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Evolutionary Pathways to Persistence of Highly Fit and Resistant Hepatitis C Virus Protease Inhibitor Escape Variants

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@article{6b65007aa7494d95bc2a2504d84c42d4,
title = "Evolutionary Pathways to Persistence of Highly Fit and Resistant Hepatitis C Virus Protease Inhibitor Escape Variants",
abstract = "Protease inhibitors (PIs) are important components of treatment regimens for patients with chronic hepatitis C virus (HCV) infection. However, emergence and persistence of antiviral resistance could reduce their efficacy. Thus, defining resistance determinants is highly relevant for efforts to control HCV. Here, we investigated patterns of PI resistance associated substitutions (RASs) for the major HCV genotypes and viral determinants for persistence of key RASs. We identified protease position 156 as RAS hotspot for genotype 1-4, but not 5 and 6 escape variants by resistance profiling using PIs grazoprevir and paritaprevir in infectious cell culture systems. However, except for genotype 3, engineered 156-RASs were not maintained. For genotypes 1 and 2, persistence of 156-RASs depended on genome-wide substitution networks, co-selected under continued PI treatment and identified by next generation sequencing with substitution linkage and haplotype reconstruction. Persistence of A156T for genotype 1 relied on compensatory substitutions increasing replication and assembly. For genotype 2, initial selection of A156V facilitated transition to 156L, persisting without compensatory substitutions. The developed genotype 1, 2, and 3 variants with persistent 156-RASs had exceptionally high fitness and resistance to grazoprevir, paritaprevir, glecaprevir and voxilaprevir. A156T dominated in genotype 1 glecaprevir and voxilaprevir escape variants, and pre-existing A156T facilitated genotype 1 escape from clinically relevant combination treatments with grazoprevir/elbasvir and glecaprevir/pibrentasvir. In genotype 1 infected patients with treatment failure and 156-RASs we observed genome-wide selection of substitutions under treatment. CONCLUSIONS: Comprehensive PI resistance profiling for HCV genotypes 1-6 revealed 156-RASs as key determinants of high-level resistance across clinically relevant PIs. We obtained in vitro proof-of-concept for persistence of highly fit genotype 1-3 156-variants, which might pose a threat to clinically relevant combination treatments. This article is protected by copyright. All rights reserved.",
author = "Jensen, {Sanne Brun} and Ulrik Fahn{\o}e and Pham, {Long V} and St{\'e}phanie Serre and Qi Tang and Lubna Ghanem and Pedersen, {Martin Schou} and Santseharay Ramirez and Daryl Humes and Pihl, {Anne Finne} and Jonathan Filskov and S{\o}lund, {Christina S{\o}hoel} and Julia Dietz and Slim Fourati and Jean-Michel Pawlotsky and Christoph Sarrazin and Nina Weis and Kristian Sch{\o}nning and Henrik Krarup and Jens Bukh and Gottwein, {Judith Margarete}",
note = "{\textcopyright} 2019 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases.",
year = "2019",
month = sep,
doi = "10.1002/hep.30647",
language = "English",
volume = "70",
pages = "771--787",
journal = "Hepatology",
issn = "0270-9139",
publisher = "Wiley",
number = "3",

}

RIS

TY - JOUR

T1 - Evolutionary Pathways to Persistence of Highly Fit and Resistant Hepatitis C Virus Protease Inhibitor Escape Variants

AU - Jensen, Sanne Brun

AU - Fahnøe, Ulrik

AU - Pham, Long V

AU - Serre, Stéphanie

AU - Tang, Qi

AU - Ghanem, Lubna

AU - Pedersen, Martin Schou

AU - Ramirez, Santseharay

AU - Humes, Daryl

AU - Pihl, Anne Finne

AU - Filskov, Jonathan

AU - Sølund, Christina Søhoel

AU - Dietz, Julia

AU - Fourati, Slim

AU - Pawlotsky, Jean-Michel

AU - Sarrazin, Christoph

AU - Weis, Nina

AU - Schønning, Kristian

AU - Krarup, Henrik

AU - Bukh, Jens

AU - Gottwein, Judith Margarete

N1 - © 2019 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases.

