1. Blood Borne Viruses Hepatitis C Overview Phlebotomists Association of Ireland Dr Ciaran Bannan Research Fellow St James’s Hospital / Trinity College Dublin 11 th April 2015

2. Aims of Talk Introduction to Hepatitis C Diagnosis Staging Treatment options –Old and New Future perspectives

3. Introduction Main causes of chronic liver disease Long term impact highly variable –Minimal changes –Chronic hepatitis –Extensive fibrosis –Cirrhosis –Hepatocellular carcinoma (HCC) Many people unaware of diagnosis

4. Hepatic Fibrosis Cirrhosis Liver Cancer Healthy Liver

7. Epidemiology 130 – 210 million affected –3% of world’s population Prevalence varies widely –Western Europe 0.3% - 3% –Higher in Eastern Europe and Middle East –Egypt – highest prevalence 9% Recent discovery – 1989/1990 –Approximately 10 years after HIV

8. Prevalence - WHO

9. Risk factors People who inject drugs (PWID) Blood transfusions / products Iatrogenic / Occupational Tattoos / Acupuncture Intranasal drug abuse e.g. cocaine Men who have sex with Men (MSM) Heterosexual and perinatal risk - v low Unknown

10. Most likely risk factor (%) for cases of hepatitis C notified 2010-2013 (where data available, n=2354, 57%)

11. Genotypes Six genotypes described –Large number of subtypes Genotype 1 most prevalent worldwide –Subtype 1a – USA / Ireland –Subtype 1b – Europe Genotype 3 – Common in European IVDU Genotype 4 – Increasing incidence Genotype 5 and 6 rarely found

13. Natural history of HCV

14. Natural history Acute HCV asymptomatic in 70-80% of cases Chronic hepatitis develops in 75% of cases –Associated with variable degrees of hepatic inflammation and fibrosis progression –Independent of genotype and viral load

15. Accelerators of liver disease progression Alcohol Diabetes mellitus / Increased BMI Older age of acquisition HIV co-infection Hepatitis A/B/D co-infection –Vaccinate! Depending on presence of co-factors 10- 40% of patients will develop cirrhosis

16. Hepatocellular Carcinoma Cirrhotic patients have 4% risk of death per year Hepatitis C has become the leading cause of primary liver cancers in Europe HCC occurs in cirrhotic patients at a rate of 1-5% per year Patients diagnosed with HCC have a 33% probability of death in the first year of diagnosis

17. Diagnosis Diagnosis is based on presence of both –Anti-HCV antibodies May not be positive until 6/12 after infection Detected by enzyme immunoassays New combined antigen-antibody test –HCV RNA Detected by molecular assays Appears before antibodies Genotyping should be requested

18. Assessment of disease severity Important in decision making in chronic Hepatitis C management and prognosis –Liver biopsy – gold standard –Requires at least day ward admission –Complications Bleeding Pain Pneumothorax Infection

19. Assessment of disease severity Non invasive methods –Fibroscan measures hepatic elastography (liver stiffness) Good for mild fibrosis and cirrhosis Not good for moderate and severe fibrosis

20. Assessment of disease severity Non invasive methods –Serological and blood markers –Coagulation – High INR –Low albumin –High Bilirublin –High LFTs –Low platelets –Low sodium

21. Diagnosis Summary HCV Antibody and PCR for RNA Genotype –Different treatment options and different responses to treatment Stage disease – invasive / non invasive

22. Treatment Goal of treatment is to eradicate infection Endpoint of treatment is a sustained virological response (SVR) –>99% chance of cure SVR is defined as no detectable virus 12 weeks after completion of treatment

23. Rationale for antiviral therapy Stop viral replication Normalisation of liver biochemistry Reduction in histologic activity Halt progression of disease Prevent Hepatocellular Carcinoma

24. Date of download: 9/23/2014 Copyright © 2014 American Medical Association. All rights reserved. From: Association Between Sustained Virological Response and All-Cause Mortality Among Patients With Chronic Hepatitis C and Advanced Hepatic Fibrosis JAMA. 2012;308(24):2584-2593. doi:10.1001/jama.2012.144878

