Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection

N Engl J Med. 1996 Jan 11;334(2):77-81. doi: 10.1056/NEJM199601113340203.


Background: A region associated with sensitivity to interferon has been identified in the nonstructural protein 5A (NS5A) of hepatitis C virus (HCV) genotype 1b. The region spans amino acid residues 2209 to 2248 (NS5A2209-2248) of HCV-J, a strain of HCV-1b whose complete genomic sequence has been identified. We examined whether the NS5A2209-2248 sequence present before therapy could be used as a predictor of the response to interferon therapy in patients with chronic HCV-1b infection.

Methods: We retrospectively analyzed 84 patients with chronic HCV-1b infection who had received interferon alfa (total dose, 516 million to 880 million units) for six months. Pretreatment serum samples were analyzed. The amino acid sequence of NS5A2209-2248 was determined by direct sequencing of the HCV genome amplified by the polymerase chain reaction (PCR) and was compared with the established sequence for HCV-J.

Results: A complete response, as evidenced by the absence of HCV RNA in serum on nested reverse-transcription PCR for six months after therapy, did not occur in any of the 30 patients whose NS5A2209-2248 sequences were identical to that of HCV-J (wild type). Five of 38 patients (13 percent) with 1 to 3 changes in NS5A2209-2248 (intermediate type) had complete responses, as did all 16 patients with 4 to 11 amino acid substitutions (mutant type), indicating that the mutant type was significantly associated with a complete response (P < 0.001). Although baseline serum HCV RNA levels, as measured by a branched-chain DNA assay, were lower in patients with the mutant type of NS5A2209-2248 than in those with the other types (P < 0.001), multivariate analyses revealed that the number of amino acid substitutions in NS5A2209-2248 was the only variable associated with an independent effect on the outcome of interferon therapy (odds ratio, 5.3; 95 percent confidence interval, 1.6 to 18; P = 0.007).

Conclusions: In patients with chronic HCV-1b infection, there is a substantial correlation between responses to interferon and mutations in the NS5A gene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Chronic Disease
  • Female
  • Hepacivirus / classification
  • Hepacivirus / genetics*
  • Hepacivirus / isolation & purification
  • Hepatitis C / therapy
  • Hepatitis C / virology*
  • Humans
  • Interferon-alpha / therapeutic use*
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Multivariate Analysis
  • Mutation*
  • RNA, Viral / blood
  • Retrospective Studies
  • Treatment Outcome
  • Viral Nonstructural Proteins / genetics*


  • Interferon-alpha
  • RNA, Viral
  • Viral Nonstructural Proteins