Norah Terrault, M.D. Professor of Medicine and Surgery Director, Viral Hepatitis Center University of California San Francisco

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1 Norah Terrault, MD Professor of Medicine and Surgery Director, Viral Hepatitis Center University of California San Francisco Disclosures Norah Terrault, M.D. Grants/Research Support AbbVie, Gilead, BMS, Biotest, Eisai Consultant: Genetech, BMS, Gilead, Janssen, Merck, Cryocrystal Stock/Shareholder: None Speakers Bureau: None Royalties: Up to date Other Financial Support: NIH Grants 1

2 Outline Review clinical trial data for currently approved HCV drugs Review the real world data and predictors of failure in this setting Optimizing treatment success across the spectrum of patients Easy Treatment naïve Non cirrhotic Med list is short Motivated (and adherent) patient Good insurance More Challenging Treatment experienced Cirrhosis Genotype 3 Drug drug interactions Risk for ribavirin toxicity Medicaid or more limited insurance Global Burden of HCV Infection ~180 Million With HCV Infection 250,000 HCV RNA+ Edlin B, Hepatology 2015;62: Messina JP et al, Hepatology, 2015; 61: Can J Gastroenterol Hepato 2014, 28:

3 Rates of SVR with HCV Therapy Peginterferon 2001 Direct Acting Antivirals Protease inhibitor 2011 Nucleoside inhibitor 2013 SVR (%) Standard Interferon 1991 Ribavirin Months IFN 12 Months 6 Months IFN + RBV 12 Months 12 Months PegIFN + RBV 6 12 Months PegIFN+ RBV+PI 8 12 weeks IFN Free HCV Can Now Be Cured in Most Patients Unlike HIV and HBV infection, HCV infection is a curable disease HCV does not archive its genome What does cure mean? Undetectable HCV RNA 12 weeks after completion of antiviral therapy for chronic HCV infection SVR12 is almost invariably durable Ghany MG, et al. Hepatology. 2009;49(4):

4 SVR and All Cause Mortality Benefits in Treated vs Untreated Patients with Advanced Fibrosis All cause Mortality (%) All cause Mortality P < With SVR Time (years) Without SVR Liver related Mortality or Liver Transplantation (%) Liver related Mortality or Liver Transplantation P < With SVR Time (years) Without SVR Hepatocellular Carcinoma (%) Hepatocellular Carcinoma P < With SVR Time (years) Without SVR Liver Failure (%) 30 Liver Failure Without SVR P < With SVR Time (years) van der Meer AJ et al. JAMA. 2012;308(24): Other Potential Non Liver Benefits Lower rates of : Diabetes Cryoglobulinemia Renal disease Lymphoma Medical follow up; 6.4 ± 5.0 years Improved quality of life Significantly better HRQoL scores in all 8 domains of SF 36 to > 3 years post treatment Improved work productivity Arase Y, et al. Hepatology 2009 Smith Palmer, J, et al. BMC Infectious Diseases,

5 Multiple Direct Antiviral Targets Replication complex RNA and Zn binding Asunaprevir Simeprevir Paritaprevir Grazoprevir Ledipasvir Daclatasvir Ombitasvir Elbasvir NS5A protease NS5A inhibitor Sofosbuvir Dasabuvir Adapted from McGovern et al, Hepatology, 2008;48: HCV Regimen by Genotype IFN Free Regimens Genotype activity 1. Sofosbuvir/Ledipasvir (+/ RBV) 1, 4, 5, 6 2. Sofosbuvir/Daclatasvir (+/ RBV) All (FDA: 1, 3) 3. Sofosbuvir/Simeprevir (+/ RBV) 1, 4 4. Sofosbuvir + RBV 2, 3 5. Ombitasvir/Paritaprevir/r/Dasabuvir (+/ RBV) 1, 4 6. Elbasvir/Grazoprevir (+/ RBV) 1, 4 IFN free option available for all genotypes 2 or more DAA class combine to achieve SVR rates 90% Two regimens backbones : SOF or a PI RBV still important component of many DAA regimens especially those more difficult to treat 5

