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
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 1963 1973 1989 1991 2013 Clinical Research Clinical Research NIH* Translational Research Translational PhRMA Basic Research Basic *NIH has invested $4B for HCV-related research (NIH Reporter ) 2
Seroprevalence of Hepatitis C: 170 to 200 Million Worldwide United States 5M Americas 12-1515 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 30-35 35 M Australia.2 M 1. World Health Organization. Wkly Epidemiol Rec.. 2000;75:17-28. 28. 2. 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 35 30 Anti-HCV seropositives, HCV RNA detectable Anti-HCV seropositives, HCV RNA undetectable Anti-HCV seronegatives 30.1% Cu umulative mortality (%) 25 20 15 10 P<0.001 for comparison among three groups P<0.001 for HCV RNA detectable vs. undetectable 12.8% 12.4% 5 0 0 2 4 6 8 10 12 14 16 18 20 Follow-up years Lee MH, et al. J Infect Dis. 2012;206(4):469-477. 3
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, % 30 20 10 P<0.001 All-cause mortality Without SVR With SVR 0 0 1 2 3 4 5 6 7 8 9 10 Time, y No. at risk Without SVR 405 393 382 363 344 317 295 250 207 164 135 With SVR 192 181 168 162 156 144 125 88 56 40 28 Liver-related mortality or liver tra ansplantation, % 30 20 10 Liver-related mortality or liver transplantation P<0.001 Without SVR With SVR 0 0 1 2 3 4 5 6 7 8 9 10 Time, y No. at risk Without SVR 405 392 380 358 334 305 277 229 187 146 119 With SVR 192 181 168 162 156 144 125 88 56 40 28 Van der Meer, et al. JAMA 2012:308:2584-2593. 75% 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. 2011 4
CDC Releases Birth Cohort Screening Guidelines Adults born during 1945 1965 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 GSK2336805 Samatasvir MK-8742 Sofosbuvir VX-135 IDX20963 ACH-3422 ABT-333 Deleobuvir BMS-791325 PPI-383 GS-9669 TMC647055 5
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 1998 34% 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
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
Strategies for Combinations Without Nucleoside Inhibitors Genotype 1 IFN-free Gen 1b Gen 1a/1b 12-24 24 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% 0 12 24-48 weeks 2014 (4 th quarter) SOF + LPV > 94% ABT-450+ 333 + 267 > 94% 2015 DCV + ASU (1b) 90% SOF + DCV > 94% 8
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;368:1878-1887. SVR % 60 70 80 90 100 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 2014-15 - TURQUOISE ABT-450+ 333 + 267 92-96% - LONESTAR ( PI failures) SOF/LDV >90% - ION SOF/LDV 93-99% 9
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% 0 10 20 30 40 50 60 70 80 90 100 Lawitz E, et al. N Engl J Med 2013;368:1878-87. Jacobson IM, et al. N Engl J Med 2013;368:1867-77. 19 Recommendations for HCV Genotype 2 Treatment-Naïve Population Recommended Regimen Duration Treatment-naïve genotype 2 Sofosbuvir (400 mg) + RBV (1000-1200 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. www.hcvguidelines.org. Accessed January 31, 2014. 10
Recommendations for HCV Genotype 2 Treatment-Experienced Population Recommended Regimen Duration Previous treatment with PEG/RBV Sofosbuvir (400 mg) + RBV (1000-1200 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 (1000-1200 mg/d) AASLD/IDSA Treatment Recommendations. www.hcvguidelines.org. Accessed January 31, 2014. Recommendations for HCV Genotype 3, Treatment Naïve/Experienced Population Recommended Regimen Duration Regardless of IFN eligibility ibilit Sofosbuvir (400 mg) + 24 weeks RBV (1000-1200 mg/d) Population Alternative Regimen Duration Consider only if eligible for IFN Sofosbuvir (400 mg) + Peginterferon + RBV (1000-1200 mg/d) 12 weeks Not recommended: PEG/RBV Telaprevir, boceprevir, simeprevir AASLD/IDSA Treatment Recommendations. www.hcvguidelines.org. Accessed January 31, 2014. 11
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 1000-1200 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 34 2 13 3a 12 4 2 Non-CC IL28B genotype, % 78 CTP score, % 5-7 96 8 5 Previous HCV treatment, % 75 Curry MP, et al. AASLD 2013. Abstract 213. 12
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: 5.5 0 30 60 90 120 150 180 210 240 270 300 330 Days With HCV RNA Continuously TND Prior to Liver Transplant Curry MP, et al. AASLD 2013. 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: 1.02-10.6) 100 100 100 CTP 7 and MELD 17 77 80 83% GT1, 33% IL28B CC, 40% with comp d cirrhosis SOF 400 mg/day 400-1200 mg/day for 24 wks 60 40 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 2013. Abstract LB-2. Reproduced with permission. 13
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 2013. Abstract 212. *Data not presented for this arm. PHOTON-1: Virologic Response Rates HC CV RNA < LLOQ (%) 100 80 60 40 20 n/n = 0 100 96 96 96 76 88 100 98 110/ 103/ 87/ 25/ 22/ 23/ 41/ 39/ 28/ 114 103 114 26 23 26 41 40 42 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 2013. Abstract 212. 14
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