1. Updates on Hepatitis C Infection Mazen Alsatie, MD SVMG Gastroenterology/Hepatology 2010 West 86 th street, Suite 111 Indianapolis, IN 46260

2. Objectives Epidemiology Natural History Diagnosis Treatment Endoscopy Unit and HCV

3. US 3-4 M Americas 12-15 M Africa 30-40 M South East Asia 30-35 M Australia 0.2 M World Health Organization, 1999. WesternEurope 5 M 170-200 Million Carriers Worldwide Hepatitis C: A Global Health Problem EasternEurope 10 M Far East Asia 60 M

4. *95% Confidence Interval Mainly IV drug use Acute Hepatitis C typically is mild to moderate and can go unnoticed. 80% becomes chronic infection (6 months) Deaths from acute liver failure Rare Persons ever infected (1.8%) 3.9 million (3.1–4.8)* Persons with chronic infection 2.7 million (2.4–3.0)* HCV-related chronic liver disease 40%–60% Deaths from chronic disease/year 8,000–10,000 Hepatitis C Virus Infection in the US

5. Disease Burden From Bloodborne Viral Infections Deaths/y New infections/y Chronic infections Outcome 5000 ~120,000 ~1.2 million HBV 8000 ~40,000 ~2.7 million HCV 18,000 ~40,000 ~0.8 million HIV

6. Screen everyone for HCV 1945-1965 by HCV Ab

7. Chronic HCV Infection Hoofnagle JH. Hepatology.1997;26:15S-20S. Hoofnagle JH. Hepatology.1997;26:15S-20S. 0 200 400 600 800 1000 02468101224123456 Anti-HCV Symptoms+++++++++++++ ALT (U/L) WeeksMonths Time After Exposure Chronic Hepatitis C HCV RNA

8. Risk Factors for Acute Hepatitis C Alter MJ. Presented at the NIH Consensus Development Conference, March 24, 1997. United States, 1991-1995 *Other High Risk 16% drug related 11% previous drug use not within last 6 months 5% intranasal cocaine use 4% history of STDs 1% prison 9% lower socio-economic status (fewer years of education) Other High Risk* 30.0% Injection Drug Use 43.0% Unknown 1.0% Household 3.0% Occupational 4.0% Transfusion** 4.0% Sexual (Multiple Partners) 15.0% **None in 1995

9. How is Hepatitis C Diagnosed? HCV Antibodies: when positive, it means prior exposure HCV RNA when positive it means chronic infection (the virus is in the liver and bloodstream) HCV Genotype ALT can be normal in 30% of chronic HCV Then the question How much fibrosis is there in the liver Liver Biopsy: determines: 1- Grade = inflammation (1-4) 2- Stage = Fibrosis (0-4) Non Invasive Testing for Fibrosis

11. Analysis of Genotype Distribution in the United States (N = 6807) by Line Probe Assay 7% 0% 5% 1% 0% 5% 8% 4%0%31% 38% 4 Mixed 2 Mixed 1 Mixed 4 3a 2b 2a 2 1b 1a 1 Blatt LM, et al, J. Viral Hepatitis. 2000;(3):196-202.

12. Hepatitis C: Spectrum of Disease Hoofnagle JH. Hepatology. 1997;26:15S-20S. Acute HCV Infection Chronic HCV Infection Recovery Cirrhosis Chronic Hepatitis HCC End-Stage Liver Disease 85%15% SevereModerate Mild

13. Natural History of HCV Infection Kenny-Walsh, New Engl J Med 1999; 340:1228. 17 year follow-up of Irish women after contaminated Ig 18% © 2000; GL Davis Univ of FL Liver Unit

14. HCV-related fibrosis, cirrhosis and hepatocellular cancer

15. Natural history of HCV infection

17. Associated Signs and Symptoms of patients with HCV Fatigue Anorexia Nausea Abdominal discomfort Pruritus Rash vitigilo Arthralgias Myalgias Parethesias Difficulty concentrating Weakness Weight loss

18. Extrahepatic Manifestations of Hepatitis C infection Dermatologic –Porphyria cutanea tarda –Lichen planus –Cutaneous vasculitis –Purpura –Vitiligo Endocrine –Autoimmune Thyroiditis –Thyroid cancer –Diabetes Mellitus Hematologic –Mixed Cryoglobulinemia –Non Hodgkin Lymphoma –Monoclonal gammapathy Rheumatologic –Raynold’s –Chronic polyarthritis –Sicca Syndrome Renal  MPGN  Membranous nephropathy  Renal Cell cancer Respiratory –Idiopathic pulmonary fibrosis Neurologic –Sensory Neuropathy –Motor Neuropahty

19. Who Should Be Treated for Hepatitis C? Those with detectable HCV RNA, liver biopsy with fibrosis and/or inflammatory changes Patients with cirrhosis without decompensation People with extra-hepatic manifestations of hepatitis C A normal ALT may mean less severe disease, but treatment should be individualized Antiviral treatment is recommended for all patients with chronic HCV infection, except those with limited life expectancy due to nonhepatic causes. (Level I-A) AASLD GUIDELINES

20. Patients Who Should Not Be Treated Decompensated liver disease ? EVOLVING (jaundice, ascites, variceal hemorrhage, encephalopathy) Severe psychiactric disorders? NOT AN ISSUE ANYMORE Early disease (wait for therapy to become cheaper)

