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Treatment of Chronic HCV Genotype 3

Treatment of Chronic HCV Genotype 3. 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 3

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  1. Treatment of Chronic HCV Genotype 3 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 3 • 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 3 Background and Definitions

  4. Treatment of Chronic HCV Genotype 3Background • HCV infects ~ 5 million people in the US today • Genotype 3 is the third most common HCV genotype in US • Up to 85% of patients have contraindications for interferon therapy • Major linkage to IVDA in epidemiological studies • Interferes with lipid metabolism in hepatocytes and linked with fatty liver • Slightly higher risk of developing cirrhosis • HCV Geno 3 is the new Geno 1 in terms of lower response 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 Responses 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 3 Treatment-Naïve and Prior Relapsers

  9. AASLD/IDSA/IAS-USA 2014 HCV Treatment RecommendationsInitial Therapy for Patients with Genotype 3 Chronic HCV Source: AASLD/IDSA/IAS-USA (www.hcvguidelines.org). Viewed April 22, 2014

  10. Treatment-Naïve & Prior Relapsers with GT3 Chronic HCVKey Studies that Support Treatment Recommendations • Sofosbuvir + Ribavirin- FISSION- POSITRON - VALENCE • Sofosbuvir + Ribavirin + Peginterferon- PROTON • Sofosbuvir + Ribavirin or Sofosbuvir + Ribavirin + Peginterferon- ELECTRON

  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 3 with 24 weeks All-Oral Therapy SVR12 for Treatment-Naïve GT 3 Source: Zeuzem S, et al. N Engl J Med. 2014 May 4. [Epub ahead of print]

  17. Sofosbuvir + Peginterferon + Ribavirin in Treatment-Naive Genotypes 1-3PROTON Trial: Design 0 12 24 48 72 Week + RVR GT 1 SOF (200 mg) +PEG + RBV PEG + RBV n =48 - RVR PEG + RBV + RVR SOF (400 mg) +PEG + RBV PEG + RBV n =47 - RVR PEG + RBV SOF + PEG + RBV n =26 GT 2, 3 SOF + PEG + RBV n = 25 N =14 Drug DosingSofosbuvir (SOF): 400 mg once daily, except as designated in arm that received 200 mg once dailyRibavirin (RBV) weight-based and divided bid: 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kgPeginterferferon alfa-2a (PEG): 180 µg once weekly Source: Lawitz E, et al. Lancet Infect Dis. 2013;13:401-8.

  18. Sofosbuvir + Ribavirin + Peginterferon in Treatment-Naive Genotypes 1-3PROTON Trial: Results SVR 24 by Genotype and Treatment Regimen 41/48 42/47 15/26 23/25 Genotype 1 Genotype 2 or 3 Source: Lawitz E, et al. Lancet Infect Dis. 2013;13:401-8.

  19. Sofosbuvir and Ribavirin +/- Peginterferon in GT 1-3ELECTRON Trial (Arms 1-8): Design 0 8 12 20 24 Week SVR12 n =10 GT 2,3Naïve SOF + RBV SVR12 n = 9 SOF + RBV + PEG (week 1-4) SVR12 n = 10 SOF + RBV + PEG (week 1-8) SVR12 n = 11 SOF + RBV + PEG SVR12 n =10 SOF SVR12 n = 10 SOF + RBV + PEG SVR12 n = 10 GT 1 Null SOF + RBV SVR12 n = 25 GT 1 Naive SOF + RBV Drug DosingSofosbuvir (SOF): 400 mg once dailyRibavirin (RBV) weight-based and divided bid: 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kgPeginterferon alfa-2a (PEG): 180 µg once weekly N =14 Source: Gane EJ, et al. N Engl J Med. 2013;368:34-44.

  20. Sofosbuvir and Ribavirin +/- Peginterferon in GT 3ELECTRON: Subset Analysis SVR 12for Treatment-Naïve Genotype 3* 6/6 6/6 6/6 7/7 10/10 Treatment-Naïve Genotype 3 *Data for sofosbuvir monotherapy not shown Source: Gane EJ, et al. N Engl J Med. 2013;368:34-44.

  21. Treatment of Chronic Hepatitis C: Genotype 3 Retreatment of Prior Nonresponders

  22. AASLD/IDSA/IAS-USA 2014 HCV Treatment RecommendationsRetreatment of Patients with Genotype 3 Chronic HCV Source: AASLD/IDSA/IAS-USA (www.hcvguidelines.org). Viewed April 22, 2014

  23. Treatment Experienced Nonresponders with GT3 Chronic HCVKey Studies that Support Treatment Recommendations • Sofosbuvir + Ribavirin- FUSION- VALENCE • Sofosbuvir + Ribavirin + Peginterferon- LONESTAR-2

  24. 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.

