5/12/2016. Learning Objectives. Management of Hepatitis C Virus Genotype 2 or 3 Infected Treatment-Naive or Experienced Patients

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1 5/12/216 Management of Hepatitis C Virus Genotype 2 or 3 Infected Treatment-Naive or Experienced Patients Alexander Monto, MD Professor of Clinical Medicine University of California San Francisco San Francisco, California AU Edited: 9/1/215 San Francisco, California: May 5, 216 Learning Objectives After attending this presentation, participants will be able to: Design optimal treatment regimens, including optional duration of treatment, for treatment-naive hepatitis C virus (HCV) genotype 2 or 3 infected patients Describe therapeutic options for HCV genotype 2 or 3 infected treatment-experienced patients Describe future options for HCV treatment in genotype 2 or 3 infected patients Slide 2 of 42 Treatment of HCV Genotype 3 Background Genotype 3 3 rd most common HCV genotype in the US (1% of cases) Linked with fatty liver disease Associated with accelerated liver disease progression Lower response rates to treatment make it the new genotype 1 Slide 3 of 42 1

2 5/12/ year-old male HCV genotype: 3a Treatment naïve HCV RNA: 1.8 million IU/ml Case 1 Transient elastography score: 8.3 KPA Other PMH: Ischemic cardiomyopathy Severe depression for which he was hospitalized 3 months ago Anemia: Baseline hemoglobin 11 g/dl Tells you: My friend just got cured of HCV, and he only had to take 1 pill a day. I want the same pill he took Slide 4 of 42 CASE 1: What do you recommend? 7% 1. Sofosbuvir + RBV x 12 weeks 11% 46% 25% 7% 4% 2. Ledipasvir + sofosbuvir x 12 weeks 3. Daclatasvir + sofosbuvir x 12 weeks 4. Daclatasvir + sofosbuvir x 24 weeks 5. Sofosbuvir + RBV + PEG-IFN x 12 weeks 6. No treatment Slide 5 of 42 Case 2 58-year-old male referred to you for treatment of HCV HCV genotype: 3a Treatment naïve HCV RNA: 1.8 million IU/ml Transient elastography score: 18.3 KPA Other PMH: Ischemic cardiomyopathy Severe depression for which he was hospitalized 3 months ago Anemia: baseline hemoglobin 11 g/dl Tells you: My friend just got cured of HCV, and he only had to take 1 pill a day. I want the same pill he took Slide 6 of 42 2

3 5/12/216 CASE 2: What do you recommend? % 1. Sofosbuvir + RBV x 12 wks % % 83% 3% 14% 2. Ledipasvir + sofosbuvir x 12 wks 3. Daclatasvir + sofosbuvir x 12 wks 4. Daclatasvir + sofosbuvir x 24 wks 5. Sofosbuvir + RBV + PEG-IFN x 12 wks 6. No treatment Slide 7 of 42 AASLD/IDSA: Recommended Regimens for HCV Genotype 3 Patients Treatment-Naïve Patients Daily daclatasvir (6 mg*) and sofosbuvir (4 mg) for 12 weeks (in patients without cirrhosis) Rating: Class 1, Level A Daily daclatasvir (6 mg*) and sofosbuvir (4 mg) +/- RBV for 24 weeks (in patients WITH cirrhosis) Rating: Class IIa, Level C Daily sofosbuvir (4 mg) and ribavirin + weekly PEG-IFN for 12 weeks (IFN eligible patients with or without cirrhosis) Rating: Class 1, Level A Alternative: Daily sofosbuvir (4mg) and ribavirin for 24 weeks (IFN Ineligible with or without cirrhosis) Rating: Class 1, Level A * Dose of daclatasvir my need to change when used with cyt P45 3A/4 inducers and inhibitors Weight-based RBV ( mg [<75 kg] to 12 mg [>75 kg]). PR: pegifn + RBV. Slide 8 of 42 AASLD/IDSA. August 31, 215. Case 3 52 y/o man with prior injection drug use Bilirubin 1.6 mg/dl, platelets 23K, SGOT 36 SGPT 49, liver bx 13 years ago showed metavir stage 1 fibrosis and steatosis HCV: genotype 3a, IL28B CT, failed PEG-IFN/RBV 6 years prior Stopped PEGIFN/RBV at 16 weeks due to nonresponse. He also suffered moderate fatigue and mild cytopenias not requiring growth factors He tells you he hated interferon and will NEVER take it again Transient elastography score: 14 KPA Slide 9 of 42 3

