What are the promising new therapies in the field of chronic hepatitis C after the first-generation direct-acting antivirals?

A number of promising new hepatitis C virus (HCV) antiviral regimens have emerged during the last few years, with a trend toward increased efficacy, safety, and tolerability, when compared with currently available therapies. The focus of recent HCV antiviral drug development has been on inhibition of HCV replication, largely by targeting specific components of the HCV replication complex itself. A significant effort has been put into generating drugs that inhibit the NS5B polymerase. A number of such drugs have been developed, and NS5B polymerase inhibitors can be divided into nucleoside polymerase inhibitors and nonnucleoside polymerase inhibitors, with each group carrying specific pharmacologic and clinical characteristics. Additional research has explored the efficacy of drugs that inhibit the HCV replication complex via other mechanisms. Second-generation NS3-4A protease inhibitors have been developed, which have generally improved on the efficacy of the currently available FDA-approved first-generation agents. NS5A inhibitors have also been studied. These medications impede HCV replication and viral particle assembly and enhance host immune activation via novel mechanisms. Alternatively, medications that target a host protein, cyclophillin B, are under evaluation. These medications block HCV replication via modification of the effects of NS5B and via other poorly understood mechanisms. Detailed below are the most important HCV antiviral agents under development, many of which show promise for use within the next few years.