Dysregulation of IFN System Can Lead to Poor Response to Pegylated Interferon and Ribavirin Therapy in Chronic Hepatitis C

PLoS One. 2011;6(5):e19799. doi: 10.1371/journal.pone.0019799. Epub 2011 May 13.

Abstract

Background: Despite being expensive, the standard combination of pegylated interferon (Peg-IFN)-α and ribavirin used to treat chronic hepatitis C (CH) results in a moderate clearance rate and a plethora of side effects. This makes it necessary to predict patient outcome so as to improve the accuracy of treatment. Although the antiviral mechanism of genetically altered IL28B is unknown, IL28B polymorphism is considered a good predictor of IFN combination treatment outcome.

Methodology: Using microarray, we quantified the expression profile of 237 IFN related genes in 87 CH liver biopsy specimens to clarify the relationship between IFN pathway and viral elimination, and to predict patients' clinical outcome. In 72 out of 87 patients we also analyzed IL28B polymorphism (rs8099917).

Principal findings: Five IFN related-genes (IFI27, IFI 44, ISG15, MX1, and OAS1) had expression levels significantly higher in nonresponders (NR) than in normal liver (NL) and sustained virological responders (SVR); this high expression was also frequently seen in cases with the minor (TG or GG) IL28B genotype. The expression pattern of 31 IFN related-genes also differed significantly between NR and NL. We predicted drug response in NR with 86.1% accuracy by diagonal linear discriminant analysis (DLDA).

Conclusion: IFN system dysregulation before treatment was associated with poor IFN therapy response. Determining IFN related-gene expression pattern based on patients' response to combination therapy, allowed us to predict drug response with high accuracy. This method can be applied to establishing novel antiviral therapies and strategies for patients using a more individual approach.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antiviral Agents
  • Drug Therapy, Combination
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects
  • Hepatitis C, Chronic / drug therapy*
  • Humans
  • Interferon alpha-2
  • Interferon-alpha / administration & dosage*
  • Interferon-alpha / pharmacology
  • Interferons / pharmacology
  • Interleukins / genetics
  • Male
  • Middle Aged
  • Pharmacogenetics / methods*
  • Polyethylene Glycols / administration & dosage*
  • Polyethylene Glycols / pharmacology
  • Polymorphism, Genetic
  • Precision Medicine / methods*
  • Predictive Value of Tests*
  • Prognosis
  • Recombinant Proteins
  • Ribavirin / administration & dosage*
  • Treatment Failure
  • Treatment Outcome

Substances

  • Antiviral Agents
  • IFNL3 protein, human
  • Interferon alpha-2
  • Interferon-alpha
  • Interleukins
  • Recombinant Proteins
  • Polyethylene Glycols
  • Ribavirin
  • Interferons
  • peginterferon alfa-2a