NS5A resistance-associated substitutions in patients with genotype 1 hepatitis C virus: Prevalence and effect on treatment outcome

Stefan Zeuzem, Masashi Mizokami, Stephen Pianko, Alessandra Mangia, Kwang Hyub Han, Ross Martin, Evguenia Svarovskaia, Hadas Dvory-Sobol, Brian Doehle, Charlotte Hedskog, Chohee Yun, Diana M. Brainard, Steven Knox, John G. McHutchison, Michael D. Miller, Hongmei Mo, Wan Long Chuang, Ira Jacobson, Gregory J. Dore, Mark Sulkowski

Research output: Contribution to journalArticle

124 Citations (Scopus)

Abstract

Background & Aims The efficacy of NS5A inhibitors for the treatment of patients chronically infected with hepatitis C virus (HCV) can be affected by the presence of NS5A resistance-associated substitutions (RASs). We analyzed data from 35 phase I, II, and III studies in 22 countries to determine the pretreatment prevalence of various NS5A RASs, and their effect on outcomes of treatment with ledipasvir-sofosbuvir in patients with genotype 1 HCV. Methods NS5A gene deep sequencing analysis was performed on samples from 5397 patients in Gilead clinical trials. The effect of baseline RASs on sustained virologic response (SVR) rates was assessed in the 1765 patients treated with regimens containing ledipasvir-sofosbuvir. Results Using a 15% cut-off, pretreatment NS5A and ledipasvir-specific RASs were detected in 13% and 8% of genotype 1a patients, respectively, and in 18% and 16% of patients with genotype 1b. Among genotype 1a treatment-naïve patients, SVR rates were 91% (42/46) vs. 99% (539/546) for those with and without ledipasvir-specific RASs, respectively. Among treatment-experienced genotype 1a patients, SVR rates were 76% (22/29) vs. 97% (409/420) for those with and without ledipasvir-specific RASs, respectively. Among treatment-naïve genotype 1b patients, SVR rates were 99% for both those with and without ledipasvir-specific RASs (71/72 vs. 331/334), and among treatment-experienced genotype 1b patients, SVR rates were 89% (41/46) vs. 98% (267/272) for those with and without ledipasvir-specific RASs, respectively. Conclusions Pretreatment ledipasvir-specific RASs that were present in 8–16% of patients have an impact on treatment outcome in some patient groups, particularly treatment-experienced patients with genotype 1a HCV. Lay summary The efficacy of treatments using NS5A inhibitors for patients with chronic hepatitis C virus (HCV) infection can be affected by the presence of NS5A resistance-associated substitutions (RASs). We reviewed results from 35 clinical trials where patients with genotype 1 HCV infection received treatments that included ledipasvir-sofosbuvir to determine how prevalent NS5A RASs are in patients at baseline, and found that ledipasvir-specific RASs were present in 8–16% of patients prior to treatment and had a negative impact on treatment outcome in subset of patient groups, particularly treatment-experienced patients with genotype 1a HCV.

Original languageEnglish
Pages (from-to)910-918
Number of pages9
JournalJournal of Hepatology
Volume66
Issue number5
DOIs
Publication statusPublished - 2017 May

All Science Journal Classification (ASJC) codes

  • Hepatology

Fingerprint Dive into the research topics of 'NS5A resistance-associated substitutions in patients with genotype 1 hepatitis C virus: Prevalence and effect on treatment outcome'. Together they form a unique fingerprint.

  • Cite this

    Zeuzem, S., Mizokami, M., Pianko, S., Mangia, A., Han, K. H., Martin, R., Svarovskaia, E., Dvory-Sobol, H., Doehle, B., Hedskog, C., Yun, C., Brainard, D. M., Knox, S., McHutchison, J. G., Miller, M. D., Mo, H., Chuang, W. L., Jacobson, I., Dore, G. J., & Sulkowski, M. (2017). NS5A resistance-associated substitutions in patients with genotype 1 hepatitis C virus: Prevalence and effect on treatment outcome. Journal of Hepatology, 66(5), 910-918. https://doi.org/10.1016/j.jhep.2017.01.007