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HCV 2014 and b eyond the i nterferon era

HCV 2014 and b eyond the i nterferon era. Patrick M. Horne, MSN, ARNP, FNP-BC Assistant Director of Hepatology Clinical Research Division of Gastroenterology, Hepatology and Nutrition University of Florida Health. Disclosures and Off-label Discussion.

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HCV 2014 and b eyond the i nterferon era

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  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 Direct Acting Antivirals Nucleoside inhibitor Protease inhibitor 2013 2011 Peginterferon 2001 Ribavirin 1998 SVR % Standard Interferon 1991 SVR (%) TIME

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

  6. Van der Meer, et al. JAMA 2012:308:2584-2593. SVR is Associated with Reduced Mortality Among HCV-infected Persons • 530 adults in Europe prospectively followed for median 8.4 years after HCV treatment • 192 (36%) achieved SVR 30 20 10 0 30 20 10 0 Liver-related mortality or liver transplantation All-cause mortality P<0.001 P<0.001 Liver-related mortality or liver transplantation, % All-cause mortality, % Without SVR With SVR Without SVR With SVR 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 Time, y Time, y

  7. 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. Combatingthe Silent Epidemic of Viral Hepatitis, Action Plan for the Prevention, Care & Treatment of Viral Hepatitis. 2011 75% of Infected Individuals Are Not Aware of Their HCV Status

  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 • 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 Peg-INF = pegylated interferon; RBV=ribavirin; DAA = direct acting antiviral AASLD/IDSA Treatment Recommendations. www.hcvguidelines.org. Accessed January 31, 2014.

  16. Neutrino Study SOF + PEG-IFN + RBV SVR by Subgroups SVR Lawitz E, et al. EASL 2013, Abstract 1411; Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. SVR %

  17. Genotype 1 Treatment OptionsPhase 3 Landscape SVR (est) 2014 (now) 90% PEG/RBV + SOF > 90% SOF + SMV (off-label) 60-70% SOF + RBV (select populations) 12 0 24-48 weeks 00 1212 2014-2015 > 94% SOF + LPV + RBV >94% ABT-450+ 333 + 267 + RBV 90% DCV + ASU (1b) SOF + DCV > 94% 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 *Patients with cirrhosis may benefit by extension of therapy to 16 weeks AASLD/IDSA Treatment Recommendations. www.hcvguidelines.org. Accessed January 31, 2014.

  23. 12 week 12 week 12 week 12 week 12 Week 12 week 5656%% Sofosbuvir + RBV in HCV GT 2/3 Genotype 2 = 3 97% GT-2 GT-3 FISSION 93% GT-2 POSITRON 61% 86% FUSION FUSION 30% 94% GT-3 16 week FUSION 16 week 62% 93% 12 week VALENCE 62% 24 week 84% SVR12 rate (%) 0 10 20 30 40 50 60 70 80 90 100 Lawitz E, et al. N Engl J Med 2013;368:1878-87. Jacobson IM, et al. N Engl J Med 2013;368:1867-77. 23

  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 • Not recommended: • PEG/RBV • Telaprevir, boceprevir, simeprevir AASLD/IDSA Treatment Recommendations. www.hcvguidelines.org. Accessed January 31, 2014.

  28. 12 week 12 week 12 week 12 week 12 Week 12 week 5656%% Sofosbuvir + RBV in HCV GT 2/3 Genotype 2 = 3 97% GT-2 GT-3 FISSION 93% GT-2 POSITRON 61% 86% FUSION FUSION 30% 94% GT-3 16 week FUSION 16 week 62% 93% 12 week VALENCE 62% 24 week 84% SVR12 rate (%) 0 10 20 30 40 50 60 70 80 90 100 Lawitz E, et al. N Engl J Med 2013;368:1878-87. Jacobson IM, et al. N Engl J Med 2013;368:1867-77. 28

  29. VALENCE: Sofosbuvir + RBVGenotype 3 IFN naïve, ineligible or treatment failures weeks 0 12 24 G3 SOF+RBV (n=250) 93 92 85 SVR 12 (%) 60 86/92 12/13 85/100 27/45 Noncirrhotic Cirrhotic Noncirrhotic Cirrhotic Naïve Treatment-experienced Zeuzem S et al, AASLD 2013, #1085

  30. 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 100 80 60 40 20 0 85 63 61 60 37 19 SVR12 (%) 85/ 100 25/ 40 14/ 38 14/ 23 27/ 45 5/ 26 n/N = No Cirrhosis Cirrhosis Genotype 3 SOF = sofosbuvir; RBV=ribavirin Lawitz E, et al. AASLD 2013. Zeuzem, et al. AASLD 2013.

  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 2-3Treatment-Naïve 24 Week Rx 0 12 24 36 Week n =16 Rx Naïve GT 2 or 3n = 44 SVR12 = 88% SOF × 7 days, then DCV + SOF n = 14 SVR12 = 93% DCV + SOF n = 14 SVR12 = 86% DCV + SOF + RBV Drug DosingDaclatasvir (DCV): 60 mg once dailySofosbuvir (SOF): 400 mg once daily Genotype 3 (n= 150) - naïve - experienced Phase 3 Trial (NCT02032901): ongoing, but closed to enrollment DCV + SOF

  34. The New Era of HCV TherapyMultiple Direct Acting Antivirals Core E1 E2 NS2 NS3 NS4B NS5A NS5B • 3’UTR • 5’UTR p7 4A • Protease • NS5A • Inhibitors • Polymerase • HCV PIs • NS5B • Nucs • NS5B • Non-nucs • Non-enzyme • Replication complex • Daclatasvir • Ledipasvir • ABT-267 • GS-5816 • ACH-3102 • PPI-668 • GSK2336805 • Samatasvir • MK-8742 • Viral enzyme • Active site • Telaprevir • BoceprevirSimeprevir • Faldaprevir • Asunaprevir • ABT-450 • MK-5172 • Sovaprevir • ACH-2684 • Viral enzyme • Active site • Sofosbuvir • VX-135 • IDX20963 • ACH-3422 • Viral enzyme • Allosteric site • ABT-333 • Deleobuvir • BMS-791325 • PPI-383 • GS-9669 • TMC647055 Courtsey of David Nelson, M.D.

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

  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!

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