TY - JOUR T1 - Mechanism of action of ribavirin in anti-HCV regimens: new insights for an age-old question? JF - Gut JO - Gut SP - 3 LP - 4 DO - 10.1136/gutjnl-2013-304528 VL - 63 IS - 1 AU - Barbara Testoni AU - Massimo Levrero AU - David Durantel Y1 - 2014/01/01 UR - http://gut.bmj.com/content/63/1/3.abstract N2 - Since the discovery of its broad antiviral activity back 40 years ago1 and as new therapeutic indications are foreseen against emerging viruses,2 ribavirin (RBV), a synthetic triazole analogue of guanosine, has not yet revealed all the secrets of its mechanism of action. Despite this lack of knowledge, RBV has been a critical component of the standard of care ‘dual’ therapy, that is, α-interferon (IFNα) and then pegylated-IFNα (PEG-IFNα) plus RBV, for the treatment of tens of thousands Hepatitis C Virus (HCV)-infected patients worldwide for almost 20 years.3 Several, quite diverse, modes of action have been proposed including: (1) a direct inhibitory effect on viral RNA-dependant RNA-polymerases; (2) lethal mutagenesis of viral nucleic acids; (3) depletion of the cell guanosine triphosphate pool by inhibiting the enzymatic activity of the inosine monophosphate dehydrogenase; (4) modulation of the Th1/Th2 T lymphocyte balance; (5) impairment of the translation via eIF4E inhibition. None of the proposed mechanisms of action convincingly explains RBV-mediated potentiation of IFN-based therapy in HCV-infected patients and, although they are not mutually exclusive, they are all still a matter of controversy (see ref 4 for review). Whereas RBV used in monotherapy has shown little or no effect on HCV viremia5 or HCV genetic heterogeneity,6 it is worth noting that about 50% … ER -