1. HCV 2014 and beyond the interferon era Patrick M. Horne, MSN, ARNP, FNP-BC Assistant Director of Hepatology Clinical Research Division of Gastroenterology, Hepatology and Nutrition University of Florida Health

2. Disclosures and Off-label Discussion Financial relationships to disclose within the past 12 months: Scientific consultant for Gilead Sciences Off-label discussion: Combination sofosbuvir + simeprevir

3. Objectives Discuss the history and worldwide prevalence of hepatitis C Review the current approved therapeutic options for HCV therapy based on genotype Discuss some future treatment options in development

4. Developments in Treatment and Cure Rates SVR (%) 1991 1998 2001 2011 Standard Interferon Ribavirin Peginterferon Direct Acting Antivirals 2013 Protease inhibitor Nucleoside inhibitor SVR % TIME

5. Seroprevalence of Hepatitis C: 170 to 200 Million Worldwide Americas 12-15 M Africa30-40M Australia.2 M Western Pacific 60 M Western Europe 5 M Eastern Europe 10 M Southeast Asia 30-35 M 1. World Health Organization. Wkly Epidemiol Rec. 2000;75:17-28. 2. Edlin B et al. AASLD; November 11-15; 2005 San Francisco, California. Oral Presentation #44. United States 5M Highest Prevalence: Egypt-4M (45% adults >40y) P-DS-D-159

6. SVR is Associated with Reduced Mortality Among HCV-infected Persons Van der Meer, et al. JAMA 2012:308:2584-2593. 530 adults in Europe prospectively followed for median 8.4 years after HCV treatment 192 (36%) achieved SVR No. at risk Without SVR405393382363344317295250207164135 With SVR19218116816215614412588564028 30 20 10 0 All-cause mortality All-cause mortality, % P<0.001 Time, y 012345678910 Without SVR With SVR No. at risk Without SVR405392380358334305277229187146119 With SVR19218116816215614412588564028 30 20 10 0 Liver-related mortality or liver transplantation Liver-related mortality or liver transplantation, % P<0.001 Time, y 012345678910 Without SVR With SVR

7. 75% of Infected Individuals Are Not Aware of Their HCV Status 1. Institute of Medicine. Hepatitis and Liver Cancer, A National Strategy for Prevention and Control of Hepatitis B and C. Washington, DC. The National Academies Press, 2010; 2.United States Department of Health and Human Services. Combating the Silent Epidemic of Viral Hepatitis, Action Plan for the Prevention, Care & Treatment of Viral Hepatitis. 2011

8. CDC Releases Birth Cohort Screening Guidelines Adults born during 1945–1965 should receive one-time testing for HCV without prior ascertainment of HCV risk All persons identified with HCV infection should receive a brief alcohol screening and intervention as clinically indicated, followed by referral to appropriate care and treatment services Smith BD, et al. MMWR Recomm Rep. 2012;61(RR-4):1-32.

9. Case 1 60 year old Caucasian male presents recently found to be HCV Ab positive. – Confirmatory testing confirms genotype 1a with a viral load of 1,245,300 IU/mL. Hx of illicit drug use in the 1960s Medical hx includes – Hypertension-well controlled – GERD-well controlled with PPI

10. Case 1 Naïve to treatment Baseline labs: – AST 66, ALT 70 – Total bilirubin 0.5 – Hemoglobin 14.0 – Platelet count 175,000 – Fibrotest=F2 disease

11. Case 1 What do you do?

12. Current options Approved options – Pegylated interferon (Peg-INF) and ribavirin (RBV), weight based times 48 weeks – Peg-INF, RBV plus either telaprevir (TVR) or bocepravir (BOC) for 24-48 weeks – Peg-INF, RBV plus simeprevir (SIM) for 24-48 weeks – Peg-INF, RBV plus sofosbuvir (SOF) times 12 weeks or SOF and RBV for 24 weeks

13. Current options Not approved option but with good data – SOF + SIM with or without ribavirin for 12 weeks- COSMOS study Wait for something else

