Stefan Zeuzem1, Masashi Mizokami2, Stephen Pianko3, Alessandra Mangia4, Kwang-Hyub Han5, Ross Martin6, Evguenia Svarovskaia6, Hadas Dvory-Sobol6, Brian Doehle6, Charlotte Hedskog6, Chohee Yun6, Diana M Brainard6, Steven Knox6, John G McHutchison6, Michael D Miller7, Hongmei Mo6, Wan-Long Chuang8, Ira Jacobson9, Gregory J Dore10, Mark Sulkowski11. 1. Goethe-Universität, Frankfurt am Main, Germany. Electronic address: zeuzem@em.uni-frankfurt.de. 2. National Center for Global Health and Medicine, Chiba, Japan. 3. Monash Health and Monash University, Melbourne, Australia. 4. IRCCS Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy. 5. Yonsei University College of Medicine, Seoul, Republic of Korea. 6. Gilead Sciences, Inc., Foster City, CA, United States. 7. University of Dundee, Dundee, United Kingdom. 8. Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan. 9. Icahn School of Medicine at Mount Sinai, New York, NY, United States. 10. The Kirby Institute, University of New South Wales, Sydney, Australia. 11. Johns Hopkins University School of Medicine, Baltimore, MD, United States.
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.
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.
Authors: Massimo Andreoni; Sergio Babudieri; Savino Bruno; Massimo Colombo; Anna L Zignego; Vito Di Marco; Giovanni Di Perri; Carlo F Perno; Massimo Puoti; Gloria Taliani; Erica Villa; Antonio Craxì Journal: Infection Date: 2017-11-02 Impact factor: 3.553