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Resistance Analysis of a 3-Day Monotherapy Study with Glecaprevir or Pibrentasvir in Patients with Chronic Hepatitis C Virus Genotype 1 Infection

Glecaprevir (an NS3/4A protease inhibitor) and pibrentasvir (an NS5A inhibitor) are potent and pangenotypic hepatitis C virus (HCV) direct-acting antivirals. This report describes the baseline polymorphisms and treatment-emergent substitutions in NS3 or NS5A detected in samples from HCV genotype 1-i...

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Autores principales: Ng, Teresa I., Pilot-Matias, Tami, Tripathi, Rakesh, Schnell, Gretja, Krishnan, Preethi, Reisch, Thomas, Beyer, Jill, Dekhtyar, Tatyana, Irvin, Michelle, Lu, Liangjun, Asatryan, Armen, Campbell, Andrew, Yao, Betty, Lovell, Sandra, Mensa, Federico, Lawitz, Eric J., Kort, Jens, Collins, Christine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6163913/
https://www.ncbi.nlm.nih.gov/pubmed/30154359
http://dx.doi.org/10.3390/v10090462
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author Ng, Teresa I.
Pilot-Matias, Tami
Tripathi, Rakesh
Schnell, Gretja
Krishnan, Preethi
Reisch, Thomas
Beyer, Jill
Dekhtyar, Tatyana
Irvin, Michelle
Lu, Liangjun
Asatryan, Armen
Campbell, Andrew
Yao, Betty
Lovell, Sandra
Mensa, Federico
Lawitz, Eric J.
Kort, Jens
Collins, Christine
author_facet Ng, Teresa I.
Pilot-Matias, Tami
Tripathi, Rakesh
Schnell, Gretja
Krishnan, Preethi
Reisch, Thomas
Beyer, Jill
Dekhtyar, Tatyana
Irvin, Michelle
Lu, Liangjun
Asatryan, Armen
Campbell, Andrew
Yao, Betty
Lovell, Sandra
Mensa, Federico
Lawitz, Eric J.
Kort, Jens
Collins, Christine
author_sort Ng, Teresa I.
collection PubMed
description Glecaprevir (an NS3/4A protease inhibitor) and pibrentasvir (an NS5A inhibitor) are potent and pangenotypic hepatitis C virus (HCV) direct-acting antivirals. This report describes the baseline polymorphisms and treatment-emergent substitutions in NS3 or NS5A detected in samples from HCV genotype 1-infected patients receiving 3-day monotherapy of glecaprevir or pibrentasvir, respectively. None of the NS3 polymorphisms detected in the 47 baseline samples collected prior to glecaprevir monotherapy conferred reduced susceptibility to glecaprevir. The NS3 A156T substitution, which conferred resistance to glecaprevir but had low replication efficiency, emerged in one genotype 1a-infected patient among the 35 patients with available post-baseline sequence data. Baseline NS5A polymorphisms were detected in 12 of 40 patients prior to pibrentasvir monotherapy; most polymorphisms were single-position NS5A amino acid substitutions that did not confer resistance to pibrentasvir. Among the 19 patients with available post-baseline NS5A sequence data, 3 had treatment-emergent NS5A substitutions during pibrentasvir monotherapy. All treatment-emergent NS5A substitutions were linked multiple-position, almost exclusively double-position, substitutions that conferred resistance to pibrentasvir. Replicons engineered with these double-position substitutions had low replication efficiency. In conclusion, resistance-conferring substitutions emerged in a small number of genotype 1-infected patients during glecaprevir or pibrentasvir monotherapy; unlike other NS5A inhibitors, pibrentasvir did not select single-position NS5A substitutions during monotherapy.
