1. Future treatment of patients with HCV cirrhosis Marc Bourlière Dept of Hepato-gastroenterology 5 th Paris Hepatitis Conference Saint Joseph Hospital, Marseille Paris, January 30 th 2012

2. Agenda Where do we come from : HCV cirrhosis treatment with PR Where are we now : HCV cirrhosis treatment with PI + PR Vision of future

3. Agenda Where do we come from : HCV cirrhosis treatment with PR Where are we now : HCV cirrhosis treatment with PI + PR Vision of future

4. HCV cirrhosis treatment with PEG-IFN + RBV Clinical trials SVR in compensated cirrhosis ranged : – 10 to 44% in HCV genotypes 1 /4 – 33 to 72% in HCV genotypes 2/3 Real-life setting cohort : 306 cirrhotic / 2011 patients SVR naive G1SVR naive G2-G3 Vezali E et al. Clin Ther 2010; 32: 2117-38. Bourlière M et al. Antivir Ther 2012; 17: 101-110.

5. HCV cirrhosis treatment with PEG-IFN + RBV Beneficial impact of SVR in cirrhosis : – Improvement of fibrosis – Regression of cirrhosis – Reduction and prevention of cirrhosis-related complications ( portal hypertension or HCC ) HCC surveillance programs should be maintained : – HCC occur years after : 0.6 to 2.5% annually Heathcote EJ et al. N Engl J Med 2000; 343: 1673-1680 Helbling B et al. J Viral Hepat 2006; 13: 762-69. Abergel A et al. J Viral Hepat 2006; 13: 811-20. Di Marco V et al. J Hepatol 2007; 47: 484-491. Roffi L et al. Antivir Ther 2008; 13: 663-673. Gianninni EG et al. J Intern Med 2009; 266: 537-46. Aghemo A et al. Antivir Ther 2009; 14: 577-84. Rumi MG et al. Gastroenterology 2010; 138: 108-115. Cheng WS et al. J Hepatol 2010; 53: 616-623. Bruno S et al. Hepatology 2010; 51: 388-397. Hadziyannis SJ et al. Ann Intern Med 2004;140 :436-55. Shiratori Y et al. Ann Intern Med 2005; 142: 105-114. Hung CH et al. J Viral Hepat 2006; 13: 409-414. Veldt BJ et al. Ann Intern Med 2007; 147: 677-684. Kobayashi S et al. Liver Int 2007; 27: 186-191

6. HCV cirrhosis treatment with PEG-IFN + RBV Predictive factors of response: – RVR is the strongest PFR – Role of type of PEG-IFN remain controversial Safety and tolerance of PR in cirrhotic is not different : – Dose modifications are more frequent ( hematological toxicity) – Rate of liver decompensation is low (0-3%) caution in real-life practice Vezali E et al. Clin Ther 2010; 32: 2117-38.

7. HCV decompensated cirrhosis treatment with PEG-IFN + RBV The most in need of treatment ( 5years survival rate : 50%) SVR rates ranged : – 7 to 16% in genotype 1-4 – 44 to 57% in genotype 2-3 Treatment limitation: – Higher risk of infection and deaths related to infection – More frequent side effects in Child Pugh C (MELD >18) Treatment benefit : – Lower rate of decompensation during follow-up – Reduced mortality in responders Fattovich G et al. Gastroenterology 1997; 112: 463-72. Forns X et al. J Hepatol 2003; 39: 389-96. Iacobellis A et al. J Hepatol 2007; 46: 206-212. Iacobellis A et al. Aliment Pharmacol Ther 2009; 27: 1081-85. Tekin F et al. Aliment Pharmacol Ther 2008; 27: 1081-85.

8. 51 patients awaiting LT treated with PEG-IFN +RBV Independent predictive factors of response – Adherence to treatment – Higher dosage of drugs Risk / benefit ratio should be assessed in patients with Child- Pugh class B on a case by case basis HCV decompensated cirrhosis treatment with PEG-IFN + RBV 15 SVR (29%) LT 10 no HCV recurrence (20%) Carrion JA et al. J Hepatol 2009; 50: 719-728.

