Current HCV Treatment by Genotype Empire Liver Foundation Ira M. Jacobson, MD

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2 Current HCV Treatment by Genotype Empire Liver Foundation Ira M. Jacobson, MD Chairman, Department of Medicine Mount Sinai Beth Israel Professor of Medicine Co-Director, Liver Institute Icahn School of Medicine at Mount Sinai New York, New York

3 Objectives To understand the prevalence of HCV and distribution of HCV genotypes Describe the HCV lifecycle and how specific drugs target the HCV polypeptide sequence Explain circumstances where it is important to test for possible drug resistance Understand the landscape in regards to advances made in the evolution of treating HCV over the past 20+ years Understand the HCV genotypes and the drug regimens that work to eradicate HCV on each genotype

4 HCV: A Major Public Health Problem Approximately 3.5 million people in the United States are chronically infected with HCV (1.3%) Including populations excluded from NHANES (e.g., the incarcerated, homeless, institutionalized, and those living on Native American reservations) brings the total estimate to 4.6 million 2 Seroprevalence is higher in birth cohort (3.5%) Non-Hispanic blacks (2.2%) Males (1.9%) vs females (1.1%) Many diagnosed patients remain untreated 3 Birth cohort screeing introduced 50% Undiagnosed 50% Diagnosed NHANES=National Health and Nutrition Examination Survey. a NHANES data as of 2010; b NHANES data, Ditah I, et al. J Hepatol. 2014;60: Edlin BR, et al. Hepatology. 2015;62: Yehia BR, et al. PLoS ONE. 2014;9:1-7.

5 Distribution of Hepatitis C Genotypes Epidemiology of Infectious Diseases. Available at: Copyright John Hopkins Bloomberg School of Public Health. Creative Commons BY-NC-SA.

6 The HCV Life Cycle

7 T. Asselah. HCV Polypeptide Sequence

8 The HCV Polymerase (NS5B) The active site of the HCV polymerase is highly conserved Explains why sofosbuvir is the backbone of several regimens

9 What s Special About the Active Site of the HCV Polymerase? Feature Therapeutic Implication Highly conserved across genotypes Pangenotypic efficacy of potent inhibitors Low replicative fitness conferred by amino acid substitutions High resistance barrier

10 Resistance Considerations Which classes are prone to resistance? Protease, NS5A, and nonnucleotide NS5B inhibitors Barrier to PI and NS5A resistance Higher for GT1b vs GT1a Most pts with failure of current DAAs have emergent resistanceassociated variants (RAVs), especially to the NS5A class NS5A RAVs persist much longer than PI RAVs 15% of pts have baseline NS5A RAVs with variable effects on GT1a response Second-generation drugs are designed to cover RAVs

11 Where HCV Therapy Stands Now Interferon is gone in the U.S.; ribavirin not quite SVR in over 95% of patients Difficult to treat populations no longer difficult African-Americans HIV coinfected Cirrhosis Older age Renal failure and transplant Liver transplant Persons who use IV drugs (PWID) Confidence that SVR12 = cure Cost and access issues persist, but improving

12 Cure Rate* Rising Cure Rates for Chronic HCV (GT1) 100% 80% Telaprevir or Boceprevir + PegIFN/RBV PR/SMV PR/SOF 80-90% IFN-Free DAA Combination Regimens >95% 70-80% 60% 40% IFN/RBV 35% PegIFN/RBV 44% 20% IFN 16% 0% Year

13 The Evolution of HCV Therapy Frequent curability of diverse populations without IFN Ledipasvir + sofosbuvir (GT1) Simeprevir + sofosbuvir (GT1) Telaprevir and boceprevir Daclatasvir: DCV+ASV (Japan) DCV+SOF (Europe) Paritaprevir/rombitasvir/ dasabuvir ± RBV (GT1) DCV + SOF (GT3) (GT1 2016) Sofosbuvir + velpatasvir (all genotypes) Interferon Era Curability of HCV without IFN Simeprevir, sofosbuvir with IFN (GT1) First approved IFN-free therapy: sofosbuvir + RBV (GT2,3) DAA: direct-acting antiviral; GT: genotype; IFN: interferon; PI: protease inhibitor; NI: nucleoside/nucleotide inhibitor; RBV: ribavirin; r: ritonavir. Grazoprevir+ Elbasvir (GT1,4

