title: NS5A resistance-associated variants undermine the effectiveness of ledipasvir and sofosbuvir for cirrhotic patients infected with HCV genotype 1b.
abstract: BACKGROUND
  Little real-world cohort data has been reported for Asians who have received interferon-free regimens with sofosbuvir (SOF) for chronic hepatitis C virus (HCV) infection. We evaluated the effectiveness and safety in clinical practice of ledipasvir (LDV) plus SOF for Japanese patients infected with HCV genotype 1.
  
  
  METHODS
  This large, multicenter, real-world cohort study consisted of 772 patients treatment-naive or -experienced, with or without compensated cirrhosis, who were treated with LDV (90 mg)/SOF (400 mg) for a fixed 12-week duration. Direct sequence analysis of the NS5A genes (L31 and Y93) was performed at baseline.
  
  
  RESULTS
  Almost all (99.6%) were infected with HCV genotype 1b. The overall sustained virological response 12 weeks after the end of treatment (SVR12) rate was 98.8% (763/772). Multivariable logistic regression analysis extracted male (odds ratio [OR] 6.62, p = 0.024), cirrhosis (OR 20.1, p = 0.0054), and baseline NS5A resistance-associated variants (RAVs) (OR 29.3, p = 0.0018) as independently associated with treatment failure. Notably, the SVR12 rate for cirrhosis patients with baseline NS5A RAVs (87.5%, 49/56) was statistically lower than for the other groups. This tendency was found except for patients with prior daclatasvir/asunaprevir failure. All patients with treatment failure had NS5A Y93H at relapse, whether or not they had NS5A RAVs at baseline. Serious adverse effects were very rare, and discontinuation was required for only five (0.6%) patients.
  
  
  CONCLUSIONS
  LDV/SOF for HCV genotype 1b was exceptionally effective, however, NS5A RAVs undermined the virological effect for cirrhosis patients. Moreover, LDV/SOF was shown to be safe, irrespective of age or fibrosis status.
authors.affiliation: Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Ogawa
authors.affiliation: Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Furusyo
authors.affiliation: The Center for Liver Disease, Shin-Kokura Hospital, Kitakyushu, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Nomura
authors.affiliation: Department of Internal Medicine, Chihaya Hospital, Fukuoka, Japan.
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Dohmen
authors.affiliation: Department of Hepatology, Steel Memorial Yawata Hospital, Kitakyushu, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Higashi
authors.affiliation: Department of Medicine, Hamanomachi Hospital, Fukuoka, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Medicine, Kitakyushu Municipal Medical Center, Kitakyushu, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kawano
authors.affiliation: Department of Medicine, Kyushu Central Hospital, Fukuoka, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Azuma
authors.affiliation: Center for Liver Disease, National Hospital Organization Kokura Medical Center, Kitakyushu, Japan.
authors.forename: Takeaki
authors.initials: T
authors.lastname: Satoh
authors.affiliation: Department of Gastroenterology, Kyushu Medical Center, National Hospital Organization, Fukuoka, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakamuta
authors.affiliation: Department of Medicine, Fukuoka City Hospital, Fukuoka, Japan.
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Koyanagi
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Shimoda
authors.affiliation: Kajiwara Clinic, Kitakyushu, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kajiwara
authors.affiliation: Kyushu General Internal Medicine Center, Haradoi Hospital, Higashi-Ku, Fukuoka, 812-8582, Japan. hayashij1949@haradoi-hospital.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Hayashi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D015331:Cohort Studies; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D005449:Fluorenes / Q000009:adverse effects / Q000627:therapeutic use*; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D008103:Liver Cirrhosis / Q000821:virology; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D012737:Sex Factors; D000069474:Sofosbuvir / Q000009:adverse effects / Q000627:therapeutic use*; D000072230:Sustained Virologic Response; D017211:Treatment Failure; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D055815:Young Adult; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D005449:Fluorenes; D000069474:Sofosbuvir; D017361:Viral Nonstructural Proteins; C586541:ledipasvir; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: Cirrhosis; DAA; Hepatitis C virus; Ledipasvir; Sofosbuvir