PY - 2019/9

Y1 - 2019/9

N2 - Protease inhibitors (PIs) are important components of treatment regimens for patients with chronic hepatitis C virus (HCV) infection. However, emergence and persistence of antiviral resistance could reduce their efficacy. Thus, defining resistance determinants is highly relevant for efforts to control HCV. Here, we investigated patterns of PI resistance associated substitutions (RASs) for the major HCV genotypes and viral determinants for persistence of key RASs. We identified protease position 156 as RAS hotspot for genotype 1-4, but not 5 and 6 escape variants by resistance profiling using PIs grazoprevir and paritaprevir in infectious cell culture systems. However, except for genotype 3, engineered 156-RASs were not maintained. For genotypes 1 and 2, persistence of 156-RASs depended on genome-wide substitution networks, co-selected under continued PI treatment and identified by next generation sequencing with substitution linkage and haplotype reconstruction. Persistence of A156T for genotype 1 relied on compensatory substitutions increasing replication and assembly. For genotype 2, initial selection of A156V facilitated transition to 156L, persisting without compensatory substitutions. The developed genotype 1, 2, and 3 variants with persistent 156-RASs had exceptionally high fitness and resistance to grazoprevir, paritaprevir, glecaprevir and voxilaprevir. A156T dominated in genotype 1 glecaprevir and voxilaprevir escape variants, and pre-existing A156T facilitated genotype 1 escape from clinically relevant combination treatments with grazoprevir/elbasvir and glecaprevir/pibrentasvir. In genotype 1 infected patients with treatment failure and 156-RASs we observed genome-wide selection of substitutions under treatment. CONCLUSIONS: Comprehensive PI resistance profiling for HCV genotypes 1-6 revealed 156-RASs as key determinants of high-level resistance across clinically relevant PIs. We obtained in vitro proof-of-concept for persistence of highly fit genotype 1-3 156-variants, which might pose a threat to clinically relevant combination treatments. This article is protected by copyright. All rights reserved.

AB - Protease inhibitors (PIs) are important components of treatment regimens for patients with chronic hepatitis C virus (HCV) infection. However, emergence and persistence of antiviral resistance could reduce their efficacy. Thus, defining resistance determinants is highly relevant for efforts to control HCV. Here, we investigated patterns of PI resistance associated substitutions (RASs) for the major HCV genotypes and viral determinants for persistence of key RASs. We identified protease position 156 as RAS hotspot for genotype 1-4, but not 5 and 6 escape variants by resistance profiling using PIs grazoprevir and paritaprevir in infectious cell culture systems. However, except for genotype 3, engineered 156-RASs were not maintained. For genotypes 1 and 2, persistence of 156-RASs depended on genome-wide substitution networks, co-selected under continued PI treatment and identified by next generation sequencing with substitution linkage and haplotype reconstruction. Persistence of A156T for genotype 1 relied on compensatory substitutions increasing replication and assembly. For genotype 2, initial selection of A156V facilitated transition to 156L, persisting without compensatory substitutions. The developed genotype 1, 2, and 3 variants with persistent 156-RASs had exceptionally high fitness and resistance to grazoprevir, paritaprevir, glecaprevir and voxilaprevir. A156T dominated in genotype 1 glecaprevir and voxilaprevir escape variants, and pre-existing A156T facilitated genotype 1 escape from clinically relevant combination treatments with grazoprevir/elbasvir and glecaprevir/pibrentasvir. In genotype 1 infected patients with treatment failure and 156-RASs we observed genome-wide selection of substitutions under treatment. CONCLUSIONS: Comprehensive PI resistance profiling for HCV genotypes 1-6 revealed 156-RASs as key determinants of high-level resistance across clinically relevant PIs. We obtained in vitro proof-of-concept for persistence of highly fit genotype 1-3 156-variants, which might pose a threat to clinically relevant combination treatments. This article is protected by copyright. All rights reserved.

UR - http://www.scopus.com/inward/record.url?scp=85071462326&partnerID=8YFLogxK

U2 - 10.1002/hep.30647

DO - 10.1002/hep.30647

M3 - Journal article

C2 - 30964552

VL - 70

SP - 771

EP - 787

JO - Hepatology

JF - Hepatology

SN - 0270-9139

IS - 3

ER -

ID: 56978088