Hepatitis C virus G Dusheiko Royal Free Hospital London London 11 - PowerPoint PPT Presentation

Hepatitis C virus G Dusheiko Royal Free Hospital London London 11 June 2015

Disclosures • Grants – AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Vertex • Advisory Boards or Safety Monitoring Boards – AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Zymogenetics, Novira • Speaker – Abbott, AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen, Merck Sharp & Dohme

Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis Choo QL et al. Science 1989;244:359 – 62

The HCV discovery team In 2000, Alter and Houghton were honoured with the Lasker Award for Clinical Medical Research

The immediate fruits of discovery • Blood tests to protect the blood supply • Reduced transmission of hepatitis C • Established that HCV was a major cause of hepatocellular carcinoma • More sensitive diagnostics for HCV antibodies and RNA were developed • Means of monitoring response to treatment (HCV RNA) • Discerned highly conserved sequence motifs • HCV encoded its own unique protease, replicase, helicase and polymerase enzymes (38) • Identification of several potential drug targets: active drug target drug discovery programmes Colombo M. Lancet 1989;2:1006 – 8. Choo QL. Proc Natl Acad Sci USA 1991;88:2451 – 5. Dodd RY. Int J Hematol 2004;80:301 – 5

Global HCV viraemic infections: prevalence and total infected • Around 9 million people in Europe are chronically infected with HCV (>185 million people worldwide) Prevalence Total Infected (Viraemic) (Viraemic) 0.0%-0.6% 0-200K 0.6%-0.8% 200K-650K 0.8%-1.3% 650K-1.9M 1.3%-2.9% 1.9M-3.5M 2.9%-7.8% 3.5M-9.2M Gower E, et al. J Hepatol 2014;61:S45 – S57; Messina J, et al. Hepatology 2015:61;77 – 87

Global HCV genotype prevalence and distribution GT 6 GT 5 (5%) (1%) GT 4 (13%) GT 1 (46%) GT 3 (22%) GT 2 (13%) • GT 4: 13% (~15 million) of global HCV infected population Gower E, et al. J Hepatol 2014;61:S45 – S57; Messina J, et al. Hepatology 2015:61;77 – 87 GBD: global burden of disease; GT: genotype

MM08 Risk of disease progression is linked to fibrosis stage CHeCS: Chronic Hepatitis Cohort Study – clinical outcomes after baseline biopsy (prior to the availability of new DAAs) LTx 35 P<0.0001 % of patients with HCC 28,6 30 Death 25 23,1 outcome Decompensation 20 P<0.0001 15 11,9 11,3 P<0.0001 10,8 10 6 5,2 4,6 3,8 5 1,7 1,1 1 0 F2 F3 F4 n=810 n=461 n=364 Achieved SVR 74.6% 55.4% 47.2% • Cirrhotic patients who achieve SVR have a significant reduction in likelihood to develop HCC, but are still at higher risk than F2 – 3 patients – Achieving SVR doesn’t prevent HCC in patients who are already cirrhotic Moorman AC, et al. AASLD 2014; Oral #174 DAA: direct-acting antiviral agent; LTx: liver transplant

MM07 Fibrosis progression occurs early after infection Analysis of 610,514 people (half were HCV positive) in the ERCHIVES database 2002 – 2012 Time to progression of liver fibrosis Time to development of cirrhosis 2.5 Persons without cirrhosis, % 100 2.0 Mean FIB-4 score 90 1.5 80 1.0 70 HCV +ve HCV +ve 0.5 60 HCV - HCV -ve HCV -ve 0 50 0 4 6 10 1 2 3 4 5 6 7 8 9 10 11 2 8 Year • FIB-4 scores doubled in the first 4 years after infection and more than 18% developed cirrhosis within 10 years after infection – need to treat early ERCHIVES: Electronically Retrieved Cohort of HCV Infected Butt AA, et al. JAMA Intern Med 2015;175:178 – 85 Veterans; FIB-4: fibrosis-4

HCV GT-3 is more commonly associated with steatosis than other genotypes 1 100 GT-3 Other 90 Prevalence of steatosis (%) 80 70 60 50 40 30 20 10 0 Westin Hourigan Rubbia-Brandt Adinolfi Poynard Castera Asselah Rubbia-Brandt 2002 5 1999 2 2000 3 2001 4 2003 6 2003 7 2003 8 2004 9 • Steatosis may be responsible for accelerated fibrosis progression and lower SVR 1 • An analysis of 14 studies from 1997 to 2004, steatosis was reported in 73% (501/685) of patients with GT-3 HCV and in 50% (1468/2932) of patients with non-GT-3 HCV infection 1 Figure adapted from 1. Asselah T, et al. Gut 2006;55:123. 2. Hourigan LF, et al. Hepatology 1999;29:1215 – 9. 3. Rubbia-Brandt L, et al. J Hepatol 2000;33:106 – 15. 4. Adinolfi LE, et al. Hepatology 2001;33:1358 – 64. 5. Westin J, et al. J Hepatol 2002;37:837 – 42. 6. Poynard T, et al. Hepatology 2003;38:75 – 85. 7. Castéra L, et al. Gut 2003;52:288 – 92. 8. Asselah T, et al. Gut 2003;52:1638 – 43. 9. Rubbia-Brandt L, et al. Gut 2004;53:406 – 12.