25. Treatment strategies Interferon alpha injections –Previously 3 times a week –Pegylated interferon Subcutaneous injection Weekly dosing Daily oral ribavirin tablets –Taken twice a day (usually 5-6 tablets daily)

26. Side Effects Common –Metabolic – loss of appetite –Psychiatric – Depression, poor sleep pattern –CNS – Headache, poor concentration –Respiratory – Cough, SOB –Gastrointestinal –Haematology – Low WCC, Hb, Plts –Skin and joint complaints –Endocrine – Thyroid disease

27. Contraindications Uncontrolled depression, psychosis, epilepsy or substance abuse Uncontrolled autoimmune disease Pregnant women Severe concurrent medical conditions Unwilling to comply with contraception Decompensated cirrhotic patients –Can consider Childs Pugh B in some circumstances

28. The Future … 2013 Directly Acting Antiviral (DAA) drugs Two drugs first to market: –NS3/NS4A Protease Inhibitors –Telaprevir –Boceprevir –Genotype 1 patients only –Given with interferon and ribavirin Multitude of new drugs in pipeline

29. Irish Results GUIDE Department in St James’s Hospital Included majority of patients with HIV –Pegylated interferon and Ribavirin –SVR rate of 58% for all genotypes –SVR rate of 37% for genotype 1 –Telaprevir / Boceprevir based therapy –SVR rate of 84% for genotype 1

30. Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011, Silver Spring, MD. SVR (%) IFN 6 mos PegIFN/ RBV 12 mos IFN 12 mos IFN/RBV 12 mos PegIFN 12 mos 2001 1998 2011 Standard IFN RBV PegIFN 1991 DAAs PegIFN/ RBV/ DAA IFN/RBV 6 mos 6 16 34 42 39 55 70+ 0 20 40 60 80 100 DAA + RBV ± PegIFN 90+ 2013 The Good News

31. Treatment Limitations Treatment is more effective but much more difficult

32. Other Issues With PI-Based Therapy Pill burden Food requirement CYP3A4 PI metabolites Drug-drug interactions Resistance BOC = 12/day RBV = 4-7/day TVR = 6/day RBV = 4-7/day

35. New DAAs: Sites of action Ref: Feeney E.R, Chung R.T. Antiviral treatment of Hepatitis C. BMJ 2014;349:g3308..

36. Not All Direct-Acting Antivirals are Created Equal Characteristic Protease Inhibitor * Protease Inhibitor ** NS5A Inhibitor Nuc Polymerase Inhibitor Non-Nuc Polymerase Inhibitor Resistance profile Pangenotypic efficacy Antiviral potency Adverse events Good profileAverage profile Least favourable profile *First generation. **Second generation. Feld J. Keeping up in HCV: Counting down the final days of interferon. Clinical Care Options Hepatitis

37. Ideal Hepatitis C treatment 100% Efficacy Oral Interferon free Short duration No resistance Pan-genotypic Well tolerated Safe Low cost

39. New Drugs – Interferon free Gilead –Sofosbuvir (NS5B polymerase inhibitor) –Ledipasvir (NS5A Inhibitor) Abbott –Ombitasvir (NS5A inhibitor) –Paritaprevir/ritonavir (Protease inhibitor) –Dasabuvir (NS5B polymerase inhibitor) Ribavirin still needed in advanced cases

41. Who to treat? Treatment should be initiated promptly in those with advanced fibrosis and strongly considered in those with moderate fibrosis In individuals with less severe disease, indication for therapy is individual –Can wait for new therapies

43. Conclusion Very exciting time for Hepatitis C Need to identify cases and prioritise treatments to those who need it most Cost is a huge factor –Finding new cases –Financing treatment –Delivering treatment Managing drug-drug interactions

44. Prevention Very effective vaccines available for Hepatitis A and B Effective safe vaccine would help Ongoing Phase 1 and 2 studies with various vaccine candidates that show good promise to date

45. Questions - ?