title: High Sustained Virologic Response to Daclatasvir Plus Asunaprevir in Elderly and Cirrhotic Patients with Hepatitis C Virus Genotype 1b Without Baseline NS5A Polymorphisms.
abstract: BACKGROUND
  Oral daclatasvir (DCV; pangenotypic NS5A inhibitor) plus asunaprevir (ASV; NS3 protease inhibitor) is approved in Japan and Korea for treatment of chronic hepatitis C virus (HCV) genotype 1. Response to DCV + ASV is affected by DCV resistance-associated polymorphisms (RAPs) in HCV NS5A. The prevalence and influence of these RAPs on 12-week sustained virologic response (SVR12) to DCV + ASV was evaluated in Asian and non-Asian patients.
  
  
  METHODS
  Data were pooled from 5 national and international studies of patients with HCV genotype 1b (GT-1b) receiving DCV + ASV at their recommended doses. Baseline NS5A RAPs and their effect on SVR12 were assessed overall, in older (≥65 years) patients, patients with cirrhosis, and in patients stratified by baseline HCV RNA or prior treatment experience with interferon-based therapy.
  
  
  RESULTS
  Baseline NS5A sequences were available from 988 patients (374 Japanese; 125 Korean/Taiwanese; 489 from non-Asian countries), 979 of whom were assessed for SVR12. Pretreatment NS5A-L31F/I/M/V and/or NS5A-Y93H polymorphisms were present in 18% of Japanese and 12-13% of non-Japanese patients; these RAPs reduced SVR12 by 54.9% overall (93.9% [787/838] SVR12 when absent, 39.0% [55/141] SVR12 when present), with comparable reductions observed in Asians and non-Asians and across all categories of treatment experience, age, and cirrhosis. RAP-associated SVR12 rates declined with increasing baseline HCV RNA (SVR12 with RAPs: 64.7% [11/17] at 5-6 log10 IU/mL, 29.8% [14/47] at 7-8 log10). Without baseline RAPs, very high SVR12 rates (92-100%) were observed in older patients and patients with cirrhosis irrespective of national origin, with similarly high rates observed among treatment-naïve and interferon-experienced patients and those with high baseline HCV RNA.
  
  
  CONCLUSIONS
  Following DCV + ASV treatment, the SVR12 rates in GT-1b patients without baseline NS5A-L31F/I/M/V and/or NS5A-Y93H polymorphisms were very high (approximately 90-100%), irrespective of age, cirrhosis, prior interferon treatment, or baseline HCV RNA.
  
  
  BACKGROUND
  Bristol-Myers Squibb.
authors.affiliation: Bristol-Myers Squibb Research and Development, Wallingford, CT, USA, fiona.mcphee@BMS.com.
authors.forename: Fiona
authors.initials: F
authors.lastname: McPhee
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Joji
authors.initials: J
authors.lastname: Toyota
authors.forename: Yoshiyasu
authors.initials: Y
authors.lastname: Karino
authors.forename: Kasuaki
authors.initials: K
authors.lastname: Chayama
authors.forename: Yoshiiku
authors.initials: Y
authors.lastname: Kawakami
authors.forename: Min Lung
authors.initials: ML
authors.lastname: Yu
authors.forename: Sang Hoon
authors.initials: SH
authors.lastname: Ahn
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ishikawa
authors.forename: Rafia
authors.initials: R
authors.lastname: Bhore
authors.forename: Nannan
authors.initials: N
authors.lastname: Zhou
authors.forename: Dennis
authors.initials: D
authors.lastname: Hernandez
authors.forename: Patricia
authors.initials: P
authors.lastname: Mendez
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kumada
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D044466:Asian People; D002219:Carbamates; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D007546:Isoquinolines / Q000008:administration & dosage / Q000627:therapeutic use*; D007564:Japan; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000209:etiology; D008875:Middle Aged; D010750:Phosphoproteins / Q000235:genetics; D011110:Polymorphism, Genetic; D011759:Pyrrolidines; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*; D014633:Valine / Q000031:analogs & derivatives; D017361:Viral Nonstructural Proteins / Q000235:genetics; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D007546:Isoquinolines; D010750:Phosphoproteins; D011759:Pyrrolidines; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C532378:nonstructural phosphoprotein 5A, GB virus type C; D014633:Valine; C549273:daclatasvir; C571889:asunaprevir