Prevalence of pre-treatment ns5a resistance associated variants in genotype 1 patients across different regions using deep sequencing and effect on treatment outcome with LDV/SOF.

Abstract

Background: The efficacy of some HCV regimens is influenced by the presence of certain NS5A resistance associated variants (RAVs). To investigate if the pretreatment prevalence of NS5A RAVs in genotypes (GT) 1a and 1b varied by country, race or ethnicity, comprehensive analyses were performed using deep sequencing of NS5A from more than 5000 patients from 17 countries. Method(s): NS5A deep sequencing analysis with a 1% cut-off was performed. GT1a RAVs were defined as K24G/N/R, M28A/G/T/V, Q30H/G/R/E/K, L31any, P32L, S38F, H58D, A92K/T, Y93any, and GT1b RAVs were L31any, P32L, P58D, A92K, Y93any. Result(s): Pretreatment samples from 5046 patients were analyzed. Prevalence of NS5A RAVs was similar between the different regions for both GT1a and GT1b HCV infected patients (Table). In addition, no significant differences were observed in NS5A RAV prevalence between patients with different race or ethnicity. In the subset of patients who were treated with LDV/SOF for 12 weeks, SVR12 rates were similar in GT1b patients with and without pretreatment NS5A RAVs across all regions. In GT1a patients with pretreatment RAVs, SVR12 rates in North America were 91% (75/82) compared to 98% without NS5A RAVs. All seven GT1a patients who relapsed had pretreatment NS5A RAVs conferring >1000-fold reduced susceptibility to LDV (H58D, Y93H/N/F or multiple RAV combinations). However, 18 GT1a patients with similar RAVs conferring >1000-fold reduced susceptibility achieved SVR12 after LDV/SOF for 12 weeks. Conclusion(s): No significant difference in prevalence of NS5A pretreatment RAVs was observed between different regions, races or ethnicities. Overall, high SVR12 rates (91-100%) were observed in patients with or without NS5A RAVs with LDV/ SOF. In GT1a patients, lower SVR rate (72%) was observed in patients with pretreatment NS5A RAVs conferring high level (>1000-fold) resistance to NS5A inhibitors. (Table Presented).