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Title: Evolution of multi-drug resistant HCV clones from pre-existing resistant-associated variants during direct-acting antiviral therapy determined by third-generation sequencing
Authors: Takeda, Haruhiko
Ueda, Yoshihide  kyouindb  KAKEN_id  orcid (unconfirmed)
Inuzuka, Tadashi
Yamashita, Yukitaka
Osaki, Yukio
Nasu, Akihiro
Umeda, Makoto
Takemura, Ryo
Seno, Hiroshi  kyouindb  KAKEN_id
Sekine, Akihiro
Marusawa, Hiroyuki
Author's alias: 竹田, 治彦
上田, 佳秀
犬塚, 義
妹尾, 浩
丸澤, 宏之
Keywords: Evolutionary genetics
Hepatitis C
Viral genetics
Issue Date: 31-Mar-2017
Publisher: Springer Nature
Journal title: Scientific Reports
Volume: 7
Thesis number: 45605
Abstract: © 2017 The Author(s).Resistance-associated variant (RAV) is one of the most significant clinical challenges in treating HCV-infected patients with direct-acting antivirals (DAAs). We investigated the viral dynamics in patients receiving DAAs using third-generation sequencing technology. Among 283 patients with genotype-1b HCV receiving daclatasvir + asunaprevir (DCV/ASV), 32 (11.3%) failed to achieve sustained virological response (SVR). Conventional ultra-deep sequencing of HCV genome was performed in 104 patients (32 non-SVR, 72 SVR), and detected representative RAVs in all non-SVR patients at baseline, including Y93H in 28 (87.5%). Long contiguous sequences spanning NS3 to NS5A regions of each viral clone in 12 sera from 6 representative non-SVR patients were determined by third-generation sequencing, and showed the concurrent presence of several synonymous mutations linked to resistance-associated substitutions in a subpopulation of pre-existing RAVs and dominant isolates at treatment failure. Phylogenetic analyses revealed close genetic distances between pre-existing RAVs and dominant RAVs at treatment failure. In addition, multiple drug-resistant mutations developed on pre-existing RAVs after DCV/ASV in all non-SVR cases. In conclusion, multi-drug resistant viral clones at treatment failure certainly originated from a subpopulation of pre-existing RAVs in HCV-infected patients. Those RAVs were selected for and became dominant with the acquisition of multiple resistance-associated substitutions under DAA treatment pressure.
Rights: © The Author(s) 2017. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit
DOI(Published Version): 10.1038/srep45605
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