IFN  2a + RBV Follow-up TVR 750 mg q8h + Peg-IFN  2a + RBV N = 260 N = 130 *eRVR = HCV RAN undetectable at W4 et W12 Weeks Zeuzem et al. NEJM 2011

28. 16 Proportion of patients with cirrhosis REALIZE Zeuzem et al. NEJM 2011 169 cirrhotic patients N=663 patients

29. SVR REALIZE study SVR (%) RelapsersPartial Responders Pbo/ PR48 T12/ PR48 LI T12/ PR48 Pbo/ PR48 T12/ PR48 LI T12/ PR48 Pbo/ PR48 T12/ PR48 LI T12/ PR48 Null responders Zeuzem et al. NEJM 2011 N=663 patients

30. 16 SVR according to Fibrosis Pol et al. AASLD 2011

31. Boceprevir in previously treated patients RESPOND-2 Bacon et al. NEJM 2011 N=403 patients

32. Bacon et al. NEJM 2011 N=403 patients 49 cirrhotic patients Proportion of patients with cirrhosis RESPOND-2

33. RVS (%) 0 15 30 45 60 75 90 RelapsersPartial responders 29 PR48 69 BOC TGR 75 BOC/PR48 7 PR48 40 BOC TGR 52 BOC/PR48 SVR with BOC in non responders RESPOND-2 study Bacon et al. NEJM 2011 N=403 patients

34. SVR according to response at W4 of Lead in phase Decrease <1 log Decrease ≥ 1 log SVR (%) 0 20 40 60 80 100 SVR (%) 0 20 40 60 80 100 PR48 25 17/67 BOC TGR 73 80/110 BOC/PR48 79 90/114 0 0/12 PR48 33 15/46 BOC TGR 34 15/44 BOC/PR48

35. Tolerance Telaprevir Boceprevir Rash (37%) Anemia x 2 (50%) (Severe 7%) Anemia Dysgueusia Discontinuation AE: 13-20% Discontinuation AE: 9-19%

36. Patient Case u What would you do ?

37. 0 10 2 10 4 10 6 HCV-RNA (log 10 ) IU/mL 10 8 4 ALT (UI/L) 50 100 200 250 0 150 ULN Time (Weeks) 12 24 48 Patient Case: 3rd retreatment Pegylated interferon alfa-2a 180 µg/w Ribavirin 1200 mg/day TVR 2250 mg/d

38. 0 10 2 10 4 10 6 HCV-RNA (log 10 ) IU/mL 10 8 4 ALT (UI/L) 50 100 200 250 0 150 ULN Time (Weeks) 12 24 48 Patient Case: 3rd retreatment Pegylated interferon alfa-2a 180 µg/w Ribavirin 1200 mg/day TVR 2250 mg/d

39. REALIZE: Laboratory Abnormalities Cirrhotics (F4) N=139 Non-cirrhotics (F0–3) N=391 Hemoglobin ≤10g/dL ≤8.5g/dL 46 % 14 % 40 % 13 % Neutrophils Grade 3 (500 to <750/mm 3 ) Grade 4 (<500/mm 3 ) Grade 3/4 25 % 7 % 32 % 17 % 2 % 19 % Platelets Grade 3 (25,000 to <50,000/mm 3 ) Grade 4 (<25,000/mm 3 ) Grade 3/4 12 % 1 % 13 % 3 % <1 % 3 % Pol et al, AASLD 2011

40. Peg-IFN α-2a + RBV TVR + Peg-IFN α-2a + RBV Follow-up Weeks BOC + Peg-IFN α-2b + RBVFollow-up Peg-IFN + RBV 48 4 16012 8 72 36 BOC : 800 mg/8h; peg-IFNα-2b : 1,5 µg/kg/week; RBV : 800 -1400 mg/d TVR : 750 mg/8h; peg-IFNα-2a : 180 µg/week; RBV : 1000 à 1200 mg/d Interim analysis Tolerance in F3-F4 non responders the French CUPIC observatory

41. CUPIC: preliminary safety findings Telaprevir Patients, n (%)Telaprevir (n=176) Serious AEs90 (51)* Discontinuation due to serious AE 21 (12) Death3 (1.7) Rash Grade 3 SCAR 12 (6.8) 0 Infection (Grade 3/4)6 (3.4) Other AEs (Grade 3/4)92 (52) Hézode C, et al, Hepdart 2011

