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Treatment of Chronic HCV Genotype 4

Treatment of Chronic HCV Genotype 4. 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 4

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  1. Treatment of Chronic HCV Genotype 4 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 21, 2014

  2. Treatment of Chronic HCV Genotype 4 • 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 4 Background and Definitions

  4. Treatment of Chronic HCV Genotype 4Background • HCV infects ~ 5 million people in the US today • Genotype 4 accounts for about 1-2% of HCV infections in US • Genotype 4 very important in Egypt, Saudi Arabia, North Africa, and Southern Europe • Approximately 70% of patients with genotype 4 HCV have moderate to severe steatosis with or without sinusoidal fibrosis • Historic SVR rates with IFN-based therapy between GT1 and GT 2,3

  5. 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

  6. AASLD/IDSA/IAS-USA 2014 HCV Treatment RecommendationsCriteria for Interferon Ineligible Source: AASLD/IDSA/IAS-USA (www.hcvguidelines.org). Viewed April 8, 2014

  7. Treatment of Chronic Hepatitis C: Genotype 4 Treatment-Naïve and Prior Relapsers

  8. AASLD/IDSA/IAS-USA 2014 HCV Treatment RecommendationsInitial Therapy for Patients with Genotype 4 Chronic HCV Source: AASLD/IDSA/IAS-USA (www.hcvguidelines.org). Viewed April 22, 2014

  9. Treatment-Naïve & Prior Relapsers with GT4 Chronic HCVKey Studies that Support Treatment Recommendations • Sofosbuvir + Ribavirin + Peginterferon- NEUTRINO • Sofosbuvir + Ribavirin- Egyptian Ancestry • Simeprevir + Ribavirin + Peginterferon- RESTORE

  10. Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6 NEUTRINO Trial: Design 0 12 24 Week 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 + PEG + RBV N =327 Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.

  11. Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6 NEUTRINO Trial: Results NEUTRINO: SVR 12 by Genotype 261/292 27/28 7/7 GT = genotype Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.

  12. Sofosbuvir and Ribavirin in HCV Genotype 4Egyptian Ancestry Trial: Design Week 0 12 24 36 GT 4 Naïveor Experienced Sofosbuvir +RBV(n = 31) SVR12 Sofosbuvir + RBV(n = 29) 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: Ruane P, et al. 49th EASL. April 2014: Abstract P1243.

  13. Sofosbuvir and Ribavirin in HCV Genotype 4Egyptian Ancestry Trial: Results SVR 12 by Regimen Duration and Treatment Experience 11/14 14/14 10/17 13/15 Treatment Naive Treatment Experienced Source: RuaneP, et al. 49th EASL. April 2014: Abstract P1243.

  14. Simeprevir + Peginterferon + Ribavirin in Genotype 4RESTORE: Study Design Week 0 12 24 48 Simeprevir Peginterferon+ Ribavirin Treatment-NaïveorPrior Relapse RGTdetermines if PEG + RBV x 24 or 48 wks Simeprevir Peginterferon+ Ribavirin Simeprevir Partial ResponseorNull Response Peginterferon+ Ribavirin Response Guided Therapy (RGT) Criteria: Week 4 HCV RNA < 25 IU/mL (detectable or undetectable) and Week 12 HCV RNA < 25 IU/mL (undetectable) Drug DosingSimeprevir: 150 mg once daily Source: Moreno C, et al. 49th EASL. April 2014: Abstract P1319.

  15. Simeprevir + Peginterferon + Ribavirin in Genotype 4RESTORE: Results RESTORE: SVR12 by Prior Treatment Status 70/107 29/35 19/22 6/10 16/40 Treatment-Naïve &Experienced Relapsers Treatment-Experienced Nonresponders Source: Moreno C, et al. 49th EASL. April 2014: Abstract P1319.

  16. Treatment of Chronic Hepatitis C: Genotype 4 Retreatment of Prior Nonresponders

  17. AASLD/IDSA/IAS-USA 2014 HCV Treatment RecommendationsRetreatment of Patients with Genotype 4 Chronic HCV Source: AASLD/IDSA/IAS-USA (www.hcvguidelines.org). Viewed April 22, 2014

  18. Treatment Experienced Nonresponders with GT4 Chronic HCVKey Studies that Support Treatment Recommendations • Sofosbuvir + Ribavirin- Egyptian Ancestry • Simeprevir + Ribavirin + Peginterferon- RESTORE

  19. Sofosbuvir and Ribavirin in HCV Genotype 4Egyptian Ancestry Trial: Design Week 0 12 24 36 GT 4 Naïveor Experienced Sofosbuvir +RBV(n = 31) SVR12 Sofosbuvir + RBV(n = 29) 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: Ruane P, et al. 49th EASL. April 2014: Abstract P1243.

  20. Sofosbuvir and Ribavirin in HCV Genotype 4Egyptian Ancestry Trial: Results SVR 12 by Regimen Duration and Treatment Experience 11/14 14/14 10/17 13/15 Treatment Naive Treatment Experienced Source: RuaneP, et al. 49th EASL. April 2014: Abstract P1243.

  21. Simeprevir + Peginterferon + Ribavirin in Genotype 4RESTORE: Study Design Week 0 12 24 48 Simeprevir Peginterferon+ Ribavirin Treatment-NaïveorPrior Relapse RGTdetermines if PEG + RBV x 24 or 48 wks Simeprevir Peginterferon+ Ribavirin Simeprevir Partial ResponseorNull Response Peginterferon+ Ribavirin Response Guided Therapy (RGT) Criteria: Week 4 HCV RNA < 25 IU/mL (detectable or undetectable) and Week 12 HCV RNA < 25 IU/mL (undetectable) Drug DosingSimeprevir: 150 mg once daily Source: Moreno C, et al. 49th EASL. April 2014: Abstract P1319.

