Hepatitis C NS5A protein: two drug targets within the same protein with different mechanisms of resistance

•Resistance mutations to daclatasvir and ledipasvir map to domain I of NS5A.•Resistance mutations to alisporivir map to domain II of NS5A.•Resistance can be delayed with drug combinations acting on both NS5A domains.

The era of interferon-free antiviral treatments for hepatitis C virus infection has arrived. With increasing numbers of approved antivirals, evaluating all parameters that may influence response is necessary to choose optimal combinations for treatment success. Targeting NS5A has become integral in antiviral combinations in clinical development. Daclatasvir and ledipasvir belong to the NS5A inhibitor class, which directly target the NS5A protein. Alisporivir, a host-targeting antiviral, is a cyclophilin inhibitor that indirectly targets NS5A by blocking NS5A/cyclophilin A interaction. Resistance to daclatasvir and ledipasvir differs from alisporivir, with mutations arising in NS5A domains I and II, respectively. Combining these two classes acting on distinct NS5A domains represents an attractive strategy for potentially effective interferon-free treatments for chronic hepatitis C infection.