Analysis of Ribavirin Mutagenicity in Human Hepatitis C Virus Infection

Abstract

The addition of ribavirin to alpha interferon therapy significantly increases response rates for patients with chronic hepatitis C virus (HCV) infection, but ribavirin's antiviral mechanisms are unknown. Ribavirin has been suggested to have mutagenic potential in vitro that would lead to "error catastrophe," i.e., the generation of nonviable viral quasispecies due to the increment in the number of mutant genomes, which prevents the transmission of meaningful genetic information. We used extensive sequence-based analysis of two independent genomic regions in order to test in vivo the hypothesis that ribavirin administration accelerates the accumulation of mutations in the viral genome and that this acceleration occurs only when HCV replication is profoundly inhibited by coadministered alpha interferon. The rate of variation of the consensus sequence, the frequency of mutation, the error generation rate, and the between-sample genetic distance were measured for patients receiving ribavirin monotherapy, a combination of alpha interferon three times per week plus ribavirin, or a combination of alpha interferon daily plus ribavirin. Ribavirin monotherapy did not increase the rate of variation of the consensus sequence, the mutation frequency, the error generation rate, or the betweensample genetic distance. The accumulation of nucleotide substitutions did not accelerate, relative to the pretreatment period, during combination therapy with ribavirin and alpha interferon, even when viral replication was profoundly inhibited by alpha interferon. This study strongly undermines the hypothesis whereby ribavirin acts as an HCV mutagen in vivo.Hepatitis C virus (HCV) infection is a major cause of chronic liver diseases and a global public health problem. Chronic HCV infection affects more than 170 million individuals worldwide, of whom an estimated 20% have or will develop cirrhosis. Furthermore, the annual risk of progression towards hepatocellular carcinoma is 1% to 4% among patients with cirrhosis (36). The combination of pegylated alpha interferon (IFN-␣) and ribavirin is the current standard treatment for chronic HCV infection. This treatment yields a sustained virological response (SVR), defined by the lack of detectable HCV RNA in serum 24 weeks after the end of therapy, in 40 to 50% of patients infected by HCV genotype 1 and in 70% to 80% of patients infected by genotype 2 or 3 (14, 17, 27). The vast majority of patients who have an SVR are cured of the infection.Ribavirin (1-␤-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a guanosine analogue with a broad spectrum of activity against DNA and RNA viruses (45). Its use in the treatment of chronic HCV infection has been essentially empirical (36). Indeed, the addition of ribavirin to standard or pegylated IFN-␣ therapy significantly increases the SVR rate over that with IFN monotherapy (14,17,27,30,39) and ribavirin can exert this antiviral effect through several possible mechanisms. HCV clearance is biphasic in responders to 33). The first rapid phase, which occurs...

Ribavirin Can Be Mutagenic for Arenaviruses

“…Notably, the mutagenic activity of ribavirin could be observed at subinhibitory concentrations of ribavirin. Nevertheless, it may be difficult to associate a therapeutic activity of ribavirin with mutagenesis during treatment of human arenavirus infections, as exemplified by the conflicting evidence in the case of ribavirin treatment of hepatitis C virus (HCV) infections (8,14,20,61,78), despite evidence of mutagenesis in HCV replicon systems (16,48,79,97). The role of mutagenesis versus inhibition in the anti-LCMV activity of ribavirin remains an open issue.…”

Effect of Ribavirin on the Mutation Rate and Spectrum of Hepatitis C Virus In Vivo

“…Previous works have studied HCV genetic variability using mutation frequencies or rates of molecular evolution and addressed how treatment modifies these parameters (3,7,19,25,32,38,41). However, no estimates of mutation rates have been reported previously for this virus.…”

“…Whereas some analyses have found increased rates of molecular evolution in NS5A and NS5B genes after initiation of the treatment (3), others have failed to detect such differences (7,32). Similarly, comparative studies of patients receiving ribavirin treatment with patients receiving placebo or interferon monotherapy have shown either a slightly accelerated rate of molecular evolution for the NS5B gene in the former group (41) or no significant differences (25).…”

A silkworm–baculovirus model for assessing the therapeutic effects of antiviral compounds: characterization and application to the isolation of antivirals from traditional medicines

“…Inhibition of the proliferation of baculovirus by ganciclovir, vidarabine and foscarnet is thought to be due to the inhibition of viral DNA replication. The mechanism of ribavirin for inhibiting baculovirus proliferation is unknown, although ribavirin reportedly acts as a mutagen (Chevaliez et al, 2007;Crotty et al, 2000;Graci et al, 2007) and as an inhibitor of IMP dehydrogenase (Lowe et al, 1977;Parker, 2005). Ribavirin might inhibit the proliferation of baculovirus by these mechanisms.…”