Sequence variation in hepatitis C virus nonstructural protein 5A predicts clinical outcome of pegylated interferon/ribavirin combination therapy

Hepatology. 2008 Jul;48(1):38-47. doi: 10.1002/hep.22339.


A substantial proportion of hepatitis C virus (HCV)-1b-infected patients still do not respond to interferon-based therapy. This study aims to explore a predictive marker for the ultimate virological response of HCV-1b-infected patients treated with pegylated interferon/ribavirin (PEG-IFN/RBV) combination therapy. Nonstructural protein 5A (NS5A) sequences of HCV in the pretreated sera of 45 patients infected with HCV-1b were analyzed. The mean number of mutations in the variable region 3 (V3) plus its upstream flanking region of NS5A (amino acid 2334-2379), referred to as IFN/RBV resistance-determining region (IRRDR), was significantly higher for HCV isolates obtained from patients who later achieved sustained virological response (SVR) by PEG-IFN/RBV than for those in patients undergoing non-SVR. The receiver operating characteristic curve analysis estimated six mutations in IRRDR as the optimal threshold for SVR prediction. Indeed, 16 (76%) of 21 SVR, but only 2 (8%) of 24 non-SVR, had HCV with six or more mutations in IRRDR (IRRDR > or = 6) (P < 0.0001). All of 18 patients infected with HCV of IRRDR of 6 or greater examined showed a significant (> or =1 log) reduction or disappearance of serum HCV core antigen titers within 24 hours after initial dose of PEG-IFN/RBV, whereas 10 (37%) of 27 patients with HCV of IRRDR of 5 or less did (P < 0.0001). The positive predictive value of IRRDR of 6 or greater for SVR was 89% (16/18; P = 0.0007), with its negative predictive value for non-SVR being 81% (22/27; P = 0.0008).

Conclusion: A high degree (> or =6) of sequence variation in IRRDR would be a useful marker for predicting SVR, whereas a less diverse (< or =5) IRRDR sequence predicts non-SVR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antiviral Agents / therapeutic use*
  • Consensus Sequence
  • Drug Therapy, Combination
  • Female
  • Genetic Variation*
  • Genotype
  • Hepacivirus / drug effects
  • Hepacivirus / genetics
  • Hepatitis C, Chronic / drug therapy*
  • Humans
  • Interferon alpha-2
  • Interferon-alpha / therapeutic use*
  • Male
  • Middle Aged
  • Mutation
  • Polyethylene Glycols
  • Predictive Value of Tests
  • Recombinant Proteins
  • Ribavirin / therapeutic use*
  • Treatment Outcome
  • Viral Nonstructural Proteins / genetics*


  • Antiviral Agents
  • Interferon alpha-2
  • Interferon-alpha
  • NS-5 protein, hepatitis C virus
  • Recombinant Proteins
  • Viral Nonstructural Proteins
  • Polyethylene Glycols
  • Ribavirin
  • peginterferon alfa-2b