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DC Field | Value | Language |
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dc.contributor.author | Vellucci V. | en |
dc.contributor.author | Zhou N. | en |
dc.contributor.author | Sievert W. | en |
dc.contributor.author | Bowden S. | en |
dc.contributor.author | McPhee F. | en |
dc.contributor.author | Ueland J. | en |
dc.date.accessioned | 2021-05-14T11:55:47Z | en |
dc.date.available | 2021-05-14T11:55:47Z | en |
dc.date.copyright | 2019 | en |
dc.date.created | 20190411 | en |
dc.date.issued | 2019-04-11 | en |
dc.identifier.citation | Antimicrobial Agents and Chemotherapy. 63 (4) (no pagination), 2019. Article Number: e02205-18. Date of Publication: April 2019. | en |
dc.identifier.issn | 0066-4804 | en |
dc.identifier.uri | https://repository.monashhealth.org/monashhealthjspui/handle/1/35322 | en |
dc.description.abstract | HCV genotype 6 (GT-6) is found predominantly in East and Southeast Asia. Clinical studies have focused on patients infected with hepatitis C virus (HCV) GT-6a, where high sustained virologic response (SVR) rates to direct-acting antivirals (DAAs) have been achieved. However, GT-6 is highly diverse, with 29 reported subtypes. We explored the diversity of GT-6 polymorphisms at residues associated with DAA resistance, their impact on DAA in vitro potency when evaluated in a GT-6a consensus replicon, and their association with specific GT-6 subtypes. GT-6 sequences from 25 patient-derived samples and 105 sequences from the U.S. HCV database were compared, and substitutions at resistance-associated residue positions were phenotyped against different DAAs. Preexisting resistance-associated substitutions (RASs) to NS3 protease (A156V and D168E) and NS5B nucleotide (L159F and S282C) inhibitors were rare (4%). Preexisting RASs to NS5A inhibitors were common, especially at L28 (A/F/G/M/T/V) and R30 (E/N/S). In vitro susceptibilities of NS5A-L28A and -L28T were dramatically reduced against all tested NS5A drugs (90% effective concentration [EC90] range, 119 to 2,032 nM) compared with susceptibilities against a GT-6a consensus replicon (EC90 range, 0.1 to 19 nM). These L28 RASs preexisted in combination with R30S (EC90 [L28A-R30S] of 720 nM or EC90 [L28T-R30S] of 128 nM against tested DAAs) or as L28T-L31I (EC90 [tested DAAs] of 5,000 nM) and were detected in evaluated GT-6b and -6f sequences. NS5A-L28A-R30A, observed in GT-6r, did not replicate. In conclusion, HCV GT-6b, GT-6f, and GT-6r sequences harbored highly resistant RASs to all evaluated NS5A drugs. Therefore, monitoring SVR in patients infected with these GT-6 subtypes treated with NS5A drug-containing regimens is suggested to confirm any association between noted NS5A polymorphisms and treatment failure.Copyright © 2019 American Society for Microbiology. All Rights Reserved. | en |
dc.language | en | en |
dc.language | English | en |
dc.publisher | American Society for Microbiology (E-mail: Journals@asmusa.org) | en |
dc.relation.ispartof | Antimicrobial Agents and Chemotherapy | en |
dc.title | Impact of preexisting hepatitis C virus genotype 6 NS3, NS5A, and NS5B polymorphisms on the in vitro potency of direct-acting antiviral agents. | en |
dc.type | Article | en |
dc.identifier.doi | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1128/AAC.02205-18 | en |
dc.publisher.place | United States | en |
dc.identifier.pubmedid | 30718256 [http://www.ncbi.nlm.nih.gov/pubmed/?term=30718256] | en |
dc.identifier.source | 2001762724 | en |
dc.identifier.institution | (McPhee, Ueland, Vellucci, Zhou) Bristol-Myers Squibb Research and Development, Wallingford, CT, United States (Bowden) Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia (Sievert) Centre for Inflammatory Diseases, Monash University and Monash Health, Melbourne, VIC, Australia (McPhee) Bristol Myers Squibb, Cambridge, MA, United States | en |
dc.description.address | F. McPhee, Bristol-Myers Squibb Research and Development, Wallingford, CT, United States. E-mail: fiona.mcphee@bms.com | en |
dc.description.publicationstatus | Embase | en |
dc.rights.statement | Copyright 2020 Elsevier B.V., All rights reserved. | en |
dc.subect.keywords | Genotype 6 HCV NS3 NS5A NS5B Ombitasvir Polymorphism Resistance Sofosbuvir Velpatasvir | en |
dc.identifier.authoremail | McPhee F.; fiona.mcphee@bms.com | en |
item.openairetype | Article | - |
item.fulltext | No Fulltext | - |
item.grantfulltext | none | - |
item.openairecristype | http://purl.org/coar/resource_type/c_18cf | - |
item.cerifentitytype | Publications | - |
crisitem.author.dept | Gastroenterology and Hepatology | - |
Appears in Collections: | Articles |
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