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Future treatment of patients with HCV cirrhosis

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. Agenda.

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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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