The French and European Approach Towards Hepatitis C Virus Elimination HEPDART 2017 USA December 3rd, 2017 Tarik Asselah (MD, PhD) Professor of Medicine Hepatology, Chief INSERM UMR 1149, Hôpital Beaujon, Clichy, France. Disclosures • Employee of Paris Public University Hospitals (AP-H P, Beaujon’s Hospital) and University of Paris • Principal investigator for research grants : Funds paid to Hospital (AP-HP) • Consultant, expert and speaker for: Abbvie, Bristol-Myers Squibb, Gilead, Janssen, Merck Sharp Dohme, Roche. • Grants from : ANR, CNRS , INSERM , University of Paris, ANRS 2 The French and European Approach Towards Hepatitis C Virus Elimination The goal of this lecture will be to present the situation of HCV in Europe and in France. Direct-acting antivirals with excellent efficacy and favourable safety, represent a unique opportunity to achieve HCV elimination. We will discuss the European & French approach towards Hepatitis Programs and to identify models to achieve Elimination. The French and European Approach Towards Hepatitis C Virus Elimination 1 Great Drugs (Direct-acting antivirals) 2 Epidemiology : Europe & France 3 HCV management : Europe & France 4 Remaining Challenges 5 Take home messages Direct-acting antivirals : a Revolution 5’NTR Structural proteins Nonstructural proteins 3’NTR Metalloprotease Envelope Serine protease RNA Capsid glycoproteins RNA helicase Cofactors polymerase C E1 E2 NS1 NS2 NS3 NS4A NS4B NS5A NS5B Protease Inhibitors NS5A Inhibitors Polymerase Inhibitors « …previr » « ….asvir » « …..buvir » Telaprevir Daclatasvir Nucs Non-Nucs Boceprevir Ledipasvir Simeprevir Velpatasvir (GS-5816) Sofosbuvir Dasabuvir Paritaprevir Ombitasvir MK 3682 GS-9669 Glecaprevir Pibrentasvir ACH-3422 MK-8876 Grazoprevir Elbasvir ALS-335 Voxilaprevir MK-8408 Sovaprevir Samatasvir ACH-2684 Odalasvir (ACH-3102) Asselah et al. Liver Int 2016; 36; S1:47-57. O H3CO O H H H H3C O F F O N N NH H CH3 N O O O O N N N O N N H C NH O 3 N N N N N N O O HN P O N H O H O H O O HN O SOF O CH3 LDV H3CO VEL OCH3 VOX HO F SOF/LDV SOF/VEL SOF + RBV ± RBV SOF/VEL/VOX ± RBV 12–24 weeks 8†–24 12 weeks 12 weeks weeks Jan 2014 May 2014 Sept 2014 Nov 2014 Jan 2015 July 2016 July 2017 SOF + SMV SOF + DCV GRZ/EBV OMV/PTV/RTV ± RBV ± RBV ± RBV GLE/PIB ± DSV ± RBV 12–24 12–24 12–16 8–12 weeks 12–24 weeks weeks weeks weeks PTV GLE SMV DCV GRZ EBV PIB OMV DSV PIB Asselah, Marcellin & Schinazi. Liver Int 2018, in press. Priorities for Direct-acting antivirals SVR > 95% Top Priorities Safety Tolerability Pangenotypic: High barrier to resistance Short duration; Low pill burden Minimal drug–drug interactions Access/cost Schinazi & Asselah. From HCV to HBV cure. Liver Int. 2017;37 S1:73-80. Priorities for Direct-acting antivirals SVR > 95% Top Priorities Safety Tolerability High barrier to resistance Short duration; Low pill burden Secondary Minimal drug–drug interactions Priorities Pan-genotypic Access/cost Schinazi & Asselah. From HCV to HBV cure. Liver Int. 2017;37 S1:73-80. SOF/VEL (Epclusa®) for 12 weeks is highly effective across