Mutagenic Effect Of Ribavirin Research Articles

Ribavirin-induced mutagenesis across the complete open reading frame of hepatitis C virus genotypes 1a and 3a.

Ribavirin (RBV) has been used for the last 20 years to treat patients with chronic hepatitis C virus (HCV) infection. This pluripotent drug is believed to induce mutagenesis in HCV RNA. However, for cell-cultured HCV (HCVcc) this phenomenon has only been investigated in genotype 2a recombinants. Here we studied the mutations that developed in HCVcc of genotypes 1a and 3a treated with RBV or ribavirin triphosphate (RBV-TP) compared to non-treated controls. Analysis was performed on the amplified full-length open reading frame (ORF) of recovered viruses following next-generation sequencing and clonal analyses. Compared to non-treated controls, the spread of TNcc(1a) and DBN3acc(3a) HCVcc was delayed by RBV and RBV-TP at concentrations of 40 µM or higher. The delay in HCVcc spread was associated with increased new single-nucleotide polymorphisms (SNP). Significantly higher numbers of new SNP were observed in TNcc(1a) viruses treated with RBV or RBV-TP compared to matched non-treated controls. RBV or RBV-TP treatment led to significantly increased proportions of new G-to-A and C-to-U SNP compared to non-treated TNcc(1a). Clonal analyses confirmed a significantly increased mutation rate in RBV-treated TNcc(1a). Synonymous pairwise distances increased in both viruses across the complete ORF under RBV and RBV-TP treatment compared to controls. Consensus-shifts in single samples of RBV- or RBV-TP-treated TNcc(1a) viruses occurred in proteins E1, p7, NS3 and NS4B. No non-synonymous consensus changes were observed in DBN3acc(3a). This study supports a biased G-to-A and C-to-U mutagenic effect of RBV and RBV-TP throughout the entire ORF of HCV genotypes 1a and 3a.

Mutagenic Effects of Ribavirin on Hepatitis E Virus-Viral Extinction versus Selection of Fitness-Enhancing Mutations.

Hepatitis E virus (HEV), an important agent of viral hepatitis worldwide, can cause severe courses of infection in pregnant women and immunosuppressed patients. To date, HEV infections can only be treated with ribavirin (RBV). Major drawbacks of this therapy are that RBV is not approved for administration to pregnant women and that the virus can acquire mutations, which render the intra-host population less sensitive or even resistant to RBV. One of the proposed modes of action of RBV is a direct mutagenic effect on viral genomes, inducing mismatches and subsequent nucleotide substitutions. These transition events can drive the already error-prone viral replication beyond an error threshold, causing viral population extinction. In contrast, the expanded heterogeneous viral population can facilitate selection of mutant viruses with enhanced replication fitness. Emergence of these mutant viruses can lead to therapeutic failure. Consequently, the onset of RBV treatment in chronically HEV-infected individuals can result in two divergent outcomes: viral extinction versus selection of fitness-enhanced viruses. Following an overview of RNA viruses treated with RBV in clinics and a summary of the different antiviral modes of action of this drug, we focus on the mutagenic effect of RBV on HEV intrahost populations, and how HEV is able to overcome lethal mutagenesis.

Triphasic decline of hepatitis C virus RNA during antiviral therapy

When patients chronically infected with hepatitis C virus (HCV) are placed on antiviral therapy with pegylated interferon (IFN)-alpha or IFN-alpha plus ribavirin (RBV), HCV RNA generally declines in a biphasic manner. However, a triphasic decline has been reported in a subset of patients. A triphasic decline consists of a first phase (1-2 days) with rapid virus load decline, followed by a "shoulder phase" (4-28 days) in which virus load decays slowly or remains constant, and a third phase of renewed viral decay. We show that by including the proliferation of both uninfected and infected cells, a viral kinetic model can account for a triphasic HCV RNA decay. The model predicts that a triphasic decline occurs only in patients in which a majority of hepatocytes are infected before therapy. The shoulder phase does not represent the intrinsic death rate of infected cells, but rather the third phase slope is close to the intrinsic death rate of infected cells when overall drug efficacy is close to 1. Triphasic responses can be predicted from a generalization of existent viral kinetic models through the inclusion of homeostatic proliferation of hepatocytes. This generalized model can also explain the viral kinetics seen in flat partial responders. Finally, the enhanced third phase in patients treated with IFN-alpha in combination with RBV versus patients treated with IFN-alpha alone can be explained by a mutagenic effect of RBV against HCV.