14 4A Approved Direct-Acting Antiviral Agents from Multiple Classes: Combination Regimens for HCV in 2016 Structural domain Nonstructural domain P 7 5 UTR Core E1 E2 NS2 NS4B NS3 NS5A NS5B 3 UTR Protease Polymerase Ribavirin (RBV) NS3 Protease Inhibitors Simeprevir (SMV) Paritaprevir/ritonavir (PTV/r) Grazoprevir (GZR) NS5A Replication Complex Inhibitors Daclatasvir (DCV) Ledipasvir (LDV) Ombitasvir (OMV) Elbasvir (EBV) Velpatasvir NS5B NUC Inhibitors Sofosbuvir (SOF) NS5B Non-NUC Inhibitors (NNI) Dasabuvir (DSV) previr = protease inhibitor; asvir = NS5A inhibitor; uvir = polymerase inhibitor Courtesy of Albert Min MD.

15 10-Year Cumulative Occurrence Rate (%) SVR and All-Cause Mortality in CHC Patients with Advanced Fibrosis 530 patients with all genotypes followed for a median of 8.4 years SVR patients Non-SVR patients Baseline factors significantly associated with all-cause mortality: Older age Genotype 3 (2-fold increase in mortality and HCC) Higher Ishak fibrosis score Diabetes Severe alcohol use 0 All-Cause Mortality Liver-Related Mortality or Liver Transplant HCC Liver Failure Van der Meer A, et al. JAMA. 2012; 308:

16 Cirrhosis Regression and Fibrosis Reduction Following SVR (any genotype) Cirrhosis Regression in 61% of Patients 100% 80% 15 Sample Liver Biopsy Pre-treatment (F4) Post-treatment (F3) 60% 40% % 0% Pre-treatment 7 Post-treatment 2 Fibrosis Reduction F1 F2 F3 F4 After treatment, the area of fibrosis decreased in 34/38 (89%) of patients Post-treatment liver biopsies showed a significantly reduced area of fibrosis, with a median individual decrease of 71.8% Prospective study of patients with pre-treatment cirrhosis and an SVR with IFN-based therapy (enrolled in ) to assess the impact of SVR on the full spectrum of histopathologic features of HCV-related cirrhosis. N=38, median f/u 67 months (range, months). Adapted from D Ambrosio R, et al. Hepatology. 2012;56:

17 HVPG (mmhg) Evolution of Portal Pressure After DAA Therapy HVPG Absolute : ± 0.38 mmhg; p<0.001 Relative : -23 ± 2.9% Subclinical portal hypertension at BL HVPG mmhg at BL Pronounced portal hypertension at BL Resolved 63% No progression Resolved 14% Regression 29% No progression No resolution Regression 5% Increase 20% 0 BL BL FU FU 13.1 ± 0.7 mmhg 10.4 ± 0.79 mmhg Earlier portal hypertension is more reversible than advanced PHT Mandorfer M, et al. EASL Barcelona. #PS005.

18 Extra-hepatic Manifestations of HCV Infection Neuropsychiatric manifestations Thyroid dysfunction Mixed cryoglobulinemia Hematological disorders/ malignancies Type II diabetes Cardiovascular/ metabolic diseases Renal impairment Peripheral neuropathy Cacoub P, et al. Dig Liver Dis 2014; 46(Suppl 5):S165 S173; Negro F, et al. Gastroenterology 2015; 149: ; Englert Y, et al. Fertil Steril 2007; 88:607 11; Samuel DG & Rees IW. Frontline Gastroenterol 2013; 4:

19 Cumulative development rate of T2DM Patients without IFG and/or T2DM Treatment of HCV Is Associated with Reduced Risk for Type 2 Diabetes Mellitus Japanese retrospective study: 2842 patients treated with IFN ± RBV were followed for a mean of 6.4 years 1 50 Spanish HCV chronic HCV cohort study: 1059 patients treated with IFN + RBV for 24/48 weeks P= p<0.001 Non-SVR (n = 1667) Follow up (years) SVR (n = 1175) SVR was associated with a 66% reduction in the development of T2DM SVR Censored NR Censored Follow-up (months) SVR reduces the risk of IFG and/or T2DM development 1.. Arase Y, et al. Hepatology 2009; 49: ; 2. Romero-Gomez M, et al. J Hepatol 2008; 47:

