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Mechanism of action of ribavirin in anti-HCV regimens: new insights for an age-old question?
  1. Barbara Testoni1,
  2. Massimo Levrero2,
  3. David Durantel1
  1. 1Team 15, INSERM U1052, CNRS UMR 5286, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL), LabEx DEVweCAN, Lyon, France
  2. 2Department of Internal Medicine (DMISM) and EAL INSERM U785, Sapienza University of Rome, Rome, Italy
  1. Correspondence to Professor Massimo Levrero, Department of Internal Medicine (DMISM) and EAL INSERM U785, Policlinico Umberto I, Viale del Policlinico 155, Rome 0061, Italy; massimo.levrero{at}uniroma1.it

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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% …

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