21. HCV Therapy: Definitions Treatment response: Clearance of HCV RNA by RT- PCR testing during therapy –Typically measured EVERY 4 WEEKS on therapy At the end of therapy Three months after end of therapy Sustained virologic response (SVR): Undetectable HCV RNA by PCR testing 12 weeks after finishing therapy. –The best definition of cure at this time Non-response: Failure to clear HCV RNA during therapy. Medications should be stopped

22. Insurance company requirements Chronic infection (more than 6 months) Fibrosis assessment (noninvasive or biopsy) Urine drug screen ? Current drug or alcohol abuse data

23. Standard of Care 2016 This is really evolving Several agents in the pipeline at different stages of development ????? MAGIC PILL ONCE A DAY, PANGENOMIC, NO VIRAL RESISTANCE AND NO DRUG INTERACTION

24. Factors affecting treatment regimen choice and length: -Cirrhosis: -Compensated -Decompensated -Prior therapy -Other meds (Interactions) -Renal Function -Regimen Simplicity Is Failure possible? Compliance Mutations leading to resistance Risk of reinfection

25. Standard of Care 2016 Approval Date 2014HarvoniSofosbuvir / LedipasvirGenotype 1,4,5,6 (Up to 100%) 2014VIEKIRA PAKOmbitasvir, Paritaprevir/Ritonavir, Dasabuvir with/without Ribavirin Genotype 1 (Up to 100%) 2015DaklinzaDaclatasvir for use with Sofosbuvir (Daklinza + Sovaldi) Genotype 3 (Up to 98%) 2015TechnivieOmbitasvir, Paritaprevir and Ritonavir plus Ribavirin Genotype 4 (Up to 100%) 2016ZEPATIERELBASVIR/GRAZOPREVIRGenotype 1, 4 (Up to 100%)

26. Genotype 1 Treatment HARVONI (Sofobuvir + Ledipasvir) –Drug Interactions 3 (Rifampin, St John’s wort, Amiodarone) –Length of therapy 8 weeks / 12 weeks/ or 24 weeks (Decompensated) –The need for RBV: minority of pts –One pill once a day with or without food ZEPATIER (elbasvir and grazoprevir) –Drug Interactions +20 VIEKERA PAK (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets), co-packaged for oral use –Drug interactions +20 –Two ombitasvir, paritaprevir, ritonavir 12.5/75/50 mg tablets once daily (in the morning) and one dasabuvir 250 mg tablet twice daily (morning and evening) with a meal

27. Antiviral treatment algorithm for chronic hepatitis C virus genotype 2 infection in adults

28. Antiviral treatment algorithm for chronic hepatitis C virus genotype 3 infection in adults

29. HCV Transmission in The Endoscopy Unit Healthcare-Associated Hepatitis B and C Outbreaks Reported to the Centers for Disease Control and Prevention (CDC) 2008-2014

30. CDC Report 44 outbreaks of viral hepatitis 2008-2014 Hepatitis B (total 23 outbreaks )175 outbreak- associated cases, >10,700 persons notified for screening) Hepatitis C (total 22 outbreaks, 239 outbreak- associated cases, >90,400 at-risk persons notified for screening):

31. Causes syringe reuse contaminating medication vials Drug diversion Use of single-dose vials for >1 patient Breaches in environmental cleaning and disinfection practices

32. Use and Reprocessing of Flexible Fiberoptic Endoscopes at VA Medical Facilities Report Report No. 09-01784-146 June 16, 2009 Recommendation 1: ensure compliance with relevant directives regarding endoscope reprocessing. Recommendation 2: explore possibilities for improving the reliability of endoscope reprocessing with VA and non- VA experts. Recommendation 3: review the VHA organizational structure and make the necessary changes to implement quality controls and ensure compliance with directives.

33. VA causes of exposure Reprocessing of Auxiliary Water Channel incorrect connector being used to link cleaning solution to endoscopes during reprocessing Required one-way valve had been absent during procedures in one VA

34. Recommended Diet for HCV-Infected Patients Alcohol abstinence Low fat Protein 1-1.5 g/kg From animal or vegetable sources Calories sufficient to maintain weight or address weight loss

35. Avoid Weight Gain!

36. Points to know about Hepatitis C Hepatitis C is transmitted primarily by IVDU, tattoos Patients with HCV should be screened for HBV and HIV. Patients with HCV should be vaccinated for HAV and HBV if not immune Sexual transmission in monogamous relationship and mother- to-fetus transmission are rare This disease is difficult to transmit to family members Alcohol consumption should be minimized, abstinence is recommended Hepatitis C is becoming curable 95 - 100% of the time There is no immunity for hepatitis C. There is risk of reinfection

37. More points on Hepatitis C Patients should refrain from donating blood, organs, tissues or semen With multiple sexual partners, the use of latex condom should be encouraged Sexual partners of infected patients should be tested for HCV Do not share razors and toothbrushes, but it is not necessary to avoid sharing meals or utensils HCV patients can participate in any social, education or employment activities

38. WHAT ABOUT EXPOSURE Transmission risk from needle exposure is about 1.8% (0-10%). (CDC.gov) Baseline testing for both patient /employee Testing employee’s HCV RNA at 4-6 weeks Follow up for 6 months. Pre-exposure and post-exposure prophylaxis with antiviral therapy is NOT recommended

39. THANK YOU QUESTIONS ????