Nucleoside/nucleotide analogue polymerase inhibitors in development.

Nucleoside/nucleotide analogue polymerase inhibitors (NPIs) are analogues of natural substrates that bind the active site of NS5B and terminate viral RNA chain generation and generally provide a high genetic barrier to resistance and are effective in all genotypes. NPIs such as sofosbuvir (GS-7977) show high antiviral activities that, together with their high genetic barrier to resistance, suggest that they are optimal backbone candidates for all-oral combination therapies. Several trials are ongoing to further define the potential of all-oral regimens with sofosbuvir (GS-7977). Recent interim analyses indicate that many patients treated with only 2 direct-acting antiviral agents experience viral breakthrough, which can be significantly reduced by the addition of ribavirin without pegylated interferon α.