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

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

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

Treatment of Chronic HCV Genotype 3 Background 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

Virologic Responses with HCV Therapy Sustained 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

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). Accessed May 12, 2014

Treatment-Naïve and Prior Relapsers Treatment of Chronic Hepatitis C: Genotype 3 Treatment-Naïve and Prior Relapsers

AASLD/IDSA/IAS-USA 2014 HCV Treatment Recommendations Initial Therapy for Patients with Genotype 3 Chronic HCV Patients with GT 3 HCV: Initial Treatment & Retreatment of Relapsers* Recommended Therapy, Regardless of Eligibility for Interferon Therapy Sofosbuvir + Ribavirin x 24 weeks Alternative Therapy, Eligible for Interferon Therapy Sofosbuvir + Peginterferon + Ribavirin x 12 weeks Not Recommended Peginterferon + Ribavirin x 24-48 weeks Monotherapy with Peginterferon, Ribavirin, or a Direct Acting Antiviral Agent Any Regimen with Telaprevir, Boceprevir, or Simeprevir *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 GT3 Chronic HCV Key Studies that Support Treatment Recommendations Sofosbuvir + Ribavirin - FISSION - POSITRON - VALENCE Sofosbuvir + Ribavirin + Peginterferon - PROTON Sofosbuvir + Ribavirin or Sofosbuvir + Ribavirin + Peginterferon - ELECTRON

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

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

Sofosbuvir + Ribavirin for HCV GT 2 or 3 (PEG not an option) POSITRON Trial: Design Week 12 24 Sofosbuvir + RBV 12 weeks N =207 SVR12 Placebo 12 weeks N =71 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: Jacobson I, et al. N Engl J Med. 2013;368:1867-77.

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.

Sofosbuvir + Ribavirin for Treatment Naïve & Experienced HCV GT 2 or 3 VALENCE: Treatment Arms Week 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 Dosing Sofosbuvir 400 mg once daily Ribavirin (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]

SVR12 for Treatment-Naïve GT 3 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]

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

SVR 24 by Genotype and Treatment Regimen Sofosbuvir + Ribavirin + Peginterferon in Treatment-Naive Genotypes 1-3 PROTON 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.

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

Treatment-Naïve Genotype 3 Sofosbuvir and Ribavirin +/- Peginterferon in GT 3 ELECTRON: Subset Analysis SVR 12 for 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.

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

AASLD/IDSA/IAS-USA 2014 HCV Treatment Recommendations Retreatment of Patients with Genotype 3 Chronic HCV Patients with GT 3 HCV: Retreatment of Prior Nonresponders* Recommended Therapy Sofosbuvir + Ribavirin x 24 weeks Alternative Therapy Sofosbuvir + Peginterferon + Ribavirin x 12 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 - FUSION - VALENCE Treatment Experienced Nonresponders with GT3 Chronic HCV Key Studies that Support Treatment Recommendations Sofosbuvir + Ribavirin - FUSION - VALENCE Sofosbuvir + Ribavirin + Peginterferon - LONESTAR-2

Sofosbuvir + RBV in Treatment-Experienced HCV GT 2 or 3 FUSION Trial: Design Week 12 16 24 28 Sofosbuvir + RBV 12 weeks Placebo N =103 SVR12 Sofosbuvir + RBV 16 weeks N =98 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: Jacobson I, et al. N Engl J Med. 2013;368:1867-77.

SVR12 for Treatment-Experienced GT3 Sofosbuvir + RBV in Treatment-Experienced HCV GT 2 or 3 FUSION 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.

Sofosbuvir + Ribavirin for Treatment Naïve & Experienced HCV GT 2 or 3 VALENCE: Treatment Arms Week 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 Dosing Sofosbuvir 400 mg once daily Ribavirin (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]

SVR12 for Treatment-Experienced GT 3 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]

Sofosbuvir + Peginterferon + Ribavirin Sofosbuvir + PEG + RBV in Treatment-Experienced HCV GT 2 or 3 LONESTAR-2 Trial: Design Week 12 24 GT 2 or 3 Sofosbuvir + Peginterferon + Ribavirin N = 47 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. 64th AASLD; Washington, DC. 2013. Abstract LB-4.

SVR12 in Treatment-Experienced by HCV Genotype Sofosbuvir + PEG + RBV in Treatment-Experienced HCV GT 2 or 3 LONESTAR-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.

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

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?

How is cost of therapy impacting treatment decisions?