20 Cumulative incidence (%) Cumulative incidence (%) Treatment of HCV Is Associated with Reduced Risk for Cardiovascular Complications Large Taiwanese chronic HCV cohort study: 12,384 patients treated with pegifn/rbv and 24,768 untreated matched controls were followed up for a mean of 3.3 years and 3.2 years, respectively Untreated cohort Treated cohort Ischemic stroke, p= Untreated cohort Treated cohort Acute coronary syndrome, p= Follow-up (years) Antiviral treatment was associated with a 38% lower risk for ischemic stroke Follow-up (years) Antiviral treatment was associated with a 23% lower risk for ACS ACS, acute coronary syndrome. Hsu YC, et al. Gut 2015; 64:

21 Treatment of HCV Is Associated with Reduced Risk for End Stage Renal Disease Cumulative incidence (%) Large Taiwanese prospective chronic HCV cohort study: 12,384 patients treated with pegifn/rbv and 24,768 untreated matched controls were followed up for a mean of 3.3 years and 3.2 years, respectively Untreated cohort Treated cohort End-stage renal disease, p< Hsu YC, et al. Gut 2015; 64: ; Follow-up (years)

22 Pre-Treatment Evaluation Quantitative PCR for HCV RNA Genotype Exclusion of other liver diseases (HBV, NAFLD) Ensuring HAV, HBV immunity Medications Comorbidity assessment Assessment of level of fibrosis remains essential Liver biopsy is OUT Noninvasive tests are IN Blood tests (APRI, FIB-4, Fibrosure, Hepascore, etc) Elastography (e.g. Fibroscan, ARFI, MRI) HCC screening w/advanced fibrosis/cirrhosis Varices screening for cirrhotics

23 Genotype 1 Regimens AASLD/IDSA Guidelines Updated October 2016 hcvguidelines.org

24 AASLD/IDSA: Recommended and Alternative Regimens for GT1 Without Cirrhosis No Distinction Between Naïve & Experienced Recommended Alternative Nucleotide No nucleotide Population LDV/SOF SOF + VEL DCV + SOF SMV + SOF GZR/EBR OBV/PTV/RTV + DSV GT1a 12 wks (8 wks if HCV RNA<6M IU/ml, non-aa, no HIV) 12 wks 12 wks 12 wks 12 wks 16 wks + RBV 12 wks + RBV GT1b 12 wks (8 wks if HCV RNA<6M IU/ml, non-aa, no HIV) 12 wks 12 wks 12 wks 12 wks 12 wks If NS5A RAVs present (GT1a only) AASLD/IDSA. hcvguidelines.org. Apirl 2017.

25 AASLD/IDSA: Recommended and Alternative Regimens for GT1 with Compensated Cirrhosis Recommended Alternative Nucleotide No nucleotide Population LDV/SOF SOF + VEL DCV + SOF SMV + SOF GZR/EBR OBV/PTV/RTV + DSV GT1a - Naive - PR exp 12 wks 12 wks + RBV or 24 wks w/o RBV 12 wks 12 wks 24 wks ± RBV 24 wks ± RBV 24 wks ± RBV* 24 wks ± RBV* 12 wks 16 wks + RBV 12 wks 16 wks + RBV 24 wks + RBV 24 wks + RBV *Not w/q80k If NS5A RAVs present. AASLD/IDSA. hcvguidelines.org. Apirl 2017.

26 AASLD/IDSA: Recommended and Alternative Regimens for GT1 with Compensated Cirrhosis Recommended Alternative Nucleotide No nucleotide Population LDV/SOF SOF + VEL DCV + SOF SMV + SOF GZR/EBR OBV/PTV/RTV + DSV GT1b - Naive 12 wks 12 wks 24 wks ± RBV 24 wks ± RBV* 12 wks 12 wks - PR exp 12 wks + RBV or 24 wks 12 wks 24 wks ± RBV 24 wks ± RBV* 12 wks 12 wks *Not w/q80k If NS5A RAVs present. AASLD/IDSA. hcvguidelines.org. April 2017.

