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

Antivir Ther. 2019;24(3):221-228. doi: 10.3851/IMP3301.


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.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology*
  • Antiviral Agents / therapeutic use
  • Drug Resistance, Viral*
  • Drug Therapy, Combination
  • Female
  • Genotype
  • Hepacivirus / drug effects*
  • Hepacivirus / genetics*
  • Hepatitis C / diagnosis
  • Hepatitis C / drug therapy
  • Hepatitis C / epidemiology*
  • Hepatitis C / virology*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Israel / epidemiology
  • Male
  • Middle Aged
  • Prevalence
  • Retreatment
  • Sequence Analysis, DNA
  • Treatment Failure
  • Viral Nonstructural Proteins / genetics


  • Antiviral Agents
  • Viral Nonstructural Proteins