Advances in Viral Hepatitis Hepatitis C Hepatitis A + B Nizar N. Zein, M.D. Endowed Chair in Liver Diseases Chief of Hepatology Medical Director of Liver Transplantation The Cleveland Clinic Final Steps Toward 100% Cure in Hepatitis C: A Story Worth of Telling Historical Perspectives 1 HCV in Ancient History • It is impossible to know the origins of HCV since there are no stored blood specimens to test for the virus that is older than 50 years. • However, studies in viral origins speculate that the beginnings of HCV can be traced back in primates to 35 million years ago! The final chapter in a 35 million year old story! Viral Origin studies HCV subtypes evolved over the past 200 years ago The six HCV genotypes had a common ancestor about 400 years ago Zein NN. J Clin Micro 2001 A Study of Malaria Transmission in Healthy “Volunteer” Prisoners in USA-1969 2 1969 • Six prisoners were injected with “Healthy donor” blood sequentially and 4 developed acute hepatitis. • Another 15 were inoculated with blood containing malaria particles from 14 donors and 6 developed acute hepatitis. • Sera were tested for HAV, HBV, CMV, EBV and were negative • Most (in both groups) continued to have fluctuating ALT beyond a year past the experiment Diestag JL, Lancet 1979 1981: Daniel Bradley (CDC) Persistent or intermittent elevation of ALT > 1 year Bradley DW, J Infect Dis 1981 1981: Daniel Bradley (CDC) • Liver biopsies obtained from 3 Chimpanzees revealed histological evidence for persistent hepatitis and liver cell injury. Bradley DW, J Infect Dis 1981 3 1981: Daniel Bradley (CDC) Acute hepatitis Bradley DW, J Infect Dis 1981 Out of the Shadows: The Discovery of HCV (Chiron Corp) 1989: George Kuo, Qui-Lim Choo and Michael Houghton A Triumph of new techniques and good old human perseverance Daniel Bradley Harvey Alter A Collaborative Effort Plasma of infected Chimp 5-1-1 antigen Michael Houghton 4 The immediate Impact was Strong! 1- Greater than 90% of post-transfusion NANB hepatitis is due to HCV 2- Approximately 300,000 yearly cases of transfusionassociated HCV infections were prevented (risk of contacting HCV through transfusion was to lowered from 30% to less than 0.01%) An Immediate Outcome • Chiron filed multiple patents on the virus and diagnostic associated assays • A competing patent was filed by CDC (Daniel Bradley) but was dropped in 1990 with agreement of Chiron to pay CDC $1.9 million and Bradley $337,000 • In 1994, Bradley sued Chiron seeking to have himself included as co-inventor but lost and dropped suit in 1998. Bradley DW, J Infect Dis 1981 In 2007, Deaths From HCV Surpassed Those From HIV Change in Mortality Rates From 1999 to 2007 Rate per 100,000 People 7 6 HIV 5 4 15,106 12,734 Hepatitis C 3 2 1 Hepatitis B 1,815 0 1999 2000 2001 2002 2003 2004 2005 2006 2007 Year Ly KN, et al. Ann Intern Med. 2012;156(4):271-278. 5 HCV-Related Cirrhosis Is Projected to Peak by 2020 1,200,000 1,000,000 Patients, N 800,000 In 2010, 25% of patients were estimated to have cirrhosis 600,000 37% of patients with HCV projected to develop cirrhosis by 2020, peaking at 1 million 400,000 200,000 0 1990 2000 2010 Year 2020 2030 Davis GL, et al. Gastroenterology. 2010;138(2):513-521. Treatment Evolution of Approved HCV Therapy Over Time Peg IFNs approved FDA approves IFN-2a FDA approves cIFN IFN in NANB trials 1957 Discovery of IFN 1986 1991 96-97 1998 01-02 FDA approves IFN-2b for HCV Rebetron approved 6 HCV RNA Structure 5' UTR Structural Structure C E1 Nucleocapsid, Assembly E2 3' UTR Non-Structural Processing p7 NS2 Protease Calcium Envelope Proteins, Channel? Assembly and Entry NS3 Replication NS4A NS4B NS3 cofactor Serine Protease, Helicase NS5A NS5B Phosphoprotein, Replication Replication? RNA-dependent RNA polymerase HCV G1: IFN Monotherapy x 6 months (1990-1993) SVR HCV G1: IFN Monotherapy x 12 months (1994-1998) SVR 7 HCV G1: IFN+RBV x 12 months (1998-2001) SVR HCV G1: PEG IFN+RBV x 12 months (2002-2010) SVR An Important lesson Learned: SVR Improves clinical outcome Annual Rate Multivariate Hazard Ratio SVR No SVR P Value 0 1.88 <0.001 NA HCC 0.66 2.10 <0.001 2.59 Liver-related mortality 0.19 1.44 <0.001 6.97 Non-liver mortality 0.37 0.52 0.2 NA Event Decompensation Bruno S, et al. Hepatology. 