title: New resistance-associated substitutions and failure of dual oral therapy with daclatasvir and asunaprevir.
abstract: BACKGROUND
  Daclatasvir (DCV) and asunaprevir (ASV) combination therapy has been primarily used in patients without NS5A L31 or Y93 resistance-associated substitutions (RASs) before treatment. We examined the characteristics of patients without these baseline RASs who did not achieve hepatitis C virus eradication with DCV and ASV combination therapy and identified new baseline NS5A RASs that are closely associated with failure of combination therapy.
  
  
  METHODS
  Three hundred thirty-five patients with hepatitis C virus genotype 1 infection with no NS5A L31, NS5A Y93, and NS3 D168 RASs before DCV and ASV combination therapy and no history of protease inhibitor therapy were enrolled. All RASs were evaluated by direct sequencing.
  
  
  RESULTS
  Sustained virologic response at 12 weeks (SVR12) was achieved in 297 patients (89%). Patients with NS5A Q24, L28, and/or R30 RASs or concomitant NS5A F37 and Q54 RASs had a significantly lower SVR12 rate than patients without these RASs (70% vs 92%, p < 0.001 and 79% vs 92%, p = 0.002 respectively). Multivariate analysis showed that NS5A Q24, L28, and/or R30 RASs and concomitant NS5A F37 and Q54 RASs were significantly associated with virologic failure. The SVR12 rate in patients without NS5A Q24, L28, and/or R30 RASs and concomitant NS5A F37 and Q54 RASs was 96.2% (202/210).
  
  
  CONCLUSIONS
  In patients without NS5A L31 or Y93 RASs, the presence of NS5A Q24, L28, and/or R30 RASs and concomitant NS5A F37 and Q54 RASs at the baseline was associated with failure of DCV and ASV combination therapy. The coexistence of baseline RASs other than NS5A L31 and Y93 may affect the therapeutic effectiveness of DCV and ASV combination therapy.
authors.affiliation: Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan. mawatari@m2.kufm.kagoshima-u.ac.jp.
authors.forename: Seiichi
authors.identifier: http://orcid.org/0000-0002-3847-1065
authors.initials: S
authors.lastname: Mawatari
authors.affiliation: Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Oda
authors.affiliation: Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Tabu
authors.affiliation: Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Ijuin
authors.affiliation: Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Kumagai
authors.affiliation: Center for Digestive and Liver Diseases, Miyazaki Medical Center Hospital, 2-16 Takamatsu-cho, Miyazaki, 880-0003, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Inada
authors.affiliation: Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.|Center for Digestive and Liver Diseases, Miyazaki Medical Center Hospital, 2-16 Takamatsu-cho, Miyazaki, 880-0003, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Uto
authors.affiliation: Department of Internal Medicine, Kagoshima Kouseiren Hospital, 22-25 Tenpozan-cho, Kagoshima, 890-0061, Japan.
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Hiramine
authors.affiliation: Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.|Department of Internal Medicine, Kagoshima Kouseiren Hospital, 22-25 Tenpozan-cho, Kagoshima, 890-0061, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kure
authors.affiliation: Department of Hepatology, Kirishima Medical Center, 3320 Hayato-cho, Kirishima, Kagoshima, 899-5112, Japan.
authors.forename: Kunio
authors.initials: K
authors.lastname: Fujisaki
authors.affiliation: Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.|Department of Hepatology, Kirishima Medical Center, 3320 Hayato-cho, Kirishima, Kagoshima, 899-5112, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Hashiguchi
authors.affiliation: Department of Gastroenterology and Hepatology, Kagoshima City Hospital, 37-1 Uearata-cho, Kagoshima, 890-8760, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hori
authors.affiliation: Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.|Department of Gastroenterology and Hepatology, Kagoshima City Hospital, 37-1 Uearata-cho, Kagoshima, 890-8760, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Oshige
authors.affiliation: Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.|Department of Gastroenteroloby, Ikeda Hospital, 1830 Shimoharaigawa-cho, Kanoya, Kagoshima, 893-0024, Japan.
authors.forename: Dai
authors.initials: D
authors.lastname: Imanaka
authors.affiliation: Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.|Department of Hepatology, Kagoshima Teishin Hospital, 1-12-1 Shimoishiki, Kagoshima, 890-8798, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Saishoji
authors.affiliation: Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
authors.forename: Oki
authors.initials: O
authors.lastname: Taniyama
authors.affiliation: Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Sakae
authors.affiliation: Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Tamai
authors.affiliation: Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Moriuchi
authors.affiliation: Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Ido
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents / Q000627:therapeutic use*; D002219:Carbamates; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007546:Isoquinolines / Q000627:therapeutic use*; D008103:Liver Cirrhosis / Q000821:virology; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines; D012737:Sex Factors; D013449:Sulfonamides / Q000627:therapeutic use*; D000072230:Sustained Virologic Response; D017211:Treatment Failure; D014633:Valine / Q000031:analogs & derivatives; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D007546:Isoquinolines; D011759:Pyrrolidines; D013449:Sulfonamides; D014633:Valine; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C549273:daclatasvir; C571889:asunaprevir
keywords: Asunaprevir; Daclatasvir; Hepatitis C virus; NS5A resistance-associated substitutions