47 th Annual Meeting AISF

Transcription

1 47 th Annual Meeting AISF Rome, 21 February 2014 Present and future treatment strategies for patients with HCV infection: chronic hepatitis and special populations (HCV/HIV coinfection, advanced cirrhosis, transplantation) IFN Based Regimens Alessio Aghemo, MD Division of Gastroenterology and Hepatology Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico University of Milan Milan, Italy

2 Is there Still a Place for PegIFN Based Regimens? Gilead Announces SVR12 Rates From Three Phase 3 Studies Evaluating a Once-Daily Fixed-Dose Combination of Sofosbuvir and Ledipasvir for Genotype 1 Hepatitis C Patients Gilead Sciences Press Release December 2013 AbbVie Demonstrates 96 percent SVR(12) in its Phase III Study of Treatment-Experienced Patients with Genotype 1 Hepatitis C AbbVie Press Release December 2013

3 Why Do Some DAAs Still Need PegIFN? Baseline HCV RNA Drug Potency Viral breakthrough HCV RNA X X X X X X X X X Resistance Barrier Before Treatment Time on Treatment with DAA Alone Resistant virus Sensitive virus

4 PegIFN The Ideal (?!) Backbone For Many DAAs NS3 1 WAVE NS3 2 WAVE NS5A NUC NS5B (TVR & BOC) ( SMV & FDV) (DCV) (SOF) Resistance Barrier Good Average Requires PegIFN + RBV in HCV-1,4 and 3 Unfavorable

5 Factors Associated with Response to HCV Therapy with PegIFN/Rbv Based Therapy Patient Factors Virus Factors Treatment Factors Cirrhosis IFN λ 3,4 Genotype HIV coinfection Race Body weight Insulin resistance Fatty liver disease HCV genotype HCV RNA level Adherence Clinician s skill EASL HCV CPG J Hepatol in press

6 Advanced Fibrosis is Associated with Reduced SVR Rates with TVR/BOC Telaprevir Boceprevir No, minimal or portal fibrosis Bridging fibrosis or cirrhosis No, minimal or portal fibrosis Bridging fibrosis or cirrhosis SVR (%) n/n= T12PR 237/290 T12PR 48/73 n/n= BOC RGT 213/319 BOC44/PR48 22/42 Jacobson I, et al NEJM 2011 & Poordad F, et al. NEJM 2011

7 The TVR EAP: SVR Rates Stratified by Disease Severity and Pattern of Previous Response 100 F3 FIBROSIS 80 72% 77% F4 FIBROSIS 63% 64% SVR (%) % 53% 41% 29% /125 59/94 160/203 94/146 35/61 41/77 49/119 50/175 Naive Relapsers Partial responders Null responders Colombo M, et al. Submitted

8 Cirrhosis Reduces SVR Rates to PegIFN/RBV and Simeprevir QUEST-1 QUEST-2 No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis SVR (%) n/n= 188/229 18/31 n/n= 189/231 11/17 Jacobson I, et al EASL 2013 & Manns MP et al, EASL 2013

9 Simeprevir plus PegIFN/Rbv in Experienced Patients SVR 12 in pooled TMC arms / /135 50/99 Relapsers Zeuzem S, et al. Gastroenterology 2014 Partial Responders Null Responders

10 Sofosbuvir plus PegIFN/Rbv in Treatment-Naive HCV-1/4/5/6 Patients Open-label, single-arm study; 327 HCV-1/4/5/6 Naïve patients, 17% cirrhosis SVR12 (%) /292 27/28 7/7 HCV 1 HCV 4 HCV 5,6 252/273 43/54 No Cirrhosis Cirrhosis Lawitz E., NEJM 2013; 368:

11 Decreased SVR With Sofosbuvir plus PegIFN/RBV in HCV-1b with Cirrhosis Lawitz, et al. NEJM 2013

12 SVR4 in HIV/HCV G1 Treated with PegIFN/Rbv Containing Regimens 4/4 16/18 13/15 178/242 72/88 16/28 7/10 13/15 17/19 169/239 17/19 229/308 Rodriguez Torres M et al IDSA 2013; Dieterich EACS 2013; Rockstroh The Liver Congress 2013 Courtesy of Massimo Puoti

13 Patients To Manage With Caution When Using PegIFN/RBV-Based Regimens Contraindications to antiviral treatment Degasperi E et al J Viral Hepatitis 2012;19:3-6 Major uncontrolled depressive illness Solid organ transplant (heart, lung, kidney) Autoimmune hepatitis Pregnancy /unwilling to comply with contraception Severe concurrent medical diseases Age < 2 years Patients requiring expert clinical management ESRD Patients on hemodialysis Decompensated liver disease Post-OLT patients

