HCV resistance - From A Virological Perspective Dr. rer. nat. - PowerPoint PPT Presentation

HCV resistance - From A Virological Perspective Dr. rer. nat. Frank Wiesmann PZB Aachen AREVIR-Meeting - Cologne 05.05.2017 t = 25 min www.pzb.de

Disclosures Within the last 5 years I received sponsoring by the following companies Abbvie, BMS, Gilead, Janssen, ViiV www.pzb.de

• Natural Resistance – Overcoming HCV diversity www.pzb.de

a) HCV and Genetic Diversity HCV-specific RNA-dependant polymerase HCV: Up to 40% diversity between genotypes Up to 30% diversity between subtypes www.pzb.de Margeridon-Thermet et al. 2010 El-Shamy A, Hotta H.,World Journal of Gastroenterology 2014; 20(24): 7555-7569

a) Global Distribution of HCV Genotypes www.pzb.de World Health Organization, 2009

a) Milestones in HCV Treatment IFN-free therapy www.pzb.de Adapted Christoph Neuman-Haefelin, 25. Jahrestagung der Paul-Ehrlich Gesellschaft, 06.10.16

a) Natural Resistance – HCV Genotypes • Different genotypes, different virological response www.pzb.de Nelson D, et al. EASL 2013

Viekirax+Dasabuvir www.pzb.de

• Genotype/subtype-dependant differences in response to therapy ⇒ An accurate genotyping/subtyping is crucial www.pzb.de

Genotyping/Resistance Analysis Advantages of genotyping by sequencing (NS5A and NS5B) - Ability to detect subtypes of all genotypes - Ability to predict HCV reinfection with same genotypes - Ability to re-analyze RAS if necessary www.pzb.de

• Detection of primary drug-specific resistance mutations www.pzb.de

b) Resistance-associated Baseline Mutations Genotype 1A Total Prevalence: NS3 <1% NS5A 10,2% NS5B 5,4% 58 155 800 0,5 1675 66740 32 30 261 RF in EC50 3 2 2 3 2 50 8965 2 3 41383 1472 www.pzb.de Krishnan P. et al., EASL 2014, #P1230

b) Resistance-associated Baseline Mutations Genotype 1B No NS3 mutations In this study Total Prevalence: NS5A 30,8% NS5B 40% RF in EC50 0,4 0,9 0,8 0,4 77 229 5 11 316N+556G = 38 (10%) www.pzb.de Krishnan P. et al., EASL 2014, #P1230

• Is there a need for HCV resistance interpretation before initiation of DAA-therapies? www.pzb.de

SVR in Patients with Genotype 1 Infection with and without Baseline-Mutations (Abbvie 3D) Genotype 1a+b Genotype 1a Only 1 Genotype 1b Patient (without Baselinemutations) did not reach SVR www.pzb.de Krishnan P. et al., EASL 2014, #P1230

Resistance-associated Baseline Mutations Genotype 1 treated with (SOF/LDV) N=1765 www.pzb.de Zeuzem S. et al., Journal of Hepatology 2017, #P1230

• What do the guidelines say? www.pzb.de

EASL Guidelines 2016 Gt DAA combination Setting Best possible Best possible treatment with NS5A treatment without RAS knowledge NS5A knowledge 1a Sofosbuvir/Ledipasvir Therapy-experienced 12 weeks 12 weeks + RBV but DAA-naive 1a Grazoprevir/Elbasvir naive&experienced 12 weeks 16 weeks + RBV (>800.000 IU/ml] 1a Sofosbuvir/Daclatasvir Therapy-experienced 12 weeks 12 weeks + RBV but DAA-naive 3 Sofosbuvir/Velpatasvir compensated cirrhosis 12 weeks 12 weeks + RBV (no Y93H) www.pzb.de www.easl.eu

• How long do Resistance-Associated Variants persist under/after therapy? www.pzb.de

c) HCV resistance develops fast under monotherapy - Resistant variants develop fast under monotherapy - Resistant quasispecies are detectable for a long time after stop of treatment www.pzb.de Sarrazin C, et al. Gastroenterology 2007; 132:1767-77

Mono- vs Dual- vs Triple-DAA ABT-450 ABT-450 ABT-267 ABT-267 ABT-333 ABT-333 10X EC 50 10X EC 50 1 active drug (10 5 cells) (10 5 cells) Frequency of Frequency of >1% >1% ~ 0.5% ~ 0.5% >1% >1% resistant colonies resistant colonies ABT-450 + ABT-450 + ABT-450 + ABT-450 + ABT-267 + ABT-267 + ABT-267 ABT-267 ABT-333 ABT-333 ABT-333 ABT-333 10X + 10X EC 50 10X + 10X EC 50 2 active drugs (10 6 cells) (10 6 cells) Frequency of Frequency of 0.0027% 0.0027% 0.0011% 0.0011% 0.0045% 0.0045% resistant colonies resistant colonies 5X + 5x + 5X + 5x + 10X + 10x + 10X + 10x + 5X EC 50 5X EC 50 10X EC 50 10X EC 50 ABT-450 + ABT-267 + ABT-450 + ABT-267 + 3 active drugs ABT-333 ABT-333 (10 6 cells) (10 6 cells) Frequency of resistant Frequency of resistant < 0.0001 % < 0.0001 % < 0.0001 % < 0.0001 % colonies colonies Pilot-Matias et al. Poster 867, EASL 2012 www.pzb.de

