title: Emergence of hepatitis C virus NS5A L31V plus Y93H variant upon treatment failure of daclatasvir and asunaprevir is relatively resistant to ledipasvir and NS5B polymerase nucleotide inhibitor GS-558093 in human hepatocyte chimeric mice.
abstract: BACKGROUND
  Resistance-associated variants (RAVs) emerge at multiple positions spanning hepatitis C virus (HCV) NS3/4A and NS5A regions upon failure of asunaprevir/daclatasvir combination therapy. It has not been determined whether the emergence of such RAVs have an impact on re-treatment by a combination of ledipasvir and sofosbuvir, a potent regimen for HCV genotype 1 infection.
  
  
  METHODS
  TK-NOG human hepatocyte chimeric mice were inoculated with sera from a patient with treatment failure of asunaprevir/daclatasvir therapy.
  
  
  RESULTS
  They developed persistent HCV infection with triple variants of NS3/4A D168V, NS5A L31V plus Y93H. Administration of ledipasvir/GS-558093 (a NS5B nucleotide analog) in these mice failed to achieve end-of-treatment response or sustained virologic response, which was in sharp contrast to the results in mice with wild-type virus infection. The administration of telaprevir/GS-558093 successfully achieved it in those mice.
  
  
  CONCLUSIONS
  Treatment failure with asunaprevir/daclatasvir may limit further treatment options. This population may represent a growing unmet medical need.
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Yugo
authors.initials: Y
authors.lastname: Kai
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Hikita
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tatsumi
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Tasuku
authors.initials: T
authors.lastname: Nakabori
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Morishita
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Nawa
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Tsugiko
authors.initials: T
authors.lastname: Oze
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Sakamori
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yakushijin
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Hiramatsu
authors.affiliation: Department of Laboratory Animal Research, Central Institute for Experimental Animals, Kawasaki, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suemizu
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. takehara@gh.med.osaka-u.ac.jp.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D001562:Benzimidazoles / Q000627:therapeutic use; D002219:Carbamates; D004338:Drug Combinations; D024921:Drug Resistance, Multiple, Viral / Q000235:genetics*; D005260:Female; D005449:Fluorenes / Q000627:therapeutic use; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006524:Hepatitis, Viral, Animal / Q000188:drug therapy* / Q000821:virology; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D007546:Isoquinolines / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines; D000069474:Sofosbuvir / Q000627:therapeutic use; D013449:Sulfonamides / Q000627:therapeutic use; D018183:Transplantation Chimera; D017211:Treatment Failure; D014633:Valine / Q000031:analogs & derivatives
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D002219:Carbamates; D004338:Drug Combinations; D005449:Fluorenes; D007093:Imidazoles; D007546:Isoquinolines; D011759:Pyrrolidines; D013449:Sulfonamides; C586541:ledipasvir; D014633:Valine; C549273:daclatasvir; C571889:asunaprevir; D000069474:Sofosbuvir
keywords: Asunaprevir/daclatasvir; Ledipasvir/sofosbuvir; Resistance-associated variants (RAVs)