1. Hepatitis C What’s New Alan Kilby, M.D. Portland Gastroenterology Center Maine Medical Center VTC Sept 27, 2013

2. Disclosures Maine Medical Ctr VTC Funding Schering, Merck, Vertex Experimental Drugs Discussed Sofosbuvir, Simeprevir, Ledipasvir This talk is not FDA approved

3. Hepatitis C What’s New 1. Test baby boomers (1945-65) 2. Exciting new treatments 2014? Sofosbuvir, Simeprevir 2014? Sofosbuvir, Simeprevir 2015? One pill a day possible 2015? One pill a day possible 3. Fibroscan-liver fibrosis test 4. ECHO-Telemedicine Project

4. Test Baby Boomers Birth Cohort 1945-1965: Prevalence of hep C=3.5% Infected in 1960’s thru 1980’s 75% of hep C cases, 2-3 million Only 45% report a risk factor At least 45% unaware; often think they are tested with routine labs Even with risk factors, test rate low Antiviral treatment rates are very low

5. Test Baby Boomers 75% Hep C Deaths: Baby Boomers Liver Failure and Liver Cancer Median Age of Death is 57 years After 20 years of infection: 20% Cirrhosis, 5% Liver mortality Cirrhosis, Liver cancers, deaths increase with each decade

6. Test Baby Boomers CDC has Patient Information Sheet Recommended testing: 1. HCV antibody 2. Positive HCV antibody triggers HCV RNA testing. HCV RNA testing. 3. I strongly encourage reflex HCV RNA testing on same sample RNA testing on same sample

7. Test Baby Boomers HCV RNA positive patients Alcohol counseling Hepatitis A and B vaccination I recommend CBC, CMP, INR, Ultrasound of Abdomen, HCV Genotype, HBsAg, HIV Ab Evaluation for HCV treatment

8. Test Baby Boomers Benefits of Rx with SVR(Cure) 1. Liver decompensation greatly reduced 2. Liver Cancer risk reduced 3. Study of 16,000 US Veterans demonstrated 55% reduction in all cause mortality

9. Hepatitis C What’s New 2014? Sofosbuvir, Simeprevir 2. Exciting new treatments 2014? Sofosbuvir, Simeprevir 2015? One pill a day possible

10. Alter et al. N Engl J Med. 1999;341;556-562. Blatt et al. J Viral Hepatitis. 2000;7:196-202. Genotype and Viral Load in US Patients Genotype 1 HVL Genotype 1 LVL Genotype 2,3 HVL Genotype 2,3 Low Viral Load 49.5% 24.5% 14.7% 7.3% Genotype 4,5,6 High Viral Load Genotype 4,5,6 Low Viral Load 2.7% 1.3%

11. Peg-Interferon Weekly + Ribavirin Daily Genotype 1SVR=40% 48 week treatment Wt-based ribavirin Genotypes 2,3 SVR=80% 24 week treatment Low dose ribavirin (800 mg) Sustained Viral Response: Before 2011

12. Side Effects of Interferon Flu-like symptoms – Headache – Fatigue or asthenia – Myalgia, arthralgia – Fever, chills Neuropsychiatric disorders – Depression – Mood lability Alopecia Thyroiditis Nausea Diarrhea Injection-site reaction Lab alterations – Neutropenia – Anemia – Thrombocytopenia

13. Side Effects of Ribavirin Hemolytic anemia Teratogenicity Cough and dyspnea Rash and pruritus Insomnia Anorexia COPEGUS™ (ribavirin, USP) [package insert]. Nutley, NJ: Hoffmann-La Roche; 2002.

14. Hepatitis C Treatment Since 2011 Direct-Acting Antivirals Protease Inhibitors Protease Inhibitors Boceprevir (Victrelis) Telaprevir (Incivek) Triple Therapy- PEG-Interferon/Ribavirin/Protease Inhibitor for genotype 1, 24-48 weeks PEG-Interferon/Ribavirin/Protease Inhibitor for genotype 1, 24-48 weeks SVR for Genotype 1: 65-75%

15. Hepatitis C Treatment Since 2011 Problems with Telaprevir/Boceprevir 1. New side effects-Rash (Telaprevir), diarrhea, nausea;increased anemia 2. Poor tolerance in cirrhotics 3. Drug Interactions (Cytochrome system): Hormonal contraceptives, HIV, transplant drugs Hormonal contraceptives, HIV, transplant drugs

16. Hepatitis C Treatment Since 2011 Problems with Telaprevir/Boceprevir triple therapy Limited to genotype 1 3x per day dosing, 6-12 pills Low barrier to drug resistance Poor efficacy: Cirrhotics, prior non-responders, genotype 1a, IL28B genotype CT and TT

17. Hepatitis C Treatment: The Future HCV Life Cycle Video

18. Hepatitis C Treatment: The Future Sofosbuvir-Nucleotide HCV polymerase (NS5B) inhibitor Once a day dosing All genotypes treated Minimal side effects/drug interactions interactions Drug resistance not observed

19. Hepatitis C Treatment: 2014 Likely FDA Approvals Sofosbuvir + Ribavirin: 1 st Interferon-free treatment available Geno 2, 12 weeks, SVR 97% Geno 3, 12 weeks, SVR 56% G3 does better with 16 weeks Cirrhosis-better with 16 weeks

20. Hepatitis C Treatment: 2014 Likely FDA Approvals 12 wks Sofosbuvir/Riba/PEG-IFN Geno 1, 4, 5, 6 SVR 90% Cirrhosis 80%

21. Hepatitis C Treatment: 2014 Likely FDA Approvals Simeprevir-once-a-day protease inhibitor Simeprevir given for 1 st 12 weeks PEG-IFN/Ribavirin started with simeprevir and given for 24 or 48 wks Genotype 1 SVR 83-85%

22. Hepatitis C Treatment: 2015 Drugs from 2+ classes, as in HIV Increases efficacy and minimizes resistance One Example (Many under study) NS5b and NS5a inhibitor Sofosbuvir + Ledipasvir; one pill a day; ?available 2015

23. Hepatitis C What’s New Fibroscan- A non-invasive liver fibrosis test FDA approved

24. FibroScan-Non-invasive test of liver fibrosis 2.5 cm 4 cm 1 cm  Explored volume The probe induces an elastic wave through the liver The velocity of the ultrasonic shear wave is a measure of elasticity (fibrosis)

25. FibroScan-Non-invasive test of liver fibrosis Good accuracy in detecting cirrhosis Combined with clinical, lab, imaging results: Will likely replace liver biopsy in detection of cirrhosis Cirrhotics require additional monitoring

26. Cirrhosis: Preventive Measures No Alcohol Vaccines: Pneumonia, Flu, Hepatitis A and B Screen for Esophageal Varices Screen for Liver Cancer

27. Hepatitis C What’s New ECHO-Telemedicine Project

28. Central site: Education/support Remote sites: Treat patients Come online together: Didactic session + Case Presentations Goal: Increase treatment at the local level, especially in remote areas Coming to Maine!

29. Dr. Kilby wants One pill a day treatment for PCP. Treats all patients regardless of genotype, severity of liver disease, presence of co-morbidities. Requires minimal monitoring and has few side effects, drug interactions or drug resistance. Non-invasive testing for cirrhosis