Hepatitis C Emerging Treatment Paradigms

Transcription

1 Hepatitis C Emerging Treatment Paradigms David R Nelson MD Assistant Vice President for Research Professor of Medicine Director, Clinical and Translational Science Institute University of Florida Gainesville, USA Disclosures I have received research grant funding from Abbvie, BI, BMS, Genentech, Gilead, Janssen, Merck, Vertex I serve as a non-paid consultant for Abbvie, BI, Gilead, Merck This talk will include discussion about unapproved new agents and off-label use of approved therapies 1

2 Outline Background Overview of treatment regimens Keys to integration of new DAAs IFN-containing IFN-free Practical approaches to treatment Genotype 1, 2, 3 Special populations Viral Hepatitis: Historical Perspective Government and Industry Partnership HBV discovered HAV discovered non-a, non-b hepatitis HCV discovered IFN approval IFN-free approval Clinical Research Clinical Research NIH* Translational Research Translational PhRMA Basic Research Basic *NIH has invested $4B for HCV-related research (NIH Reporter ) 2

3 Seroprevalence of Hepatitis C: 170 to 200 Million Worldwide United States 5M Americas M Eastern Europe 10 M Western Europe 5 M Highest Prevalence: Egypt-4M (45% adults >40y) Africa 30-40M Western Pacific 60 M Southeast Asia M Australia.2 M 1. World Health Organization. Wkly Epidemiol Rec ;75: Edlin B et al. AASLD; November 11-15; 15; 2005 San Francisco, California. Oral Presentation #44. P-DS-D-159 HCV Increases All Cause Mortality All Causes Anti-HCV seropositives, HCV RNA detectable Anti-HCV seropositives, HCV RNA undetectable Anti-HCV seronegatives 30.1% Cu umulative mortality (%) P<0.001 for comparison among three groups P<0.001 for HCV RNA detectable vs. undetectable 12.8% 12.4% Follow-up years Lee MH, et al. J Infect Dis. 2012;206(4):

4 SVR is Associated with Reduced Mortality Among HCV-infected Persons 530 adults in Europe prospectively followed for median 8.4 years after HCV treatment 192 (36%) achieved SVR All-cause mortality, % P<0.001 All-cause mortality Without SVR With SVR Time, y No. at risk Without SVR With SVR Liver-related mortality or liver tra ansplantation, % Liver-related mortality or liver transplantation P<0.001 Without SVR With SVR Time, y No. at risk Without SVR With SVR Van der Meer, et al. JAMA 2012:308: % of Infected Individuals Are Not Aware of Their HCV Status 1. Institute of Medicine. Hepatitis and Liver Cancer, A National Strategy for Prevention and Control of Hepatitis B and C. Washington, DC. The National Academies Press, 2010; 2.United States Department of Health and Human Services. Combating the Silent Epidemic of Viral Hepatitis, Action Plan for the Prevention, Care & Treatment of Viral Hepatitis

5 CDC Releases Birth Cohort Screening Guidelines Adults born during should receive one-time testing for HCV without prior ascertainment of HCV risk All persons identified d with HCV infection should receive a brief alcohol l screening and intervention as clinically indicated, followed by referral to appropriate care and treatment services Smith BD, et al. MMWR Recomm Rep. 2012;61(RR-4):1-32. The New Era of HCV Therapy Multiple Direct Acting Antivirals 5 UTR Core E1 E2 NS2 NS3 NS4B NS5A NS5B p7 4A 3 UTR Protease Polymerase HCV PIs NS5A Inhibitors NS5B Nucs NS5B Non-nucs Viral enzyme Active site Non-enzyme Replication complex Viral enzyme Active site Viral enzyme Allosteric site Telaprevir Boceprevir Simeprevir Faldaprevir Asunaprevir ABT-450 MK-5172 Sovaprevir ACH-2684 Daclatasvir Ledipasvir ABT-267 GS-5816 ACH-3102 PPI-668 GSK Samatasvir MK-8742 Sofosbuvir VX-135 IDX20963 ACH-3422 ABT-333 Deleobuvir BMS PPI-383 GS-9669 TMC

