Screening for hepatitis C virus non-nucleotide resistance mutations in treatment-naive women

J Antimicrob Chemother. 2009 Nov;64(5):945-8. doi: 10.1093/jac/dkp328. Epub 2009 Sep 18.

Abstract

Objectives: Hepatitis C virus (HCV) non-nucleoside inhibitors (NNIs) target the viral RNA-dependent RNA polymerase encoded by the NS5B gene. Several NNIs share a similar allosteric binding site, and their antiviral efficacy is attenuated by a cysteine-to-tyrosine mutation at amino acid 316 (C316Y). In the current study, we assessed NS5B resistance mutations in treatment-naive individuals from a prospective natural history study of viral infections in women.

Methods: Partial NS5B sequences from HCV-positive women were amplified by RT-PCR. Additionally, subcloning was performed to evaluate intrapatient variability in selected samples.

Results: HCV NS5B genotypes were 45 genotype 1a (57.0%), 11 genotype 1b (13.9%), 5 genotype 2a (6.3%), 3 genotype 2b (3.8%), 9 genotype 3a (11.4%) and 6 genotype 4a (7.6%). One HCV genotype 1a-infected patient was found to have the C316Y mutation (1.3%). Clonal analysis further revealed that all NS5B sequences from this individual--representing three serum samples collected 4 years apart--contained the C316Y mutation. In contrast, the S282T resistance mutation was not found in any samples.

Conclusions: The C316Y polymerase resistance mutation was found in 1.3% of samples from HCV-infected women. The presence of this mutation over time suggests significant replicative fitness of this variant and has implications for development of new specifically targeted antiviral therapies against HCV (STAT-C) targeting this region.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Antiviral Agents / pharmacology*
  • Cloning, Molecular
  • DNA Mutational Analysis
  • Drug Resistance, Viral*
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Hepacivirus / drug effects*
  • Humans
  • Molecular Sequence Data
  • Mutation, Missense*
  • RNA, Viral / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Alignment
  • Viral Nonstructural Proteins / antagonists & inhibitors
  • Viral Nonstructural Proteins / genetics*

Substances

  • Antiviral Agents
  • Enzyme Inhibitors
  • NS-5 protein, hepatitis C virus
  • RNA, Viral
  • Viral Nonstructural Proteins