27 The Most Recently Approved Regimen in the US (June 2016) Sofosbuvir/Velpatasvir

28 SVR12* (%) ASTRAL-1: SOF/VEL FDC for 12 Weeks in G1, 2, 4, 5, 6 Patients with and Without Cirrhosis: ASTRAL-1 Study Velpatasvir (VEL, GS-5816) is a pangenotypic HCV NS5A inhibitor GT3 pts evaluated in separate study 19% cirrhosis, 32% treatment-experienced / / / / 104 Overall G1a G1b G2 G4 G5 G6 116/ / 35 41/ 41 *HCV RNA <15 IU/mL Feld JJ, Jacobson IM, Hezode C, et al. N Engl J Med Dec 31;373(27):

29 Genotype 2

30 SVR12 (%) ASTRAL-2: SOF/VEL FDC for 12 Weeks Compared to SOF + RBV for 12 Weeks in GT2 Patients Wk 0 Wk 12 Wk 24 SOF/VEL SOF + RBV 266 patients with G2 HCV infection in the US were randomized and treated 134 with SOF/VEL 132 with SOF + RBV 59% male 88% white 38% IL28B CC 15% prior treatment failure 14% cirrhosis SVR12 SVR LTFU SOF/VEL SVR12 p= relapses 2 LTFU 133/ /132 SOF + RBV Sulkowski M, et al. AASLD San Francisco. #205; Foster GR, Afdhal N, Roberts SK, et al. N Engl J Med Dec 31;373(27):

31 SVR12 (%) ASTRAL-2: SOF/VEL FDC for 12 Weeks Compared to SOF + RBV for 12 Weeks in GT2 Patients Wk 0 Wk 12 Wk 24 SOF/VEL SOF + RBV patients with G2 HCV infection in the US were randomized and treated SOFOSBUVIR 134 with SOF/VEL + RIBAVIRIN SHOULD 80 NOT BE USED FOR GT2 132 with SOF + RBV 59% male 88% white 38% IL28B CC 15% prior treatment failure 14% cirrhosis SVR12 SVR LTFU 133/ /132 SOF/VEL SVR12 p= relapses 2 LTFU SOF + RBV Sulkowski M, et al. AASLD San Francisco. #205; Foster GR, Afdhal N, Roberts SK, et al. N Engl J Med Dec 31;373(27):

32 Genotype 3

33 ASTRAL-3: SOF/VEL FDC for 12 Weeks Compared to SOF + RBV for 24 Weeks in G3 HCV Infected Patients * SOF/VEL SOF + RBV Resistance Analysis % SVR12 225/ 231 n=274 84% No BL NS5A RAVs n=231 16% BL NS5A RAVs n=43 88% SVR12 38/ Cirrhosis No Yes No Yes Treatment-Naive Treatment-Experienced * *One reinfection: 94% without this patient Mangia A, et al. AASLD San Francisco. #249; Foster GR, Afdhal N, Roberts SK, et al. N Engl J Med. 2015;373:

34 Management of Patients with Genotype 3 Trt Experience Cirrhosis? Y93H RAV? Recommended Regimens Naive No Testing not recommended Naive Yes No Naive Yes Yes PegIFN/RBV No No PegIFN/RBV No Yes PegIFN/RBV Yes -- AASLD/IDSA. HCV Guidance. April 2017.

35 Management of Patients with Genotype 3 Trt Experience Cirrhosis? Y93H RAV? Recommended Regimens Naive No wks DCV + SOF Naive Yes No 24 wks DCV + SOF ± RBV Naive Yes Yes 24 wks DCV + SOF + RBV PegIFN/RBV No No 12 wks DCV + SOF PegIFN/RBV No Yes 12 wks DCV + SOF + RBV PegIFN/RBV Yes wks DCV + SOF + RBV AASLD/IDSA. HCV Guidance. April 2017.

36 Management of Patients with Genotype 3 Trt Experience Cirrhosis? Y93H RAV? Recommended Regimens Naive No wks SOF/VEL Naive Yes No 12 wks SOF/VEL Naive Yes Yes 12 wks SOF/VEL + RBV PegIFN/RBV No No 12 wks SOF/VEL PegIFN/RBV No Yes 12 wks SOF/VEL + RBV PegIFN/RBV Yes wks SOF/VEL + RBV AASLD/IDSA. HCV Guidance at hcvguidelines.org April 2017.