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spelling pubmed-61639132018-10-11 Resistance Analysis of a 3-Day Monotherapy Study with Glecaprevir or Pibrentasvir in Patients with Chronic Hepatitis C Virus Genotype 1 Infection Ng, Teresa I. Pilot-Matias, Tami Tripathi, Rakesh Schnell, Gretja Krishnan, Preethi Reisch, Thomas Beyer, Jill Dekhtyar, Tatyana Irvin, Michelle Lu, Liangjun Asatryan, Armen Campbell, Andrew Yao, Betty Lovell, Sandra Mensa, Federico Lawitz, Eric J. Kort, Jens Collins, Christine Viruses Article Glecaprevir (an NS3/4A protease inhibitor) and pibrentasvir (an NS5A inhibitor) are potent and pangenotypic hepatitis C virus (HCV) direct-acting antivirals. This report describes the baseline polymorphisms and treatment-emergent substitutions in NS3 or NS5A detected in samples from HCV genotype 1-infected patients receiving 3-day monotherapy of glecaprevir or pibrentasvir, respectively. None of the NS3 polymorphisms detected in the 47 baseline samples collected prior to glecaprevir monotherapy conferred reduced susceptibility to glecaprevir. The NS3 A156T substitution, which conferred resistance to glecaprevir but had low replication efficiency, emerged in one genotype 1a-infected patient among the 35 patients with available post-baseline sequence data. Baseline NS5A polymorphisms were detected in 12 of 40 patients prior to pibrentasvir monotherapy; most polymorphisms were single-position NS5A amino acid substitutions that did not confer resistance to pibrentasvir. Among the 19 patients with available post-baseline NS5A sequence data, 3 had treatment-emergent NS5A substitutions during pibrentasvir monotherapy. All treatment-emergent NS5A substitutions were linked multiple-position, almost exclusively double-position, substitutions that conferred resistance to pibrentasvir. Replicons engineered with these double-position substitutions had low replication efficiency. In conclusion, resistance-conferring substitutions emerged in a small number of genotype 1-infected patients during glecaprevir or pibrentasvir monotherapy; unlike other NS5A inhibitors, pibrentasvir did not select single-position NS5A substitutions during monotherapy. MDPI 2018-08-28 /pmc/articles/PMC6163913/ /pubmed/30154359 http://dx.doi.org/10.3390/v10090462 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ng, Teresa I.
Pilot-Matias, Tami
Tripathi, Rakesh
Schnell, Gretja
Krishnan, Preethi
Reisch, Thomas
Beyer, Jill
Dekhtyar, Tatyana
Irvin, Michelle
Lu, Liangjun
Asatryan, Armen
Campbell, Andrew
Yao, Betty
Lovell, Sandra
Mensa, Federico
Lawitz, Eric J.
Kort, Jens
Collins, Christine
Resistance Analysis of a 3-Day Monotherapy Study with Glecaprevir or Pibrentasvir in Patients with Chronic Hepatitis C Virus Genotype 1 Infection
title Resistance Analysis of a 3-Day Monotherapy Study with Glecaprevir or Pibrentasvir in Patients with Chronic Hepatitis C Virus Genotype 1 Infection
title_full Resistance Analysis of a 3-Day Monotherapy Study with Glecaprevir or Pibrentasvir in Patients with Chronic Hepatitis C Virus Genotype 1 Infection
title_fullStr Resistance Analysis of a 3-Day Monotherapy Study with Glecaprevir or Pibrentasvir in Patients with Chronic Hepatitis C Virus Genotype 1 Infection
title_full_unstemmed Resistance Analysis of a 3-Day Monotherapy Study with Glecaprevir or Pibrentasvir in Patients with Chronic Hepatitis C Virus Genotype 1 Infection
title_short Resistance Analysis of a 3-Day Monotherapy Study with Glecaprevir or Pibrentasvir in Patients with Chronic Hepatitis C Virus Genotype 1 Infection
title_sort resistance analysis of a 3-day monotherapy study with glecaprevir or pibrentasvir in patients with chronic hepatitis c virus genotype 1 infection
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6163913/
https://www.ncbi.nlm.nih.gov/pubmed/30154359
http://dx.doi.org/10.3390/v10090462
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