9. Agenda Where do we come from : HCV cirrhosis treatment with PR Where are we now : HCV cirrhosis treatment with PI + PR Vision of future

10. Virological efficacy of Boceprevir or Telaprevir Naive genotype 1 patients Increased SVR compared to Peg-IFN/RBV Boceprevir SVR increases from 38% to 63/66% Telaprevir SVR increases from 44% to 72/75% + 30% Treatment-experienced patients Relapsers SVR increases from 29% to 75% Partial-Responders SVR increases from 7% to 52% Relapsers SVR increases from 24% to 83/88% Partial-responders SVR increases from 15% to 54-59% Null-responders SVR increases from 5% to 29/33% Null-responders SVR : 38 % + 60% + 40% + 25% + 46% + 45% Sherman KE et al. N Engl J Med 2011; 365: 1014-1024. Jacobson IM et al. N Engl J Med 2011; 364 : 2405-16. Poordad F et al. N Engl J Med 2011: 364: 1195-1206 Vierling J. et al. Hepatology 2011: 54: 796A. Bacon BR. et al. N Engl J Med 2011; 364:1207-1217. Zeuzem S. et al. N Engl J Med 2011;364:2417–28

11. TREATMENT EFFICACY WITH PI IN GENOTYPE 1 PATIENTS WITH SEVERE FIBROSIS OR CIRRHOSIS

12. Treatment response with Boceprevir in genotype 1 patients with severe fibrosis or cirrhosis Naive patients ( Sprint 2 study)  100/ 1097 patients had F3 (47) or F4 (53)  SVR rates in patients with advanced fibrosis : 52% BOC/PR48, 41% BOC RGT, 38% PR Poordad F et al. N Engl J Med 2011: 364: 1195-1206 Bruno S et al. J Hepatol 2011: 54: S4 3283193131118 131624 % patients with SVR Sustained virological response

13. Treatment response with Boceprevir in genotype 1 patients with severe fibrosis or cirrhosis Treatment-experienced patients ( Respond 2 study)  78/ 403 patients had F3 (29) or F4 (49)  SVR rates in patients with advanced fibrosis : 68% BOC/PR48, 44% BOC RGT, 13% PR Bruno S et al. J Hepatol 2011: 54: S4 611171195159101722 % patients with SVR Sustained virological response Bacon BR. et al. N Engl J Med 2011; 364:1207-1217.

14. SVR with Boceprevir is increased by 14% compared with PR Relapse rate is more frequent (12-18% vs 9%) RVR during triple therapy is less frequent (25% vs 46%) SVR in RVR patients is higher in patients receiving 48 weeks of treatment ( 92%) compared with those receiving RGT (75%) Treatment response with Boceprevir in genotype 1 patients with severe fibrosis or cirrhosis Naive patients ( Sprint 2 study) Naive genotype 1 patients with severe fibrosis or cirrhosis Benefit from triple therapy with Boceprevir but should received 48 weeks of treatment Poordad F et al. N Engl J Med 2011: 364: 1195-1206 Bruno S et al. J Hepatol 2011: 54: S4

15. Treatment response with Boceprevir in genotype 1 patients with severe fibrosis or cirrhosis RESPOND-2 SVR by Fibrosis Score and Historical Response F 0/1/2F 3/4 Bruno S et al. J Hepatol 2011: 54: S4 Bacon BR. et al. N Engl J Med 2011; 364:1207-1217.

16. SVR with Boceprevir is increased by 42% compared with PR Relapse rate is more frequent (21% vs 11%) RVR during triple therapy is less frequent (25% vs 53%) SVR in RVR patients is higher in patients receiving 48 weeks of treatment ( 90%) compared with those receiving RGT (80%) Treatment response with Boceprevir in genotype 1 patients with severe fibrosis or cirrhosis Treatment-experienced genotype 1 patients with severe fibrosis or cirrhosis Benefit from triple therapy with Boceprevir but should received 48 weeks of treatment Bruno S et al. J Hepatol 2011: 54: S4 Treatment-experienced patients ( Respond 2 study) Bacon BR. et al. N Engl J Med 2011; 364:1207-1217.