HCV GT-3 patients are at a higher risk for late-stage liver disease events and death GT-1 Cirrhosis GT-2 Decompensated GT-3 cirrhosis Other Liver-related hospitalisation HCC 0 0,5 1 1,5 2 Hazard ratio Observational cohort study of 28,769 patients with HCV from the VA CCR, which compiled electronic medical records data from 1999 to the present. CCR, HCV clinical registry; VA, Veterans Affairs. Adapted from McCombs J, et al. JAMA Intern Med 2014;174:204 – 12.

B cell homeostasis in chronic hepatitis C virus – related mixed cryoglobulinemia is maintained through naïve B cell apoptosis B cell numbers paradoxically reduced in HCV-infected patients with MC HCV patients Increased sensitivity of naıve B cells to apoptosis: reduction in size of naıve B cell subset. Holtz et al, Hepatology Volume 56 pages 1602-1610, 14 OCT 2012

Faster progression with age even when controlling for alcohol and other co-morbidities Liver fibrosis and age among HIV/HCV co-infected patients and HCV mono-infected patients 14 HIV/HCV Predicted fibrosis score (KPa) 12 HCV 10 8 9.2 years 6 55 60 30 35 40 50 45 Age (years) Kirk D, et al. Ann Intern Med 2013;158:658 – 66

Splenorenal shunt Large varices

Treatment of NANBH with interferon alpha Serial determinations of alanine aminotransferase (ALT) levels in two patients (no. 3 and 4) with chronic non-A, non-B hepatitis who were treated for one year with two courses of recombinant human alpha interferon The doses of alpha interferon, 1 to 5 million units (MU) daily, every other day (qod), or three times weekly (tiw), are indicated above the stippled areas Pilot study of 10 patients receiving alpha-interferon for up to 12 months Hoofnagle et al. NEJM 1986; 315:1575 – 8

Hepatitis C: the evolution of the treatment landscape 100 2013 SOF+ RBV 90 ± PegIFN 2011 80 PegIFN + RBV+ DAA 70 % response 60 2001 – 2004 1998 PegIFN + RBV 50 IFN + RBV 48 weeks 40 30 20 1998 IFN 2013:FDA 48 weeks 1998 IFN approves 24 weeks 10 SOF 2010 2020 1950 1960 1990 2000 1957: 1989: 1991: FDA 2001:FDA 2009 2011:FDA Discovery Discovery approves approves IL28 approves of IFN of HCV injectable PegIFN First DAA’s IFN Adapted from Cornberg M et al. In: Hepatology A Clinical Textbook; 2013. Flying Publisher

HCV Life Cycle and Targets for Direct-Acting Antivirals (DAAs) Receptor binding Transport and endocytosis and release Fusion and uncoating Virion (+) RNA assembly Translation and NS3/4 Membranous NS5B polymerase polyprotein protease web RNA replication inhibitors processing inhibitors Nucleos(t)ide Non-nucleoside NS5A inhibitors replication and assembly Adapted from Manns MP, et al. Nat Rev Drug Discov . 2007;6:991-1000.

Treatment Options 2015 IFN-free regimens GT Sofosbuvir + RBV 2, 3 Sofosbuvir/Ledipasvir ( ± RBV) 1, 4, 5, 6 Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir ( ± RBV) 1 Sofosbuvir + Simeprevir (± RBV) 1, 4 Sofosbuvir + Daclatasvir (± RBV) All Ombitasvir/Paritaprevir/Ritonavir ( ± RBV) 4 IFN-containing regimens PegIFN a + RBV + sofosbuvir All PegIFN a + RBV + simeprevir 1, 4 EASL HCV guidelines 2015

Effect of NS5a inhibitor on membranous web biogenesis Wild type versus Y93H Berger et al Gastroenterology epub 2014

Major categories of response rates with DAA therapy 2015 Duration RBV Duration RBV, NS5a? Third DAA, pan genotypic 100 RBV Third DAA, pan Earlier treatment 90 genotypic Earlier treatment 80 70 60 50 40 30 20 10 0 95-100% 90-95% 85-90% Less than 85% Non cirrhotic, 1b Cirrhosis CPA, 1a/b Cirrhosis CPB,C G3, TE, CP C sofosbuvir ledipasvir ombitavir, paritaprevir/r dasabuvir sofosbuvir simeprevir daclatasvir

HCV treatment landscape – 2015 Protease ¥ , NS5B # and NS5A* inhibitors Sofosbuvir # + Daclatasvir* Ombitasvir * Paritaprevir ¥ Sofosbuvir # + Simeprevir¥ Ritonavir ¥ Sofosbuvir # + Ledipasvir* Dasabuvir # Sofosbuvir # ± RBV ± RBV IFN-free GS-5816* GS5816* Asunaprevir ¥ Grazoprevir ¥ Sofosbuvir # Sofosbuvir # Daclatasvir* Elbasvir* Elbasvir* Ledipasvir* Sofosbuvir # Beclabuvir # + RBV + MK3682 # ± RBV ± RBV Jul – Dec Jan – Jun Jul – Dec Jan – Jun Jul – Dec Jan – Jun Jul – Dec Jan – Jun Jul – Dec With IFN and RBV 2011 2012 2013 2014 2015 2016-2017 Simeprevir ¥ Telaprevir ¥ Sofosbuvir # (GT 1, 4) Daclatasvir* Boceprevir ¥ (GT 4) Triple therapy Webster D, Klenerman P Dusheiko G The Lancet online February 14 GT: genotype; IFN: interferon; RBV: ribavirin