title: Successful Retreatment of Chronic HCV Genotype-1 Infection With Ledipasvir and Sofosbuvir After Initial Short Course Therapy With Direct-Acting Antiviral Regimens.
abstract: BACKGROUND
  The optimal retreatment strategy for chronic hepatitis C virus (HCV) patients who fail directly-acting antiviral agent (DAA)-based treatment is unknown. In this study, we assessed the efficacy and safety of ledipasvir (LDV) and sofosbuvir (SOF) for 12 weeks in HCV genotype-1 (GT-1) patients who failed LDV/SOF-containing therapy.
  
  
  METHODS
  In this single-center, open-label, phase 2a trial, 34 participants with HCV (GT-1) and early-stage liver fibrosis who previously failed 4-6 weeks of LDV/SOF with GS-9669 and/or GS-9451 received LDV/SOF for 12 weeks. The primary endpoint was HCV viral load below the lower limit of quantification 12 weeks after completion of therapy (sustained virological response [SVR]12). Deep sequencing of the NS3, NS5A, and NS5B regions were performed at baseline, at initial relapse, prior to retreatment, and at second relapse with Illumina next-generation sequencing technology.
  
  
  RESULTS
  Thirty-two of 34 enrolled participants completed therapy. Two patients withdrew after day 0. Participants were predominantly male and black, with median baseline HCV viral load of 1.3 × 10(6) IU/mL and Metavir fibrosis stage 1 and genotype-1a. Median time from relapse to retreatment was 22 weeks. Prior to retreatment, 29 patients (85%) had NS5A-resistant variants. The SVR12 rate was 91% (31/34; intention to treat, ITT) after retreatment. One patient relapsed.
  
  
  CONCLUSIONS
  In patients who previously failed short-course combination DAA therapy, we demonstrate a high SVR rate in response to 12 weeks of LDV/SOF, even for patients with NS5A resistance-associated variants.
  
  
  BACKGROUND
  NCT01805882.
authors.affiliation: Division of Infectious Diseases, Institute of Human Virology, University of Maryland, Baltimore.|Critical Care Medicine Department, Clinical Center.
authors.forename: Eleanor M
authors.initials: EM
authors.lastname: Wilson
authors.affiliation: Division of Infectious Diseases, Institute of Human Virology, University of Maryland, Baltimore.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kattakuzhy
authors.affiliation: Critical Care Medicine Department, Clinical Center.
authors.forename: Sreetha
authors.initials: S
authors.lastname: Sidharthan
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Zayani
authors.initials: Z
authors.lastname: Sims
authors.affiliation: Division of Infectious Diseases, Institute of Human Virology, University of Maryland, Baltimore.
authors.forename: Lydia
authors.initials: L
authors.lastname: Tang
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Mary
authors.initials: M
authors.lastname: McLaughlin
authors.affiliation: Division of Infectious Diseases, Institute of Human Virology, University of Maryland, Baltimore.
authors.forename: Angie
authors.initials: A
authors.lastname: Price
authors.affiliation: Division of Infectious Diseases, Institute of Human Virology, University of Maryland, Baltimore.
authors.forename: Amy
authors.initials: A
authors.lastname: Nelson
authors.affiliation: Division of Infectious Diseases, Institute of Human Virology, University of Maryland, Baltimore.
authors.forename: Rachel
authors.initials: R
authors.lastname: Silk
authors.affiliation: Division of Infectious Diseases, Institute of Human Virology, University of Maryland, Baltimore.
authors.forename: Chloe
authors.initials: C
authors.lastname: Gross
authors.affiliation: Division of Infectious Diseases, Institute of Human Virology, University of Maryland, Baltimore.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Akoth
authors.affiliation: Gilead Sciences Inc., Foster City, California.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Mo
authors.affiliation: Gilead Sciences Inc., Foster City, California.
authors.forename: G Mani
authors.initials: GM
authors.lastname: Subramanian
authors.affiliation: Gilead Sciences Inc., Foster City, California.
authors.forename: Phillip S
authors.initials: PS
authors.lastname: Pang
authors.affiliation: Gilead Sciences Inc., Foster City, California.
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.affiliation: Gilead Sciences Inc., Foster City, California.
authors.forename: Anu
authors.initials: A
authors.lastname: Osinusi
authors.affiliation: Critical Care Medicine Department, Clinical Center.
authors.forename: Henry
authors.initials: H
authors.lastname: Masur
authors.affiliation: Critical Care Medicine Department, Clinical Center.|Department of Hepatology, St. Joseph's Hospital and Medical Center, Creighton University, Phoenix, Arizona.
authors.forename: Anita
authors.initials: A
authors.lastname: Kohli
authors.affiliation: Division of Infectious Diseases, Institute of Human Virology, University of Maryland, Baltimore.
authors.forename: Shyam
authors.initials: S
authors.lastname: Kottilil
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D005449:Fluorenes / Q000008:administration & dosage* / Q000009:adverse effects; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000235:genetics / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D019233:Retreatment / Q000009:adverse effects; D017422:Sequence Analysis, DNA; D000069474:Sofosbuvir / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D019562:Viral Load; D017361:Viral Nonstructural Proteins / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D005449:Fluorenes; D017361:Viral Nonstructural Proteins; C586541:ledipasvir; D000069474:Sofosbuvir
keywords: direct-acting antiviral agents; hepatitis C; ledipasvir; retreatment; sofosbuvir