Future treatment of patients with HCV cirrhosis Marc Bourlière Dept of Hepato-gastroenterology Saint Joseph Hospital, Marseille 5th Paris Hepatitis Conference Paris, January 30 th 2012 Agenda • Where do we come from : HCV cirrhosis treatment with PR • Where are we now : HCV cirrhosis treatment with PI + PR • Vision of future Agenda • Where do we come from : HCV cirrhosis treatment with PR • Where are we now : HCV cirrhosis treatment with PI + PR • Vision of future 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. Clin Ther 2010; 32: 2117-38. Bourlière M et al. Antivir Ther 2012; 17: 101-110. 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 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. 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. HCV decompensated cirrhosis treatment with PEG-IFN + RBV • 51 patients awaiting LT treated with PEG-IFN +RBV 15 SVR (29%) LT 10 no HCV recurrence (20%) • Independent predictive factors of response – Adherence to treatment – Higher dosage of drugs • Risk / benefit ratio should be assessed in patients with ChildPugh class B on a case by case basis Carrion JA et al. J Hepatol 2009; 50: 719-728. Agenda • Where do we come from : HCV cirrhosis treatment with PR • Where are we now : HCV cirrhosis treatment with PI + PR • Vision of future Virological efficacy of Boceprevir or Telaprevir Naive genotype 1 patients Increased SVR compared to Peg-IFN/RBV Boceprevir SVR increases from + 38% 30%to 63/66% Telaprevir SVR increases from 44% to 72/75% + 30% Treatment-experienced patients Relapsers SVR increases from 29% to 75% Relapsers SVR increases from 24% to 83/88% Partial-Responders SVR increases from 7% to 52% Partial-responders SVR increases from 15% to 54-59% Null-responders SVR : 38 % Null-responders SVR increases from 5% to 29/33% + 46% + 45% Poordad F et al. N Engl J Med 2011: 364: 1195-1206 Bacon BR. et al. N Engl J Med 2011; 364:1207-1217. Vierling J. et al. Hepatology 2011: 54: 796A . + 60% + 40% + 25% Sherman KE et al. N Engl J Med 2011; 365: 1014-1024. Jacobson IM et al. N Engl J Med 2011; 364 : 2405-16. Zeuzem S. et al. N Engl J Med 2011;364:2417–28 TREATMENT EFFICACY WITH PI IN GENOTYPE 1 PATIENTS WITH SEVERE FIBROSIS OR CIRRHOSIS Treatment response with Boceprevir in genotype 1 patients with severe fibrosis or cirrhosis Naive patients ( Sprint 2 study) % patients with SVR 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 328 319 313 Bruno S et al. J Hepatol 2011: 54: S4 11 18 18 13 16 24 Poordad F et al. N Engl J Med 2011: 364: 1195-1206 Treatment response with Boceprevir in genotype 1 patients with severe fibrosis or cirrhosis Treatment-experienced patients ( Respond 2 study) % patients with SVR 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 61 117 119 Bruno S et al. J Hepatol 2011: 54: S4 5 15 9 10 17 22 Bacon BR. et al. N Engl J Med 2011; 364:1207-1217. 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 Treatment response with Boceprevir in genotype 1 patients with severe fibrosis or cirrhosis RESPOND-2 SVR by Fibrosis Score and Historical Response F 0/1/2 Bruno S et al. J Hepatol 2011: 54: S4 F 3/4 Bacon BR. et al. N Engl J Med 2011; 364:1207-1217. 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. 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 288 290 279 52 52 59 21 21 26 Jacobson IM et al. N Engl J Med 2011; 364 : 2405-16. 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 124 127 76 20 21 18 12 42 Sherman KE et al. N Engl J Med 2011; 365: 1014-1024. 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. Treatment response with Telaprevir in genotype 1 patients with severe fibrosis or cirrhosis Treatment-experienced patients ( Realize study) % patients with SVR 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 73 273 29 118 30 139 Zeuzem S. et al. N Engl J Med 2011;364:2417–28 Treatment response with Telaprevir in genotype 1 patients with severe fibrosis or cirrhosis Treatment-experienced patients ( Realize study) Sustained virological response Prior relapsers 38 167 15 62 Prior Partial responders 15 57 17 47 5 18 5 32 Prior Null responders 18 59 9 38 10 50 Pol.S et al. Hepatology 2011: 54: 374A 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 TREATMENT SAFETY WITH PI IN GENOTYPE 1 PATIENTS WITH SEVERE FIBROSIS OR CIRRHOSIS 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 • REALIZE3 = 139 247 – Boceprevir : • SPRINT-24 = 40 • RESPOND-25 = 39 79 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 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 PegIFN + 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 α2a + RBV Follow-up Peg-IFN α-2a + RBV TVR : 750 mg/8h; peg-IFNα-2a : 180 µg/week; RBV : 1000 à 1200 mg/d 0 4 8 12 16 Weeks 36 48 72 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 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 Treatment-emergent AE Serious AE Discontinuation due to AE Dose modification due to AEb Death F0/1/2 N=868 n (%) F3/4 N=139 n (%) 862 (99) 99 (11) 116 (13) 301 (35) 3c (<1) 138 (99) 21 (15) 17 (12)a 57 (41) 0 a 11/79 (14%) discontinuations due to AE in F4 group; 6/60 (10%) in F3. Any study drug c All deaths were in F0/1/2 group and were suicides. b Bruno S et al. J Hepatol 2011: 54: S4 Safety: Most Common (>20%) AEs by Fibrosis Score, % Adverse Events Fatigue Anemia Dysgeusia Headache Nausea Chills Pyrexia Insomnia Myalgia Diarrhea Influenza-like illness Rash Decreased appetite Dry Skin Vomiting Irritability PR F0/1/2 N=389 98 58 28 16 44 41 28 32 31 25 21 26 20 23 18 15 21 PR F3/4 N=39 100 56 26 18 33 46 26 31 28 18 18 23 13 23 3 8 28 BOC/PR BOC/PR F0/1/2 F3/4 N=868 N=139 99 99 55 56 47 53 41 44 44 42 46 38 34 37 31 34 32 30 23 29 24 28 24 25 22 23 25 22 21 22 18 21 22 21 Bruno S et al. J Hepatol 2011: 54: S4 CUPIC: Boceprevir – preliminary safety findings Patients, n (%) Boceprevir (n=134) Phase III study (79) 39 (29)* 21 (15) Discontinuation due to serious AE 8 (6) 14% Death 1(1) 0 Serious AEs Rash Grade 3 SCAR 23% 0 0 Infection (Grade 3/4) 2 (1,4) Other AEs (Grade 3/4) Anemia Grade 2 (8.0 – <10.0 g/dL) Grade 3/4 (<8.0 g/dL) EPO use Transfusion 41 (31) Neutropenia Grade 3 (500 – <1000/mm3) Grade 4 (<500/mm3) G-CSF use Thrombopenia Grade 3 (25,000 – <50,000) Grade 4 (<25,000) 53% 41 (31) 8 (6) 70 (52) 8 (6) 10 (7) 5 (4) 7 (5) 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 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 10 (7) 17 (4) 27 (5) 1 (<1) 1 (<1) 2 (<1) Anemia 0 3 (<1) 3 (<1) Pruritus 1 (<1) 0 1 (<1) 0 2 (<1) 2 (<1) 21 (15) 46 (12) 67 (13) Rash 4 (3) 6 (2) 10 (2) Anemia 3 (2) 9 (2) 12 (2) Pruritus 2 (1) 2 (<1) 4 (<1) 1 (<1) 2 (<1) 3 (<1) Rash Anorectal signs and symptoms* Discontinuation of TVR or Pbo during TVR treatment phase, n (%) Any AE Anorectal signs and symptoms* *Grouped term including several different AEs in the anorectal area; Pbo = placebo Pol.S et al. Hepatology 2011: 54: 374A REALIZE: Laboratory Abnormalities Cirrhotics (F4) N=139 Non-cirrhotics (F0–3) N=391 ≤10g/dL 63 (46) 156 (40) ≤8.5g/dL 19 (14) 49 (13) Grade 3 (500 to <750/mm3) 35 (25) 68 (17) Grade 4 (<500/mm3) 10 (7) 9 (2) Grade 3/4 45 (32) 77 (19) 16 (12) 12 (3) 2 (1) 1 (<1) 18 (13) 13 (3) n (%) Hemoglobin Neutrophils Platelets Grade 3 (25,000 to <50,000/mm3) Grade 4 (<25,000/mm3) Grade 3/4 Pol.S et al. Hepatology 2011: 54: 374A CUPIC: telaprevir – preliminary safety findings Patients, n (%) Telaprevir (n=176) Phase III studies (n=139) Serious AEs 90 (51)* Discontinuation due to serious AE 21 (12) 10 (7) 21 (15) Death 3 (1.7) 0 Rash Grade 3 SCAR 58 (42) 12 (6.8) 0 Infection (Grade 3/4) 8(4.5) Other AEs (Grade 3/4) Anemia Grade 2 (8.0 – <10.0 g/dL) Grade 3/4 (<8.0 g/dL) EPO use Transfusion 84 (48) Neutropenia Grade 3 (500 – <1000/mm3) Grade 4 (<500/mm3) G-CSF use Thrombopenia Grade 3 (25,000 – <50,000) Grade 4 (<25,000) 58 (33) 23 (13) 96 (55) 32 (18) 54 (39) 46% 14% 20 (11) 2 (1) 5 (3) 25% 7% 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 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. 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 Agenda • Where do we come from : HCV cirrhosis treatment with PR • Where are we now : HCV cirrhosis treatment with PI + PR • Vision of future HCV treatment: future perspectives 2014/2015? 2016/2017? Protocols for HCV cirrhotic patients are expected NS5B Polymerase inhibitor + PR PI + PR 83% BI 201335 + PR SVR G1 TMC435 + PR 86% SVR G1 PSI-7977 + PR 91% SVR G1 100% SVR G2/3 PI: protease inhibitor; PR: peginterferon + ribavirin; DAA: direct-acting antiviral QUAD therapy Interferon free/sparing regimens BMS-650032 + BMS-790052 + PR BMS-650032 + BMS-790052 100% SVR G1 PSI-7977 + RBV 100% SVR G2/3 Lok AS et al. N Engl J Med 2012; 366: 216-224.