Mutation rate of the hepatitis C virus NS5B in patients undergoing treatment with ribavirin monotherapy.
OBJECTIVE
Error catastrophe from an increase in mutation rate may be a possible mechanism of action of ribavirin in chronic hepatitis C (CHC). We sought to evaluate the mutagenic potential of ribavirin in vivo and to determine if conserved regions of hepatitis C virus (HCV) NS5B are mutated during ribavirin therapy.


METHODS
Thirty-one patients with CHC genotype 1 who participated in a randomized, placebo-controlled trial of ribavirin for 48 weeks were studied. After 48 weeks, patients on placebo were crossed-over to open-label ribavirin for 48 weeks. Viral RNA was extracted from paired, stored sera at day 0 and week 24 during the randomized phase and weeks 48, 52, and 72 during the cross-over phase. The entire NS5B region was sequenced and the mutation rates were calculated.


RESULTS
An increase in mutation rate was observed after 4 weeks (4.4 x 10(-2) vs 2.1 x 10(-3) per site/y, P = .02) but not after 24 weeks (4.0 x 10(-3) vs. 5.5 x 10(-3) per site/y, P = .1) in patients who crossed over to ribavirin. Similarly, during the randomized phase no increase in the number of mutations or the mutation rate was observed at week 24 between the ribavirin- and placebo-treated patients 6.6 vs 4.3 x 10(-3) per site/y, respectively (P = .4). No mutations were observed in conserved regions of NS5B.


CONCLUSIONS
Ribavirin therapy is associated with an early, transient increase in the mutation rate of HCV. Lethal mutagenesis and error catastrophe is unlikely to be the sole mechanism of action of ribavirin during therapy for CHC.
Lutchman
Glen
G
Liver Diseases Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1800, USA.
Danehower
Susan
S
Song
Byung-Cheol
BC
Liang
T Jake
TJ
Hoofnagle
Jay H
JH
Thomson
Michael
M
Ghany
Marc G
MG
D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004279:DNA, Viral / Q000235:genetics; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016296:Mutagenesis / Q000187:drug effects*; D012254:Ribavirin / Q000627:therapeutic use*; D013997:Time Factors; D017361:Viral Nonstructural Proteins / Q000187:drug effects / Q000235:genetics*; D014764:Viral Proteins / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D004279:DNA, Viral; D012254:Ribavirin; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase