Hepatitis C virus treatment failure: Clinical utility for testing resistance-associated substitutions

Abstract

The hepatitis C virus has a high mutation capacity that leads to the emergence of resistance-associated substitutions (RAS). However, the consequence of resistance selection during new direct-acting antiviral drug (DAA) treatment is not necessarily the therapeutic failure. In fact, DAA treatment has shown a high rate (> 95%) of sustained virological response even when high baseline RAS prevalence has been reported. In the context of RAS emergence and high rates of sustained viral response, the clinical relevance of variants harboring RAS is still controversial. Therefore, in order to summarize the data available in international guidelines, we have reviewed the clinical utility of testing RAS in the era of new pangenotypic DAA drugs.

Keywords: Direct-acting antiviral; Hepatitis C virus; Resistance; Treatment failure.

Figure 1

Quasispecies distribution. Simplified representation of quasispecies infecting an individual. Each genome is identified with a letter. The mutation highlighted by a red triangle in the wild-type (WT) confers a selective advantage that results in dominance of that mutation after a given number of replication rounds in an untreated patient. After the pressure generated by direct-acting antiviral (DAA) treatment, a modification of the consensus sequence is observed, where a green circle confers resistance to treatment and becomes dominant. In the upper example, mutant classes are represented as circles of sizes proportional to the number of genomes in each class. Red circles represent the WT, green circles represent a variant with resistance-associated substitutions (RAS). Yellow, light blue, and purple circles are variants with changes of the WT that are not associated with treatment response.