14 TVR with reduced RBV Plus PegIFN in HCV Hemodialysis Patients Wk 12 Wk 24 Wk 36 Wk 48 Pts with GT 1 HCV; on hemodialysis (N = 36) n = 12 n = 12 n = 12 TVR + PegIFN/RBV 200 mg PegIFN/RBV 400 mg TVR + PegIFN + Placebo PegIFN/RBV 400 mg Placebo + PegIFN/RBV 400 mg PegIFN alfa-2a dosed at 135 µg/wk 100 HCV RNA Undetectable (%) n/ N = 67 8/ / 12 EOT 25 3/ / / 12 SVR 25 3/ 12 Increased incidence of select AEs (TVR arms vs pegifn/rbv) Anemia (54% vs 33%) Neutropenia (50% vs 33%) Basu P, et al. EASL 2013.

15 CUPIC Baseline Characteristics: F4 Treatment-experienced Patients Baseline characteristic, % TVR CUPIC 1 N=292 REALIZE F4 2 N=169* BOC CUPIC 1 N=205 RESPOND 2 3 (BOC44/PR48) F0 F4 N=161 Male Mean/median age, years (range) 57.2 (27 83) 54 (24 68) 56.9 (34 81) 52.3 F Platelets, /mm 3 (range) 152,000 (18, ,000) 167,000 (88, ,000) 146,000 (33, ,000) 88% >150,000 Serum albumin, g/l (range) 40.1 ( ) ( ) - Total bil, µmol/l (range) 15.4 ( ) ( ) - Esophageal varices 33 excluded 40 - Exclusion criteria REALIZE RESPOND *All arms (TVR arms + control arm) 1. Hézode C, et al. J Hepatol. 2013;59: Pol S, et al. AASLD 2011; Abstract Bacon B, et al. N Engl J Med 2011;364:

16 CUPIC Week 60 analysis: safety overview Outcomes, % TVR CUPIC N=299 BOC CUPIC N=205 Serious adverse event Discontinuation due to SAE Death, n (%) 8 (2.7) 3 (1.4) Infections (grade 3/4) EPO use Transfusion RBV dose reduction Hézode C, et al. Unpublished data

17 CUPIC: SVR12 and the risk of occurrence of severe complications Platelets count Platelets count 100,000/mm 3 >100,000/mm 3 Albumin <35 g/l N Complications, n (%) SVR12, n (%) (51.4%) 8 (21.6%) 31 5 (16.1%) 8 (29.0%) Albumin 35 g/l N Complications, n (%) SVR12, n (%) 74 9 (12.2%) 25 (33.8%) (6.2%) 165 (53.9%) Hézode C, et al. Unpublished data

18 EAP TVR: Serious Adverse Events Variable Bridging Fibrosis (F3) (N=752) Cirrhosis (F4) (N=835) Overall (N=1587) Subjects with one or more SAE 76 (10%) 110 (13%) 186 (12%) Anaemia 32 (4%) 43 (5%) 75 (5%) Rash 12 (2%) 16 (2%) 28 (2%) Infection 6 (1%) 20 (2%) 26 (2%) Pyrexia 4 (1%) 8 (1%) 12 (1%) Death 1 (0.1%) 6 (0.7%) 7 (0.4%) Colombo M, et al. GUT in press

19 Safety and Efficacy of TVR/BOC For HCV after OLT BOC (n= 18) TVR (n=19) Death, No (%) 2 (11) 1 (5) Infections, No (%) 5 (27) 5 (26) Hb <8 g/dl, No (%) 7 (39) 5 (26) Renal Failure, No (%) 1 (5) 4 (21) Rehospitalization, No (%) 6 (33) 6 (32) Coilly A et al, J Hepatol 2014;60:78-86

20 Recurrent HCV Treatment by TVR-BOC + PegIFN/Rbv: Cohort and Clinical Studies DAA Pts Population HCV-1a SVR-12 Disco Faisal, et al TVR BOC 76 F0-F2 72% 58% 44% Stravitz et al TVR 125 F3-F4 =48% 58% 59% 20% Coilly et al TVR 79 F3-F4,FCH =78% 33% 46% 55% BOC Pungpapong et al TVR 60 F3-F4 50% 68% 50% 20% FCH 8% SVR predictors: Cya; (RVR, EVR), Treatment Duration, Predictors of infections: FCH, Bilirubin; Anemia, Trombocytopenia

21 Conclusions PegIFN/Rbv based DAA regimens share the strengths and limits of PegIFN/Rbv Reduced Efficacy in Cirrhotics & Null Responders Sub-optimal Safety in Advanced Cirrhosis, ESRD Require expert management in post-olt Access to IFN free regimens should be prioritized in these groups