Hepatitis C Virus A New Era Begins HCV • Prevalence • Clinical Issues • HCV Life Cycle • Emerging DAAs Global HCV Prevalence HCV Regional Prevalence Region Anti-HCV (%) No. HCV-infected Asia 3.8% 116,000,000 China, Pakistan, Japan, Thailand N.Africa/Middle East 3.6 15,00,000 Africa 2.5 18,000,000 Europe 2.4 20,000,000 North America 1.3 4,000,000 World Pop (2005) 2.8 >184,000,000 6.5 billion Hanafiah KM et al Hep 2013 ;57: 1333 Diagnostic Barriers USA Only 50% had screening HCV-Ab 50% + HCV-Ab had HCV-RNA testing 7-11% had a liver bx or treated Overall SVR estimated 5-6% Holmberg SD et al NEJM 2013 368;1859 Screening IOM – 75% of Americans unaware Missed diagnosis M- ALT 30 IU/ml, F- 19 IU/ml Ann Int Med 2002;137:1-37 Risked-based vs birth-cohort screening – >800,000 additional cases identified – Cost-saving $35,700/life-saved with DAA+PR Ann Int Med 2012;156:263 Birth-cohort screening – USP-STF – designation “B” • ACA – covers grades A, B Clinical Spectrum ACUTE HCV ASYMPTOMATIC CHRONIC RESOLVES DIAGNOSIS 80-85% 15-20% MILD/MOD CIRRHOSIS DEATH/HCC CHC 80% 20% 1-4%/yr 0 5 10 20 30 YEARS Clinical Decisions – Who To Treat Pathology Outlines.com 2012 The HCV Life Cycle HCV Cell Cultures 1) Replicons- engineered HCV genomes NS3-5B sufficient for replication only intracellular steps Lohmann V et al Science 1999; 285:110 2) HCVpp- HCV E1 and E2 surrounded by a lipid membrane, host cell binding, entry and uncoating J Exp Med 2003; 197:633 3) HCVcc- replication in-vitro and in-vivo provides key insights into the assembly and release Kato T et al Gastroenterology 2003;125:1808 Lindenbach BD et al Science 2005, 309:623 NS3/4A protease inhibitors Drug name Lead Companies Study Phase Simeprevir Medivir/Janssen approved ABT-450/r AbbVie NDA Asunaprevir Bristol-Myers Squibb NDA Faldaprevir Boehringer Ingelheim NDA Danoprevir/r Roche Vedroprevir Gilead Sovaprevir Achillion MK-5172 Merck & Co. Nature Review/Drug Discovery June/2013 NS5B polymerase inhibitors Drug name Companies Study Phase Nucleoside/nucleotide Sofosbuvir Gilead approved uridine nucleotide Mericitabine Roche Cytidine nucleoside VX-135 Vertex uridine nucleotide Non-nucleoside Dasabuvir AbbVie NDA BI-207127 Boehringer Ingelheim Tegobuvir Gilead ABT-072 AbbVie BMS-791325 Bristol-Myers Squibb TMC-647055 Janssen NS5A inhibitors Drug Name Lead companies Phase Obitasvir AbbVie NDA Daclatasvir Bristol-Myers Squibb NDA Ledipasvir Gilead NDA ACH-3102 Achillion GSK2336805 GlaxoSmithKline MK-8742 Merck & Co PPI-668 Presidio NEUTRINO STUDY Sofosbuvir + Peg + Riba 12wks, n=327 naïve, GT 1, 4, 5, 6 100 99 80 99 90 60 91 40 20 Viral clearance clearance Viral 0 wk 2 wk 4 wk 12 SVR12 SVR12 80% cirrhosis n=54 ; SVR12 87% AA n=54 Lawitz E et al NEJM 2013;368:1878 FISSION STUDY Sofosbuvir + Riba 12 wks, naïve, GT 2,3 12 SVR n=103 n=24 n=284 n=75 Jacobson IM et al NEJM 2013;368:1867 FUSION STUDY Sofosbuvir + Riba Non-responders, GT2,3 Jacobson IM et al NEJM 2013;368:1867 100 96 100 80 78 12 60 63 61 60 SOF+R 12wks 40 SOF+R 16wks