37 Decompensated Cirrhosis

38 SVR12 (%) SOLAR-1: LDV/SOF + RBV in Decompensated Cirrhotics: Genotypes 1 and 4, Childs-Pugh B and C LDV/SOF + RBV 12 Weeks LDV/SOF + RBV 24 Weeks /52 42/47 Overall 26/30 24/27 19/22 18/20 CPT B CPT C Charlton M, et al. Gastroenterology. 2015;149:

39 Ledipasvir + Sofosbuvir + Ribavirin in Decompensated Cirrhotics: Genotypes 1 and 4, Childs-Pugh B and C Changes in MELD Score CPT B CPT C 4 12 wk (n=30) 24 wk (n=29) 12 wk (n=23) 24 wk (n=26) (+10) n=5 n=5 n=2 n= Flamm SL, et al. AASLD Boston. # (-8)

40 SOF/VEL FDC for Treatment of HCV in Patients with Decompensated Liver Disease: Phase 3 ASTRAL-4 Study 267 treatment naive or experienced G1 6 with Child B cirrhosis Wk 0 Wk 12 Wk 24 Wk 36 n=90 n=87 n=90 SOF/VEL SOF/VEL + RBV SOF/VEL SVR12 SVR12 SVR12 Charlton MR, et al. AASLD San Francisco. #LB-13; O Leary J, et al. EASL Barcelona. #SAT-169.

41 ASTRAL-4: SOF/VEL FDC for Treatment of HCV in Patients with Decompensated Liver Disease SVR24 rates (%) / 90 82/ 87 79/ 90 60/ 68 65/ 68 Safety d/c due to AE 3%; death 3% (9) AE more frequent with RBV Fatigue (29%); nausea (23%); HA (22%); anemia (13%; 31% in RBV arm) 67/ 71 Overall G1 G3 G2, 4, 6 BT Relapse LTFU Death / 14 11/ / 12 G2: 4/4 G4: 4/4 G2: 4/4 G4: 2/2 G2: 4/4 G4: 2/2 G6: 1/ Charlton MR, et al. AASLD San Francisco. #LB-13; O Leary J, et al. EASL Barcelona. #SAT-169. RBV dose: Hb <10 = 23%; Hb <8.5 = 7% RBV decreased in 37% and d/c in 17% Bili <3 x ULN

42 What Therapy Should Be Used for Decompensated Cirrhotics? 1. Only regimens containing an NS5A inhibitor and polymerase inhibitor should be used for decompensated cirrhotic patients 2. Protease inhibitors should not be used in decompensated cirrhotics because they accumulate to potentially toxic levels 3. Decompensated cirrhotics should be treated at a transplant center or in close coordination with a transplant center hcvguidelines.org. Feb 24; EASL Recommendations. J Hepatol

43 Renal Failure

44 C-SURFER Study: CKD Stage 4/5 Grazoprevir + Elbasvir N=122 Placebo N= weeks 55% on dialysis 55% with diabetes 52% GT1a, 48% GT1b 6% cirrhosis Active treatment Roth D, et al. Lancet Oct 17;386(10003):

45 C-SURFER: On Treatment Virologic Response Immediate and Deferred Treatment Arms 100% 95% 100% 100% 100% 99% 99% 98% 90% 80% 60% 66% 60% Immediate treatment group 40% Deferred treatment group 20% 0% 81 / / / / / /101 TW2 TW4 TW12 FW4 FW12 (SVR12) 118 / / / /99 *Efficacy is presented for the modified full analysis set population (mfas). Roth D, et al. Lancet Oct 17;386(10003):

46 SVR12 (%) LDV/SOF for 12 or 24 Weeks in Kidney Transplant Recipients with Chronic G1 or 4 HCV Infection / 57 55/ 57* Overall 51/ 51/ 51 53* 6/6 4/4 G1 G4 *2 lost to follow-up: NO VIROLOGIC FAILURES Colombo M, et al. EASL Barcelona. #GS13.

47 New Paradigm of HCV Therapy for Renal Failure Patients Past: Difficult to use interferon + ribavirin in renal failure Renal transplantation historically withheld for HCV+ patients with hepatic fibrosis ( we won t transplant till HCV cured ) Concern about progression of fibrosis post-transplant

48 New Paradigm of HCV Therapy for Renal Failure Patients Past: Difficult to use interferon + ribavirin in renal failure Renal transplantation historically withheld for HCV+ patients with hepatic fibrosis ( we won t transplant till HCV cured ) Concern about progression of fibrosis post-transplant Present Effective and safe DAA therapy available for renal failure patients Non-renal transplant candidates should be offered treatment If wait list is much shorter for an HCV+ kidney, may be better to proceed with transplant and treat the HCV after transplant

