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, KwangHyub 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

99 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 1

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Hepacivirus
Genotype
Therapeutics
Virus Diseases
Clinical Trials
High-Throughput Nucleotide Sequencing
Chronic Hepatitis C
ledipasvir

All Science Journal Classification (ASJC) codes

  • Hepatology

Cite this

Zeuzem, Stefan ; Mizokami, Masashi ; Pianko, Stephen ; Mangia, Alessandra ; Han, KwangHyub ; Martin, Ross ; Svarovskaia, Evguenia ; Dvory-Sobol, Hadas ; Doehle, Brian ; Hedskog, Charlotte ; Yun, Chohee ; Brainard, Diana M. ; Knox, Steven ; McHutchison, John G. ; Miller, Michael D. ; Mo, Hongmei ; Chuang, Wan Long ; Jacobson, Ira ; Dore, Gregory J. ; Sulkowski, Mark. / NS5A resistance-associated substitutions in patients with genotype 1 hepatitis C virus : Prevalence and effect on treatment outcome. In: Journal of Hepatology. 2017 ; Vol. 66, No. 5. pp. 910-918.
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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-na{\"i}ve 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-na{\"i}ve 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.",
author = "Stefan Zeuzem and Masashi Mizokami and Stephen Pianko and Alessandra Mangia and KwangHyub Han and Ross Martin and Evguenia Svarovskaia and Hadas Dvory-Sobol and Brian Doehle and Charlotte Hedskog and Chohee Yun and Brainard, {Diana M.} and Steven Knox and McHutchison, {John G.} and Miller, {Michael D.} and Hongmei Mo and Chuang, {Wan Long} and Ira Jacobson and Dore, {Gregory J.} and Mark Sulkowski",
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Zeuzem, S, Mizokami, M, Pianko, S, Mangia, A, Han, K, Martin, R, Svarovskaia, E, Dvory-Sobol, H, Doehle, B, Hedskog, C, Yun, C, Brainard, DM, Knox, S, McHutchison, JG, Miller, MD, Mo, H, Chuang, WL, Jacobson, I, Dore, GJ & Sulkowski, M 2017, 'NS5A resistance-associated substitutions in patients with genotype 1 hepatitis C virus: Prevalence and effect on treatment outcome', Journal of Hepatology, vol. 66, no. 5, pp. 910-918. https://doi.org/10.1016/j.jhep.2017.01.007

NS5A resistance-associated substitutions in patients with genotype 1 hepatitis C virus : Prevalence and effect on treatment outcome. / Zeuzem, Stefan; Mizokami, Masashi; Pianko, Stephen; Mangia, Alessandra; Han, KwangHyub; Martin, Ross; Svarovskaia, Evguenia; Dvory-Sobol, Hadas; Doehle, Brian; Hedskog, Charlotte; Yun, Chohee; Brainard, Diana M.; Knox, Steven; McHutchison, John G.; Miller, Michael D.; Mo, Hongmei; Chuang, Wan Long; Jacobson, Ira; Dore, Gregory J.; Sulkowski, Mark.

In: Journal of Hepatology, Vol. 66, No. 5, 01.05.2017, p. 910-918.

Research output: Contribution to journalArticle

TY - JOUR

T1 - NS5A resistance-associated substitutions in patients with genotype 1 hepatitis C virus

T2 - Prevalence and effect on treatment outcome

AU - Zeuzem, Stefan

AU - Mizokami, Masashi

AU - Pianko, Stephen

AU - Mangia, Alessandra

AU - Han, KwangHyub

AU - Martin, Ross

AU - Svarovskaia, Evguenia

AU - Dvory-Sobol, Hadas

AU - Doehle, Brian

AU - Hedskog, Charlotte

AU - Yun, Chohee

AU - Brainard, Diana M.

AU - Knox, Steven

AU - McHutchison, John G.

AU - Miller, Michael D.

AU - Mo, Hongmei

AU - Chuang, Wan Long

AU - Jacobson, Ira

AU - Dore, Gregory J.

AU - Sulkowski, Mark

PY - 2017/5/1

Y1 - 2017/5/1

N2 - 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.

AB - 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.

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