4 5/12/216 CASE 3: What do you recommend? 5% 1. Await something better 38% % 8% 4% 2. Daclatasvir + sofosbuvir + RBV x 24 weeks 3. Sofosbuvir + RBV + PEG-IFN + RBV x 12 weeks 4. Sofosbuvir + Simeprevir x 24 weeks 5. Ledipasvir + sofosbuvir (FDC) x 12 weeks Slide 1 of 42 AASLD/IDSA: Recommended Regimens for HCV Genotype 3 Patients Failure of Prior PR Treatment Daily daclatasvir (6 mg*) and sofosbuvir (4 mg) for 12 weeks (in patients without cirrhosis) Rating: Class 1, Level A Daily daclatasvir (6 mg*) and sofosbuvir (4 mg) with WB RBV for 24 weeks (in patients WITH cirrhosis) Rating: Class IIa, Level B Daily sofosbuvir (4 mg) and ribavirin + weekly PEG-IFN for 12 weeks (IFN eligible patients with or without cirrhosis ) Rating: Class 1, Level A Failure of Prior SOF + RBV Treatment Daily daclatasvir (6 mg*) and sofosbuvir (4 mg) + RBV for 24 weeks (IFN ineligible) Rating: Class IIa, Level C Daily sofosbuvir (4 mg) and ribavirin + weekly PEG-IFN for 12 weeks (IFN eligible patients) Rating: Class IIa, Level C Weight-based RBV ( mg [<75 kg] to 12 mg [>75 kg]). PR: pegifn + RBV. Slide 11 of 42 AASLD/IDSA. August 31, 215. AASLD/IDSA: HCV Regimens That Are NOT Recommended for Genotype 3 Patients Treatment-naïve patients PEG-IFN and RBV for 24 to 48 weeks Monotherapy with pegifn, RBV, or a direct-acting antiviral agent Telaprevir-, boceprevir-, or simeprevir-containing regimens Failure of prior PR treatment PEG-IFN and RBV for 24 to 48 weeks Monotherapy with pegifn, RBV, or a direct-acting antiviral agent Telaprevir-, boceprevir-, or simeprevir-containing regimens Slide 12 of 42 AASLD/IDSA. August 31, 215 4

5 5/12/216 AASLD/IDSA Criteria for IFN Ineligible Interferon ineligible is defined as one or more of the following Intolerance to IFN Autoimmune hepatitis and other autoimmune disorders Hypersensitivity to PEG or any of its components Decompensated hepatic disease Major uncontrolled depressive illness A baseline neutrophil count below 15/µL, a baseline platelet count below 9,/µL, or a baseline hemoglobin below 1 g/dl A history of preexisting cardiac disease Interferon unwilling Slide 13 of 42 AASLD/IDSA. August 31, 215 Slide 14 of 42 Key Studies That Support GT 3 Treatment Recommendations Daclatasvir and Sofosbuvir ALLY-3 Sofosbuvir + Ribavirin or Sofosbuvir + Ribavirin + PEG-IFN BOSON ELECTRON Sofosbuvir + Ribavirin VALENCE FISSION POSITRON Sofosbuvir + Ribavirin + PEG-IFN LONESTAR-2 PROTON Studies in red will not be discussed ALLY-3 Study: Daclatasvir + Sofosbuvir in HCV Genotype 3 Open-label trial Genotype 3 Treatment-naïve or experienced Treatment-Naïve With or without cirrhosis Primary outcome: SVR12 Treatment-Experienced Baseline demographics: Male: 57%-63%. Mean age: years. White: 88%-91%. HCV RNA >K IU/mL: 69%-75%. IL28B non-cc: 6%-61%. : 19%-25%. Prior treatment failure: Relapse: 61%. Null response: 14%. Partial response: 4%. Daclatasvir 6 mg + Sofosbuvir 4 mg qd (n=11) Daclatasvir 6 mg + Sofosbuvir 4 mg qd (n=11) Week 12 Slide 15 of 42 Nelson DR, et al. Hepatology

