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In theory, any step of the hepatitis C virus (HCV) lifecycle can be a target for direct-acting antiviral (DAA) drugs (drugs that directly block a viral function), and/or host-targeted agents (HTA, drugs that block a cellular function essential to the viral lifecycle). Four classes of HCV DAAs and two classes of HTAs have reached late clinical development. The HCV DAAs include: inhibitors of the NS3/4A protease that block HCV polyprotein processing; inhibitors of the RNA-dependent RNA polymerase (RdRp), including nucleoside/nucleotide analogues and non-nucleoside inhibitors that block viral replication; and NS5A inhibitors that block viral replication, virion assembly and release. The HCV HTAs in development interact with cellular factors required for HCV replication; they include cyclophilin A inhibitors and microRNA-122 antagonists.1
In 2014, three drugs were approved in the European Union, including the nucleotide analogue sofosbuvir, the protease inhibitor simeprevir and the NS5A inhibitor daclatasvir. They can be used in combination with pegylated interferon α (IFNα) and ribavirin, or as part of sofosbuvir-based IFN-free combinations.1 Other compounds will likely be approved before the end of 2014, including the NS5A inhibitor ledipasvir in combination with sofosbuvir in a single tablet, and the triple combination of the ritonavir-boosted protease inhibitor ABT-450 and the NS5A inhibitor ombitasvir in one tablet plus the non-nucleoside RdRp inhibitor dasabuvir. A number of other drugs from the same classes currently are in Phase II or III clinical development.
In vitro studies showed that other steps of the HCV lifecycle, such as entry, fusion, polyprotein translation, assembly, virion maturation or viral particle release can be blocked by means of specific or non-specific antiviral approaches. Viral entry appears as an attractive target, as suggested by the experience in other chronic viral infections. Two HIV entry inhibitors, maraviroc and enfuvirtide, have been approved and numerous other compounds have reached …