Ribavirin is often used for the treatment of hepatitis C virus (HCV) infection. Although its mechanisms of action remain to be clearly elucidated, ribavirin plays a beneficial role for achieving virological response and decreasing the rate of virological relapse after treatment cessation. However, ribavirin may induce side effects leading to early treatment discontinuation. Among them, hemolytic anemia is the most frequent and results from intraerythrocyte accumulation. Pharmacological studies have shown that early ribavirin exposure assessed by the area under the curve (AUC) at day 0 and ribavirin trough concentration during the first three months of therapy were correlated with sustained virological response (SVR). These studies highlighted the relevance of ribavirin pharmacologic monitoring and early dose adaptation during therapy. Although the role of ribavirin within new direct acting antiviral (DAA) combinations will probably decrease in the future, its potential benefit in difficult-to-treat patients such as patients with severe hepatopathy or patients who failed triple therapy including patients with multiresistance will need to be further investigated. 1. Introduction Ribavirin (1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a nucleotide analogue of guanosine and a broad-spectrum direct antiviral agent (DAA). Ribavirin was discovered 30 years ago and is efficient in vitro and/or in vivo against several RNA or DNA viruses [1–3]. This DAA is mostly used for hepatitis C virus (HCV) treatment, severe human respiratory syncytial-virus (RSV) infection, some hemorrhagic fevers, and more recently for immunosuppressed patients infected by hepatitis E virus (HEV) [4]. Partly based on the authors’ own work [5–13], this paper focuses, in the context of HCV infection, on the ribavirin mechanism of action, its efficacy according to different therapeutic schedules, and its side effects and toxicity. Since clinical and pharmacological data suggest that an adequate and early exposure to ribavirin improves virological response, the relevance of ribavirin pharmacological monitoring in different patient populations and in different therapeutic situations including new promising treatment strategies is also discussed. 2. Pharmacological Data After a single oral dose, three different phases may be distinguished in ribavirin plasma concentration: a quick absorption phase with a mean time of 1.5 hours to reach the maximum concentration (), a quick distribution phase (half-life around 3.7 hours), and a long elimination phase with a last measurable concentration
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