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Standard treatment with pegylated alpha interferon (IFN-\u03b1) in combination with the nucleoside analogue ribavirin leads to a sustained virologic response in approximately half of the patients. IFN-\u03b1 is classified as an indirect treatment, as it interacts with the host's immune response. The mechanism of action of ribavirin is still unknown. The benefit of triple therapy by adding other antiviral agents, e.g., amantadine, is controversial. Currently, new direct antiviral drugs (HCV protease\/polymerase inhibitors) are being evaluated in phase 1\/phase 2 trials. Phenotypic resistance to antiviral therapy has been attributed to amino acid variations within distinct regions of the HCV polyprotein. While sensitivity to IFN-\u03b1-based antiviral therapy in vivo is clearly correlated with the number of mutations within the HCV NS5A protein, the underlying functional mechanisms for this association are unknown. 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