6 DAA Therapy in Genotype 1 Patients SVR 90% across different most subgroups with DAA combos Ribavirin used to optimize SVR rates in some combos Treatment duration = 8, 12 or 24 weeks Specific treatment influenced by: Presence of cirrhosis, especially Child Pugh class Renal function Comorbidities: eligibility for ribavirin Medications: drug drug interactions Insurer preferred therapy 6

7 HCV DAA Combinations for Genotype 1 Preferred per AASLD Guidance Ombitasvir Paritaprevir/r + Dasabuvir + RBV Elbasvir Grazoprevir ±RBV Simeprevir + Sofosbuvir ± RBV Preferred per AASLD Guidance Daclatasvir + Sofosbuvir ± RBV Ledipasvir Sofosbuvir ±RBV SOF/LDV ± RBV for 12 or 24 Wks in GT1 Patients Wk 12 ION 1 SOF/LDV (n = 214) Treatment naive HCV GT1; cirrhosis in SOF/LDV + RBV (n = 217) 15% to 17% per arm SOF/LDV (n = 217) (N = 865) SOF/LDV + RBV (n = 217) Wk 12 Wk 24 Wk 24 SVR ION 2 Treatment experienced HCV GT1; 20% cirrhotics (N = 440) SOF/LDV (n = 109) SOF/LDV + RBV (n = 111) SOF/LDV (n = 109) SOF/LDV + RBV (n = 111) ION 1 and 2: no difference in outcomes according to cirrhosis status, type of treatment failure Afdhal et al. N Eng J Med 2014;370: ; Afdhal et al. N Engl J Med 2014;370:

8 Treatment of Patients with Cirrhosis with LDV/SOF 12 vs 24 Weeks in Compensated Cirrhotics: Pooled Analysis SIRIUS Study Overall SVR12 Total Treatment Naïve 96% 98% 95% Treatment Experienced Duration Regimen Duration/ ± RBV 12 wk 24 wk LDV/SOF LDV/SOF + RBV LDV/SOF 12 wk LDV/SOF + RBV 12 wk LDV/SOF 24 wk LDV/SOF + RBV 24 wk 95% 97% 94% 98% 99% 98% 95% 96% 95% LDV/SOF+RBV LDV/SOF 12 Weeks 97% 24 Weeks 99% 96% 92% 96% 90% 96% 98% 96% 98% 97% 98% 100% 100% 100% SVR12, % Rates of SVR12 with LDV SOF for 8 Weeks GT 1, no cirrhosis, treatment naïve, HCV VL <6 million IU/mL* 97% 95% 98% 99% 100% 98% 97% SVR12 (%) ION 3 Study* TRIO Cohort HCV- TARGET GECCO 172 IFI/ 202Buggisch VA-Ohio Overall Real World Experience * A small % of patients in each real-life cohort did not meet all these criteria; GECCO cohort included 28% HIV/HCV coinfected Kowdley KV, et al. N Engl J Med 2014;370: ; Curry M, et al AASLD 2015; Terrault N, et al AASLD 2015; Buggisch P, et al. AASLD 2015; Christensen, et al. AASLD 2015; Marshall et al. AASLD

9 Underutilization of LDV SOF for 8 Weeks in Patients Who Qualify 8 wks eligible but received 12 wks 42% 60% 50% N=1014 N=808 N=131 N=192 N=254 N=456 Backus L, AASLD 2015,bstract 93 Terrault, AASLD 2015, Abstract 94 Curry M, AASLD 2015, Abstract 1108 HCV TARGET: SVR12 with LDV/SOF Therapy by Subgroups Includes patients receiving 8 (n=154), 12 (n=627), 24 (n=161) and other (n=27) week of therapy OR:2.5 SVR12: SVR at 12 (±1) weeks post treatment Terrault N, et al AASLD

