The impact of treatment emerging resistance associated substitutions on outcomes of re-treatment using new generation HCV treatments: Nation-wide real-world analysis

Yael Gozlana, Efrat Bucrisa, Rachel Shirazia, Avia Rakovskya, Ziv Ben-Arib,c, Ella Veizmand , Tarek Saadid, Helena Katchmanc,f, Oren Shiboletc,f, Ehud Zigmondc,f, Yoram Menachemc,f, Marius Braunc,e, Michal Cohen- Naftalyc,e, Amir Shlomaic,e, Rawi Hazzank, Yana Davidovb, Rifaat Safadih, Eitan Galung, Eli Zuckermanh, Assy Nimerj,i, Yaakov Maorl, Abu Moch Saifm, Ohad Etzionn, Yoav Lurieo, Ella Mendelsona,c, Orna Mora,c

aCentral Virology Laboratory, Ministry of Health, , ; bLiver Disease Center, Sheba Medical Center, Ramat- Gan, Israel; cThe Sackler School of Medicine, University, Tel Aviv, Israel; dLiver Unit, Rambam Medical Center, , Israel; eLiver Institute, , , Israel; fDepartment of Gastroenterology, Tel-Aviv Medical Center, Tel Aviv, Israel; gLiver Unit, , , Israel; hLiver Unit, Carmel Medical Center, Haifa, Israel; iFaculty of Medicine in the , Bar- Ilan University, , Israel; jInternal Medicine Department, , , Israel; kLiver Unit, Haemek Medical Center, , Israel; lThe Institute of Gastroenterology and Hepatology, , . The Hebrew University Faculty of Medicine, Jerusalem.; mLiver Unit, Hillel Yaffe Medical Center, , Israel; nDepartment of Gastroenterology & Liver Diseases, Soroka University Medical Center, Beer Sheva, Israel; oLiver Unit, Shaare Zedek Medical Center, Jerusalem, Israel.

INTRODUCTION RESULTS All patients treated Table 1: Demographics of patients failing DAAs N=? The revolution in HCV treatment options results in >95% GT1a Patients failing DAAs (N=65) GT1b sustained virological response (SVR). Resistance associated DAA Failures GT1d Gender N=65 substitutions (RAS) mark the rare cases of HCV patients who fail Males, N (%) 43 (66) GT3a second-generation direct-acting antivirals (DAAs). Previously, Females, N (%) 22 (34) GT3b at: presented Poster SOF+ VEL/ VEL+VOX/ GT4a Birth place N (%) GRZ+/-EBV DCV+/- ASV OBV/PTV/r/DSV GLE/PIB using both population and next-generation sequencing (NGS) DCV/ LDV/ SIM Misclassified Israel 14 (22) N=13 N=3 N=18 N=1 N=28 technologies, we have reported that 86% (42/49) of treatment Former USSR 34 (52) Romania 5 (7.6) failures in Israel harbor RAS. Here we expanded this cohort of RAS detected RAS detected RAS detected RAS detected RAS detected India 2 (3.1) N=23 (82%) second-generation DAA treatment failures attempting to assess N=12 (92%) N=2 (67%) N=12 (67%) N=1 (100%) Morocco 2 (3.1) Figure 2: HCV genotypes identified in 65 DAA the rate of re-treatment success. Switzerland 1 (1.5) Figure 1: Flow chart describing patients’ included in this study failures. Germany 1 (1.5) This postUnknowner was6 (9.2)not submitted by the author AIM Table 2: Number and frequency of NS3 and NS5A RAS 120 Patient 1 Patient 2 100 GT 1b, oncology DAA Target RAS/ Genotype Frequency GT 3, F4 patient, F4 NS3 D168V/E/G/A/N 15/49 )30.6%( The purpose of this study was to investigate the influence of 80 3/3 3/3 5/5 1a 3/15 )20%( 15/17 treatment-emerging RAS on re-treatment outcome in real life. st st

SVR 60 1 : SOF/LED 1 : SOF/LED, 12/15 )80%(

1b % Non-responder Relapse (?) NS5A L31I/M/V 21/65 )32.3%( 40 RAS: Y93H in NS5A RAS: Y93 in NS5A 1a 2/21 )10%( 20 1b 17/21 )80%( 2nd: SOF/VEL 2nd: SOF/VEL/VOX+RIB 1d 1/21 )5%( 0 Non-responder Relapse 1/21 )5%( SOF/VEL+/-VOX G/P, GRZ/ELB+/-SOF, SOF/LDV RAS: Y93H in NS5A RAS: Y93H in NS5A METHOD 4a DAA NS5A Y93H/C/N Between September 2015 and February 2019, 65 patients were 38/65 )58.5%( No relevant RAS With relevant RAS 1a 4/38 /11%( reported to have failed DDA treatment in Israel. Failure was 1b 29/38 )76%( determined as follows: Figure 3: Outcome of DAAs re-treatment with and without RAS. N=28. Clinically Figure 4: Description of two patients’ who failed re- 3a 5/38 )13%( relevant RAS were determined according to Sorbo et. al 2018 treatment 1. No response to treatment

2. Viral relapse following successful end of treatment. 3. Viral breakthrough during treatment CONCLUSIONS REFERENCES CONTACT INFORMATION 4. Shortening treatment duration RAS are common in second-generation treatment failures Gozlan Y, Bucris E, Shirazi R, Rakovsky A, Ben-Ari Z, Davidov Y, Veizman E, Saadi T, Braun M, Cohen-Naftaly M, Shlomai A, Shibolet O, Zigmond E, Samples from all these treatment failures were collected. NGS

Viral hepatitis Viral [email protected] Gozlan Yael (49/65, 75%). However, SVR rates of patients re-treated with Katchman H, Menachem Y, Safadi R, Galun E, Zuckerman E, Nimer A, Hazzan and/or population sequencing analysis of NS5A and NS3 third-generation therapies is high. Assessment of RAS in R, Maor Y, Saif AM, Etzion O, Lurie Y, Mendelson E, Mor O. High frequency of multiclass HCV resistance-associated mutations in patients failing direct- proteins was performed. RAS and HCV genotypes were Orna Mor Ph.D., MBA Director, National HIV reference DAA failures (using either NGS or population sequencing) acting antivirals: real-life data. Antivir Ther. 2019;24(3):221-228. laboratory head, clinical virology laboratory. determined using Geno2Pheno HCV algorithm. Follow-up clinical could still be beneficial in reducing length, cost and Sorbo MC, Cento V, Di Maio VC, Howe AYM, Garcia F, Perno CF, et al. Hepatitis Public health services, Israel ministry of health Chaim Sheba data (including subsequent treatment regimen and treatment C virus drug resistance associated substitutions and their clinical relevance: simplification of re-treatment. medical center, Israel. Tel: 972-50-6242639; 972-3-5302458 Update 2018. Drug Resist Updat. 2018 Mar;37:17-39. P03-05 outcome) was also collected. VHC2020