In This Article

DAA Resistance

The efficacy of certain HCV regimens is influenced by the presence of NS5A resistance-associated variants (RAVs), which have been reported to be present at baseline in approximately 10% of patients or may arise during DAA treatment.

Pre-existing HCV Resistance-Associated Variants

Hu and colleagues[17] investigated the global prevalence of pre-existing RAVs to DAAs using published GenBank data. Of 1459 full-length HCV sequences, 71% carried at least one dominant resistance variant. Geographically, the highest RAV frequency occurred in Asia (88%), followed by Africa (74%), Europe (69%), and America (63%). The highest RAV frequency was observed in HCV genotype 6 sequences (84%), followed by genotype 2 (83%), genotype 4 (78%), genotype 1 (68%), and genotype 3 (50%). Furthermore, 46%, 31%, and 11% of sequences were RAVs to NS5A inhibitors, NS3 protease inhibitors, and their combinations, respectively. In contrast, NS5B nucleos(t)ide inhibitor-based multi-DAA regimens had a low prevalence of RAVs.

Holodniy and colleagues[18] detected DAA resistance mutations in 16% of VA medical center patients treated for HCV. In both treatment-naive and treatment-experienced patients with prior DAA exposure, approximately 60% had one or more resistance mutations.

The Impact of Pretreatment NS5A RAVs

Zeuzem and colleagues[19] investigated the impact of pretreatment NS5A RAVs in patients with HCV genotype 1. They conducted a comprehensive analysis using deep sequencing of NS5A from more than 5000 patients from 17 countries. The prevalence of NS5A RAVs was similar between the different geographic regions. In addition, no significant differences were observed in NS5A RAV prevalence between patients with different races or ethnicities. In the subset of patients who were treated with LDV/SOF for 12 weeks, SVR12 rates were similar in genotype 1b patients with and without pretreatment NS5A RAVs. In genotype 1a patients, a lower SVR rate (72%) was observed in patients with pretreatment NS5A RAVs conferring high-level (more than 1000-fold) resistance to NS5A inhibitors. All patients with genotype 1a who relapsed had pretreatment NS5A RAVs conferring more than 1000-fold reduced susceptibility to LDV.

In the ASTRAL trials, the existence of baseline NS5A RAVs had a variable effect on response. There was no impact on the SVR rates in patients with HCV genotype 2; however, the SVR12 rate was lower in patients with HCV genotype 3 who had baseline RAVs.[20,21]

Impact of Baseline RAVs on the Efficacy of Elbasvir/Grazoprevir

After a 12-week elbasvir/grazoprevir (EBR/GZR) regimen, virologic failure occurred primarily in patients who were identified to have baseline substitutions at NS5A resistance-associated positions that reduce EBR potency 5-fold or more in vitro.

Jacobson and colleagues[22] assessed the clinical relevance of these baseline NS5A RAVs using a sensitive next-generation sequencing assay on baseline samples from treatment-naive or -experienced patients with HCV genotype 1a. A small group of patients harbored NS5A RAVs that reduced the efficacy of the EBR/GZR regimen. The 12-week regimen with no RBV yielded a 99% SVR12 in patients lacking these baseline RAVs. The impact of such RAVs on efficacy was no longer seen among patients who were given 16 weeks of treatment with EBR/GZR plus RBV.

Genotypic resistance testing may be helpful to guide the initial and subsequent use of DAA regimens in view of pre-existing or posttreatment HCV DAA resistance mutations.

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