10 Baseline NS5A RAVs and SVR *LDV RAVs at 24, 28, 30, 31, 32, 58, and cutoff SVR12 (%) The largest impact of RAVs on treatment outcome was observed in treatment experienced patients (and no ribavirin) SVR12 to guideline recommended regimens of LDV/SOF by LDV RAV* status Zeuzem S. #91 AASLD Real World Safety and Effectiveness of OBV/PTV/r ± DSV ± RBV in HCV GT1 and 4 German Hepatitis C Registry Safety population: started treatment (N=1017) Effectiveness population: completed treatment with post treatment F/U data available or discontinued treatment (N=558) Completed follow up (N=543) Without cirrhosis With cirrhosis Treatment Experienced 96% (46/48) in TVR/BOC experience SAE in (21/1017) 2.1% = more frequent in those receiving RBV Total bilirubin Grade 2 was rare in patients without cirrhosis (6% to 7% in patients with cirrhosis) Elevations in ALT or AST were infrequent in all groups Hinrichsen H, EASL 2016 GS07 10

11 TRIO: Factors Influencing SVR in Real World Practice 100% 80% 94% 97% 78% 91% HCV Target: Efficacy of SMV SOF ± RBV 94% n = 1685 p= % p= % p=0.949 age <65 (n=1191) age 65+ (n=492) Female (n=710) Male (n=975) Non African American (n=259) African American (n=1019) 88% 60% SVR 40% Relapse 3 DC 3 LTFU 6 p< p=0.198 p=0.598 p=0.249 Relapse 6 DC 4 LTFU 16 Death 2 Sulkowski M Gastroenterology 2016;150: p=0.386 Academic (n=718) Community (n=967) HIV Co infection (n=107) No HIV Co infection (n=1551) Post Transplant (n=46) No Post Transplant (n=1588) GT1a (n=1128) GT1b (n=482) <6MM IU/ml (n=1317) 6MM+ IU/ml (n=356) 20% p< p< Platelet<100K/ml (n=170) Platelet 100K+/ml (n=1320) Cirrhosis (n=504) No Cirrhosis (n=1138) 0% 1432/ /76 32/41 43/47 LDV SOF LDV SOF±RBV SMV SOF OBV/PTVr/ DBV ±RBV p=0.194 p= % 70% 80% 90% 100% TE (n=640) TN (n=1029) LDV SOF (n=1521) LDV SOF+RBV (n=76) SMV+SOF+/ RBV (n=41) VKP+/ RBV (n=47) Afdhal N, AASLD 2015, LB17 Grazoprevir/Elbasvir (GZR/EBR): No Real World Results Yet Most recently approved DAA combo for genotype 1 Treatment duration weeks C EDGE: Treatment naive Patients, (%) / / 157 All Patients GT 1a GT 1b No Cirrhosis Cirrhosis Baseline resistance associated substitutions guide use of ribavirin and duration of therapy in G 1A patients 129/ / / 70 Zeuzem S, Ann Intern Med ( on 24APR15. 11

12 Integrated Analysis of the Prevalence and Impact of Baseline NS5A RAVs in Patients Treated with EBR GZR Jacobson I, AASLD 2015, LB 22 Prevalence of NS5A RAVs = 20% EBR RAVs=~5% TN/relapsers EBR RAVs=~10% if TE non responders GT1B: minimal impact of baseline EBR RAVs GT1A: 12 wks EBR/GZR 16/18 wks EBR/GZR + RBV Treatment of GT 1 HCV in the Real World What Have We Learned? Efficacy mirrors that in clinical trials * With exception of SMV/SOF, all approved regimens appear to achieve SVR rates 90% Subgroups at higher risk of treatment failure seen across real world cohorts Cirrhosis, especially if prior decompensation Treatment experienced Sub genotype 1A New predictors of relapse are emerging: PPI use, baseline RAVs * From Soriano V, AIDS Rev

