Challenge to overcome: Nonstructural protein 5A-P32 deletion in direct-acting antiviral-based therapy for hepatitis C virus

Interferon (IFN)-based therapy for hepatitis C virus (HCV) infection has recently been replaced by IFN-free direct-acting antiviral (DAA)-based therapy, which has been established as a 1(st) line therapy with high efficacy and tolerability due to its reasonable safety profile. Resistance-associated substitutions (RASs) have been a weakness of DAA-based therapy. For example, combination therapy with daclatasvir and asunaprevir (DCV/ASV) is less effective for HCV genotype 1-infected patients with Y93H as a nonstructural protein 5A RAS. However, the problem regarding RASs has been gradually overcome with the advent of recently developed DAAs, such as sofosbuvir-based regimens or combination therapy with glecaprevir and pibrentasvir. Despite the high efficiency of DAA-based therapy, some cases fail to achieve viral eradication. P32 deletion, an NS5A RAS, has been gradually noticed in patients with DCV/ASV failure. P32 deletion has been sporadically reported and the prevalence of this RAS has been considered to be low in patients with DCV/ASV failure. Thus, the picture of P32 deletion has not been fully evaluated. Importantly, currently-commercialized DAA-based combination therapy was not likely to be effective for patients with P32 deletion. Exploring and overcoming this RAS is essential for antiviral therapy for chronic hepatitis C.