6 SVR12 (%) SVR12 (%) SVR12 (%) 5/12/216 ALLY-3 Study: Treatment Outcomes With Daclatasvir + Sofosbuvir x 12 weeks in HCV Genotype 3 No virologic breakthroughs Virologic relapse (n=16) (n=11) Y93H at relapse (n=9) Generally safe and well tolerated No discontinuations due to adverse events Most common AEs Headache, fatigue, nausea Slide 16 of SVR12 Rates Treatment-naïve Treatment-experienced 97% 9% 94% 86% 69% 58% Overall No Yes (n=11/51) (n=75/34) (n=19/13) Nelson DR, et al. Hepatology. 215 ALLY-3: DCV + SOF x12 wks in GT3 by treatment experience No cirrhosis n/n = 15/ 2/ Overall 73/ 11/ Treatment-Naive Pts 32/ 9/ Treatment- Experienced Pts Nelson DR, et al. Hepatology. 215;61: Slide 17 of 42 ALLY-3+: DCV + SOF + RBV in GT 3 F3/F4 Liver Disease No virologic failures or AE-related discontinuations 12 wks DCV + SOF + RBV 16 wks DCV + SOF + RBV / 24/ n/n = All Pts Leroy V, et al. AASLD 215. Abstract LB-3. 6/ 8/ 6 8 Advanced Fibrosis (F3) 15/ 16/ / 12/ Treatment Experienced Slide 18 of 42 6

7 SVR12 (%) SVR12 (%) 5/12/216 VALENCE Trial: Sofosbuvir + RBV in HCV Genotypes 2 and 3 Phase 3 study (Europe) Open label Genotype 2 or 3 Treatment-naïve and experienced With or without cirrhosis Primary end point SVR 12 Genotype 2 or 3 Genotype 3 (amended protocol) SOF + RBV (n=73) SOF + RBV (n=25) Week Slide 19 of 42 Baseline demographics Male: 55% to 62%. IL28B non-cc: 64% to 74%. HCV RNA (log 1 IU/mL): : 14% to 23%. Prior pegifn + RBV nonresponder: 24% to 44%. Prior pegifn + RBV relapser: 56% to 68%. Drug Dosing Sofosbuvir (SOF): 4 mg daily Ribavirin (RBV): Weight-based mg (<75kg) to 12mg (>75 Kg) in 2 divided doses Zeuzem S, et al. N Engl J Med. 214;37; VALENCE Trial: SVR12 Rates With Sofosbuvir + RBV in HCV Genotype 3 85% 94% 92% 87% 6 62% 4 2 Overall (n=25) Noncirrhotic (n=92) Cirrhotic (n=13) Noncirrhotic (n=) Cirrhotic (n=45) Treatment-Naive Treatment-Experienced Slide 2 of 42 No resistance detected in patients with relapse. Zeuzem S, et al. N Engl J Med. 214 LONESTAR-2 Study: Sofosbuvir + PR in Treatment-Experienced, HCV Genotype 3 Open-label, phase 2 study Non-randomized, uncontrolled Failed prior PR therapy GT 2 or 3, No HBV or HIV 96% white, 68% male, 55% cirrhotic Sofosbuvir + pegifn + RBV for 12 weeks % SVR12 Rates 83% 83% Drug Dosing Sofosbuvir (SOF): 4 mg daily Ribavirin (RBV): Weight-based mg (<75kg) to 12mg (>75 Kg) in 2 divided doses Pegylated Interferon (PEG-IFN): alfa 2a 1Ųg SC weekly 2 Overall (n=24) No (n=12) (n=12) Slide 21 of 42 Lawitz E, et al. Hepatology. 215;61:

