Gene expression profile may predict response to
peginterferon plus ribavirin in chronic hepatitis C
By Jillian L Lokere, MS
June 12, 2005
The expression profile of a subset of 8
interferon-responsive genes appears to predict whether a
patient with chronic HCV infection will respond to
peginterferon plus ribavirin therapy, according to a small
Canadian study.
Peginterferon plus ribavirin treatment results in a
sustained virologic response in 50% to 80% of patients with
chronic hepatitis C. Although treatment is expensive and
produces significant side effects, currently the only way to
determine if a patient will respond is to initiate therapy and
look for an early virologic response at 12 weeks. In this
study, Chen and colleagues decided to test the idea that
genome-wide gene expression profiling would reveal differences
between responders and nonresponders.
A total of 31 chronic hepatitis C patients from the
University Health Network, University of Toronto, Ontario,
Canada, were enrolled in the study. Patients were
treatment-naive, and were considered candidates for
peginterferon and ribavirin treatment. Patients underwent
liver biopsy before beginning treatment. Serum HCV RNA levels
were determined at baseline, at the completion of therapy, and
6 months after completion of therapy. Patients were considered
nonresponders if HCV RNA was detectable at the end of
treatment or if HCV RNA was undetectable at the end of
treatment but reappeared at the 6-month follow-up.
The 23 patients with genotype 1 infection and 1 patient
with genotype 6 infection were treated with peginterferon
alfa-2a 180 μg once weekly plus ribavirin 800-1200 mg daily
for 48 weeks. The remaining 7 patients infected with genotype
2/3 infection were treated with the same dosages for 24
weeks.
Total RNA was extracted from a liver biopsy sample from
each patient and from 20 healthy controls. Messenger RNA was
then amplified and used to conduct a microarray analysis on
human single-spot microarrays with 19,000 human genes. Any
differential gene expression found between responders and the
nonresponders was confirmed using real-time polymerase chain
reaction (PCR).
At the end of therapy, 16 patients were responders and 15
were nonresponders; all of the nonresponders were infected
with genotype 1. The gene expression analysis revealed that 18
genes differed significantly between responders and
nonresponders. Most of the differences were an upregulation of
gene expression in the nonresponders.
Using a cluster analysis technique, the investigators found
a subset of 8 genes that could consistently classify responder
and nonresponder samples. The expression levels of this gene
subset were able to correctly identify 29 of 31 samples as
responder or nonresponder.
These 8 genes are all responsive to interferon, which,
according to the investigators, suggests "that the
nonresponder patients have adopted a different, yet
characteristic, equilibrium in their host-virus immune
response."
Reference
Chen L, Borozan I, Feld J, et al. Hepatic gene expression
discriminates responders and nonresponders in treatment of
chronic hepatitis C viral infection. Gastroenterology.
2005;128:1437-1444.