6 Direct-Acting Antiviral Profiles Resistance profile Pan-genotypic efficacy Efficacy Adverse events Direct-Acting Antiviral NS3 1 NS3 2 NS5A 1 NS5A 2 Nuc Non NS5B Nuc NS5B Drug-drug interactions 1 1st generation. 2 2nd generation. Good profile Average profile Least favorable profile Direct Acting Antivirals Cure Rates for Chronic Hepatitis C Therapy Peginterferon 2001 Protease inhibitor 2011 Nucleoside inhibitor 2013 >90% SVR (%) Standard Interferon 1991 Ribavirin % 42% 55% >70% 6% 16% 6 Months 12 Months 6 Months 12 Months 12 Months IFN IFN PegIFN 6-12 Months PegIFN+ RBV+PI 12 weeks IFN-Free 6

7 Practical Applications Role of Interferon in Future Regimens Can Patient Tolerate IFN Yes No IL28B CC IFN/RBV + DAA vs IFN-Free CT/TT IFN-Free IFN-Free Strategies for Combinations With Nucleoside Inhibitors Genotype 1 IFN-containing IFN-free 12 weeks 8-12 weeks PEG-IFN + SOF SOF + NS5A SOF+ PI NI: nucleoside inhibitor; SOF: Sofosbuvir PI: protease inhibitor, NS5A: NS5A replication complex inhibitor 7

8 Strategies for Combinations Without Nucleoside Inhibitors Genotype 1 IFN-free Gen 1b Gen 1a/1b weeks 12 weeks PI + NNI PI + NS5A PI + NS5A + NNI NNI: non-nucleotide polymerase inhibitor PI: protease inhibitor, NS5A: NS5A replication complex inhibitor Genotype 1 Treatment Options Phase 3 Landscape 2014 (now) SVR (est) PEG/RBV + SOF 90% SOF + SMV (off-label) > 90% SOF (select populations) 60-70% weeks 2014 (4 th quarter) SOF + LPV > 94% ABT > 94% 2015 DCV + ASU (1b) 90% SOF + DCV > 94% 8

9 Practical Applications Case 1 PMH: 55 yo caucasian male, Gen 1a, LVL, IL28bCC, F4 fibrosis, naïve Treatment decision: PEG-IFN/RBV + SOF for 12 weeks (>95% SVR) SOF + PEG-IFN SVR by Subgroups Overall HCV GT Cirrhosis Race HCV RNA level IL28B 1 (1a, 1b, 1a/b) 1a 1b 4, 5, 6 No Yes Black Non-black <6 log 10 IU/mL 6 log 10 IU/mL CC Non-CC Lawitz E, et al. EASL 2013, Abstract 1411; Lawitz E, et al. N Engl J Med. 2013;368: SVR % Practical Applications Gen 1, Treatment experienced 67 yo male, HCV, cirrhosis, gen 1a, and failed therapy with PEG/RBV. Treat now or wait?; My decision: SMV/SOF(off label) Options Now Wk 0 Wk 6 Wk 8 Wk 12 - Neutrino PEG-IFN + SOF -COSMOS-2 ( Null responders) SOF/SMV SVR12 No data (FDA model 50-71%) >90% Options TURQUOISE ABT % - LONESTAR ( PI failures) SOF/LDV >90% - ION SOF/LDV 93-99% 9

10 Sofosbuvir in HCV GT 2/3 Genotype 2 = 3 FISSION POSITRON GT-2 GT-3 12 Week 97% 12 week 56% 12 week 93% 12 week 61% FUSION 12 week 12 week 30% 86% FUSION VALENCE SVR12 rate (%) 16 week 94% 16 week 62% 12 week 93% 24 week 84% Lawitz E, et al. N Engl J Med 2013;368: Jacobson IM, et al. N Engl J Med 2013;368: Recommendations for HCV Genotype 2 Treatment-Naïve Population Recommended Regimen Duration Treatment-naïve genotype 2 Sofosbuvir (400 mg) + RBV ( mg/d) 12 weeks Alternative regimens: none Regimens e specifically ca not recommended: e PEG/RBV x 24 weeks Monotherapy with PEG, RBV, or DAA PEG = pegylated interferon; RBV=ribavirin; DAA = direct acting antiviral AASLD/IDSA Treatment Recommendations. Accessed January 31,