8 SVR12 (%) 5/12/216 BOSON STUDY: Sofosbuvir-Based Regimens in HCV Genotype 3 Open-label, phase 3 trial Genotype 2 SOF + RBV N=196 Treatment-experienced With cirrhosis SOF + RBV Genotype 3 GT 3 N=199 Treatment-naïve or SOF + PEG-IFN + experienced RBV N=197 With or without cirrhosis Week Baseline demographics: Male: 55%-68%. Mean age: years. White: 83%-84%. IL28B CC: 37%-4%. : 37%-38%. Drug Dosing Sofosbuvir (SOF): 4 mg daily Ribavirin (RBV): Weight-based mg (<75kg) to 12mg (>75 Kg) in 2 divided doses Pegylated Interferon (PEG-IFN): alfa 2a 1Ųg SC weekly Slide 22 of 42 Foster GR et al. Gastroenterology 215. PR: pegifn + RBV. Slide 23 of 42 BOSON Study: Sofosbuvir-Based Regimens in HCV Genotype 3 Virologic failure (n=3) Virologic relapse (n=83) RBV x 16 wks (n=5 (28%)) RBV x 24 wks (n=24 (18%)) PEG-IFN x 12 wks (n=9 (5%)) Tolerability Similar frequencies of serious AEs across all groups. Most common AEs Fatigue, headache, insomnia, nausea Sofosbuvir and 83% No (n= ) SVR12 (Genotype 3) RBV 16 weeks RBV 24 weeks PR 12 weeks 96% 94% 9% 91% 57% 82% (n= ) Treatment Naive 76% 82% No (n= ) 47% 77% 86% (n= ) Treatment Experienced Foster GR, et al. EASL 215 Gastroenterology 215. Other regimens to consider Grazoprevir/Elbasvir Sofosbuvir/Velpatasvir Slide 24 of 42 8

9 SVR12 (%) SVR12 (%) 5/12/216 C-SWIFT: Grazoprevir/Elbasvir + Sofosbuvir in Treatment-Naïve, HCV Genotype 3 Phase 2 study Open label Genotype 3 Treatment naive With (compensated) or without cirrhosis Primary outcome: SVR12 No Compensated Grazoprevir/elbasvir /5 mg qd + sofosbuvir 4 mg qd. Baseline demographics: Male: 57%-83%. Mean age: years. White: %. IL28B CC: 21%-5%. HCV RNA (log 1 IU/mL): Grazoprevir/Elbasvir + Sofosbuvir (n=15) Grazoprevir/Elbasvir + Sofosbuvir (n=14) Grazoprevir/Elbasvir + Sofosbuvir (n=12) Week 8 12 Slide 25 of 42 Poordad F et al EASL 215. C-SWIFT: Treatment Outcomes With Grazoprevir/Elbasvir + Sofosbuvir x 12 weeks in HCV Genotype 3 SVR12 Rates No virologic breakthroughs Relapse (n=2) 8-week group(n=1) 12-week group (n=1) 6 Non-cirrhotic 93% Cirrhotic % 91% 4 2 Modified ITT (excluded 1 patient in the cirrhotic arm due to non-virologic failure). 8 Weeks (n=15) 12 Weeks (n=14) 12 Weeks (n=11) Slide 26 of 42 Poordad F, et al. EASL 215. ASTRAL-3 Open-Label: Sofosbuvir/Velpatasvir x 12 wks in GT3 HCV SVR12 rate numerically lower with vs without BL NS5A RAVs (88% vs 97%) Safety profile similar to ASTRAL-1 P <.1 (superiority) SOF/VEL 12 wks SOF + RBV 24 wks n/n = 264/ 221/ 191/ 163/ 73/ 55/ 2/ 176/ 64/ 45/ All Pts No Yes Naive Experienced Treatment History Slide 27 of 42 Foster GR, et al. N Engl J Med. 215;[Epub ahead of print]. 9

