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Treatment of Chronic HCV Genotype 2

Treatment of Chronic HCV Genotype 2. Robe rt G. Gish MD Staff Physician, Stanford University Medical Center Senior Medical Director, St Josephs Hospital and Medical Center, Liver Program, Phoenix , Arizona Clinical Professor of Medicine, University of Nevada, Las Vegas

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Treatment of Chronic HCV Genotype 2

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  1. Treatment of Chronic HCV Genotype 2 Robert G. Gish MD Staff Physician, Stanford University Medical Center Senior Medical Director, St Josephs Hospital and Medical Center, Liver Program, Phoenix, Arizona Clinical Professor of Medicine, University of Nevada, Las Vegas Medical Director, Hepatitis B Foundation Vice Chair, Executive Committee, National Viral Hepatitis Roundtable (NVHR) Last Updated: May 14, 2014

  2. Treatment of Chronic HCV Genotype 2 • Background and Definitions • Initial Treatment and Retreatment of Prior Relapsers • Retreatment of Prior Nonresponders • Issues and Controversies • Future Therapies • Summary

  3. Treatment of Chronic Hepatitis C: Genotype 2 Background and Definitions

  4. Treatment of Chronic HCV Genotype 2Background • HCV infects ~ 5 million people in the US today • Genotype 2 is second most common HCV genotype in US • Up to 85% of patients have contraindications for interferon therapy • Small proportion of untreated patients are genotype 2 today due to historically high treatment and cure rates

  5. Virologic Responses with HCV TherapySustained Virologic Response at 12 Weeks Post Therapy (SVR12) Treatment Post Treatment SVR12 End of Treatment 12 Weeks Undetectable Sustained Virologic Response (SVR12) = Undetectable HCV RNA 12 Weeks Post Treatment

  6. Virologic Failure with HCV TherapyRelapser and Nonresponder (Null and Partial) Different Types of Virologic Failure with HCV Therapy Treatment Relapser Nonresponder Null Responder Nonresponder Partial Responder Undetectable

  7. AASLD/IDSA/IAS-USA 2014 HCV Treatment RecommendationsCriteria for Interferon Ineligible Source: AASLD/IDSA/IAS-USA (www.hcvguidelines.org). Accessed May 12, 2014

  8. Treatment of Chronic Hepatitis C: Genotype 2 Treatment-Naïve and Prior Relapsers

  9. AASLD/IDSA/IAS-USA 2014 HCV Treatment RecommendationsInitial Therapy for Patients with Genotype 2 Chronic HCV Source: AASLD/IDSA/IAS-USA (www.hcvguidelines.org). Viewed April 22, 2014

  10. Treatment-Naïve & Prior Relapsers with GT2 Chronic HCVKey Studies that Support Treatment Recommendations • Sofosbuvir + Ribavirin- FISSION- POSITRON- VALENCE

  11. Sofosbuvir + Ribavirin for Treatment-Naïve HCV GT 2 or 3FISSION Trial: Design Week 0 12 24 36 Sofosbuvir + RBV (weight-based) N =256 SVR12 Peginterferon + RBV (fixed-dose) N =243 SVR12 Drug DosingSofosbuvir: 400 mg once dailyPeginterferon alfa-2a: 180 µg once weeklyWeight-based Ribavirin (in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kgFixed-dose Ribavirin (in 2 divided doses): 800 mg/day Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.

  12. Sofosbuvir + Ribavirin for Treatment-Naïve HCV GT 2 or 3FISSION Trial: Results SVR12 by Genotype 170/253 162/243 68/70 52/67 102/183 110/176 RBV = Ribavirin; PEG = Peginterferon Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.

  13. Sofosbuvir + Ribavirin for HCV GT 2 or 3 (PEG not an option)POSITRON Trial: Design 0 12 24 Week Sofosbuvir+ RBV 12 weeks N =207 SVR12 Placebo12 weeks N =71 SVR12 Drug DosingSofosbuvir: 400 mg once dailyWeight-Based Ribavirin (in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg Source: Jacobson I, et al. N Engl J Med. 2013;368:1867-77.

  14. Sofosbuvir + Ribavirin for HCV GT 2,3 (PEG not an option)POSITRON: Results with Sofosbuvir + Ribavirin SVR12 by HCV Genotype 101/109 60/98 Placebo arm = 0% SVR12 Source: Jacobson I, et al. N Engl J Med. 2013;368:1867-77.

  15. Sofosbuvir + Ribavirin for Treatment Naïve & Experienced HCV GT 2 or 3 VALENCE: Treatment Arms Week 0 12 24 36 GT 2 Sofosbuvir +RBV(n = 73) SVR12 GT 3 Sofosbuvir +RBV(n = 250) SVR12 Note: 85 patients enrolled in placebo arm Original Study Protocol: Placebo versus 12 weeks treatment for GT 2 and 3. Amended Protocol: GT3 treatment extended from 12 to 24 weeks; Placebo arm offered alternative treatment Drug DosingSofosbuvir 400 mg once dailyRibavirin (weight-based and divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg Source: Zeuzem S, et al. N Engl J Med. 2014 May 4. [Epub ahead of print]

  16. Sofosbuvir + Ribavirin for Treatment Naïve & Experienced HCV GT 2 or 3 VALENCE: Results for Treatment-Naïve GT 2 SVR12 for Treatment-Naïve GT 2 Source: Zeuzem S, et al. N Engl J Med. 2014 May 4. [Epub ahead of print]

  17. Treatment of Chronic Hepatitis C: Genotype 2 Retreatment of Prior Nonresponders

  18. AASLD/IDSA/IAS-USA 2014 HCV Treatment RecommendationsRetreatment of Patients with Genotype 2 Chronic HCV Source: AASLD/IDSA/IAS-USA (www.hcvguidelines.org). Viewed April 22, 2014

  19. Treatment Experienced Nonresponders with GT2 Chronic HCVKey Studies that Support Treatment Recommendations • Sofosbuvir + Ribavirin- FUSION- VALENCE • Sofosbuvir + Ribavirin + Peginterferon- LONESTAR-2

  20. Sofosbuvir + RBV in Treatment-Experienced HCV GT 2 or 3FUSION Trial: Design Week 0 12 16 24 28 Sofosbuvir+ RBV 12 weeks Placebo N =103 SVR12 Sofosbuvir+ RBV 16 weeks N =98 SVR12 Drug DosingSofosbuvir: 400 mg once dailyWeight-Based Ribavirin (in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg Source: Jacobson I, et al. N Engl J Med. 2013;368:1867-77.

  21. Sofosbuvir + RBV in Treatment-Experienced HCV GT 2 or 3FUSION Trial: Results for GT2 SVR12 for Treatment-Experienced GT2 31/36 30/32 25/26 23/23 6/10 7/9 SOF = Sofosbuvir; RBV = Ribavirin Source: Jacobson I, et al. N Engl J Med. 2013;368:1867-77.

  22. Sofosbuvir + Ribavirin for Treatment Naïve & Experienced HCV GT 2 or 3VALENCE: Treatment Arms Week 0 12 24 36 GT 2 Sofosbuvir +RBV(n = 73) SVR12 GT 3 Sofosbuvir +RBV(n = 250) SVR12 Note: 85 patients enrolled in placebo arm Original Study Protocol: Placebo versus 12 weeks treatment for GT 2 and 3. Amended Protocol: GT3 treatment extended from 12 to 24 weeks; Placebo arm offered alternative treatment Drug DosingSofosbuvir 400 mg once dailyRibavirin (weight-based and divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg Source: Zeuzem S, et al. N Engl J Med. 2014 May 4. [Epub ahead of print]

  23. Sofosbuvir + Ribavirin for Treatment Naïve & Experienced HCV GT 2 or 3 VALENCE: Results for Treatment Experienced GT 2 SVR12 for Treatment-Experienced GT 2 Source: Zeuzem S, et al. N Engl J Med. 2014 May 4. [Epub ahead of print]

  24. Sofosbuvir + PEG + RBV in Treatment-Experienced HCV GT 2 or 3LONESTAR-2 Trial: Design 0 12 24 Week GT 2 or 3 SVR12 Drug DosingSofosbuvir: 400 mg once dailyPeginterferon alfa-2a: 180 µg once weeklyRibavirin (weight-based and in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg Sofosbuvir + Peginterferon + Ribavirin N = 47 Source: Lawitz E, et al. 64th AASLD; Washington, DC. 2013. Abstract LB-4.

  25. Sofosbuvir + PEG + RBV in Treatment-Experienced HCV GT 2 or 3LONESTAR-2 Trial: Results SVR12 in Treatment-Experienced by HCV Genotype 42/47 22/23 20/24 Source: Lawitz E, et al. 64th AASLD; Washington, DC. 2013. Abstract LB-4.