17. Treatment response with Telaprevir in genotype 1 patients with severe fibrosis or cirrhosis Naive patients ( ADVANCE study) 288 290 27952 5921 26  231/ 1088 patients had advanced fibrosis F3 (163) or F4 (68)  SVR rates in patients with advanced fibrosis : 62% T12PR48, 53% T8PR48, 33% PR Sustained virological response Jacobson IM et al. N Engl J Med 2011; 364 : 2405-16.

18. Treatment response with Telaprevir in genotype 1 patients with severe fibrosis or cirrhosis Naive patients ( ILLUMINATE study) 124 127 762021181242  149/ 540 patients had advanced fibrosis F3 (88) or F4 (61)  SVR rates in patients with advanced fibrosis : 63% vs 75% F0/1/2 Sustained virological response Sherman KE et al. N Engl J Med 2011; 365: 1014-1024.

19. SVR with Telaprevir (T12) is increased by 30% compared with PR eRVR during triple therapy is less frequent (46 - 49% vs 58 - 60%) SVR in RVR patients is higher in patients receiving 48 weeks of treatment ( 88%) compared with those receiving 24 weeks (82%) Treatment response with Telaprevir in genotype 1 patients with severe fibrosis or cirrhosis Naive patients ( Advance and Illuminate studies) Naive genotype 1 patients with severe fibrosis or cirrhosis Benefit from triple therapy with Telaprevir but should received 48 weeks of treatment in case of cirrhosis Sherman KE et al. N Engl J Med 2011; 365: 1014-1024. Jacobson IM et al. N Engl J Med 2011; 364 : 2405-16.

20. Treatment response with Telaprevir in genotype 1 patients with severe fibrosis or cirrhosis Treatment-experienced patients ( Realize study)  316/ 663 patients had advanced fibrosis F3 (147) or F4 (169)  SVR rates in patients with advanced fibrosis : 67% T12PR48 vs 7% PR (F3) 47% T12 PR 48 vs10% PR (F4) 732732911830139 % patients with SVR Sustained virological response Zeuzem S. et al. N Engl J Med 2011;364:2417–28

21. Treatment response with Telaprevir in genotype 1 patients with severe fibrosis or cirrhosis Treatment-experienced patients ( Realize study) Pol.S et al. Hepatology 2011: 54: 374A Sustained virological response Prior relapsers Prior Partial responders Prior Null responders 38 167 15 62155717 47 5 18 5321859938 10 50

22. SVR with Telaprevir (T12) is increased compared with PR irrespective of fibrosis stage. SVR rates are lower in patients with cirrhosis except in relapsers. Relapse rate is higher in cirrhotic patients with previous partial or null response (10% vs 4%). No relation between advanced fibrosis and RAVs occurrence Predictive factors of response : – Previous PR response – High baseline ALT or AST Treatment response with Telaprevir in genotype 1 patients with severe fibrosis or cirrhosis Treatment –experienced genotype 1 patients with severe fibrosis or cirrhosis benefit from triple therapy with Telaprevir Treatment-experienced patients ( Realize study) Zeuzem S. et al. N Engl J Med 2011;364:2417–28 Pol.S et al. Hepatology 2011: 54: 374A

