Prevalence of NS5A resistance associated substitutions in patients with hepatitis C virus genotypes 1a and 3: Impact on current therapeutic strategies

J Med Virol. 2018 Jun;90(6):1094-1098. doi: 10.1002/jmv.25048. Epub 2018 Mar 12.

Abstract

The presence of resistance-associated substitutions (RASs) at NS5A region might compromise the efficacy of Direct Acting Antiviral agents (DAAs). HCV resistance at NS5A region is mainly focused on patients with hepatitis C virus (HCV) genotypes 1a (G1a) and 3 (G3) with other factors of poor treatment response (ie cirrhosis, prior treatment-exposure, or HCV-RNA >800 000 IU/mL). Herein, we evaluated in a cohort of HCV G1a and G3 infected patients the prevalence of RASs at domain I NS5A using population-based sequencing and the impact of RASs on the optimization of current therapeutic strategies. The RASs considered as clinically relevant were: M28A/G/T, Q30D/E/H/G/K/L/R, L31M/V/F, H58D, and Y93C/H/N/S for G1a and Y93H for G3. A total of 232 patients naïve to NS5A inhibitors were included (166 G1a, 66 G3). The overall prevalence of NS5A RASs for G1a and G3 patients was low (5.5%) or null, respectively. A high proportion of patients harbored, at least, one factor of poor response (78.9% for G1a, and 75.8% for G3). Overall, the rates of patients harboring NS5A RASs in combination with any of the other factors were low and the vast majority of patients (G1a> 94% and G3 100%) could be treated with standard treatments of 12 weeks without ribavirin. In conclusion, testing NS5A RASs in specific HCV-infected populations (ie G1a & G3, cirrhosis, prior treatment experienced, HCV-RNA >800 000 IU/mL) might be useful to optimize current NS5A-based therapies avoiding ribavirin-related toxicities, and shortening treatment duration in the majority of patients.

Keywords: HCV-infection; NS5A; RASs; genotype 1a; genotype 3.

Publication types

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

MeSH terms

  • Adult
  • Amino Acid Substitution
  • Antiviral Agents / pharmacology
  • Antiviral Agents / therapeutic use*
  • Drug Resistance, Viral*
  • Follow-Up Studies
  • Genotype*
  • Hepacivirus / classification
  • Hepacivirus / drug effects
  • Hepacivirus / genetics*
  • Hepatitis C, Chronic / drug therapy
  • Hepatitis C, Chronic / virology*
  • Humans
  • Male
  • Middle Aged
  • Mutant Proteins / genetics
  • Mutation, Missense*
  • Prevalence
  • Ribavirin / pharmacology
  • Ribavirin / therapeutic use
  • Sequence Analysis, DNA
  • Viral Nonstructural Proteins / genetics*

Substances

  • Antiviral Agents
  • Mutant Proteins
  • Viral Nonstructural Proteins
  • Ribavirin
  • NS-5 protein, hepatitis C virus