The Role of RASs /RVs in the Current Management of HCV

Abstract

The approval of combination therapies with direct-acting antiviral (DAA) regimens has led to significant progress in the field of hepatitis C virus (HCV) treatment. Although most patients treated with these agents achieve a virological cure, resistance to DAAs is a major issue. The rapid emergence of resistance-associated substitutions (RASs), in particular in the context of incomplete drug pressure, has an impact on sustained virological response (SVR) rates. Several RASs in NS3, NS5A and NS5B have been linked with reduced susceptibility to DAAs. RAS vary based on HCV characteristics and the different drug classes. DAA-resistant HCV variant haplotypes (RVs) are dominant in cases of virological failure. Viruses with resistance to NS3-4A protease inhibitors are only detected in the peripheral blood in a time frame ranging from weeks to months following completion of treatment, whereas NS5A inhibitor-resistant viruses may persist for years. Novel agents have been developed that demonstrate promising results in DAA-experienced patients. The recent approval of broad-spectrum drug combinations with a high genetic barrier to resistance and antiviral potency may overcome the problem of resistance.

Keywords: DAA; HCV; RAS; viral resistance.

Figure 1

(A) The “cloud” of HCV quasispecies in the space of sequences; Mixture of virions that are genetically distinct but closely related. The assay methods for the detection of major populations should report the presence of RASs with a validated and repeatable sensitivity of 15%, equivalent to population sequencing. The number of different variants and their relative frequency give estimated measures of complexity and the genetic distances measures of diversity. (B) Viral variants are individual full-length viruses that constitute the HCV quasispecies in a patient. Resistant variants contain one or several RASs, which are single amino acid changes that reduce susceptibility to a DAA or a class of DAAs. Fitness associated substitution(s) are single amino acid changes that do not alter DAA susceptibility but increase the fitness of the resistant variants.

Figure 2

Summary of substitutions associated with resistance to protease inhibitors (A), NS5A inhibitors (B), and nucleoside and non-nucleoside NS5 B inhibitors (C). HCV genotypes and subtypes are represented by different colors: 1a–red, 1b-blue, 2a/b/c–green, 3a–purple, 4a/d–yellow, 5–light blue, 6–brown. Amino acid substitutions detected in vivo in DAA failing patients are underlined, independently of in vitro data information.

Figure 2

Summary of substitutions associated with resistance to protease inhibitors (A), NS5A inhibitors (B), and nucleoside and non-nucleoside NS5 B inhibitors (C). HCV genotypes and subtypes are represented by different colors: 1a–red, 1b-blue, 2a/b/c–green, 3a–purple, 4a/d–yellow, 5–light blue, 6–brown. Amino acid substitutions detected in vivo in DAA failing patients are underlined, independently of in vitro data information.