2007;45:579-587. n=920, including 124 SVRs 8 The Era of DAA Therapy (2011- ) PEG IFN RBV DAA Telaprevir and Boceprevir Triple Therapy with Telaprevir and Boceprevir (2011-2013) SVR A very short lived era While improved SVR rate, it is far from Ideal Therapy! • Efficacy is limited to G1 infection • Drug-drug interactions • Adverse effects • Emergence of resistance • Can only be used in combination with PEG IFN and RBV 9 The Ideal Therapy Pan-Genotypic No Viral Resistance All-oral Short Duration Excellent safety profile QD (or BID) dosing Second-Generation DAA (Dec 2013- ) An Even shorter era! NS5b Polymerase inhibitors • Advantages of nucleoside inhibitors –N No evidence of resistance mutations –U Urinary excretion (not hepatic): less risk of drug interactions –C Chain terminators: means greater pangenotypic potency Sofosbuvir (Sovaldi) The Most Exciting Group of New Anti-virals Pawlotsky JM, et al. Antivir Ther 2012 Mar 8. doi: 10.3851/IMP2088; Gane EJ, et al. AASLD 2011 Abstract 34. 10 Sofosbuvir (Sovaldi) • Once daily, no food requirement. • Pan-genotypic (GT1-6) efficacy • High barrier for resistance • Excellent safety profile and minimal drug-drug interaction • Short duration of therapy Sofosbuvir Phase 3 Studies Total Patients Regimen SVR NEUTRINO GT 1,4,5,6 Treatment Naïve 327 S+PEG+RBV 12 weeks 90% (82%-100%) FISSION GT 2 & 3 Treatment Naïve 499 S+RBV 12 weeks G2: 97% G3: 56% FUSION GT 2 & 3 Interferon Failure 201 S+RBV 12 or 16 weeks 12 w: 50% 16 w: 73% GT 2 & 3 IFN Intolerant 278 S+RBV 12 weeks 78% Study Population POSITRON Sofosbuvir FDA Approval Genotype Regimen Duration Regimen S+PEG+RBV 12 weeks 90% G2 S+RBV 12 weeks 97% G3 S+RBV 24 weeks 75% G1 ineligible to IFN S+RBV 24 weeks 70% G1 and G4 11 Simeprevir (Olysio): An improved PI • Simeprevir is a one-pill, once daily HCV NS3/4A PI • Higher SVR rates than 1st generation PIs • Better safety and tolerability profile: –Anemia –Rash • Transient and mild bilirubin elevations due to inhibition of transporters by SMV Simeprevir Phase 3 Trials Total Patients Regimen SVR* GT 1 Treatment Naïve 785 Sim+PEG+RBV 12 weeks then PEG/RBV G1a: 75% G1b: 85% GT 1 Relapse 393 Sim+PEG+RBV 12 weeks then PEG/RBV 80% GT 1 Interferon Failure 462 Sim+PEG+RBV 12-48 weeks 67% Study Quest 1 and Quest 2 Population PROMISE ASPIRE *Efficacy reduced in patients with NS3 Q80K polymorphism Simeprevir FDA Approval Population Regimen Naïve and relapse Nonresponders Sim+PEG+RBV x 12 weeks Sim+PEG+RBV x 12 weeks Total Duration 24 weeks 48 weeks SVR 80% 67% 12 The All Oral Treatment Regimens! Current Possibilities • Sofosbuvir + RBV for HCV G2 and 3 and for HCV G1 with contraindication to interferon. • Sofosbuvir + Simeprevir SOF + SMV: COSMOS Trial (n=167) Population: 46% naïve 54% Null responders 13 SOF + SMV: COSMOS Trial (n=167) SVR12: Naïve: 100% Null R with F3-4 fibrosis: 96% Null R with F0-2 fibrosis: 79% With or without RBV 12 or 24 weeks Near-Future Possibilities • G1: –Sofosbusvir+Daclatasvir+RBV: SVR 93%-100% –Asunaprevir+Daclatasvir+BMS-791325: SVR 88%-94%(PI unresponsive) –ABT450/r+ABT333+RBV: SVR 93%-95% (naïve) • G 2: – SVR 90%-97% with all regimens • G3: – SVR 30%-60% (may require > 12 weeks therapy) So What is Next? SVR 14 Is Global Eradication of HCV a Realistic Goal Now? In support of possible Global Eradication of HCV • Highly accurate diagnostic tests • Highly effective therapy • Lack of non-human reservoir • Limited modes of transmission Eradication Strategies Cost Screening HCV infected Patients New Therapies Defined Guaranteed Outcome 15 Screening Recommendations? Against successful Global Eradication of HCV • Lack of universal screening strategies • Very expensive therapy • Most cases are in economically depressed populations and countries Success of Therapy to Date Holemberg SD, NEJM May 2013 16 Advances in HAV Advances in HBV 17