49 New Paradigm of HCV Therapy for Renal Failure Patients Past: Difficult to use interferon + ribavirin in renal failure Renal transplantation historically withheld for HCV+ patients with hepatic fibrosis ( we won t transplant till HCV cured ) Concern about progression of fibrosis post-transplant Present Effective and safe DAA therapy available for renal failure patients Non-renal transplant candidates should be offered treatment If wait list is much shorter for an HCV+ kidney, may be better to proceed with transplant and treat the HCV after transplant Future Transplant HCV- patients with HCV+ kidneys? Being studied

50 HCV Therapy: Almost at the Summit But Still Climbing The Quest: Pangenotypic regimens that cover resistant variants associated with first generation NS5A and protease inhibitors

51 HCV Therapy: Almost at the Summit But Still Climbing The Quest: Pangenotypic regimens that cover resistant variants associated with first generation NS5A and protease inhibitors

52 Second Generation Regimens Protease Inhibitor Glecaprevir + + NS5A Inhibitor Pibrentasvir Nucleotide Polymerase Inhibitor GS-9857 Velpatasvir Sofosbuvir + Grazoprevir Ruzasvir Uprifosbuvir + +

53 Phase 3 Trial of SOF/VEL/VOX for 8 Weeks vs SOF/VEL for 12 Weeks in DAA-Naive GT1 6: POLARIS-2 Study Wk n=501 SOF/VEL/VOX SVR12 SVR12 n=440 SOF/VEL Jacobson IM, et al. AASLD Boston. #LB-12.

54 POLARIS-2: Efficacy SVR12, % relapses 4 LTFU 476/501 SOF/VEL/VOX 8 Weeks Failed to meet non-inferiority endpoint 3 relapses 1 DC due to AE 4 LTFU 432/440 SOF/VEL 12 Weeks Only 1/21 relapsers had treatmentemergent resistant variants Proportional difference -3.4 (-6.2% to -0.6%) noninferiority not met; error bars represent 95% confidence intervals. Jacobson IM, et al. AASLD. LB-12.

55 SVR12, % POLARIS-2: SVR12 by Genotype (GT 1) SOF/VEL/VOX 8 weeks, n=501 SOF/VEL 12 weeks, n= relapses 4 LTFU 16 relapses 14 relapses 2 relapses relapses 1 W/C 1 LTFU 1 relapse 2 LTFU 1 relapse 1 LTFU 1 LTFU Overall 1 1a 1b Overall GT 1 GT 1a GT 1b of 2 patients (100%) with GT 1 Other achieved SVR12 (1 each in SOV/VEL/VOX and SOF/VEL arm); Error bars represent 95% confidence intervals.

56 POLARIS-2: SVR12 by Cirrhosis Status 100 No Cirrhosis N= Cirrhosis N= relapses 3 LTFU 2 relapses 4 LTFU 1 DC due to AE relapses 1 LTFU 1 relapse / 411 SOF/VEL/VOX 8 Weeks 349/ 356 SOF/VEL 12 Weeks / 90 SOF/VEL/VOX 8 Weeks 83/ 84 SOF/VEL 12 Weeks Error bars represent 95% confidence intervals.

57 POLARIS-2: AEs in >10% of Patients Patients, n (%) SOF/VEL/VOX 8 weeks n=501 SOF/VEL 12 weeks n=440 Headache 134 (27) 99 (23) Fatigue 106 (21) 90 (20) Diarrhea 88 (18) 32 (7) Nausea 80 (16) 40 (9)

58 SOF/VEL/VOX 12 Weeks in NS5A Inhibitor-Experienced GT1 6 patients: Phase 3 POLARIS-1 Study G1 (n=262) NS5A inhibitorexperienced G2 6 (n=152) NS5A inhibitorexperienced 46% cirrhosis Placebo 1:1 SOF/VEL/VOX (400 mg/100 mg/100 mg QD) FDC SOF/VEL/VOX (400 mg/100 mg/100 mg QD) FDC Time (weeks) Bourlière M, et al. AASLD Boston. #194.

59 SVR12, % SOF/VEL/VOX 12 Weeks in NS5A Inhibitor-Experienced GT1 6 patients: Phase 3 POLARIS-1 Study G1 (n=262) NS5A inhibitorexperienced G2 6 (n=152) NS5A inhibitorexperienced 46% cirrhosis Placebo 1:1 SOF/VEL/VOX (400 mg/100 mg/100 mg QD) FDC SOF/VEL/VOX (400 mg/100 mg/100 mg QD) FDC Time (weeks) relapses 1 on-tx failure 2 withdrew consent 1 LTFU 253/263 Bourlière M, et al. AASLD Boston. #194.