13 A More Difficult Group: Genotype 3 Sofosbuvir containing regimens SOF RBV SOF RBV IFN SOF DCV (Daclatasvir) ± RBV SVR Rates by Treatment Regimen No Cirrhosis VALENCE ALLY 3 BOSON Not head to head comparisons Nelson DR, et al. Hepatology 2015;61: ; Zeuzem S, et.al. NEJM 2014;370: ; Foster GR, et.al.gastroent.2015;149:

14 SVR Rates by Treatment Regimen With Cirrhosis VALENCE ALLY 3 BOSON ALLY 3+ Not head to head comparisons Nelson DR, et al. Hepatology 2015;61: ; Zeuzem S, et.al. NEJM 2014;370: ; Foster GR, et.al.gastroent.2015;149: Real World Experience of SOF + DCV ± RBV in Patients with GT3 Cirrhosis DCV/SOF DCV/SOF/RBV 23/ 33 4/4 116/ / 48 6/7 5/7 36/ 42 24/ 26 18/ 21 Most patients treated for 24 wks No clear evidence of benefits from adding RBV DCV Competing risk of dying makes interpretation difficult 12/ 12 23/ 28 17/ 21 Welzel T, AASLD 2015, Abstract 37; Hezode C, A206 AASLD

15 Genotype 3: Role of Baseline RAVs ALLY 3: SOF + DCV for 12 weeks Y93H detected in 9% of patients at baseline SVR 54% overall in this group 7/13 6/9 1/4 Nelson D, Hepatology 2015;61: Key Points: Genotype 3 Genotype 3 is currently the most difficult to cure genotype SOF/DCV for 12 wks in non cirrhotics achieves >90% SVR; preferred over SOF/RBV for 24 wks Presence of baseline Y93H reduces SVR: add RBV Cirrhotics are more challenging, need to add RBV; SVR rates ~80 85% Benefits of RBV plus extension less clear If decompensated cirrhosis, adding RBV and extend to 24 weeks best strategy Still room to improve on SVR rates 15

16 ERSD/Renal Failure Decompensated Cirrhosis DAA Failures Guidance for Renal Impairment Recommendations if CrCl 30 ml/min No dosage adjustment needed for: DCV LDV/SOF OBV/PTV/r OBV/PTV/r + DSV SMV SOF EBR/GZP Recommendations if CrCl < 30 ml/min or ESRD* GT subtype Regimen Duration GT1a, 1b or 4 GZR/EBR 12 wks GT1b OBV/PTV/r + DSV 12 wks GT2, 3, 5 or 6 PEG IFN + dose adjusted RBV (200 mg/d) * Not recommended/approved for use in decompensated cirrhosis AASLD, IDSA, IAS USA. Recommendations for testing, managing, and treating hepatitis C. Updated 2/24/16. 16

17 Efficacy of Approved DAAs in Genotype 1 Patients with Stage 4 5 CKD, Including Dialysis Ombitasvir/paritaprevir/r + dasabuvir (GT1B) + RBV (GT1A) for 12 wks, non cirrhotic RUBY 1 Elbasvir/grazoprevir for 12 wks, G1, only 6% cirrhosis C SURFER 1 relapse 6 discontinued (not due to AE) 9/13 anemia requiring dose reduction None discontinued 1 death 1 relapse 115/ /122 Pockros P, Gastroenterology Mar 11. Roth D, Lancet 2015;386: Spectrum of Advanced HCV Disease Concurrent evaluation for liver transplant Compensated cirrhosis Child Pugh A MELD <10 No portal hypertensive complications Decompensated cirrhosis Child Pugh B Less severe portal HT MELD>10 Decompensated cirrhosis Child Pugh C Severe/refractory portal hypertensive complications MELD typically >20 Risk of dying of liver related complications 17

