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, Kwang-Hyub
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
N1 - This study was sponsored by Gilead Sciences, Inc who was also involved with the study design, as well as the analysis and interpretation of data.
PY - 2017/5
Y1 - 2017/5
N2 - BACKGROUND: 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 1, 2, and 3 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 5,397 patients in Gilead clinical trials. The effect of baseline RASs on sustained virologic response (SVR) rates was assessed in the 1,765 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) with and without ledipasvir-specific RASs, respectively. Among treatment-experienced genotype 1a patients, SVR rates were 76% (22/29) vs 97% (409/420) with and without ledipasvir-specific RASs, respectively. Among treatment-naïve genotype 1b patients, SVR rates were 99% for both those with and without LDV-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 in particular 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 in particular treatment-experienced patients with genotype 1a HCV.
AB - BACKGROUND: 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 1, 2, and 3 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 5,397 patients in Gilead clinical trials. The effect of baseline RASs on sustained virologic response (SVR) rates was assessed in the 1,765 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) with and without ledipasvir-specific RASs, respectively. Among treatment-experienced genotype 1a patients, SVR rates were 76% (22/29) vs 97% (409/420) with and without ledipasvir-specific RASs, respectively. Among treatment-naïve genotype 1b patients, SVR rates were 99% for both those with and without LDV-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 in particular 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 in particular treatment-experienced patients with genotype 1a HCV.
KW - NS5A
KW - RAS
KW - HCV genotype 1
KW - ledipasvir-sofosbuvir
U2 - 10.1016/j.jhep.2017.01.007
DO - 10.1016/j.jhep.2017.01.007
M3 - Article
C2 - 28108232
SN - 0168-8278
VL - 66
SP - 910
EP - 918
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 5
ER -