60 SVR12, % SVR12, % SOF/VEL/VOX 12 Weeks in NS5A Inhibitor-Experienced GT1 6 patients: Phase 3 POLARIS-1 Study G1 (n=262) NS5A inhibitorexperienced G2 6 (n=152) NS5A inhibitorexperienced 46% cirrhosis Placebo 1:1 SOF/VEL/VOX (400 mg/100 mg/100 mg QD) FDC SOF/VEL/VOX (400 mg/100 mg/100 mg QD) FDC Time (weeks) relapses 1 on-tx failure 2 withdrew consent 1 LTFU 253/ withdrew consent 1 LTFU 140/142 No Cirrhosis 6 relapses 1 on-tx failure 1 withdrew consent 113/121 Cirrhosis Bourlière M, et al. AASLD Boston. #194.

61 POLARIS-3: Phase 3 Trial of SOF/VEL/VOX for 8 Weeks and SOF/VEL for 12 Weeks for GT3 HCV Infection and Cirrhosis G3 Cirrhosis n=110 n=109 SOF/VEL/VOX SOF/VEL SVR12 SVR Week SVR Foster GR, et al. AASLD Boston. # relapses 1 withdrew consent 1 death SOF/VEL/VOX 8 Weeks 1 on-treatment failure 1 relapse 1 discontinued due to AE 1 LTFU SOF/VEL 12 Weeks

62 TakeAway Points From POLARIS Studies Triplet regimen very effective when given for 8 weeks but probably will not replace current 12 week regimens (failed to meet noninferiority vs SOF/VEL for 12 weeks) Triplet regimen for 12 weeks very promising as rescue for DAA failure patients Very effective regimen for GT3

63 SVR12 (%) ENDURANCE-1, 2, 4 Studies: Efficacy of GLE/PIB for Treating GT1, 2, 4, 5, 6 HCV No cirrhosis * 99.7 * / / Wks 12 Wks 195/ Wks 120/ Wks ENDURANCE-1 (GT1) [1] ENDURANCE-2 ENDURANCE-4 (GT2) [2] (GT4-6) [3] 1. Zeuzem S, et al. AASLD Abstract Kowdley KV, et al. AASLD Abstract Asselah T, et al. AASLD Abstract 114.

64 ENDURANCE-3: Glecaprevir/Pibrentasvir 8 or 12 Wksin GT3 HCV Without Cirrhosis / / /115 G/P 8 wks G/P 12 wks DCV/SOF 12 wks Foster GR, et al. EASL Abstract GS-007. Arms A and B not inferior to C

65 EXPEDITION-1: Glecaprevir/Pibrentasvir in GT1, 2, 4, 5, or 6 HCV and Compensated Cirrhosis, 12 Weeks SVR12 (%) / / 90 31/ 31 16/ 16 2/ 2 7/ 7 0 All Pts Genotype Forns X, et al. EASL Abstract GS-006. ClinicalTrials.gov. NCT

66 SVR12(%) mitt Glecaprevir + Pibrentasvir for Prior DAA Failures, n=50: Genotype 1, 12 Weeks /6 20/21 19/20 0 Arm A Arm B Arm C ABT-493 (mg) ABT-530 (mg) Poordad F, et al. EASL GS-11.

67 Management of Patients After SVR Follow patients till SVR48 HCC screening continues in F3 or F4 Fibroscan, serum markers may improve but not reliable for decisions re: d/c of HCC screening Can d/c variceal screening if no varices prior to treatment Continue surveillance, treatment as needed in patients who received primary prophylaxis for varices or previously bled No alcohol consumption with advanced fibrosis/cirrhosis

68 Summary We are now in an era of highly effective interferon free treatment Historically difficult to treat patients are no longer considered difficult to treat HIV coinfected patients have similar efficacy, must be mindful of drug-drug interactions PWID should be treated with appropriate avaliable expertise in addiction medicine w/harm reduction There is significant fibrosis regression, reduction in liver complications, and all-cause mortality post-svr There is no justification for withholding treatment from HCV infected patients regardless of degree of fibrosis Post-SVR patients with advanced fibrosis or cirrhosis must be monitored for liver cancer