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

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

Background and Definitions Treatment of Chronic Hepatitis C: Genotype 4 Background and Definitions

Treatment of Chronic HCV Genotype 4 Background 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

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

AASLD/IDSA/IAS-USA 2014 HCV Treatment Recommendations Criteria for Interferon Ineligible Interferon Ineligible is defined as one or more of the following: Intolerance to interferon Autoimmune hepatitis and other autoimmune disorders Hypersensitivity to peginterferon or any of its components Decompensated hepatic disease Major uncontrolled depressive illness A baseline neutrophil count below 1500/μL, a baseline platelet count below 90,000/μL or baseline hemoglobin below 10 g/dL A history of preexisting cardiac disease Source: AASLD/IDSA/IAS-USA (www.hcvguidelines.org). Viewed April 8, 2014

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

AASLD/IDSA/IAS-USA 2014 HCV Treatment Recommendations Initial Therapy for Patients with Genotype 4 Chronic HCV Patients with GT 4 HCV: Initial Treatment & Retreatment of Relapsers* Recommended Therapy Interferon Eligible Sofosbuvir + Peginterferon + Ribavirin x 12 weeks Not Interferon Eligible Sofosbuvir + Ribavirin x 24 weeks Alternative Therapy Interferon Eligible Simeprevir x 12 weeks + [Peginterferon + Ribavirin] x 24-48 weeks Not Recommended Peginterferon + Ribavirin x 48 weeks Monotherapy with Peginterferon, Ribavirin, or a Direct-Acting Antiviral Agent Telaprevir- or Boceprevir-based regimens *Patients who experienced relapse after Peginterferon plus Ribavirin therapy Source: AASLD/IDSA/IAS-USA (www.hcvguidelines.org). Viewed April 22, 2014

Treatment-Naïve & Prior Relapsers with GT4 Chronic HCV Key Studies that Support Treatment Recommendations Sofosbuvir + Ribavirin + Peginterferon - NEUTRINO Sofosbuvir + Ribavirin - Egyptian Ancestry Simeprevir + Ribavirin + Peginterferon - RESTORE

Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6 NEUTRINO Trial: Design Week 12 24 Sofosbuvir + PEG + RBV N =327 SVR12 Drug Dosing Sofosbuvir: 400 mg once daily Peginterferon alfa-2a: 180 µg once weekly Ribavirin (weight-based and in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.

NEUTRINO: SVR 12 by Genotype 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.

Sofosbuvir and Ribavirin in HCV Genotype 4 Egyptian Ancestry Trial: Design Week 12 24 36 GT 4 Naïve or Experienced Sofosbuvir + RBV (n = 31) SVR12 Sofosbuvir + RBV (n = 29) SVR12 Drug Dosing Sofosbuvir: 400 mg once daily Weight-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.

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

Simeprevir + Peginterferon + Ribavirin in Genotype 4 RESTORE: Study Design Week 12 24 48 Simeprevir Treatment-Naïve or Prior Relapse RGT determines if PEG + RBV x 24 or 48 wks Peginterferon + Ribavirin Simeprevir Peginterferon + Ribavirin Partial Response or Null Response Simeprevir 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 Dosing Simeprevir: 150 mg once daily Source: Moreno C, et al. 49th EASL. April 2014: Abstract P1319.

Simeprevir + Peginterferon + Ribavirin in Genotype 4 RESTORE: 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.

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

AASLD/IDSA/IAS-USA 2014 HCV Treatment Recommendations Retreatment of Patients with Genotype 4 Chronic HCV Patients with GT 4 HCV: Retreatment of Prior Nonresponders* Recommended Therapy Sofosbuvir + Peginterferon + Ribavirin x 12 weeks Alternative Therapy Sofosbuvir + Ribavirin x 24 weeks Not Recommended Peginterferon + Ribavirin +/- [Boceprevir or Simeprevir or Telaprevir] Monotherapy with Peginterferon, Ribavirin, or a Direct-Acting Antiviral Agent Treatment of Decompensated Cirrhosis with Peginterferon *Patients who experienced nonresponse (partial or null) with Peginterferon plus Ribavirin therapy Source: AASLD/IDSA/IAS-USA (www.hcvguidelines.org). Viewed April 22, 2014

Sofosbuvir + Ribavirin - Egyptian Ancestry Treatment Experienced Nonresponders with GT4 Chronic HCV Key Studies that Support Treatment Recommendations Sofosbuvir + Ribavirin - Egyptian Ancestry Simeprevir + Ribavirin + Peginterferon - RESTORE

Sofosbuvir and Ribavirin in HCV Genotype 4 Egyptian Ancestry Trial: Design Week 12 24 36 GT 4 Naïve or Experienced Sofosbuvir + RBV (n = 31) SVR12 Sofosbuvir + RBV (n = 29) SVR12 Drug Dosing Sofosbuvir: 400 mg once daily Weight-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.

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

Simeprevir + Peginterferon + Ribavirin in Genotype 4 RESTORE: Study Design Week 12 24 48 Simeprevir Treatment-Naïve or Prior Relapse RGT determines if PEG + RBV x 24 or 48 wks Peginterferon + Ribavirin Simeprevir Peginterferon + Ribavirin Partial Response or Null Response Simeprevir 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 Dosing Simeprevir: 150 mg once daily Source: Moreno C, et al. 49th EASL. April 2014: Abstract P1319.

Simeprevir + Peginterferon + Ribavirin in Genotype 4 RESTORE: 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.

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

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?

How is cost of therapy impacting treatment decisions?

Hepatitis C Genotype 4 Estimated Medication Costs for Treatment-Naïve & Prior Relapsers Patients with GT 4 HCV: Initial Treatment & Retreatment of Relapsers Regimen and Duration Regimen Cost Recommended Therapy Sofosbuvir + Peginterferon + Ribavirin x 12 weeks $97,000 Sofosbuvir + Ribavirin x 24 weeks $169,000 Alternative Therapy Simeprevir x 12 weeks + [Peginterferon + Ribavirin] x 24-48 weeks $79,000- $104,000

Hepatitis C Genotype 4 Estimated Medication Costs for Retreatment of Nonresponders Patients with GT 4 HCV: Retreatment of Nonresponders Regimen and Duration Regimen Cost Recommended Therapy Sofosbuvir + Peginterferon + Ribavirin x 12 weeks $97,000 Alternative Therapy Sofosbuvir + Ribavirin x 24 weeks $169,000

When to defer therapy?

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 cm or 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

Future Treatment Options Hepatitis C: Genotype 4 Future Treatment Options

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

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

Treatment-Experienced ABT450/r + Ombitasvir +/- Ribavirin in GT4 PEARL-I (Noncirrhotic Patients): Genotype 4 Analysis PEARL I: Genotype 4 SVR SVR 12 40/44 SVR 12 42/42 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.

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

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

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