23. TREATMENT SAFETY WITH PI IN GENOTYPE 1 PATIENTS WITH SEVERE FIBROSIS OR CIRRHOSIS

24. Safety issue in phase III trials In Phase III trial safety issue were reported : – Rash, pruritus and anemia with Telaprevir (TVR) – Anemia and dysgeusia with Boceprevir (BOC) Few patients with cirrhosis were included : – Telaprevir : ADVANCE 1 = 47 ILLUMINATE 2 = 61 247 REALIZE 3 = 139 – Boceprevir : SPRINT-2 4 = 40 79 RESPOND-2 5 = 39 1. Jacobson IM, et al, N Engl J Med 2011;364:2405-16 2. Sherman KE, et al, N Engl J Med 2011;365:1014-24 3. Zeuzem S, et al, N Engl J Med 2011;364:2417-28 4. Poordad F, et al, N Engl J Med 2011;364:1195-206 5. Bacon BR, et al, N Engl J Med 2011;364:1207-17

25. http://www.afssaps.fr/var/afssaps_site/storage/original/application/4b8c53711bab9d8f7d4c3f947caa90f6.pdf http://www.afssaps.fr/var/afssaps_site/storage/original/application/fa78af08e029caf9d82bcd9d3e77eb09.pdf Peg-IFN α-2a + RBV TVR + Peg-IFN α- 2a + RBV Follow-up 48 4 16012 8 Weeks 72 SVR assessment BOC + Peg-IFN α-2b + RBVFollow-up Peg- IFN + RBV 36 BOC : 800 mg/8h; peg-IFNα-2b : 1,5 µg/kg/week; RBV : 800 à 1400 mg/d TVR : 750 mg/8h; peg-IFNα-2a : 180 µg/week; RBV : 1000 à 1200 mg/d Interim safety analysis From February 2011 to September 1th 2011 430 patients were included in 51 sites 310 patients were included in this analysis HCV genotype 1 patients Compensated cirrhosis (Child Pugh A) genotype 1 Non-responders – Relapsers – Partial responders (  >2 log 10 HCV RNA decline at Week 12) – Null responders theoretically excluded Treated in the French ATU Hezode C et al. Hepdart 2011

26. Adverse Experience (AE) Summary in Combined SPRINT-2 and RESPOND-2 BOC/PR Groups by Fibrosis Score Median Treatment Duration 201 days SPRINT-2 and RESPOND-2 BOC/PR F0/1/2 N=868 n (%) F3/4 N=139 n (%) Treatment-emergent AE862 (99)138 (99) Serious AE99 (11)21 (15) Discontinuation due to AE116 (13)17 (12) a Dose modification due to AE b 301 (35)57 (41) Death3 c (<1)0 a 11/79 (14%) discontinuations due to AE in F4 group; 6/60 (10%) in F3. b Any study drug c All deaths were in F0/1/2 group and were suicides. Bruno S et al. J Hepatol 2011: 54: S4

27. Safety: Most Common (>20%) AEs by Fibrosis Score, % PR F0/1/2 N=389 PR F3/4 N=39 BOC/PR F0/1/2 N=868 BOC/PR F3/4 N=139 Adverse Events9810099 Fatigue58565556 Anemia28264753 Dysgeusia16184144 Headache44334442 Nausea4146 38 Chills28263437 Pyrexia3231 34 Insomnia31283230 Myalgia25182329 Diarrhea21182428 Influenza-like illness26232425 Rash20132223 Decreased appetite23 2522 Dry Skin1832122 Vomiting1581821 Irritability21282221 Bruno S et al. J Hepatol 2011: 54: S4

28. CUPIC: Boceprevir – preliminary safety findings Patients, n (%)Boceprevir (n=134)Phase III study (79) Serious AEs39 (29)*21 (15) Discontinuation due to serious AE8 (6)14% Death1(1)0 Rash Grade 3 SCAR 0000 23% Infection (Grade 3/4)2 (1,4) Other AEs (Grade 3/4)41 (31) 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) 53% 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) *86serious AEs in 39 patients; SCAR: severe cutaneous adverse reaction; EPO: erythropoetin; G-CSF: granulocyte-colony stimulating factor Hezode C et al. Hepdart 2011

