Mechanisms of Hepatitis C Viral Resistance to Direct Acting Antivirals

Abstract

There has been a remarkable transformation in the treatment of chronic hepatitis C in recent years with the development of direct acting antiviral agents targeting virus encoded proteins important for viral replication including NS3/4A, NS5A and NS5B. These agents have shown high sustained viral response (SVR) rates of more than 90% in phase 2 and phase 3 clinical trials; however, this is slightly lower in real-life cohorts. Hepatitis C virus resistant variants are seen in most patients who do not achieve SVR due to selection and outgrowth of resistant hepatitis C virus variants within a given host. These resistance associated mutations depend on the class of direct-acting antiviral drugs used and also vary between hepatitis C virus genotypes and subtypes. The understanding of these mutations has a clear clinical implication in terms of choice and combination of drugs used. In this review, we describe mechanism of action of currently available drugs and summarize clinically relevant resistance data.

Keywords: breakthrough variants; direct acting antivirals; hepatitis C; resistance.

Figure 1

The HCV genome encodes a single open reading frame flanked by 5’ and 3’ untranslated regions (UTR). Cleavage of this polyprotein by host endopeptidases (for structural proteins) and viral non-structural protein NS3/4A results in producing structural proteins core (C), Envelope proteins 1 and 2 (E1, E2), and non-structural proteins p7, NS2, NS3, NS4A, NS4B, NS4A, and NS5B. Enzymatic function of non-structural proteins has been the basis of DAAs (outlined in red). These can be overcome by common breakthrough mutations (circled and highlighted).