14. Package inserts

15. Recommendations for HCV Genotype 1 Treatment-Naïve PopulationRecommended RegimenDuration Treatment-naïve genotype 1Sofosbuvir (400 mg) + PEG-INF + RBV (1000-1200 mg/d) 12 weeks Alternative regimens: Simeprevir + PEG-INF+ RBV x 12 wks SIM + SOF+/- RBV x 12 wks SOF + RBV x24 wks Regimens specifically not recommended: Peg-INF/RBV x 48 wks with or without TVR or BOC Monotherapy with PEG, RBV, or DAA AASLD/IDSA Treatment Recommendations. www.hcvguidelines.org. Accessed January 31, 2014. Peg-INF = pegylated interferon; RBV=ribavirin; DAA = direct acting antiviral

16. Neutrino Study Overall HCV GT 1 (1a, 1b, 1a/b) 1a 1b 4, 5, 6 Cirrhosis No Yes Race Black Non-black HCV RNA level <6 log 10 IU/mL ≥6 log 10 IU/mL IL28B CC Non-CC SVR % Lawitz E, et al. EASL 2013, Abstract 1411; Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. SOF + PEG-IFN + RBV SVR by Subgroups SVR

17. Genotype 1 Treatment Options Phase 3 Landscape 2014 (now) PEG/RBV + SOF DCV + ASU (1b) SOF + LPV + RBV SVR (est) ABT-450+ 333 + 267 + RBV 2014-2015 00 1212 90% > 94% 90% SOF + SMV (off-label) > 90% SOF + DCV > 94% weeks SOF + RBV (select populations) 60-70% > 94 % 0 24-48 12 Courtesy of David Nelson, M.D.

18. Case 2 55 year old African-American female with HCV genotype 2b who was a prior relapser to Peg-INF + RBV times 24 weeks. Liver biopsy in 2013-F3 fibrosis Other medical hx: – Diabetes – Hyperlipidemia – Anxiety

19. Case 2 Labs: – HCV RNA 550,000 IU/mL – AST 100, ALT 98 – Total bilirubin 1.0 – Hemoglobin 12.5 – Platelet count 110,000

20. Case 2 What do you do?

21. Options Re-treat with Peg-INF + RBV for 48 weeks – Prior treatment she required multiple dose reductions of Peg-INF due to side effects SOF + RBV for 12 weeks Wait

22. Recommendations for HCV Genotype 2 Treatment-Experienced PopulationRecommended RegimenDuration Previous treatment with PEG/RBV Sofosbuvir (400 mg) + RBV (1000-1200 mg/d) 12 weeks* AASLD/IDSA Treatment Recommendations. www.hcvguidelines.org. Accessed January 31, 2014. *Patients with cirrhosis may benefit by extension of therapy to 16 weeks PopulationAlternative RegimenDuration Previous treatment with PEG/RBV Sofosbuvir (400 mg) + PEG-IFN + RBV (1000-1200 mg/d) 12 weeks

23. 23 GT-2GT-3 SVR12 rate (%) FISSION POSITRON FUSION 16 week 62% 12 week 12 Week 5656% 12 week 0102030405060708090100 Sofosbuvir + RBV in HCV GT 2/3 Genotype 2 = 3 Lawitz E, et al. N Engl J Med 2013;368:1878-87.Jacobson IM, et al. N Engl J Med 2013;368:1867-77. 24 week VALENCE 12 week FUSION 97% 93% 61% 86% 30% 94% 62% 93% 84% GT-2 GT-3

24. Case 3 54 year old Hispanic male with HCV genotype 3. – Diagnosed 5 years ago – Relapser to Peg-INF and RBV – Liver biopsy 2013-F1 fibrosis Other medical history: – Bipolar disorder – GERD – Arthritis

25. Case 3 Labs: – HCV RNA 1,200,000 IU/mL – AST 55, ALT 80 – Total bilirubin 0.6 – Hemoglobin 13.4 – Platelet count 200,000

26. Treatment options Peg-INF + RBV for 24 weeks SOF + RBV for 24 weeks Peg-INF + RBV + SOF for 12 weeks

27. Recommendations for HCV Genotype 3, Treatment – Naïve/Experienced PopulationRecommended RegimenDuration Regardless of IFN eligibilitySofosbuvir (400 mg) + RBV (1000-1200 mg/d) 24 weeks AASLD/IDSA Treatment Recommendations. www.hcvguidelines.org. Accessed January 31, 2014. PopulationAlternative RegimenDuration Consider only if eligible for IFN Sofosbuvir (400 mg) + Peginterferon + RBV (1000-1200 mg/d) 12 weeks Not recommended: PEG/RBV Telaprevir, boceprevir, simeprevir