29. REALIZE: AEs Leading to Study Drug Discontinuation (FAS, Pooled TVR arms, N=530) Cirrhotics (F4) N=139 Non-cirrhotics (F0–3) N=391 Total N=530 Discontinuation of all study drugs during TVR treatment phase, n (%) Any AE Rash Anemia Pruritus Anorectal signs and symptoms* 10 (7) 1 (<1) 0 1 (<1) 0 17 (4) 1 (<1) 3 (<1) 0 2 (<1) 27 (5) 2 (<1) 3 (<1) 1 (<1) 2 (<1) Discontinuation of TVR or Pbo during TVR treatment phase, n (%) Any AE Rash Anemia Pruritus Anorectal signs and symptoms* 21 (15) 4 (3) 3 (2) 2 (1) 1 (<1) 46 (12) 6 (2) 9 (2) 2 (<1) 67 (13) 10 (2) 12 (2) 4 (<1) 3 (<1) *Grouped term including several different AEs in the anorectal area; Pbo = placebo Pol.S et al. Hepatology 2011: 54: 374A

30. REALIZE: Laboratory Abnormalities n (%) Cirrhotics (F4) N=139 Non-cirrhotics (F0–3) N=391 Hemoglobin ≤10g/dL ≤8.5g/dL 63 (46) 19 (14) 156 (40) 49 (13) Neutrophils Grade 3 (500 to <750/mm 3 ) Grade 4 (<500/mm 3 ) Grade 3/4 35 (25) 10 (7) 45 (32) 68 (17) 9 (2) 77 (19) Platelets Grade 3 (25,000 to <50,000/mm 3 ) Grade 4 (<25,000/mm 3 ) Grade 3/4 16 (12) 2 (1) 18 (13) 12 (3) 1 (<1) 13 (3) Pol.S et al. Hepatology 2011: 54: 374A

31. CUPIC: telaprevir – preliminary safety findings Patients, n (%)Telaprevir (n=176)Phase III studies (n=139) Serious AEs90 (51)* Discontinuation due to serious AE21 (12)10 (7) 21 (15) Death3 (1.7)0 Rash Grade 3 SCAR 12 (6.8) 0 58 (42) Infection (Grade 3/4)8(4.5) Other AEs (Grade 3/4)84 (48) 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) 54 (39) 46% 14% Neutropenia Grade 3 (500 – <1000/mm 3 ) Grade 4 (<500/mm 3 ) G-CSF use 20 (11) 2 (1) 5 (3) 25% 7% Thrombopenia Grade 3 (25,000 – <50,000) Grade 4 (<25,000) 26 (15) 12 (7) 12% 1% *228serious AEs in 90 patients; SCAR: severe cutaneous adverse reaction; EPO: erythropoetin; G-CSF: granulocyte-colony stimulating factor Hezode C et al. Hepdart 2011

32. Conclusion Triple therapy with first generation PI is a major step forward in treatment of both naïve and treatment-experienced genotype 1 compensated cirrhotic patients. Cirrhotic patients with prior relapse or partial response have the greatest benefit in SVR rate with both PI. Triple therapy with PI appears to be less beneficial in cirrhotic patients with prior null-response and this should be weighed against the increase of side effects.

33. Conclusion The safety profile of PI among compensated cirrhotic patients treated in the CUPIC cohort is poor, however, it is compatible with use in real-life practice. Patients with cirrhosis should treated with cautious and should be carefully monitored due to High incidence of anemia with poor response to EPO. There is no data on the efficacy and safety of triple therapy with PI in decompensated cirrhosis

34. Agenda Where do we come from : HCV cirrhosis treatment with PR Where are we now : HCV cirrhosis treatment with PI + PR Vision of future

35. HCV treatment: future perspectives PI: protease inhibitor; PR: peginterferon + ribavirin; DAA: direct-acting antiviral 2014/2015? 2016/2017? 100% SVR G1 83% SVR G1 86% SVR G1 91% SVR G1 100% SVR G2/3 Protocols for HCV cirrhotic patients are expected Lok AS et al. N Engl J Med 2012; 366: 216-224.