  22. Simeprevir + Peginterferon + Ribavirin in Genotype 4RESTORE: Results RESTORE: SVR12 by Prior Treatment Status 70/107 29/35 19/22 6/10 16/40 Treatment-Naïve &Experienced Relapsers Treatment-Experienced Nonresponders Source: Moreno C, et al. 49th EASL. April 2014: Abstract P1319.

  23. Treatment of Chronic Hepatitis C: Genotype 4 Issues and Controversies

  24. Issues and Controversies • Cost of Therapy • When to Defer Therapy- Decisions on when to warehouse? • (Non) Role of IL-28b Testing • Degree of Liver Fibrosis- How to stage?

  25. How is cost of therapy impacting treatment decisions?

  26. Hepatitis C Genotype 4EstimatedMedication Costs for Treatment-Naïve & Prior Relapsers

  27. Hepatitis C Genotype 4EstimatedMedication Costs for Retreatment of Nonresponders

  28. When to defer therapy?

  29. Factors Favoring Treat Now for GT4 • Advanced Fibrosis (F3-F4)- Platelet count < 150,000/uL- Large spleen and/or portal vein(Over 12 rule = Spleen >12 cmor PV > 12 mm)- Esophageal varices • Synthetic dysfunction, low albumin, high INR • Systemic disease- Cryoglobulinemia (+RhF) • Highly motivated patients/symptoms • Patients with Increased Mortality Risk- All cause- HCC risk

  30. Hepatitis C: Genotype 4 Future Treatment Options

  31. Future Regimens for GT-4 • ABT-450/r-Ombitasvir +/- Ribavirin- ABT-450/r: NS3 protease inhibitor with ritonavir boosting- Ombitasvir (formerly ABT-267): NS5A replication inhibitor • Ledipasvir + Sofosbuvir- Lepidasvir: NS5A replication inhibitor- Sofosbuvir+ NS5 NS5b polymerase inhibitor • Daclatasvir+ Sofosbuvir?- Daclatasvir: NS5A replication inhibitor- Sofosbuvir+ NS5 NS5b polymerase inhibitor

  32. ABT450/r + Ombitasvir+/- Ribavirin in GT 1b or 4PEARL-I (Noncirrhotic Patients): Substudy1 Design 0 12 24 Week n =44 SVR12 GT 4: Naïve ABT-450/r + Ombitasvir n = 42 SVR12 GT 1b: Naïve ABT-450/r + Ombitasvir n = 40 SVR12 GT 1b: Null ABT-450/r + Ombitasvir n =42 SVR12 GT 4: Naïve ABT-450/r + Ombitasvir + RBV n = x SVR12 GT 4: Experienced* ABT-450/r + Ombitasvir n = 49 SVR12 GT 4: Experienced* ABT-450/r + Ombitasvir + RBV *Experienced = Treatment Experienced (Partial/Null Responders and Relapsers) N =14 Drug DosingABT-450/r (150/100 mg once daily)Ombitasvir: 25 mg once dailyRibavirin (RBV): GT1, given weight-based and divided bid(1000 mg/day if < 75kg or 1200 mg/day if ≥ 75kg) Source: Hezode C, et al. 49th EASL. April 2014. Abstract O58.

  33. ABT450/r + Ombitasvir +/- Ribavirin in GT4PEARL-I (Noncirrhotic Patients): Genotype 4 Analysis PEARL I: Genotype 4 SVR SVR 1240/44 SVR 1242/42 SVR 4*37/37 Treatment-Naïve Treatment-Experienced *Note: for the two GT4 treatment experienced arms, limited available data (only SVR4 for 37 of 49 enrolled in one arm) Source: Hezode C, et al. 49th EASL. April 2014. Abstract O58.

  34. Ledipasvir-Sofosbuvir for GT-4 • *Ledipasvir-Sofosbuvir in Patients with GT 4 or 5 - Phase 2 open-label study- Treatment-naïve and treatment-experienced- All patients receive 12 weeks of ledipasvir-sofosbuvir (fixed dose) • *Ledipasvir-Sofosbuvir in Patients with GT 1 or 4 & HIV Coinfection- Phase 3 open-label study- Treatment-naïve and treatment-experienced (including intolerant)- Initial treatment: 12 weeks of ledipasvir-sofosbuvir (fixed dose)- Retreatment: 24 weeks of ledipasvir-sofosbuvir (fixed dose) + ribavirin *Studies are ongoing and treatment data not available

  35. Summary Points for Treatment of Chronic HCV GT-4 • HCV GT4 uncommon in US, but prevalent in Egypt, Saudi Arabia, North African, and southern Europe as well as immigrants from these regions to the US including Coptic population and horn of Africa (Sudan, Ethiopia and Eritrea) • For treatment-naïve and treatment-experienced patients with GT4, the recommended regimen is SOF + PEG + RBV x 12 weeks • For treatment-naïve and treatment-experienced patients with GT4, the alternative regimen is SOF + RBV x 24 weeks • For interferon ineligible or cost reduction: SOF + SIM (Cosmos protocol) • Several investigational agents appear promising for GT4

  36. 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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