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Future treatment of patients with HCV cirrhosis

Explore the evolution of HCV cirrhosis treatment from PEG-IFN + RBV to potential future options, including insight on clinical trials, predictive factors, and treatment outcomes. Understand the impact of SVR in cirrhosis and the need for effective strategies in managing HCV-related complications.

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Future treatment of patients with HCV cirrhosis

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  1. Future treatment of patients with HCV cirrhosis Marc Bourlière Dept of Hepato-gastroenterology 5th 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 G1 SVR naive G2-G3 Vezali E et al. ClinTher 2010; 32: 2117-38. Bourlière M et al. AntivirTher 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. AntivirTher 2008; 13: 663-673. Gianninni EG et al. J Intern Med 2009; 266: 537-46. Aghemo A et al. AntivirTher 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. ClinTher 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 PharmacolTher 2009; 27: 1081-85. Tekin F et al. Aliment PharmacolTher 2008; 27: 1081-85.

  8. HCV decompensated cirrhosis treatment with PEG-IFN + RBV • 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 LT 15 SVR (29%) 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% + 60% + 46% Treatment-experienced patients + 40% + 45% 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% + 30% + 30% + 25% Null-responders SVR : 38 % Poordad F et al. N Engl J Med 2011: 364: 1195-1206 Sherman KE et al. N Engl J Med 2011; 365: 1014-1024. Jacobson IM et al. N Engl J Med 2011; 364 : 2405-16. Bacon BR. et al. N Engl J Med 2011; 364:1207-1217. Vierling J. et al. Hepatology 2011: 54: 796A . Zeuzem S. et al. N Engl J Med 2011;364:2417–28

  11. Treatment efficacy with PIin 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 Sustained virological response % patients with SVR 328 319 313 11 18 18 13 16 24 Bruno S et al. J Hepatol 2011: 54: S4 Poordad F et al. N Engl J Med 2011: 364: 1195-1206

  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 Sustained virological response % patients with SVR 61 117 119 5 15 9 10 17 22 Bruno S et al. J Hepatol 2011: 54: S4 Bacon BR. et al. N Engl J Med 2011; 364:1207-1217.

  14. Treatment response with Boceprevir in genotype 1 patients with severe fibrosis or cirrhosis Naive patients ( Sprint 2 study) • 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%) Naive 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 Poordad F et al. N Engl J Med 2011: 364: 1195-1206

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

  16. Treatment response with Boceprevir in genotype 1 patients with severe fibrosis or cirrhosis Treatment-experienced patients ( Respond 2 study) • 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-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 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) • 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 290 288 279 52 52 59 21 21 26 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) • 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 127 124 76 20 21 18 12 42 Sherman KE et al. N Engl J Med 2011; 365: 1014-1024.

  19. Treatment response with Telaprevir in genotype 1 patients with severe fibrosis or cirrhosis Naive patients ( Advance and Illuminate studies) • 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%) 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) Sustained virological response % patients with SVR 73 273 29 118 30 139 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) Sustained virological response Prior relapsers Prior Partial responders Prior Null responders 38 5 15 47 18 10 167 62 15 57 17 5 32 18 59 9 38 50 Pol.S et al. Hepatology 2011: 54: 374A

  22. Treatment response with Telaprevir in genotype 1 patients with severe fibrosis or cirrhosis Treatment-experienced patients ( Realize study) • 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 –experienced genotype 1 patients with severe fibrosis or cirrhosis benefit from triple therapy with Telaprevir 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 : • ADVANCE1 = 47 • ILLUMINATE2 = 61 247 • REALIZE3 = 139 • Boceprevir : • SPRINT-24 = 40 79 • RESPOND-25 = 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. 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 log10 HCV RNA decline at Week 12) • Null responders theoretically excluded • Treated in the French ATU Interim safety analysis Peg-IFN + RBV BOC + Peg-IFN α-2b + RBV Follow-up BOC : 800 mg/8h; peg-IFNα-2b : 1,5 µg/kg/week; RBV : 800 à 1400 mg/d TVR + Peg-IFN α-2a + RBV Peg-IFN α-2a + RBV Follow-up TVR : 750 mg/8h; peg-IFNα-2a : 180 µg/week; RBV : 1000 à 1200 mg/d 72 36 4 0 12 16 48 8 Weeks SVR assessment http://www.afssaps.fr/var/afssaps_site/storage/original/application/4b8c53711bab9d8f7d4c3f947caa90f6.pdf http://www.afssaps.fr/var/afssaps_site/storage/original/application/fa78af08e029caf9d82bcd9d3e77eb09.pdf Hezode C et al. Hepdart 2011

  26. Adverse Experience (AE) Summary in Combined SPRINT-2 and RESPOND-2 BOC/PR Groups by Fibrosis ScoreMedian Treatment Duration 201 days 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, % Bruno S et al. J Hepatol 2011: 54: S4

  28. CUPIC: Boceprevir – preliminary safety findings *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) *Grouped term including several different AEs in the anorectal area; Pbo = placebo Pol.S et al. Hepatology 2011: 54: 374A

  30. REALIZE: Laboratory Abnormalities Pol.S et al. Hepatology 2011: 54: 374A

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

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