28. 28 GT-2GT-3 SVR12 rate (%) FISSION POSITRON FUSION 16 week 62% 12 week 12 Week 5656% 12 week 0102030405060708090100 Sofosbuvir + RBV in HCV GT 2/3 Genotype 2 = 3 Lawitz E, et al. N Engl J Med 2013;368:1878-87.Jacobson IM, et al. N Engl J Med 2013;368:1867-77. 24 week VALENCE 12 week FUSION 97% 93% 61% 86% 30% 94% 62% 93% 84% GT-2 GT-3

29. VALENCE: Sofosbuvir + RBV Genotype 3 IFN naïve, ineligible or treatment failures SOF+RBV (n=250) G3 93 92 85 60 Naïve Treatment-experienced Noncirrhotic Cirrhotic SVR 12 (%) 86/92 12/13 85/100 27/45 Zeuzem S et al, AASLD 2013, #1085 12240 weeks

30. 100 80 60 40 20 0 37 63 85 19 61 60 No Cirrhosis Cirrhosis Impact of Duration on Efficacy of SOF in Tx-experienced GT 3 FUSION: 12 Weeks SOF/RBV FUSION: 16 Weeks SOF/RBV VALENCE: 24 Weeks SOF/RBV Lawitz E, et al. AASLD 2013. Zeuzem, et al. AASLD 2013. SVR12 (%) 14/ 38 25/ 40 85/ 100 5/ 26 14/ 23 27/ 45 Genotype 3 n/N = SOF = sofosbuvir; RBV=ribavirin

31. Lonestar-2 Peg-INF + RBV + SOF times 12 weeks Lawitz E AASLD 2013

32. What about waiting? What may be coming?

33. Sulkowski MS, et al. N Engl J Med. 2014;370:211-21.; Clinical Trials.gov Daclatasvir + Sofosbuvir +/- Ribavirin for HCV GT 2-3 Treatment-Naïve 24 Week Rx SOF × 7 days, then DCV + SOF SVR12 = 88% Week 02436 Rx Naïve GT 2 or 3 n = 44 n = 14 n = 16 12 DCV + SOF n = 14 DCV + SOF + RBV SVR12 = 93% SVR12 = 86% Drug Dosing Daclatasvir (DCV): 60 mg once daily Sofosbuvir (SOF): 400 mg once daily Phase 3 Trial (NCT02032901): ongoing, but closed to enrollment DCV + SOF Genotype 3 (n= 150) - naïve - experienced

34. The New Era of HCV Therapy Multiple Direct Acting Antivirals 3’UTR 5’UTR CoreE1E2NS2 NS4B NS3NS5ANS5B p7 4A HCV PIs NS5A Inhibitors NS5B Nucs NS5B Non-nucs Protease Viral enzyme Active site Telaprevir Boceprevir Simeprevir Faldaprevir Asunaprevir ABT-450 MK-5172 Sovaprevir ACH-2684 Non-enzyme Replication complex Daclatasvir Ledipasvir ABT-267 GS-5816 ACH-3102 PPI-668 GSK2336805 Samatasvir MK-8742 Viral enzyme Active site Sofosbuvir VX-135 IDX20963 ACH-3422 Viral enzyme Allosteric site ABT-333 Deleobuvir BMS-791325 PPI-383 GS-9669 TMC647055 Polymerase Courtsey of David Nelson, M.D.

35. HCV Future Treatment Paradigm Many Options to Choose From NS5A + PI + NNI + RBV NS5A + PI + NNI + RBV SOF + RBV PEG-IFN + RBV + DAA PEG-IFN + RBV + DAA SOF + NS5A + RBV SOF + NS5A + RBV NI: nucleotide polymerase inhibitor (SOF), NNI: non-nucleotide polymerase inhibitor PI: protease inhibitor, NS5A: NS5A replication complex inhibitor SOF + PI + RBV SOF + PI + RBV Direct Acting Antivirals IL28B CC

36. Summary Large cohort of patients that have yet to be diagnosed. Treatment options are becoming better and short and more individualized. More patients will have access to medications options as we will no longer be limited by contraindications to treatment due to medical co-morbidities or side effects

37. Thank you!