title: Prevalence and characteristics of naturally occurring sofosbuvir resistance-associated variants in patients with hepatitis C virus genotype 1b infection.
abstract: OBJECTIVE
  Sofosbuvir (SOF), a nucleotide analog pro-drug, targets hepatitis C virus (HCV) NS5B polymerase and shows potential for treating HCV infection, given its high efficacy and good barrier to resistance. However, in addition to the rare resistant-associated variant (RAV) of non-structural protein NS5B S282T, several new potential RAVs of SOF have been reported, especially related to HCV genotype 1b. However, the prevalence and characteristics of these RAVs have not been clarified.
  
  
  METHODS
  We analyzed the prevalence of variants in the NS3/NS5A/NS5B regions in 96 patients treated with simeprevir (SMV) combination therapy, and the prevalence of RAVs in patients showing treatment failure was determined by direct- or deep-sequencing methods. Associations between these potential RAVs and clinical factors were also analyzed.
  
  
  RESULTS
  Prevalence of NS5B RAV C316N was high (46.9%, 45/96), whereas that of NS5B L159F was relatively low (1.04%, 1/96); however, deep sequencing showed that 30.0% of patients with C316N also had NS5B RAV L159F. Additionally, there was no significant relationship between the existence of potential NS5B and NS5A or NS3 RAVs. However, the presence of NS5B C316N was significantly associated with an HCV core amino acid 91 substitution. No significant difference was detected between each RAV and sustained virological response in simeprevir combination therapy.
  
  
  CONCLUSIONS
  We provide clear evidence of the high prevalence of two potential naturally occurring NS5B RAVs (C316N and L159F) in Japan. It may be important to pay particular attention to these new potential RAVs, especially when using SOF-based therapy in patients with RAVs due to previous direct-acting antiviral therapy failure.
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo.
authors.forename: Jun
authors.initials: J
authors.lastname: Ito
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo.
authors.forename: Goki
authors.initials: G
authors.lastname: Suda
authors.affiliation: Department of Gastroenterology, Hakodate City General Hospital, Hakodate.
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Gastroenterology, Sapporo City General Hospital, Sapporo.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nagasaka
authors.affiliation: Department of Gastroenterology, JCHO Hokkaido Hospital, Sapporo.
authors.forename: Ken
authors.initials: K
authors.lastname: Furuya
authors.affiliation: Department of Gastroenterology, Hakodate Medical Association Hospital, Hakodate.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Kumagai
authors.affiliation: Department of Gastroenterology, Obihiro-Kosei General Hospital, Obihiro.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kikuchi
authors.affiliation: Department of Internal Medicine and Gastroenterology, Kushiro Rosai Hospital, Kushiro.
authors.forename: Takuto
authors.initials: T
authors.lastname: Miyagishima
authors.affiliation: Department of Gastroenterology, Tomakomai City Hospital, Tomakomai, Japan.
authors.forename: Tomoe
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo.
authors.forename: Megumi
authors.initials: M
authors.lastname: Kimura
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo.
authors.forename: Kazushi
authors.initials: K
authors.lastname: Yamasaki
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo.
authors.forename: Machiko
authors.initials: M
authors.lastname: Umemura
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Izumi
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo.
authors.forename: Seiji
authors.initials: S
authors.lastname: Tsunematsu
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo.
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Sato
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Tsukuda
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Terashita
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo.
authors.forename: Masato
authors.initials: M
authors.lastname: Nakai
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo.
authors.forename: Takuya
authors.initials: T
authors.lastname: Sho
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo.
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Natsuizaka
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Morikawa
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo.
authors.forename: Koji
authors.initials: K
authors.lastname: Ogawa
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo.
authors.forename: Naoya
authors.initials: N
authors.lastname: Sakamoto
keywords: direct-acting antiviral; hepatitis C virus; resistance-associated-variant