Resistance to cyclophilin inhibitors

Abstract

The best approach to avoid hepatitis C virus (HCV) resistance to a specific therapy is rapid and massive suppression of viral replication. This is best accomplished by combining several drugs with potent antiviral activity across multiple genotypes, with each possessing a high barrier to resistance, different mechanisms of action, and no cross-resistance. A novel class of anti-HCV agents that have shown great promise in HCV patients - the cyclophilin inhibitors (CypI) - possess such properties. CypI are host-targeting antivirals (HTAs) with a mechanism of action that differs from those of all existing direct-acting antivirals (DAAs). CypI are pan-genotypic due to their distinct mechanism of action that targets the host protein cyclophilin A (CypA), which is required for HCV replication. HCV has to develop a lengthy mutational strategy to efficiently replicate in vitro independently of the host factor CypA leading to a high genetic barrier that the virus has to cross to develop resistance to CypI. CypI mediate rapid and profound viral load suppression in patients. Very low viral breakthrough rates are associated with the CypI treatment, which result mostly from suboptimal drug exposure rather than viral resistance. The high genetic barrier and the lack of cross-resistance to DAAs make CypI attractive drug candidates to be part of a regimen with one or two DAAs that may constitute the backbone of a new, safe, and effective IFN-free therapy. The characteristic resistance profile of CypI offers an exceptional opportunity to cure HCV.