Mutagenic effect of ribavirin on hepatitis C nonstructural 5B quasispecies in vitro and during antiviral therapy.
OBJECTIVE
Addition of ribavirin to interferon alfa treatment has substantially increased sustained virologic response rates in patients with chronic hepatitis C (CHC). Ribavirin acts as an RNA virus mutagen in vitro, thereby leading to error catastrophe. However, data in CHC are controversial.


METHODS
The nonstructural (NS) 5B quasi-species heterogeneity was analyzed in Huh7 cells harboring a subgenomic hepatitis C virus (HCV) replicon system treated with ribavirin or levovirin. Accordingly, NS5B quasi-species were studied in 14 patients with CHC who received ribavirin alone or combined with pegylated interferon alfa both at baseline and during the first weeks of therapy. Analysis of NS3 quasi-species served as control.


RESULTS
Cultivation of HCV replicon cells with ribavirin led to higher NS5B mutational frequencies compared with levovirin-treated or untreated cells (P < .05). Patients receiving ribavirin monotherapy showed higher overall mutational frequencies within NS3 and NS5B during therapy as compared with baseline (P < .01). Proportions of ribavirin-specific G-to-A and C-to-T transitions increased (P < .01). Paired analysis confirmed significant mean increases of mutational frequencies of approximately 5%. Ribavirin serum concentrations were positively correlated with mutational frequency changes (P < .05). In patients receiving combination therapy, a decrease of NS5B mutational frequencies ( approximately 10%) and lower proportions of G-to-A and T-to-C mutations (P < .01) were detectable.


CONCLUSIONS
Ribavirin, but not its L-enantiomer levovirin, is a mutagen in HCV replicon cells. In patients with CHC, ribavirin monotherapy exhibits a moderate mutagenic effect early during therapy that is not detectable in combination with pegylated interferon alfa.
Hofmann
Wolf Peter
WP
Department of Internal Medicine II, Saarland University Hospital, Homburg, Germany.
Polta
Andreas
A
Herrmann
Eva
E
Mihm
Ulrike
U
Kronenberger
Bernd
B
Sonntag
Tanja
T
Lohmann
Volker
V
Schönberger
Barbara
B
Zeuzem
Stefan
S
Sarrazin
Christoph
C
D000328:Adult; D000998:Antiviral Agents / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000097:blood / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009005:Monosaccharides / Q000494:pharmacology; D009153:Mutagens / Q000494:pharmacology* / Q000627:therapeutic use; D009154:Mutation / Q000187:drug effects*; D012367:RNA, Viral / Q000097:blood; D012093:Replicon / Q000187:drug effects; D012189:Retrospective Studies; D012254:Ribavirin / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D014230:Triazoles / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D016898:Interferon-alpha; D009005:Monosaccharides; D009153:Mutagens; D012367:RNA, Viral; D012254:Ribavirin; D014230:Triazoles; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C502685:levovirin valinate hydrochloride