11 Recommendations for HCV Genotype 2 Treatment-Experienced Population Recommended Regimen Duration Previous treatment with PEG/RBV Sofosbuvir (400 mg) + RBV ( mg/d) 12 weeks* *Patients with cirrhosis may benefit by extension of therapy to 16 weeks Population Alternative Regimen Duration Previous treatment with Sofosbuvir (400 mg) + PEG-IFN + 12 weeks PEG/RBV RBV ( mg/d) AASLD/IDSA Treatment Recommendations. Accessed January 31, Recommendations for HCV Genotype 3, Treatment Naïve/Experienced Population Recommended Regimen Duration Regardless of IFN eligibility ibilit Sofosbuvir (400 mg) + 24 weeks RBV ( mg/d) Population Alternative Regimen Duration Consider only if eligible for IFN Sofosbuvir (400 mg) + Peginterferon + RBV ( mg/d) 12 weeks Not recommended: PEG/RBV Telaprevir, boceprevir, simeprevir AASLD/IDSA Treatment Recommendations. Accessed January 31,

12 Populations With Limited Data Genotype 4-6 PEG/RBV + Sofosbuvir best choice for now Prior treatment failures to DAA regimens Advanced cirrhosis (very small #s) Childs B/C/ decompensation Special populations Pre and post-liver transplant HIV-coinfected Renal failure Pre-transplant Sofosbuvir to Prevent Post-transplant HCV Recurrence Study 025: single-arm, open-label phase II study from 16 liver transplantation sites Listed for LT due to HCC meeting Milan criteria MELD exception for HCC CTP score 7 Excluded decompensated cirrhosis, renal impairment, living donor LT Pre-LT therapy: SOF 400 mg/day mg/day for 48 wks or until time of LT Characteristic SOF (N = 61) Median age, yrs (range) 59 (46-73) HCV genotype, % 1a 39 1b a Non-CC IL28B genotype, % 78 CTP score, % Previous HCV treatment, % 75 Curry MP, et al. AASLD Abstract

13 Duration of Undetectable HCV RNA Before Transplant Predicted Lack of Recurrence > 30 days TND No recurrence (n = 28) Recurrence (n = 10) 64% of pts HCV RNA negative 12 wks post-lt (93% at LT) Continuous days TND pre-lt only factor predicting HCV recurrence in multivariate analysis Only 1/24 pts with > 30 days TND experienced recurrence Median days TND (P <.001) - No recurrence: 95 - Recurrence: Days With HCV RNA Continuously TND Prior to Liver Transplant Curry MP, et al. AASLD Abstract 213. Sofosbuvir for Treatment of Post-LT HCV Recurrence Ongoing prospective, e multicenter, Virologic i Response Rates single-arm, open-label pilot study Median time since LT: 4.3 yrs (range: ) CTP 7 and MELD % GT1, 33% IL28B CC, 40% with comp d cirrhosis SOF 400 mg/day mg/day for 24 wks RBV started at 400 mg/day and 20 increased based on hemoglobin levels 0 40/40 39/39 27/35 Week 4 EOT* SVR4 Re esponse (%) *1 patient still on treatment 4 patients had not reached SVR4 visit Charlton MR, et al. AASLD Abstract LB-2. Reproduced with permission. 13

14 PHOTON-1: Sofosbuvir + Ribavirin in GT1, 2, or 3 HCV Patients Coinfected With HIV Ongoing, nonrandomized, open-label phase III study Stable ART (HIV-1 RNA < 50 copies/ml for > 8 wks before enrollment) CD4+ cell count > 200 cells/mm 3 if on ART, > 500 cells/mm 3 if not on ART Wk 12 Wk 24 Tx-naive GT1 patients t Tx-naive GT2/3 patients Tx-experienced GT2/3 patients* Sofosbuvir + Ribavirin (n = 114) Sofosbuvir + Ribavirin (n = 68) Sofosbuvir + Ribavirin* (n = 41) Sulkowski M, et al. AASLD Abstract 212. *Data not presented for this arm. PHOTON-1: Virologic Response Rates HC CV RNA < LLOQ (%) n/n = / 103/ 87/ 25/ 22/ 23/ 41/ 39/ 28/ Genotype 1 Genotype 2 Genotype 3 SOF 24 Wks SOF 12 Wks 67 Wk 4 EOT SVR12 Breakthrough only in the setting of noncompliance Regimen effective across several types of ART: PIs, NNRTIs, integrase inhibitors Sulkowski M, et al. AASLD Abstract

15 HCV Future Treatment Paradigm Many Options to Choose From Direct Acting Antivirals IL28B CC SOF SOF + PI SOF + NS5A NS5A + PI + NNI PEG-IFN +DAA NI: nucleotide polymerase inhibitor (SOF), NNI: non-nucleotide polymerase inhibitor PI: protease inhibitor, NS5A: NS5A replication complex inhibitor 15