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Original article

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 Hazzan, Yaakov Maor, Abu Moch Saif, Ohad Etzion, Yoav Lurie, Ella Mendelson, Orna Mor

Corresponding author name: Orna Mor
Corresponding author e-mail:

doi: 10.3851/IMP3301


Background: Direct-acting antiviral (DAA) therapy has dramatically increased sustained virologic response rates (SVR) in hepatitis C (HCV)-infected patients. However, resistance-associated substitutions (RAS) interfering with NS3- and NS5A-targeted therapy, still emerge. This real-life study analyzed the type and frequency of RAS in rare cases of patients failing DAA regimens in 12 clinical centers 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 GT1b strain, while 12.2% (6/49) carried GT1a and 16.3% GT3a/b (6) 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 genotype and DAA in patients failing therapy or those with more than two-fold 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 4 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 DAAs failure, when cost related and suboptimal regimens must be employed.


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