SVR 37 20 19 26 23 10 9 38 40 26 23 0 no cirrhosis cirrhosis no cirrhosis cirrhosis Genotype 2 Genotype 3 COSMOS STUDY 12wks,GT-1, Nonresponders, F0-2 Simeprevir + Sofosbuvir + Simeprevir + Sofosbuvir Riba N=40 N=40 SVR 96% SVR 93% Sulkowski M, et al EASL Annual Meeting April 2014 Current AASLD/IDSA Rec's • Naive GT-1 – Sofosbuvir 400mg + Peg + Riba: 12 wks • GT1a SVR 92% • GT1b SVR 82% • Cirrhosis SVR 78% • Ineligible for Interferon Therapy – Sofosbuvir + Simeprevir Current AASLD/IDSA Rec's • GT-2 (+/- cirrhosis) – Sofosbuvir 400mg + Riba for 12 wks – SVR 94% • GT-3 (without cirrhosis) – Sofosbuvir + Riba for 24 wks – SVR 93% naive, 77% tx-experienced Interferon-Free Trials For GT-1 Study NS3/4a PI NS5B – NI NS5B - NNI NS5A Ribavirin Abbvie ABT-450/r Dasabuvir Obitasvir +/- Gilead Sofosbuvir Ledipasvir yes Sofosbuvir Daclatasvir +/- Sofosbuvir yes BMS Asunaprevir BMS791325 Daclatasvir Asunaprevir Daclatasvir +/- Vertex Teleprevir VX-222 yes ION-I Ledipasvir and Sofosbuvir Naive HCV GT 1 +/- cirrhosis 12 wk 12 wk 24 wk 24 wk LDV/SOF + R LDV/SOF LDV/SOF + R LDV/SOF n=214 n=217 n=217 n=217 SVR 211 SVR 211 SVR 212 SVR 215 (99%) (97%) (98%) (99%) GT 1a > 97%, > 94% cirrhosis, > 91% AA AE: Fatigue, HA, Nausea, Insomnia 8-25%, 0 discontinuation 12wk arms Afdhal N et al: N Engl J Med 2014;370:1889-98 ION-II Ledipasvir and Sofosbuvir for Previously Treated HCV Genotype 1, +/- Cirrhosis 12 wks 12 wks 24 wks 24 wks LDV/SOF LDV/SOF+R LDV/SOF LDV/SOF+R N=109 N=111 N=109 N=111 SVR 102 SVR 107 SVR 108 SVR 110 (94%) (96%) (99%) (99%) Afdhal N et al. N Engl J Med 2014; 370:1483-1493 ION-III Ledipasvir and Sofosbuvir for 8 or 12 Weeks for Chronic HCV without Cirrhosis 8 wks 8 wks 12 wks LDV/SOF LDV/SOF + Riba LDV/SOF n=215 n=216 n=216 SVR 202 SVR 201 SVR 206 (94%) (93%) (95%) Kowdley K et al N Engl J Med 2014;370:1879-88 Abbvie Pharmaceutical non-interferon based clinical trials: 3DAAs +/- Ribavirin • ABT-450/r Protease inhibitor • Ombitasvir NS5a • Dasabuvir NS5b (bid) PEARL-III Naïve GT1b PEARL IV Naïve GT 1a No Cirrhosis GT 1b GT 1b GT 1a GT 1a 3 DAAs + R 3DAAs no R 3 DAAs + R 3DAAs no R 12 wks 12 wks 12 wks 12 wks N=210 N=209 N=100 N=205 SVR 209 SVR 207 SVR 97 SVR 185 (99.5%) (99%) (97%) (90.2%) F/R 1/0 F/R 0/2 F/R 1/2 F/R 6/10 Ferenci P et al. N Engl J Med 2014;370:1983-1992. SAPPHIRE-II Previously Treated GT1 GT 1a GT 1b 3DAAs + R 3 DAAs + R N=173 N=123 SVR 166 SVR 119 (96%) (96.7%) F/R 0/3 F/R 0/4 Prior Relapse, Partial Responders or Null Responders: SVR 95%, 100%, 95%, respectively Zeuzem S et al. N Engl J Med 2014;370:1604-1614. TURQUOISE-II 3 DAAs + Riba HCV with Cirrhosis- Naïve and Failed Therapy Poordad F et al. N Engl J Med 2014;370:1973-1982. Milestones of HCV Therapy 1989-98 1998-01 2001-11 2011-13 2013-14 2015 100 95 90 80 80 70 70 60 50 45 SVR 40 30 30 20 20 10 0 IFN mono IFN/RIBA PEG/Riba PEG/R/PI PEG/R/NS5b NS5b/NS5a Kabiri M, et al Ann Int Med 2014;161:170-180 Final Thoughts Diagnosis Oral Regimen Pill burden Effective Safety Cost ? Treating mild HCV .