Anti-HCV drugs in the pipeline

Several directly acting and host targeting antivirals that inhibit hepatitis C virus replication have entered clinical trials. Among the most advanced of these are RG7128, an inhibitor of the NS5B polymerase; BMS-790052, an inhibitor of NS5A; and alisporivir, an inhibitor of human cyclophilins. These agents have potent antiviral activity in chronic HCV patients, act additively or synergistically with inhibitors of the HCV NS3/4A protease, and improve the rate of virologic response produced by traditional pegylated interferon plus ribavirin therapy. No cross resistance has been observed; moreover, nucleoside NS5B and cyclophilin inhibitors appear to suppress resistance to non-nucleoside NS5B and NS3/4A inhibitors. Several recent reports of virologic responses produced by combinations of agents that inhibit HCV replication in the absence of interferon provide optimism that eradication of HCV will be possible without interferon in the future.

► New antivirals in clinical trials for chronic HCV have viral and host targets. ► RG7128 is a classic active site inhibitor of the HCV NS5B RNA-dependent RNA polymerase. ► BMS-790052 targets the HCV NS5A protein to inhibit viral replication. ► Alisporivir inhibits formation of active viral replicases by targeting host cyclophilins. ► SVR12 in patients treated with DAAs suggests that an IFN-free cure may be possible.