High frequency of multiclass HCV resistance-associated mutations in patients failing direct-acting antivirals: Real-life data

Yael Gozlan, Efrat Bucris, Rachel Shirazi, Avia Rakovsky, Ziv Ben-Ari, Yana Davidov, Ella Veizman, Tarek Saadi, Marius Braun, Michal Cohen-Naftaly, Amir Shlomai, Oren Shibolet, Ehud Zigmond, Helena Katchman, Yoram Menachem, Rifaat Safadi, Eitan Galun, Eli Zuckerman, Assy Nimer, Rawi HazzanYaakov Maor, Abu Moch Saif, Ohad Etzion, Yoav Lurie, Ella Mendelson, Orna Mor

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Background: Direct-acting antiviral (DAA) therapy has dramatically increased sustained virological response rates in HCV-infected patients. However, resistance-associated substitutions (RAS) interfering with NS3- and NS5A-targeted therapy, still emerge. This real-life study analysed the type and frequency of RAS in rare cases of patients failing DAA regimens in 12 clinical centres in Israel. Methods: Blood samples and clinical data from 49 patients who failed various DAAs were collected. RAS identified in the NS3 and NS5A regions by population (Sanger) and next-generation sequencing (NGS) were compared by treatment regimen and HCV subtypes. Results: The majority (71.4%, 35/49) of patients were infected with the genotype (GT)1b strain, while 12.2% (6/49) carried GT1a and 14.3% GT3a/b (7), GT4a (1) and GT1b/GT3a. RAS were identified in 85.7% (42/49) of failures, of which 90.5% (38/42) were clinically relevant RAS (known to be associated with a specific GT and DAA in patients failing therapy or those with more than twofold change in in vitro replicon assays). The most abundant RAS were 168A/E/Q/G/N/V (32.6%, 16/49) identified in NS3, and 93H/N (61.2%, 30/49), 31I/M/V (34.7%, 17/49) and 30R/H/K (12.2%, 6/49), identified in NS5A. Significantly more clinically relevant RAS were identified in NS5A (82.2%, 37/45) than in NS3 (35.7%, 10/28; P<0.01). While RAS were identified in all GT1a, GT3b and GT4a failures (100%, 10/10), only 71.8% (28/39) of GT1b or GT3a failures had RAS (P=0.09). In four cases, NGS identified additional clinically relevant RAS and in one patient, NGS deciphered coexistence of GT3a and GT1b infections. Conclusions: Our findings, together with additional real-life data, will contribute to the optimization of retreatment in DAA failure, when cost-related and suboptimal regimens must be employed.

Original languageEnglish
Pages (from-to)221-228
Number of pages8
JournalAntiviral Therapy
Issue number3
StatePublished - 2019

Bibliographical note

Publisher Copyright:
© 2019 International Medical Press 1359-6535 (print) 2040-2058 (online)


This study was supported by the Israel Association for the Study of the Liver Young Investigator Grant 2016 to YG and OM.

FundersFunder number
Israel Association for the Study


    Dive into the research topics of 'High frequency of multiclass HCV resistance-associated mutations in patients failing direct-acting antivirals: Real-life data'. Together they form a unique fingerprint.

    Cite this