all genotypes (ASTRAL-1, ASTRAL-2 and ASTRAL-3) 2 relapses 11 2 LTFU 1 D/C relapses 1 death 1 D/C 2 D/C SVR12 (%) SVR12 1015/ 323/ 237/ 264/ 116/ 34/ 41/ 1035 328 238 277 116 35 41 • 2% of patients experienced one or more SAE; no SAEs were considered study drug related • 2 patients discontinued treatment due to AEs Agarwal K, et al. EASL 2016; Poster #SAT-195; AE: adverse event; D/C: discontinuation; LTFU: lost to follow-up; SAE: serious adverse event Jacobson I, et al. EASL 2016; Poster #SAT-168 SOF/VEL (Epclusa®) for 12 weeks is highly effective in patients with advanced fibrosis and cirrhosis (ASTRAL 1, 2 & 3) 98 99 96 100 80 (%) 60 40 490/ 278/ 212/ Patients Patients with SVR 20 501 281 220 0 Overall Advanced Cirrhosis fibrosis Asselah T, et al. Liver Int 2017;doi: 10.1111/liv.13534 Glecaprevir/Pibrentasvir (Maviret) in Patients with HCV GT1, 2, 4-6 Infection with or without Compensated Cirrhosis MAVIRET for 8 Weeks in MAVIRET for 12 Weeks in TN/TE NC Patients: TN/TE CC Patients: ENDURANCE-1 and SURVEYOR-2 EXPEDITION-1 98 99 98 100 100 99 99 100 100 100 100 100 93 80 60 383 193 177 387 197 186 SVR12 (%) SVR12 40 20n 596 348 193 43 2 10 145 89 31 16 2 7 N 606 351 197 46 2 10 146 90 31 16 2 7 0 Overall GT1 GT2 GT4 GT5 GT6 Overall GT1 GT2 GT4 GT5 GT6 BT 1 1 Relapse 2 2 1 1 Non-VF* 7 2 2 3 All analyses are using the ITT population. TN, treatment-naïve; TE, treatment-experienced with IFN or pegIFN ± RBV, or SOF + RBV ± pegIFN; NC, non-cirrhotic; CC, compensated cirrhotic; ITT, intent-to-treat; BT, breakthrough; VF, virologic failure. *Includes patients who discontinued due to adverse events, lost to follow-up, or withdrew. MAVIRET Summary of Product Characteristics; Accessed August 2017. Asselah T, et al. Clin Gastroenterol Hepatol. 2017 Glecaprevir/Pibrentasvir (Maviret) in Patients with HCV GT3 Infection with or without Compensated Cirrhosis MAVIRET for 8 or 12 Weeks in MAVIRET for 12 Weeks in TN CC TN NC Patients: Patients, or 16 Weeks in TE NC/CC ENDURANCE-3 Patients: SURVEYOR-2 Part 3 95 95 97 98 100 100 96 80 80 60 60 40 40 SVR12 (%) SVR12 (%) 20n 149 222 111 20n 39 66 N N 0 157 233 115 0 40 69 MAVIRET1 MAVIRET2 DCV 3+ SOF TNTN CCCC TETE, NC/CC NC/CC 8 weeks 12 weeks 12 weeks 12 weeks 16 weeks BT 1 1 BT 1 Relapse 5 3 1 Relapse 2 Non-VF* 2 7 3 Non-VF* 1 All analyses are using the ITT population. TN, treatment-naïve; TE, treatment-experienced with IFN or pegIFN ± RBV, or SOF + RBV ± pegIFN; BT, breakthrough; CC, compensated cirrhosis; NC, noncirrhotic; DCV, daclatasvir; ESRD, end-stage renal disease; SOF, sofosbuvir; TE, treatment experienced; TN, treatment naive; VF, virologic failure. *Includes patients who discontinued due to adverse events, lost to follow-up, or withdrew. MAVIRET Summary of Product Characteristics; Accessed August 2017. Elbasvir/Grazoprevir (Zepatier): Efficacy in Different Patient Populations Phase 3 studies vs placebo 99 10 100 96 96 94 97 94 % 0 , 80 Overall mFASa 60 Treatment- SVR12 rates from experienced 40 the Phase 3 clinical SVR12 Achieving trial program 20 299 115 189 100 210 97 