Studies Suggest Ribavirin Does Not Work by Causing Excessive HCV Mutation By
Liz Highleyman
Research
clearly demonstrates that the addition of ribavirin improves the efficacy of interferon-based
therapy for hepatitis C virus (HCV) infection,
but it is not completely clear how the drug works against the virus.
One
theory is that ribavirin increases the rate of HCV mutation to such an extent
that the virus is rendered unfit and unable to continue replicating, a phenomenon
known as "error catastrophe." Two recently published studies, however,
shed doubt on this hypothesis.
Study
1
In
the first study, reported in the May 2007 issue of Gastroenterology, researchers
sought to determine if conserved regions of the HCV NS5B polymerase mutate during
ribavirin therapy. The study included 31 patients with genotype 1 chronic hepatitis
C participating in a randomized, placebo-controlled trial who were assigned to
receive ribavirin or placebo for 48 weeks; after 48 weeks, patients in the placebo
arm were offered open-label ribavirin for an additional 48 weeks.
HCV
RNA was extracted from paired, stored serum samples at day 0 and at week 24 during
the randomized phase, and at weeks 48, 52, and 72 during the cross-over (open-label)
phase. The entire NS5B region was sequenced and mutation rates were calculated.
Results
• During the randomization
phase, there was no significant increase in the number of NS5B region mutations
or the mutation rate at week 24 between the ribavirin- and placebo-treated patients
(6.6 vs 4.3 x 10-3 per site/y, respectively; P = 0.4).
•
No mutations were observed in conserved regions of NS5B.
•
In the cross-over group, an increase in the mutation rate was observed
at week 4 in patients who switched from placebo to ribavirin, but this was no
longer apparent at week 24.
Conclusion
"Ribavirin
therapy is associated with an early, transient increase in the mutation rate of
HCV," the authors concluded. However, they added, "Lethal mutagenesis
and error catastrophe is unlikely to be the sole mechanism of action of ribavirin
during therapy for chronic hepatitis C.
Study
2
In the
second study, reported in the May 9, 2007 advance online edition of the Journal
of Virology, investigators sought to test the hypothesis that ribavirin administration
accelerates the accumulation of mutations in the HCV genome only when HCV replication
is profoundly inhibited by co-administration of interferon.
They
performed an extensive sequence-based analysis of 2 independent genomic regions
of HCV in patients receiving ribavirin monotherapy and those treated with ribavirin
plus interferon alfa either daily or 3 times per week.
Results
• Ribavirin monotherapy did
not increase the rate of variation of the consensus sequence, the mutation frequency,
the error-generation rate, or the between-sample genetic distance.
•
Compared with the pre-treatment period, the accumulation of nucleotide
substitutions did not accelerate during combination therapy with ribavirin plus
interferon.
• This
remained true even when viral replication was profoundly inhibited by interferon.
Conclusion
The
authors of this study also concluded that the outcome "strongly undermines
the hypothesis whereby ribavirin acts as an HCV mutagen in vivo.
06/29/07
References
G
Lutchman, S Danehower, BC Song, and others. Mutation Rate of the Hepatitis C Virus
NS5B in Patients Undergoing Treatment With Ribavirin Monotherapy. Gastroenterology
132(5): 1757-1766. May 2007.
AS
Perelson and TJ Layden. Ribavirin: Is It a Mutagen for Hepatitis C Virus? [Editorial].
Gastroenterology 132(5): 2050-2052. May 2007.
S.
Chevaliez, R Brillet, F Lazaro, and others. Analysis of Ribavirin Mutagenicity
in Human Hepatitis C Virus Infection. Journal of Virology. May 9, 2007
[Epub ahead of print].
