title: Deep sequencing reveals mutagenic effects of ribavirin during monotherapy of hepatitis C virus genotype 1-infected patients.
abstract: The preeminent mode of action of the broad-spectrum antiviral nucleoside ribavirin in the therapy of chronic hepatitis C is currently unresolved. Particularly under contest are possible mutagenic effects of ribavirin that may lead to viral extinction by lethal mutagenesis of the hepatitis C virus (HCV) genome. We applied ultradeep sequencing to determine ribavirin-induced sequence changes in the HCV coding region (nucleotides [nt] 330 to 9351) of patients treated with 6-week ribavirin monotherapy (n = 6) in comparison to placebo (n = 6). Baseline HCV RNA levels maximally declined on average by -0.8 or -0.1 log10 IU/ml in ribavirin- versus placebo-treated patients. No general increase in rates of nucleotide substitutions in ribavirin-treated patients was observed. However, more HCV genome positions with high G-to-A and C-to-U transition rates were detected between baseline and treatment week 6 in ribavirin-treated patients in comparison to placebo-treated patients (rate of 0.0041 transitions per base pair versus rate of 0.0022 transitions per base pair; P = 0.049). Similarly, the sensitive detection of low-frequency minority variants by statistical filtering indicated significantly more positions with G-to-A and C-to-U transitions in ribavirin-treated patients than in placebo-treated patients (rate of 0.0331 transitions versus rate of 0.0186 transitions per G/C-containing position at baseline; P = 0.018). In contrast, non-ribavirin-associated A-to-G and U-to-C transitions were not enriched in the ribavirin group (P = 0.152). We conclude that ribavirin exerts a mutagenic effect on the virus in patients with chronic hepatitis C by facilitating G-to-A and C-to-U nucleotide transitions.
authors.affiliation: Department of Internal Medicine 1, J. W. Goethe University Hospital, Frankfurt, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Dietz
authors.forename: Sven-Eric
authors.initials: SE
authors.lastname: Schelhorn
authors.forename: Daniel
authors.initials: D
authors.lastname: Fitting
authors.forename: Ulrike
authors.initials: U
authors.lastname: Mihm
authors.forename: Simone
authors.initials: S
authors.lastname: Susser
authors.forename: Martin-Walter
authors.initials: MW
authors.lastname: Welker
authors.forename: Caterina
authors.initials: C
authors.lastname: Füller
authors.forename: Martin
authors.initials: M
authors.lastname: Däumer
authors.forename: Gerlinde
authors.initials: G
authors.lastname: Teuber
authors.forename: Heiner
authors.initials: H
authors.lastname: Wedemeyer
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.forename: Thomas
authors.initials: T
authors.lastname: Lengauer
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.forename: Eva
authors.initials: E
authors.lastname: Herrmann
authors.forename: Christoph
authors.initials: C
authors.lastname: Sarrazin
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D001483:Base Sequence; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000187:drug effects*; D011446:Prospective Studies; D012254:Ribavirin / Q000627:therapeutic use*
chemical_list: D000998:Antiviral Agents; D012254:Ribavirin
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