  26. Treatment of Chronic Hepatitis C: Genotype 2 Issues and Controversies

  27. Treatment of Genotype 2 Chronic HCVIssues and Controversies • Cost of Therapy: wait for price competition? • With cure rates as high as 96%, are we over-treating most patients?- Can we shorten therapy to 4 or 6 weeks to save treatment costs? • When to Defer Therapy:- Decisions on when to warehouse?- Based on mild histology or lack of evidence of systemic disease • (Non) Role of IL-28b Testing, now obviated • Degree of Liver Fibrosis- How to stage?- MRE, Fibroscan, Supersonic, Spleen Size, APRI score, platelet count

  28. How is cost of therapy impacting treatment decisions?

  29. Hepatitis C Genotype 2EstimatedMedication Costs for Treatment-Naïve & Prior Relapsers

  30. Hepatitis C Genotype 2EstimatedMedication Costs for Retreatment of Nonresponders

  31. HCV Therapy for Genotype 2 Chronic HCVCost Analysis Based on Cost per SVR Source for Figure: Camilla Graham, MD, MPH. Beth Israel Deaconess Medical Center Data Sources: (1) Lawitz E, et al. NEJM 2013; 368:1878-87. (2) Jacobson I, et al. NEJM 2013; 368:1867-77. (3) Antiviral Drugs Advisory Committee Meeting, FDA and Gilead reviews, 10/25/2013. (4) Package Insert, Gilead.com 12/7/2013.

  32. Treat now or defer therapy?

  33. Factors Favoring Treat GT2 Now • Advanced Fibrosis (F3-F4)- Platelet count < 150,000/uL- Large spleen and/or portal vein- Esophageal varices • Synthetic dysfunction • Systemic disease- Cryoglobulinemia ([+] Rheumatoid Factor) • Highly motivated patients/symptomatic patients • Patients with Increased Mortality Risk- All cause- HCC risk

  34. Hepatitis C: Genotype 2 Future Treatment Options

  35. Future Regimens for GT-2 • Daclatasvir+ Sofosbuvir- Daclatasvir: NS5A replication inhibitor- Sofosbuvir: NS5B polymerase inhibitor • ABT-450/r-Ombitasvir +/- Ribavirin- ABT-450/r: NS3 protease inhibitor with ritonavir boosting- Ombitasvir (formerly ABT-267): NS5A replication inhibitor

  36. Daclatasvir + Sofosbuvir +/- Ribavirin for HCV GT 1-3A1444-040 Design: Treatment-Naïve 24 Week Rx 0 12 24 36 Week n =16 Rx Naïve GT 2 or 3n = 44 SVR12 SOF × 7 days, then DCV + SOF n = 14 SVR12 DCV + SOF n = 14 SVR12 DCV + SOF + RBV n =15 Rx Naïve GT 1a/1bn = 44 SVR12 SOF × 7 days, then DCV + SOF n = 14 SVR12 DCV + SOF n = 15 SVR12 DCV + SOF + RBV Drug DosingDaclatasvir (DCV): 60 mg once dailySofosbuvir (SOF): 400 mg once dailyRibavirin (RBV): GT1, given weight-based and divided bid(1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg)Ribavirin (RBV): GT 2 or 3 (800 mg/day) N =14 Source: Sulkowski MS, et al. N Engl J Med. 2014;370:211-21.

  37. Daclatasvir+ Sofosbuvir +/- Ribavirin for HCV GT 1-3A1444-040: Results for Treatment-Naïve GT 2 SVR12 for Patient with GT 2, by Treatment Regimen 9/9 8/8 5/7 DCV = daclatasvir; SOF = sofosbuvir; RBV = ribavirin Source: Sulkowski MS, et al. N Engl J Med. 2014;370:211-21.

  38. Summary Points for Treatment of Chronic HCV GT-2 • Genotype 2 highly responsive to 12 weeks of all-oral therapy • Relatively little retreatment data since high SVR rates with therapy in naïve patients • Few GT2 studies moving forward with new therapies • Will be difficult to enroll large studies required for licensing trials • New pangenotypic drugs will be used for genotype 2 off-label (prediction)

  39. This slide deck is from the University of Washington’s Hepatitis C Online and Hepatitis Web Study projects. Hepatitis C Onlinewww.hepatitisc.uw.edu Hepatitis Web Studyhttp://depts.washington.edu/hepstudy/ Funded by a grant from the Centers for Disease Control and Prevention.

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