104 103 104 Patients Patients 312 116 198 106 217 0 Stage 4-5 OAT/PWID Comorbidity - IBLD ± HIV HIV ± HIV ± HIV CKD ± HIV Genotypes 1,4,6 1 1,4,6 1,4 1,4,6 1,4,6 1,4,6 Treatment Experience TN TN/PR-PTF TN TN/PR-PTF TN PR-PTF PR-PTF 16 Weeks 12 Weeks EBR/GZR Without RBV EBR/GZR + RBV amFAS excludes patients who failed for reasons unrelated to study medication. EBR/GZR = elbasvir/grazoprevir; SVR12 = sustained virologic response 12 weeks after the cessation of treatment; CKD = chronic kidney disease; OAT = opioid agonist therapy; PWID = people who inject drugs; IBLD = inherited blood disorders; TN = treatment naive; HIV = human immunodeficiency virus; TE = treatment experienced; RBV = ribavirin; PR = peginterferon + ribavirin; PTF = prior-treatment failure; mFAS= modified full analysis set. 1. Roth D et al. Lancet. 2015;386:1537–1545. 2. Dore GJ et al. EASL 2016, SAT-163. 3. Hezode C et al. EASL 2016, SAT-128. 4. Zeuzem S et al. Ann intern Med. 2015;163:1–13. 5. Rockstroh JK et al. Lancet HIV. 2015;2:e319–e327. 6. Kwo P et al. Gastroenterology. 2017;152:164–175. Tools for HCV screening • Enzyme immunoassays (EIAs) – Anti-HCV antibodies – HCV core antigen • Point-of-care (POC) tests – Rapid diagnostic tests (RDTs) – Molecular tests • Dried blood spot (DBS) The French and European Approach Towards Hepatitis C Virus Elimination 1 Great Drugs (Direct-acting antivirals) 2 Epidemiology : Europe & France 3 HCV management : Europe & France 4 Remaining Challenges 5 Take home messages Estimated 70 Million Persons Living With HCV Prevalence (Viremic) 0% to < 0.6% 0.6% to < 0.8% 0.8% to < 1.3% 1.3% to < 2.9% 2.9% to < 6.7% Polaris Observatory HCV Collaborators. Lancet Gastroenterol Hepatol. 2017;2:161-176. Policies for HCV elimination Total Viremic Infections by Country (2015) Angelos Hatzakis PHC 2017 Virus Diversity : The prevalence of the 6 different HCV genotypes varies across countries in Europe Italy Czech Republic Germany Poland France Russia GT 1a GT 1b GT 1 other GT 2 UK Romania GT 3 GT 4 GT 5 GT 6 Portugal Hungary Spain Croatia • Gower E, et al. J Hepatol 2014;61:S45–57 • GT: genotype Patient’s Diversity, Prevalence of comorbidities Patient’s Diversity, Prevalence of comorbidities Alcohol: A Major Medical Need Alcohol Consumption in France Worldwide : Diagnosis and treatment rates Estimated chronic HCV prevalence, diagnosis rate and treatment rate in 2013 6 France 5 Germany Austria 4 England Sweden 3 Czech Republic Treatment rate (%) rate Treatment Egypt Spain 2 Canada Turkey Switzerland 1 Belgium Australia Portugal Denmark Brazil 0 0 20 40 60 80 100 Diagnosis rate (%) Dore GJ, et al. J Viral Hepat 2014;21(Suppl 1):1–4 Note: size of bubble depicts viraemic HCV prevalence Worldwide : Diagnosis and treatment rates Estimated chronic HCV prevalence, diagnosis rate and treatment rate in 2013 6 France 5 Germany Austria 4 England Sweden 3 Czech Republic Treatment rate (%) rate Treatment Egypt Spain 2 Canada Turkey Switzerland 1 Belgium Australia Portugal Denmark Brazil 0 0 20 40 60 80 100 Diagnosis rate (%) Dore GJ, et al.