Hepatitis C Genotype 3 Estimated Medication Costs for Treatment-Naïve & Prior Relapsers Patients with GT 3 HCV: Initial Treatment & Retreatment of Relapsers Regimen and Duration Regimen Cost Recommended Therapy Sofosbuvir + Ribavirin x 24 weeks $169,000 Alternative Therapy Sofosbuvir + Peginterferon + Ribavirin x 12 weeks $97,000

Hepatitis C Genotype 3 Estimated Medication Costs for Retreatment of Nonresponders Patients with GT 3 HCV: Retreatment of Nonresponders Regimen and Duration Regimen Cost Recommended Therapy Sofosbuvir + Ribavirin x 24 weeks $169,000 Alternative Therapy Sofosbuvir + Peginterferon + Ribavirin x 12 weeks $97,000

HCV Therapy for Genotype 3 Chronic HCV Cost Analysis Based on Cost per SVR Patient Characteristics Regimen Options SVR Cost per SVR Naïve, no cirrhosis SOF + RBV x 24 wks 93% $194,624 SOF + PEG + RBV x 12 wks ? Naïve, cirrhosis 92% $196,739 Treatment experienced, no cirrhosis Wait until….? 85% $212,941 Treatment experienced, cirrhosis 60% $301,667 83% $126,915 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

Treat now or defer therapy?

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

How do you treat patient that failed Sofosbuvir + Ribavirin?

Retreatment of Sofosbuvir + Ribavirin Failure: Features Retreatment of SOF + RBV Failure with SOF-Containing Regimens in GT 2 or 3 Study Features Retreatment of Sofosbuvir + Ribavirin Failure: Features Design: Open-label, study for patients with GT 2 or 3 who had failure with sofosbuvir + ribavirin in FISSION, POSITRON, or FUSION trial Setting: Europe, United States, and Canada Entry Criteria - N = 107 patients with chronic HCV - HCV genotype 2 (10%) or HCV genotype 3 (90%) - Previous relapse on sofosbuvir plus ribavirin - Patients with compensated cirrhosis allowed to enroll Regimens (patients offered 2 possible regimens) - Sofosbuvir + Ribavirin x 24 weeks - Sofosbuvir + Peginterferon + Ribavirin x 12 weeks Primary End-Point: SVR12 Source: Esteban R, et al. 49th EASL; April 2014. Abstract 08.

GT2 or GT3 Sofosbuvir + PEG + RBV Sofosbuvir + RBV Retreatment of SOF + RBV Failure with SOF-Containing Regimens in GT 2 or 3 Study Design Week 12 24 36 GT2 or GT3 Sofosbuvir + PEG + RBV N = 34 SVR12 Sofosbuvir + RBV N = 73 SVR12 Drug Dosing Sofosbuvir: 400 mg once daily Peginterferon alfa-2a: 180 µg once weekly Weight-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.

SVR12 by Regimen and HCV Genotype Retreatment of SOF + RBV Failure with SOF-Containing Regimens in GT 2 or 3 Results, 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.

Future Treatment Options Hepatitis C: Genotype 3 Future Treatment Options

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

Sofosbuvir-Ledipasvir +/- Ribavirin in GT 1 & 3 ELECTRON 2: Study Design Week 12 24 GT1 Prior Sofobuvir n = 19 LDV-SOF + RBV SVR12 GT1 CTP Class B n = 20 LDV-SOF SVR12 GT3 Treatment Naive n = 25 LDV-SOF SVR12 n = 26 LDV-SOF + RBV SVR12 Drug Dosing Ledipasvir-sofosbuvir (90/400 mg): fixed dose combination; one pill once daily Ribavirin (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.

SVR 12, by GT and Treatment Regimen Sofosbuvir-Ledipasvir +/- Ribavirin in GT 1 & 3 ELECTRON 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.

Daclatasvir + Sofosbuvir +/- Ribavirin for HCV GT 1-3 A1444-040 Design: Treatment-Naïve 24 Week Rx 12 24 36 Rx Naïve GT 2 / 3 n = 44 n = 16 SOF × 7 days, then DCV + SOF SVR12 n = 14 DCV + SOF SVR12 n = 14 DCV + SOF + RBV SVR12 Rx Naïve GT 1a/1b n = 44 n = 15 SOF × 7 days, then DCV + SOF SVR12 n = 14 DCV + SOF SVR12 n = 15 DCV + SOF + RBV SVR12 Drug Dosing Daclatasvir (DCV): 60 mg once daily Sofosbuvir (SOF): 400 mg once daily Ribavirin (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.

SVR12 by GT 3, by Treatment Regimen Daclatasvir + Sofosbuvir +/- Ribavirin for HCV GT 1-3 A1444-040: 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.

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

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.