Abstract
Recent advances in molecular biology have led to the development of new antiviral drugs that target specific steps of the Hepatitis C Virus (HCV) lifecycle. These drugs, collectively termed direct-acting antivirals (DAAs), include non-structural (NS) HCV protein inhibitors, NS3/4A protease inhibitors, NS5B RNA-dependent RNA polymerase inhibitors (nucleotide analogues and non-nucleoside inhibitors), and NS5A inhibitors. Due to the high genetic variability of HCV, the outcome of DAA-based therapies may be altered by the selection of amino-acid substitutions located within the targeted proteins, which affect viral susceptibility to the administered compounds. At the drug developmental stage, preclinical and clinical characterization of HCV resistance to new drugs in development is mandatory. In the clinical setting, accurate diagnostic tools have become available to monitor drug resistance in patients who receive treatment with DAAs. In this review, we describe tools available to investigate drug resistance in preclinical studies, clinical trials and clinical practice.
Highlights
Hepatitis C virus (HCV) is a positive-polarity, single-stranded RNA virus belonging to the Flaviviridae family, genus Hepacivirus
The advent of interferon-free combination regimens with “direct-acting antiviral” (DAA) drugs comes with high expectations for very highly sustained virological response (SVR) rates and ultimate control of the epidemics [3,4]
Available HCV DAAs are classified into four categories on the basis of their molecular target and mechanism of action: NS3/4A protease inhibitors, NS5A inhibitors, nucleotide analogue inhibitors of NS5B RNA-dependent RNA polymerase (RdRp), and non-nucleoside inhibitors of RdRp
Summary
Hepatitis C virus (HCV) is a positive-polarity, single-stranded RNA virus belonging to the Flaviviridae family, genus Hepacivirus. HCV is prone to develop resistance to DAAs, as a result of the lack of proof-reading activity of the viral RdRp coupled with the highly replicative nature of HCV. This leads to the daily generation of large numbers of genetically distinct viral variants within each infected individual [5,6]. The presence of minor populations of resistance-associated variants (RAVs) at the start of treatment may affect the outcome of antiviral therapy, because they can become dominant in the context of the selective pressure exerted by the drugs, subsequently leading to a virological breakthrough during treatment or, more frequently with interferon-free regimens, a relapse after treatment cessation [8]. We describe tools available to investigate HCV DAA resistance in preclinical and clinical research as well as in clinical practice
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