Abstract:

The story of ribavirin (1--D-ribofuranosyl-1,2,4-triazole-3-carboxamide), a purine nucleoside analogue, began when Drs. Joseph T. Witkowski and Roland K. Robins synthesized the compound in 1970. The broad-spectrum antiviral activity was reported in 1972. The aerosol form of ribavirin was approved for the treatment of respiratory syncytial virus infection in children with respiratory distress in mid-1980, before the discovery of hepatitis C virus (HCV) reported in 1989. The ribavirin/interferon alpha (IFN-) combination therapy was approved by the United States Regulatory Authorities in 1998. Three decades of research efforts, including the life-long effort of a number of unsung scientists, finally allowed ribavirin to establish its position in the history of medicine.

The success of ribavirin/IFN- combination therapy for chronic HCV infection, a viral infection affecting 170 million people worldwide, has provoked a renewed and intense effort to further explore the mechanism(s) of action of ribavirin, with the belief that such information will guide the design of better therapies against HCV. Such a task is not straightforward. IFN- has been shown to possess direct antiviral, antiproliferative, and immunomodulatory activities. The mechanistic pathways involved in the mediation of IFN- effects, including 2'-5' oligoadenylate synthase and induction of Mx and PKR proteins, are well established. However, the exact mechanism of action of IFN- in the treatment of chronic HCV infection is not known. In chronic hepatitis B virus (HBV) infection, the presence of hepatitis flare before hepatitis B e antigen (HBeAg) seroconversion during IFN- monotherapy suggested that immune-mediated mechanisms may be involved. Similar hepatitis flare was not observed in patients with chronic HCV infection who respond to IFN- monotherapy. However, a number of studies showed the involvement of the host immune system in the response to IFN- therapy. Whether the host immune response is induced directly by IFN- or secondary to treatment response is not clear.

Our knowledge on the mechanism of action of ribavirin is no better than that of IFN-. Ribavirin is not a potent direct antiviral agent in vitro with EC50 in the high micromolar (µmol/L) range against most viruses. The most interesting clinical observation is that ribavirin monotherapy had minimal effect on HCV viremia despite the fact that serum alanine transaminase (ALT) levels were reduced significantly in a considerable proportion of patients with chronic HCV infection. Hence, it was proposed that ribavirin may exert its effect on the host immune response. Another important clinical observation is that the combination of ribavirin and IFN- provides a clinically synergistic effect, i.e., the clinical efficacy of this combination exceeds that of the summation of the individual monotherapies. However, the exact nature of this synergism will not be elucidated until the mechanism of action of each agent is firmly established.

At present there are 4 proposed mechanisms of action of ribavirin. They can be divided into 2 groups. The first group consists of 2 possible indirect mechanisms: (1) enhancement of host T-cell-mediated immunity against viral infection through switching the T-cell phenotype from type 2 to type 1 and (2) inhibition of the host enzyme inosine monophosphate dehydrogenase (IMPDH). The second group consists of 2 other hypotheses: (1) direct inhibition of HCV, including NS5B-encoded RNA-dependent RNA polymerase (RdRp) and (2) as an RNA mutagen that drives a rapidly mutating RNA virus over the threshold to "error catastrophe."