18 Drug Options More Limited in Decompensated Cirrhosis DAAs Sofosbuvir ± Ledipasvir Primary Metabolic Pathway Suitable in Patients With Cirrhosis CP A CP B CP C Suitable if Renal Impairment Renal Yes Yes Yes Not if CrCl < 30 ml/min Daclatasvir Hepatic Yes Yes Yes Yes, but not studied in dialysis Simeprevir Hepatic Yes No No Not if CrCl < 15 ml/min Ombitasvir/Pari taprevir/r Hepatic Yes No No Yes but not if dialysis Dasabuvir Hepatic Yes No No Yes but not if dialysis Elbasvir/grazop revir Hepatic Yes No No Yes Ribavirin Renal Yes Yes Yes Yes, adjusted Bifano M, et al. AASLD Abstract Garimella K, et al. Clin Pharm P43. Sofosbuvir [package insert]. Simeprevir [package insert]. Khatri A, et al. AASLD Abstract 758. German et al. AASLD Abstract 467. Kirby R, et al. 8th International Workshop on Clinical Pharmacology of Hepatitis Therapy PO20 SVR Rates are Lower in Patients with CP C versus CP B Cirrhosis LDV SOF + RBV (for 12 or 24 weeks) in decompensated cirrhotics Genotypes 1 and % 81% 80 SVR12 (%) relapses 3 deaths 6 relapses 9 deaths 20 0 CPT B CPT C Overall: 96/108 75/91 GT1: 91/102 73/86 GT4: 5/6 2/5 Gane E, APASL

19 SOF + DCV plus RBV for Decompensated Cirrhosis: ALLY 1 N=48 Child Pugh Class 67% CP B 33% CP C G1 4 included (71% G1) 60% Rx experienced MELD range % MELD >15 Median RBV dose 445 mg/day CP B 398 mg/day CP C 10 relapses No deaths 30/32 22/24 3/3 9/16 5/10 2/3 Poordad F. Hepatology Jan 11. Sofosbuvir/Velpatasvir for HCV Patients With Decompensated Liver Disease: ASTRAL 4 Week n=75 n=75 n=75 SOF/VEL SOF/VEL+RBV SOF/VEL HCV GT 1 6 patients with CPT B cirrhosis Randomized to once daily, oral, FDC SOF 400 mg/vel 100 mg ± RBV SVR12 SVR12 Patients (%) N= SVR Overall GT 1 GT 3 GT 2, 4, 6 GT1 GT3 GT2,4, 6 Relapse VBT 1 1 Death/LTFU Charlton M, AASLD 2015: LB #13 19

20 Safety of DAA Therapy in Patients with Decompensated Cirrhosis Overall, DAAs appear to be safe and AEs consistent with clinical sequelae of advanced liver disease, RBV toxicity Ribavirin associated anemia is common and more problematic to manage: best to start with 600 mg daily Difficult to determine if DAAs increases risk of adverse events as majority of studies are uncontrolled In few controlled studies, AEs predicted by severity of liver disease and not treatment per se Saxena V, Hepatology, 2015 Lactic acidosis occurred in 5/35 (14%) patients during therapy, while no event of lactic acidosis was observed prior to therapy Welker T J Hepatol 2016 Is There a Point of No Return? Probably Insufficient time to improve Inability to recovery/reverse Some clues: Older age regenerative capacity? Significant portosystemic shunting? Severity of liver synthetic dysfunction: CP C? Need better tools to assess regenerative/repair capacity 20

21 What is the Timeline for Improvement in Patients with Decompensated Cirrhosis? 247 patients with decompensated cirrhosis who achieved SVR12 CPT score change from baseline to 24 Weeks sost Cure in CPT B/C patients CPT Class improved in 40% (72/180) CPT B patients CPT Class improved in 76% (51/67) CPT C patients 64% (43/67) improved to CPT B; 12% (8/67) improved to CPT A Gane E, APASL 2016 Improved Clinical Status of DAA Treated Patients on Waiting List Leads to Delisting French multicenter cohort study Complete response: Tbili <2, PT<1.2, albumin<3.5 + no ascites or HE Partial response: change in CP class No response Cirrhosis N=53 Cirrhosis N=77 36% 36% 28% 72% Child A 21% Child B 25% Child C LT N=24 (31%) Delisting N=14 (18%) Improve ment N=12 (16%) Mean follow up: 68 wks (12 95) Other* N=2 (3%) Coilly A, AASLD 2015, Abstract 95 21