  25. Sofosbuvir + RBV in Treatment-Experienced HCV GT 2 or 3FUSION Trial: Results for GT3 SVR12 for Treatment-Experienced GT3 19/64 39/63 14/38 25/40 5/26 14/23 SOF = Sofosbuvir; RBV = Ribavirin Source: Jacobson I, et al. N Engl J Med. 2013;368:1867-77.

  26. 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]

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

  28. 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.

  29. 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.

  30. Treatment of Chronic Hepatitis C: Genotype 3 Issues and Controversies

  31. Issues and Controversies • Cost of Therapy • Sofosbuvir + PEG + RBV higher SVR than all oral (LONESTAR data)- Treat selected Geno 3 patients with Sofosbuvir + PEG + RBV?- Wait for FDC Ledipasvir-Sofosbuvir + RBV with 100% SVR? • When to Defer Therapy- Decisions on when to warehouse? • (Non) Role of IL-28b Testing • Degree of Liver Fibrosis- How to stage?

  32. How is cost of therapy impacting treatment decisions?

  33. Hepatitis C Genotype 3EstimatedMedication Costs for Treatment-Naïve & Prior Relapsers

  34. Hepatitis C Genotype 3EstimatedMedication Costs for Retreatment of Nonresponders

  35. HCV Therapy for Genotype 3 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

  36. Treat now or defer therapy?

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

  38. How do you treat patient that failed Sofosbuvir + Ribavirin?

  39. Retreatment of SOF + RBV Failure with SOF-Containing Regimens in GT 2 or 3Study Features Source: Esteban R, et al. 49th EASL; April 2014. Abstract 08.

  40. Retreatment of SOF + RBV Failure with SOF-Containing Regimens in GT 2 or 3Study Design Week 0 12 24 36 GT2 or GT3 Sofosbuvir + PEG + RBV N = 34 SVR12 Sofosbuvir + RBV N = 73 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 kg Source: Esteban R, et al. 49th EASL; April 2014. Abstract 08.

  41. Retreatment of SOF + RBV Failure with SOF-Containing Regimens in GT 2 or 3Results, by Genotype SVR12 by Regimen and HCV Genotype 4/4 1/2 20/22 24/38 Source: Esteban R, et al. 49th EASL; April 2014. Abstract 08.

  42. Hepatitis C: Genotype 3 Future Treatment Options

  43. Future Regimens for GT-3 • Ledipasvir + Sofosbuvir- Lepidasvir: NS5A replication inhibitor- Sofosbuvir: NS5B polymerase inhibitor • 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

  44. Sofosbuvir-Ledipasvir +/- Ribavirin in GT 1 & 3ELECTRON 2: Study Design 0 12 24 Week GT1Prior Sofobuvir n =19 SVR12 LDV-SOF + RBV GT1CTP Class B n = 20 SVR12 LDV-SOF GT3Treatment Naive n = 25 SVR12 LDV-SOF n = 26 SVR12 LDV-SOF + RBV Drug DosingLedipasvir-sofosbuvir (90/400 mg): fixed dose combination; one pill once dailyRibavirin (weight-based and divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg N =14 Abbreviations: LDV= ledipasvir; SOF = sofosbuvir; RBV = ribavirin Source: Gane EJ, et al. 49th EASL. 2014: Abstract O6.

  45. Sofosbuvir-Ledipasvir +/- Ribavirin in GT 1 & 3ELECTRON 2: Study Design SVR 12, by GT and Treatment Regimen 19/19 13/20 16/25 26/26 SOF-Experienced CTP Class B Treatment Naive LDV= ledipasvir; SOF = sofosbuvir; RBV = ribavirin Source: Gane EJ, et al. 49th EASL. 2014: Abstract O6.

  46. 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 / 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.

  47. Daclatasvir + Sofosbuvir +/- Ribavirin for HCV GT 1-3A1444-040: Subset Analysis for Treatment-Naïve GT 3 SVR12 by GT 3, by Treatment Regimen 5/7 6/6 5/5 DCV = daclatasvir; SOF = sofosbuvir; RBV = ribavirin Source: Sulkowski MS, et al. N Engl J Med. 2014;370:211-21.

  48. Summary Points for Treatment of Chronic HCV GT-3 • Treat now with Sofosbuvir + Ribavirin x 24 weeks • Consider IFN-based Rx in select patient who can tolerate IFN to shorten therapy, save costs and have a nominally higher SVR rate • Stage patient for liver disease and systemic disease • Look for signs of fatty liver and metabolic syndrome • GT 3 may be the new “GT 1” but high SVR rates can be seen in selected patients

  49. 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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