Saphire-I: Resistenz-associated Variants At Time of Therapy Failure (3D+RBV) N=473 62.5% with 3-class resistance www.pzb.de Feld J., EASL 2014

Persistance of NS3 Resistance Mutations • Loss of detectable resistance mutations in patients with resistant variants at *1 *2 therapy failure (TVR + pegIFN/RBV) 1.0 0.8 V36M + R155K (n = 124) R155K Probability alone(n = 41) 0.6 0.4 V36M alone (n = 22) 0.2 0 0 2 4 6 8 10 12 14 16 18 Months after therapy failure R155K alone *1 V36M alone V36M + R155K % 1a Therapy Failure 10 20 46 Median Months until loss 6 (4-9) 10 (9-13) 13 (10-13) 1. Sullivan J, et al. EASL 2011. Abstract 8. 2. Liverton N. et al. EASL 2010. www.pzb.de

>96 weeks=82% Wyles et al. et al. , EASL 2015, Abstract O059 www.pzb.de

Persistance of resistant HCV Transmission Therapy Resistant Virus ? After Months/Years Still minor knowledge about transmission www.pzb.de

• Does a resistance test guide decisions in patients with prior failure of DAA-based therapy? www.pzb.de

RASs www.pzb.de

Lawitz et al. et al. , EASL 2015, Abstract O005 www.pzb.de

Real-World Data (European Resistance Database) Persons failing on DAA-therapy in clinical trials (N=310) www.pzb.de Vermehren J. et al., EASL 2016, Abst. PS103

Real-World Data (European Resistance Database) www.pzb.de Vermehren J. et al., EASL 2016, Abst. PS103

• Future treatment options after DAA-failure www.pzb.de

Milestones in HCV Treatment IFN-free therapy 2017/2018 - 8 weeks - One-pill regimen / no RBV - Price reduction - Use in dialysis - Therapies after DAA failure - pangenotypic www.pzb.de Adapted Christoph Neuman-Haefelin, 25. Jahrestagung der Paul-Ehrlich Gesellschaft, 06.10.16

Treatment Options after DAA-failure www.pzb.de

Selection of most recent clinical trials SOF/VEL/VOX POLARIS-1 [1] 12 wks for NS5A inhibitor experienced GT1-6 HCV PBO POLARIS-2 [2] 8 wks for DAA-naive GT1-6 HCV SOF/VEL POLARIS-3 [3] 8 wks for cirrhotic GT3 HCV SOF/VEL SOF/VEL POLARIS-4 [4] 12 wks for DAA-experienced (no NS5A inhibitors) GT1-6 HCV GLE/PIB GLE/PIB ENDURANCE-1 [5] 8 or 12 wks for noncirrhotic pts with GT1 HCV PBO ENDURANCE-2 [6] 12 wks for noncirrhotic pts with GT2 HCV ENDURANCE-4 [7] 12 wks for noncirrhotic pts with GT4-6 HCV None SURVEYOR-II/3 [8] 12 or 16 wks for pts with GT3 HCV ± tx exp ± cirrhosis GLE/PIB EXPEDITION-IV [9] 12 wks for pts with GT1-6 HCV and stage 4/5 CKD None MK-3682/GZR/RZR C-CREST Part B [10] 8/12/16 wks ± RBV for GT1-3 HCV ± tx exp ± cirrhosis MK-3682/GZR/RZR C-CREST Part C [11] 16 wks + RBV for 8-wk MK-3682/GZR/(RZR or EBR) failures None C-SURGE [12] 16 or 24 wks ± RBV for GT1 HCV pts relapsing on DAAs MK-3682/GZR/RZR Future treatment 8-16 weeks irrespective of genotype, disease status and therapy experience www.pzb.de

MAGELLAN-1, Part 2: Glecaprevir/Pibrentasvir Demonstrates Promising Activity in Patients With Genotype 1 or 4 HCV Infection Who Failed Previous DAA Therapy 56% Poordad F et al., EASL 2017, PS 156 www.pzb.de

Voxilaprevir/Sofosbuvir/Velpatasvir Sarrazin et al., EASL 2017, THU-248 www.pzb.de

Grazoprevir/Uprifosbuvir/Ruzasvir Wedemeyer et al., EASL 2017, PS-159 www.pzb.de

Conclusion • HCV Resistance occurs frequently but is rarely clinically significant (SVR >90%) • Patients with viral breakthrough or Relapse show in almost every case development of viral resistance • Drug-recycling is theoretically possible particularly in combination with additional substances (RBV, IFN or other DAAs) • Limited knowledge / often individual cases • Resistance mutations detected after therapy failure disappear in general after stop of therapy until wildtype-Variants dominate the viral population. This process can take months/years. • Many additional pan-genotypic treatment options are expected to come up in the following year for treatment of patients with prior DAA-failure www.pzb.de

Thank you for your attention! www.pzb.de