Mutagenic effects of ribavirin in vivo

Abstract

Almost 200 million people worldwide are infected with hepatitis C virus (HCV). For these people treatment options are relatively limited, and they have recently evolved from IFN-a monotherapy to IFN-a/ribavirin to the present standard of PEG-IFN-a/ribavirin combination therapy. Ribavirin (RBV), a synthetic guanosine analogue, when used as monotherapy against HCV has little antiviral effect, decreasing HCV viral load by less than 0.5 log10 [1,2]. Yet, RBV when used in combination with IFN yields substantial increases in end of treatment and sustained virological responses over those observed with interferon alone [3–7]. How RBV accomplishes this is unknown and intriguing [8,9]. Many hypotheses have been proposed and they include inhibition of inosine monophosphate dehydrogenase (IMPDH) that would lead to a depletion of intracellular GTP pools [10,11], inhibition of HCV RNA-dependent RNA polymerase [8, 9], immunomodulation towards Th1 responses that could increase cell-mediated immune responses against HCV infected cells [12], and mutagenesis [13]. Because other IMPDH inhibitors, such as mycophenolic acid and VX497, do not have a significant anti-HCV effect it is unlikely that this is ribavirin’s major mode of action. However, depletion of GTP pools could enhance the mutation rate. Similarly, the observations that RBV monotherapy only causes a minor decrease in HCV RNA and does not seem to enhance the first phase decline of HCV when given with high-dose daily IFN [14,15] argue against ribavirin being a potent HCV polymerase inhibitor. There have also been arguments against RBV acting as an immunomodulator and as a mutagen [16–18], thus leaving the field in a state of some confusion. In this issue of the journal, Asahina et al. [19] report on a clinical trial designed to assess the merits of the mutagenesis