42. CUPIC: preliminary safety findings Telaprevir Telaprevir (n=176) Anemia Grade 2 (8.0 – <10.0 g/dL) Grade 3/4 (<8.0 g/dL) EPO use Transfusion 58 (33) 23 (13) 96 (55) 32 (18) Neutropenia Grade 3 (500 – <1000/mm 3 ) Grade 4 (<500/mm 3 ) G-CSF use 20 (11) 2 (1) 5 (3) Thrombopenia Grade 3 (25,000 – <50,000) Grade 4 (<25,000) 26 (15) 12 (7) Hézode C, et al, Hepdart 2011

43. Patients, n (%)Boceprevir (n=134) Serious AEs39 (29)* Discontinuation due to serious AE 8 (6) Death1(1) Rash Grade 3 SCAR 0000 Infection (Grade 3/4)0 Other AEs (Grade 3/4)43 (32) Hézode C, et al, Hepdart 2011 CUPIC: preliminary safety findings Boceprevir

44. Patients, n (%)Boceprevir (n=134) Anemia Grade 2 (8.0 – <10.0 g/dL) Grade 3/4 (<8.0 g/dL) EPO use Transfusion 41 (31) 8 (6) 70 (52) 8 (6) Neutropenia Grade 3 (500 – <1000/mm 3 ) Grade 4 (<500/mm 3 ) G-CSF use 10 (7) 5 (4) 7 (5) Thrombopenia Grade 3 (25,000 – <50,000) Grade 4 (<25,000) 8 (6) 3 (2) Hézode C, et al, Hepdart 2011 CUPIC: preliminary safety findings Boceprevir

45. 0 10 2 10 4 10 6 HCV-RNA (log 10 ) IU/mL 10 8 4 ALT (UI/L) 50 100 200 250 0 150 ULN Time (Weeks) 12 24 48 Patient Case: 3rd retreatment Pegylated interferon alfa-2a 180 µg/w Ribavirin 1200 mg/day TVR 2250 mg/d

46. Patient Case: rash

47. > 90% mild or moderate Incidence of rash (%) 55 33 0 20 40 60 80 100 TLR control Cutaneous reaction with Telaprevir phase II & III studies MildModeratesevere (n=1346) (n=764) Cacoub P et al, J Hepatol 2012;56:455-63

48. 0 10 2 10 4 10 6 HCV-RNA (log 10 ) IU/mL 10 8 4 ALT (UI/L) 50 100 200 250 0 150 ULN Time (Weeks) 12 24 48 Patient Case: 2nd retreatment Pegylated interferon alfa-2a 180 µg/w Ribavirin 1200 mg/day TVR 2250 mg/d

49. % of patients with rectal burning T12/PR (750 mg q8h) N=1346 Placebo/PR 48 N=764 AE26.25 AE of at least Grade 30.70 AE leading to permanent discontinuation of telaprevir/placebo 0.50 1. http://www.fda.gov/downloads/AdvisoryCommittees/Committees/Meeting Materials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252562.pdf 2. Telaprevir EU SmPC  In clinical trials, the majority of these events (e.g., haemorrhoids, anorectal discomfort, anal pruritus, and rectal burning) were mild to moderate, very few led to treatment discontinuation and resolved after completion of telaprevir dosing 2 Rectal burning with Telaprevir phase II & III studies

50. 0 10 2 10 4 10 6 HCV-RNA (log 10 ) IU/mL 10 8 4 ALT (UI/L) 50 100 200 250 0 150 ULN Time (Weeks) 12 24 48 Patient Case: 2nd retreatment Pegylated interferon alfa-2a 180 µg/w Ribavirin 1200 mg/day TVR 2250 mg/d

51. 0 10 2 10 4 10 6 HCV-RNA (log 10 ) IU/mL 10 8 4 ALT (UI/L) 50 100 200 250 0 150 ULN Time (Weeks) 12 24 48 Patient Case: 2nd retreatment 72 SVR !! Pegylated interferon alfa-2a 180 µg/w Ribavirin 1200 mg/day TVR 2250 mg/d