The Changing World of Hepatitis C Alnoor Ramji Gastroenterology & Hepatology Clinical Associate Professor Division of Gastroenterology University Of British Columbia St. Paul s Hospital Site
Disclosures Company Name Abbvie BI BMS Gilead Sci. Inc Hoffman LaRoche Janssen (J. & J.) Novartis Merck & Co. Vertex Pharmaceuticals Relationship Investigator, consultant Investigator, Consultant Investigator, Consultant, Speaker Investigator, Consultant, Speaker Investigator, Consultant, Speaker Nursing Support Investigator, Consultant, Speaker Investigator Investigator, Consultant, Speaker Nursing Support Investigator, Consultant, Speaker
Objectives Epidemiology and natural history Burden of disease in Canada Screening Treatment options & Outcomes Fibrosis evaluation
Estimated 170 Million Persons With HCV Infection Worldwide 3-4 million newly infected each yr worldwide Prevalence of infection > 10% 2.5%-10% 1%-2.50% NA World Health Organization 2008. Available at: http://www.who.int/ith/es/index.html. Accessed October 28, 2009.
HCV Infection: Worldwide Genotype Distribution 1a, 1b 2a, 2b, 3a 1a, 1b 2a, 2b, 2c, 3a 4 4 1b, 3a 2a 1b, 6 1b 1a, 1b, 2b, 3a 5a 3b 1b, 3a Fang et al. Clin Liver Dis. 1997.
HCV Prevalence Age and gender distribution of anti-hcv positive cases in Canada (2011). 3.0% 2.5% 2.0% 1.5% 1.0% 0.5% 0.0% Males (2011) Females (2011) Myers R. et al.. Can J Gastroenterol Hepatol. 2014 May;28(5):243-50.
Prevalence (000) Total number of viremic HCV cases (with uncertainty intervals) by year (1950-2035). 400 350 300 250 200 150 100 50 0 Myers R. et al.. Can J Gastroenterol Hepatol. 2014 May;28(5):243-50.
Proportion of all viremic HCV cases according to disease stage (1950-2035). 100% 90% Liver Transplant HCC Decomp Cirrhosis Cirrhosis F3 F2 F1 Chronic HCV (F0) 80% 70% 60% 50% 40% 30% 20% 10% 0% Myers R. et al.. Can J Gastroenterol Hepatol. 2014 May;28(5):243-50.
Importance of Screening and Treating HCV HCV-related mortality exceeds mortality from HCV 1 HIV: human immunodeficiency virus 1. Ly et al. Ann Intern Med. 2012;156:271-278 11
HCV Prevalence According to Exposure *Other modes of transmission include sexual, occupational, nosocomial and vertical transmission. IDU: injection drug use. 1. Remis RS. Final Report. Public Health Agency of Canada. 2007. Available from: http://www.phac-aspc.gc.ca/sti-its-surv-epi/model/pdf/model07-eng.pdf. 12
CDC Recommendations (August 2012) Screening of those born between 1945-1965 1,2 *** In Canada : CLF suggests 1945-1975 One-time testing during a yearly checkup or as a part of insurance blood work In the US, >75% of adults with chronic hepatitis C are baby boomers 73.4% of HCV-related deaths were in persons 45-64 years of age CDC: Centers for Disease Control and Prevention 1. Hepatitis C: Proposed Expansion of Testing Recommendations, 2012. Available from: http://www.cdc.gov/nchhstp/newsroom/docs/hcv-testingfactsheetnoembargo508.pdf; 2. Centers for Disease Control and Prevention. Available from: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6104a1.htm?s_cid=rr6104a1_w. 13
Liver Related Mortality % What about patients with advanced disease? Long-term follow-up of patients with F3/F4 post-treatment LR-Mortality, % 30 10-year 10-year occurence occurrence SVR: SVR: 1.9% %(95%CI CI 0.0-4.1) 0.0-4.1) Non-SVR: non-svr: 27.4% ((5% (95%CI 22.0-32.8) 20 10 Non-SVR p<0.001 SVR Van de Meer et al JAMA 2012 0 0 1 2 3 4 5 6 7 8 9 10 Follow-up time, years SVR eliminates liver failure & liver-related death
SVR (%) The Advancing Present DAAs 100 PegIFN 2011 2014 90 80 60 Standard IFN 1991 RBV 1998 2001 55 70+ 40 34 42 39 20 0 6 IFN 6 mos 16 IFN 12 mos IFN/RBV 6 mos IFN/RBV 12 mos PegIFN 12 mos PegIFN/ RBV 12 mos Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011, Silver Spring, MD. PegIFN/ RBV/ DAA PegIFN/ RBV/ DAA Or DAA+RBV
HCV Lifecycle and DAA Targets Receptor binding and endocytosis Fusion and uncoating Transport and release (+) RNA LD ER lumen LD Virion assembly Translation NS3/4 and polyprotein protease processing inhibitors ER lumen Membranous web LD NS5B polymerase RNA replication inhibitors NS5A* inhibitors *Role in HCV lifecycle not well defined Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.
The Present: SVR Rates With Boceprevir or Telaprevir in Genotype 1 Treatment-Naive Patients Triple Therapy for upto 48 Weeks SVR (%) 100 80 67-81 60 40 38-44 52-62 20 0 PegIFN/RBV Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. F0-2 F3-4 BOC or TVR + PegIFN/RBV
2014 /2015 :Virologic Response to PEG-INF + RBV + Simeprevir or Sofosbuvir in Genotype 1 Treatment-Naive Patients SVR (%) Jacobson I, et al. EASL 2013. Abstract 1425. Reproduced with permission. Lawitz E, et al. EASL 2013. Abstract 1411. Reproduced with permission. 100 85% 90% 80% 80 60 60% 40 20 0 No Cirrhosis Cirrhosis Simeprevir No Cirrhosis Sofosbuvir Cirrhosis
2014 /2015 :Virologic Response to PEG-INF + RBV vs. Sofosbuvir + RBV (all-oral) in Genotype 2 and 3 Treatment-Naive Patients SVR (%) 100 97% 92-94% 80 70-80% 60 40 20 0 PegIFN/RBV X 24 wks Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. Geno 2 SOF+RBV X 12 wks Geno 3 SOF+RBV X 24 wks Gane E, et al. J Hepatol. 2013;58(suppl 1):S3. Abstract 5. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.
2015 /2016 :Virologic Response to Non-interferon based therapy: Genotype 1 :Treatment-Naive Patients: Non-cirrhotic and cirrhotic sub-groups SVR (%) 100 97-100% 93-100% 80 60 40 20 0 SOF/ LDV +/- RBV x12 wks ABT 450/rtv + ombitasvir + dasabuvir+/-rbv X 12 wks Feld JJ, et al. N Engl J Med. 2014;370:1594-1603. Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12 Poordad F, et al. EASL 2014. Abstract O163
Fibrosis is the key
Hepatitis C: Summary HCV is common Screening for HCV is imperative baby-boomers and immigrants Viral eradication / cure in 70-90% Viral eradication has a mortality benefit