22 Challenges with Treating Decompensated Cirrhosis Antiviral options are more limited Protease inhibitors contraindicated Concurrent renal dysfunction may limit use of sofosbuvir SVR rates with DAA therapy in decompensated cirrhosis (CP B/C) are generally lower than in compensated cirrhosis (CP A) Benefits of therapy are great but competing risk of dying before attaining benefits Drug toxicity Viral resistance Other New Concerns 22

23 Drug Toxicities: Continued Vigilance October 22, 2015 Prospective study from France, N=415 5 cases of severe arrhythmias (1.3%) All occurred within days of starting SOF 3 had pacemaker placed 1 recurred on re challenge Coadministration of sofosbuvir and amiodarone is not recommended reports of symptomatic bradycardia and a fatal cardiac arrest Ombitasvir paritaprevir ritonavir ± dasabuvir in cirrhotics hepatic decompensation, need for LT and death Most cases occurred within one to four weeks of drug initiation Some of the cases occurred in patients for whom these medicines were contraindicated or not recommended Lactic acidosis in Cirrhotics Treated with Ribavirin/Sofosbuvir N=35 patients with advanced fibrosis/cirrhosis treated with various SOF/RBV containing regimens 16 CP A, 12 CP B/C; 8 post transplant Pre treatment During treatment SAEs 43% 34% Infectious complications 16% 21% De novo or worsening 49% 39% decompensation Renal complications 11% 21% Lactic acidosis* 0% 14% *Lactic acidosis more frequent in those with advanced cirrhosis and/or renal dysfunction Welker M, J Hepatol 2016, in press 23

24 DAA Failures: Conceptual Framework for Treatment Success vs. Failure Sarrazin C, J Hepatol 2016;64: Impact of Multiple Negative Predictors on SVR Retrospective analysis of phase2/3 studies of SOF+RBV+/ PEG >850 patients, genotypes 1, 2 and 3 Treatment experienced Cirrhosis HCV RNA Male >75kg IL28B non CC Baseline RAVs Foster G. EASL

25 Differing Rates of RAV Persistence Post Therapy Median time to disappearance of NS3 RAVs = ~8 months Majority of NS5A RAVs remain detectable at 2 years Soriano V, AIDS Rev Not All RAVs are Created Equal Fold change in EC50 1a 1b Position M28T Q30R L31M/V Y93H/N L31V Y93H/N Ledipasvir 20x >100x Ombitasvir >1000x >100x Daclatasvir >100x >1000x Elbasvir 20x >100x >100x/ >100x >1,000x/ >10,000 <3x >10,000x/ >100x >10,000x >100x/ >1000x Velpatasvir <10x <3x 20x/50x >1,000x/ >10,000x >10x >1,000x/ >100x >1,000x 100x/ >1000x 20X >100x/? <10x 20x/50x <10x 20x/50x <10x >100x/ <3x/ <3x/ Cross resistance at positions Q30R, L31M/V, Y93H/N (G1A) >100 fold change appears to be clinically significant Cross resistance and persistence over time limits use of NS5A inhibitors in retreatment regimens Wang C. AAC Cheng G. #1172. EASL Zhao Y. #A845 EASL Yang G. EASL Ng T. #639 CROI

26 Presence of NS5A RAVs Associated with Retreatment Failure SOF/LDV N=41 SVR weeks Failed SOF/LDV 8 12 wks Regimen SVR: >94% Cirrhosis: 46% NS5A RAVs: 73% SVR12 (%) 29/4 1 11/1 18/ /5 4/5 2/6 Lawitz E. #O005 EASL 2015 General Approach to Patient Who Has Failed DAA Therapy How urgent is retreatment? Virologic evaluation Exclude genotype shift Exclude HCV reinfection Assess for RAVs Strategic plan: add RBV, use non cross resistance drug class, extend treatment Genotypic Resistance Testing No RAVS NS5A RAVs alone (even if Q80K) NS3 RAVs (R155, A156, D168) 2 RAV Classes As treatmentexperienced SOF + SMV + RBV 24 weeks SOF/LDV or DCV + RBV 24 wks Defer retreatment 26