Mutagenic effects of ribavirin and response to interferon/ribavirin combination therapy in chronic hepatitis C

To elucidate whether ribavirin acts as a mutagen in the clinical setting and to clarify the relationship between ribavirin-induced mutations and virological response to combined therapy. Thirty-four patients with hepatitis C virus (HCV) genotype 1b received ribavirin monotherapy for 4 weeks, followed by a 24-week course of IFN/ribavirin therapy. HCV mutations during a non-treatment observation period and during subsequent ribavirin monotherapy were determined, and the relationship between mutations and response to subsequent IFN/ribavirin therapy was evaluated. Serum HCV significantly decreased from 6.90 to 6.56 log10copy/ml in response to ribavirin monotherapy (P < 0.0001). Nucleotide mutations in the NS5A and NS5B regions occurred during ribavirin monotherapy at a rate of 2.9 x 10(-2)/site/year and 1.3 x 10(-2)/site/year, respectively, a significantly higher rate than the mutation rates during the prior non-treatment observation period (0.60 x 10(-2)/site/year and 0.24 x 10(-2)/site/year, P = 0.02, respectively). Mutation rates in the NS5A region were significantly higher in sustained viral responders (SVRs, n = 10) than in non-responders (8.8 x 10(-2)/site/year vs. 0.38 x 10(-2)/site/year, P = 0.0005, respectively). In the NS5A region, non-synonymous mutations only occurred in SVRs. Ribavirin may act as a mutagen, and mutations occurring during ribavirin therapy correlate with the virological response to subsequent IFN/ribavirin combination therapy.

In vivochromosome damaging effects of an inosine monophosphate dehydrogenase inhibitor: Ribavirin in mice

OBJECTIVE: To investigate the <i>in vivo </i>mutagenic effects of ribavirin in mice.<br>METHODS: Mice were injected (i.p.) 20, 100, or 200 mg/kg ribavirin (single exposure) for bone marrow micronucleus, peripheral blood micronucleus and bone marrow chromosome aberration tests. Five treatments of 200 mg/kg ribavirin was given (i.p.) for sperm morphology test. The tests were performed as per the standard procedures. <br>RESULTS: Ribavirin induced significant number of micronucleated polychromatic erythrocytes (MNPCEs) at 24, 48 and 72 h following the exposure with more effects at 24 h (p<0.05-0.001). Micronucleated PCEs were more at 48 h in lower dose-levels and at 72 h in highest dose-level in the peripheral blood (p<0.05-0.001). Ribavirin induced structural chromosomal damage hence producing the fragments for the micronucleus formation. Ribavirin decreased the PCE%, P/N ratio and the mitotic index indicating that it prevents cell division in mouse bone marrow. Ribavirin also decreased the testis weight and induced the formation of abnormal sperms. <br>CONCLUSION: Ribavirin is a potent mutagen and cytotoxic agent in mice <i>in vivo</i>. Further, it also induces point mutations in germ cells yielding abnormal sperms. The genotoxic effects of ribavirin are not exerted in a dose-dependent pattern in mouse.

Mutagenic effect of ribavirin in NS5A and NS5B regions and response to inteferon/ribavirin combination therapy in patients with chronic hepatitis C

Mutagenic effect of ribavirin in NS5A and NS5B regions and response to inteferon/ribavirin combination therapy in patients with chronic hepatitis C