10 5/12/216 Treatment of HCV Genotype 2 Background Genotype 2 Accounts for 13-15% of all hepatitis C infections in the US Associated with historically high sustained virologic response (SVR) rates Limited data regarding retreatment of GT 2 disease Slide 28 of year-old Caucasian female HCV genotype 2b HCV RNA 7.4 million IU/ml Case 4 Transient elastography score 2.3 KPA Treatment with PEG-IFN + RBV 3 years prior Relapse 4 weeks post treatment Treatment complicated by significant mood changes and fatigue. Fatigue persistent for 2 years. Now improving Slide 29 of 42 CASE 4: What do you recommend? 46% 1. Sofosbuvir + RBV x 24 weeks 23% 23% % 8% 2. Daclatasvir + Sofosbuvir x 12 weeks 3. Sofosbuvir + Ledipasvir x 12 weeks 4. PegIFN + RBV x 24 weeks 5. No treatment Slide 3 of 42 1

11 5/12/216 AASLD/IDSA: Recommended Regimens for HCV Genotype 2 Patients Treatment-Naïve and PEG-IFN treatment experienced patients Daily sofosbuvir (4 mg) and ribavirin for 12 weeks (in patients without cirrhosis) Rating: Class 1, Level A Daily sofosbuvir (4 mg) and ribavirin for weeks (in patients WITH compensated cirrhosis) Rating: Class IIa, Level C Daily daclatasvir (6 mg*) and sofosbuvir (4 mg) for 12 weeks (in patients without cirrhosis who cannot tolerate RBV) Rating: Class IIa, Level B Daily daclatasvir (6 mg*) and sofosbuvir (4 mg) for weeks (in patients WITH cirrhosis who are not eligible to receive RBV) Rating: Class IIa, Level B Dose of daclatasvir may need to be or when used with Cyt P45 3A/4 inducers and inhibitors Slide 31 of 42 Weight-based RBV ( mg [<75 kg] to 12 mg [>75 kg]). PR: pegifn + RBV. hcvguidelines.org. April 12, 216 AASLD/IDSA: Recommended Regimens for HCV Genotype 2 Patients Failure of Prior PR Treatment- Compensated Cirrhotic Alternative Daily sofosbuvir (4 mg) and ribavirin + weekly PEG-IFN for 12 weeks (IFN-eligible patients) Rating: Class IIa, Level B Failure of Prior SOF + RBV Treatment Daily daclatasvir (6 mg*) and sofosbuvir (4 mg) with or without RBV for 24 weeks (in patients with or without cirrhosis who are not eligible to receive PEGIFN and/ RBV) Rating: Class IIa, Level C Daily sofosbuvir (4 mg) and ribavirin + weekly PEG-IFN for 12 weeks (in IFN eligible patients with or without cirrhosis) Rating: Class IIa, Level C Dose of daclatasvir may need to be or when used with Cyt P45 3A/4 inducers and inhibitors Slide 32 of 42 Weight-based RBV ( mg [<75 kg] to 12 mg [>75 kg]). PR: pegifn + RBV. hcvguidelines.org. April 12, 216 AASLD/IDSA: HCV Regimens That Are NOT Recommended for Genotype 2 Patients Treatment-naïve patients PEG-IFN and RBV for 24 weeks Monotherapy with pegifn, RBV, or a direct-acting antiviral agent Telaprevir-, boceprevir-, or ledipasvir-containing regimens Failure of prior PR treatment PEG-IFN and RBV with or without telaprevir or boceprevir Fixed-dose combination ledipasvir-sofosbuvir Monotherapy with peginterferon, ribavirin, or a direct-acting antiviral Slide 33 of 42 AASLD/IDSA. August 31,