27 SOF + DCV + SMV for CP A/B Cirrhosis IMPACT Study HCV RNA, median CP A, N=19 CP B N= ( ) 5.60 ( ) % TE 47% 48% HCV Genotype 1A/ (NS3 Q80K) 1B 4 79% (60%) 16% 5% 52% (30%) 48% 0 % non CC IL28B 79% 86% MELD < >15 63% 37% 0 48% 43% 10% 1/3 of CP B had hyperbilirubinemia but no other evidence of hepatotoxicity SMV exposure: 2.2 fold higher in CP B than A No early discontinuations or deaths SVR12 19/19 21/21 Change in CP Score with Treatment Lawitz E, AASLD 2015, Abstract 39 Treatment of Elbasvir/Grazoprevir Failures with EBR/GZR + SOF + RBV X 12 Wks C SWIFT RETREATMENT N=25 GT1 patients who failed a prior short course (4 8wks) Mean time from virologic failure to retreatment = 214 days (range ) SVR12* * *Including: NR5A: N=4 Y93C/H/N NS3: n=1 D168E AEs related to RBV Dose reductions in 2 patients for anemia No ALT elevations *Excludes 2 patients lost to follow up at day 3 and week 4 Lawitz E, AASLD 2015, LB12 27

28 Summary: DAA Failures and Resistance DAA resistance is common among those failing therapy Patients failing in clinical practice may have other (multiple) negative predictors Treatment approach Confirm genotype and RAVs presence DAA failures need: Choose drugs without cross resistance RBV and/or extending treatment Waiting for more data and/or better therapies may be best option for many Alternatives and/or New Drug Combos Looking to the Future 28

29 The Ideal HCV Therapy Desirable characteristics Pangenotypic No ribavirin Short duration No side effects Low cost One-Pill-a-Day ASTRAL 1: Phase 3 Sofosbuvir/Velpatasvir for 12 weeks SVR12 Rates by HCV Genotype 1 relapse 2 LTFU 1 WC 1 relapse 1 death 618/624 Total 206/ / / /116 34/35 41/41 1a 1b LTFU = lost to follow up; WC = withdrew consent Genotype Feld J, LB 2 29

30 Another Pangenotypic DAA Combo: ABT ABT 530 ± RBV for 8 Weeks SURVEYOR I and II Genotypes 1 and 2: TN and TE 97% 98% 97% Genotype 3: TN 100% 100% SVR12 (%) SVR12 (%) Genotype 1 (n=34) All patients non cirrhotic No virologic failures Genotype 2 (n=54) No RBV No Cirrhosis 8 Weeks (n=29) No RBV (n=24) Cirrhosis 12 Weeks RBV (n=24) Muir AJ, et al. J Hepatol. 2016;64(suppl 2):S186. Abstract PS098. Kwo PY, et al. J Hepatol. 2016;64(suppl 2):S208. Abstract LBO1. Poordad F, et al. J Hepatol. 2016;64(suppl 2):S768. Abstract SAT-157. PI GZR/MK EBR or MK 8408/for 8 Wks in GT1 3 Patients, Treatment Naïve, No Cirrhosisks C CREST, Phase 2 NS5B polymerase inhibitor NS5A inhibitors Gane E, AASLD 2015, LB15 30

31 Conclusions Currently approved drugs achieve SVR rates in clinical practice similar to that of clinical trials Large real life cohorts are identifying the factors associated with treatment failure Availability and success of therapies in traditional and new special populations : ESRD, decompensated cirrhosis, PWID More intense scrutiny of the impact of baseline and treatmentemergent RAVs on SVR rates Small but important studies on treatment strategies Exciting drug pipeline that is focused on attaining DAA combinations that are pangenotypic, safe, high efficacy AND short duration Novel solutions to address enhance awareness, diagnosis and linkage to care first steps on the cascade of care Thank you 31