Mutagenic effects of ribavirin and response to interferon/ribavirin combination therapy in chronic hepatitis C☆
Introduction
Ribavirin, a synthetic guanosine analog, has broad antiviral effects against both DNA and RNA viruses. Although ribavirin monotherapy has minimal efficacy on hepatitis C viral (HCV) eradication [1], [2], [3], studies have reported higher sustained response rates following combination therapy with interferon (IFN)-alfa and ribavirin than following IFN-alfa monotherapy [4], [5], [6], [7]. Several mechanisms of action of ribavirin have been proposed [8]. In vitro and animal studies, in particular, have demonstrated that the antiviral activity of ribavirin is exerted through its potent mutagenic effects on RNA viruses after being incorporated into newly synthesized genomes by viral RNA-dependent RNA polymerase (RdRp) [9], [10], [11]. Still, little information is available regarding the mechanisms responsible for the increased virological efficacy associated with concurrent administration of ribavirin and IFN. No clinical studies to date have determined whether ribavirin induces mutations in the clinical setting nor examined the relationship between the mutagenic effects of ribavirin and viral response to IFN/ribavirin combination therapy.
The present study evaluated a set of patients with chronic hepatitis C. To elucidate whether ribavirin acts as a mutagen in the clinical setting, for each subject the sequential nucleotide mutations occurring during ribavirin monotherapy were compared with mutations occurring in the same patient during the non-treatment observation period immediately preceding the initiation of ribavirin monotherapy as a control. The relationship between mutations observed during ribavirin monotherapy and viral response to subsequent IFN/ribavirin combination therapy was also determined.
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Patients
Among patients with biopsy-proven chronic hepatitis C hospitalized at the Musashino Red Cross Hospital from December 2001 to June 2002, 34 patients of HCV genotype 1b with a high viral load (>100 kcopies/ml by Amplicor-HCV monitor assay; Roche Molecular Diag. Co., Tokyo, Japan) were included in the present study (Table 1). Patients with liver cirrhosis, autoimmune hepatitis, and alcoholic liver injury were excluded from the study. No patient was positive for hepatitis B virus-associated
HCV dynamics
During the 4-week period of ribavirin monotherapy, the mean serum HCV-RNA level significantly decreased from 6.90 to 6.56 log10 copy/ml (P<0.0001, paired t test) (Fig. 1). Serum HCV dynamics after the start of subsequent IFN/ribavirin combination therapy demonstrated a biphasic kinetic pattern of HCV-RNA decline. The exponential decay slopes for the first phase and the second phase were 2.00±0.77 log10/day and 0.15±0.14 log10/day, respectively.
The effect of ribavirin on HCV gene mutation and the relationship between mutations and virological response to IFN/ribavirin combination therapy
In a pairwise comparison of the NS5 sequences
Discussion
In the present study, we identified HCV gene mutations occurring during ribavirin monotherapy and found that the mutation rate was associated with the virological response to subsequent IFN/ribavirin combination therapy. Since the mutation rate was significantly higher during ribavirin monotherapy than during non-treatment observation periods in the same patients, at least some of the mutations observed during ribavirin treatment were likely an effect of ribavirin administration. Therefore,
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The authors who have taken part in this study declared that they have not a relationship with the manufacturers of the drugs involved either in the past or present and did not receive funding from the manufacturers to carry out their research. The nucleotide sequences reported in this paper will appear in the DDBJ/EMBL/GenBank with accession numbers AB207766 through AB207801.