12 5/12/216 Key Studies That Support GT 2 Treatment Recommendations Daclatasvir and Sofosbuvir ALLY 2 Sofosbuvir + Ribavirin FISSION FUSION (Treatment experienced) POSITRON VALENCE Sofosbuvir + Ribavirin + PEG-IFN LONESTAR-2 (Treatment experienced) Sofosbuvir + Ribavirin or Sofosbuvir + Ribavirin + PEG-IFN BOSON (Treatment experienced) Studies in red will not be discussed Slide 34 of 42 Sofosbuvir + RBV in GT 2 Registration Trials FISSION 12 Week 97% POSITRON 12 week 93% FUSION 12 week 86% FUSION 16 week 94% VALENCE 12 week 93% SVR12 rate (%) Lawitz E, et al. N Engl J Med 213;368: Zeuzem S et al, N Engl J Med 214;37: Jacobson IM, et al. N Engl J Med 213;368: Slide 35 of 42 ALLY 2 Daclatasvir + Sofosbuvir in HIV Co-infected Genotypes 1-4 Phase 3, open label GT 1 treatment naïve and experienced GT 2/3 treatment naïve HIV co-infected Week Treatment-Naïve GT 2 N=17 DCV + SOF N=6 DCV + SOF N=11 SVR 12=85% (5/6) SVR 12=% 11/11 Drug Dosing Daclatasvir (DCV): 6 mg daily Sofosbuvir (SOF): 4 mg daily Slide 36 of 42 Wyles DL et al. N Engl J Med

13 SVR12 (%) SVR12 (%) 5/12/216 BOSON Study: Sofosbuvir-Based Regimens in HCV Genotype 2 Cirrhotics Open-label study Genotype 2 Treatment-experienced Genotype 3 also included Treatment-naïve or experienced With or without cirrhosis Primary outcome: SVR SVR12 (Genotype 2) % 94% 87% PR: pegifn + RBV. Sofosbuvir RBV 16 Weeks (n=15) Sofosbuvir RBV 24 Weeks (n=17) Sofosbuvir PR 12 Weeks (n=16) Slide 37 of 42 Foster GR, et al. Gastroenterology 215. Sofosbuvir + Velpatasvir Drugs on the horizon Slide 38 of 42 ASTRAL-2: Sofosbuvir/Velpatasvir in HCV GT 2 Sofosbuvir/velpatasvir Sofosbuvir + RBV 99%* 99% % % 96% 94% 93% % % 81% Overall (n= ) No (n= 96) (n=15 15) No (n=15 16) (n=4 4) Treatment-Naïve Treatment Experienced Slide 39 of 42 Foster GR, et al. N Engl J Med. 215; Nov 17. [Epub ahead of print]. 13

14 SVR12 (%) 5/12/216 Summary There are an increasing number of options for treatment of GT 2 or 3 disease GT 3 disease remains somewhat harder to cure with all oral DAA therapy Recommended treatment course varies by status Prior treatment experience Interferon eligibility Other issues When to defer therapy The cost of therapies Slide 4 of 42 Oluwaseun Falade-Nwulia Arthur Kim Acknowledgements Slide 41 of 42 ELECTRON II: Ledipasvir/Sofosbuvir in HCV Genotype 3 Phase 2, open-label trial Treatment-experienced GT 1 Treatment-naïve GT 3 Treatment centers in New Zealand Ledipasvir/sofosbuvir 9/4 mg qd +/- RBV for 12 weeks 6 64% SVR12 Rates % Week GT 3 Tx Naïve Randomized LDV-SOF (n=25) LDV-SOF + RBV (n=26) SVR12 SVR /25 26/26 LDV-SOF LDV-SOF + RBV (n=25) (n=26) Slide 42 of 42 Gane EJ, et al. Gastroenterology 215. EASL. 214: Abstract 6. 14