Hepatic gene expression discriminates responders and nonresponders in treatment of chronic hepatitis C viral infection.
OBJECTIVE
Pegylated interferon (IFN)-alpha plus ribavirin is the most effective treatment of chronic hepatitis C but has unpleasant side effects and high costs. A large proportion of patients do not respond to therapy for reasons that are unclear. We used gene expression profiling to investigate the molecular basis for treatment failure.


METHODS
Expression profiling was performed on percutaneous needle liver biopsy specimens taken before therapy. Gene expression levels were compared among 15 nonresponder, 16 responder, and 20 normal liver biopsy specimens. Differential gene expression was confirmed using real-time polymerase chain reaction.


RESULTS
We identified 18 genes whose expression differed significantly between all responders and all nonresponders (P < .005). Many of these 18 genes are IFN sensitive and 2 (ISG15/USP18) are linked in a novel IFN-regulatory pathway, suggesting a possible rationale for treatment resistance. Using a number of independent classifier analyses, an 8-gene subset accurately predicted treatment response for 30 of 31 patients. The classifier analyses were applicable to patients with genotype 1 infection and were not correlated with viral load, disease activity, or fibrosis.


CONCLUSIONS
Hepatic gene expression profiling identified consistent differences in patients who subsequently fail treatment with pegylated IFN-alpha plus ribavirin: up-regulation of a specific set of IFN-responsive genes predicts nonresponse to exogenous therapy. These data may be of use in predicting clinical responses to treatment.
Chen
Limin
L
Banting and Best Department of Medical Research, University of Toronto, Ontario, Canada.
Borozan
Ivan
I
Feld
Jordan
J
Sun
Jing
J
Tannis
Laura-Lee
LL
Coltescu
Catalina
C
Heathcote
Jenny
J
Edwards
Aled M
AM
McGilvray
Ian D
ID
D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage*; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage*; D008099:Liver / Q000473:pathology / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D011994:Recombinant Proteins; D012254:Ribavirin / Q000008:administration & dosage
D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C100416:peginterferon alfa-2a