title: Ledipasvir-sofosbuvir in patients with hepatitis C virus genotype 5 infection: an open-label, multicentre, single-arm, phase 2 study.
abstract: BACKGROUND
  Data about the response of hepatitis C virus (HCV) genotype 5 to approved and experimental treatment regimens are scarce. We assessed the efficacy and safety of combination therapy with the NS5A inhibitor ledipasvir and the NS5B polymerase inhibitor sofosbuvir in patients with HCV genotype 5.
  
  
  METHODS
  We did this open-label, multicentre, single-arm, phase 2 trial at five hospitals in France. Eligible patients were at least 18 years old and had chronic infection with HCV genotype 5, with plasma HCV RNA of at least 10,000 IU/mL. We used BLAST analyses of NS5B partial sequences to establish the genotype and subtype at screening. Patients were given a fixed-dose combination tablet of 90 mg ledipasvir and 400 mg sofosbuvir orally once per day for 12 weeks. The primary endpoint was the proportion of patients with a sustained viral response, defined as HCV RNA concentration less than 15 IU/mL at 12 weeks after the end of treatment (SVR12). We analysed efficacy and safety in all patients who received at least one dose of ledipasvir-sofosbuvir. This trial is registered with EudraCT, number 2013-003978-27, and with ClinicalTrials.gov, number NCT02081079.
  
  
  RESULTS
  From March 7 to June 10, 2014, we recruited 41 patients, including 21 who were treatment naive and 20 who were treatment experienced. All patients were of white ethnic origins. All 41 patients who started treatment completed the full 12 weeks of treatment and had undetectable HCV RNA at their final treatment visit. In the overall study population, 39 (95%, 95% CI 83-99) of 41 patients achieved SVR12. SVR12 was achieved by 20 (95%, 76-100) of the 21 patients who were treatment naive and 19 (95%, 75-100) of the 20 patients who were treatment experienced. Eight (89%) of nine patients with cirrhosis achieved SVR12, whereas 31 (97%) of the 32 patients without cirrhosis achieved SVR12. The two patients who did not reach SVR12 both had IL28B TT genotype and had viral relapse within 4 weeks of the end of treatment. The most common adverse events were asthenia (16 [39%] patients), headache (11 [27%] patients), and fatigue (four [10%] patients). One patient had a serious adverse event, worsening depression, which we judged to be unrelated to study treatment.
  
  
  CONCLUSIONS
  The oral regimen of ledipasvir-sofosbuvir is an effective and well-tolerated treatment for patients with HCV genotype 5 infection who are treatment naive or treatment experienced.
  
  
  BACKGROUND
  Gilead Sciences.
authors.affiliation: Department of Hepatology and Gastroenterology, Centre Hospitalier Universitaire Estaing, Université d'Auvergne, UMR CNRS 6284, Clermont-Ferrand, France. Electronic address: aabergel@chu-clermontferrand.fr.
authors.forename: Armand
authors.initials: A
authors.lastname: Abergel
authors.affiliation: Department of Hepatology, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, University Paris-Diderot Clichy, France; INSERM Centre de Recherche sur l'Inflammation, UMR 1149, Clichy, France.
authors.forename: Tarik
authors.initials: T
authors.lastname: Asselah
authors.affiliation: Department of Hepatology and Gastroenterology, Centre Hospitalier Universitaire Purpan, Toulouse, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Metivier
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Kersey
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Deyuan
authors.initials: D
authors.lastname: Jiang
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Mo
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Phillip S
authors.initials: PS
authors.lastname: Pang
authors.affiliation: Centre Hépato-Biliaire, Hôpital Paul Brousse, Assistance Publique-Hôpitaux de Paris, UMR S785, Université Paris-Sud, INSERM U785, Villejuif, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Samuel
authors.affiliation: Department of Hepatology and Gastroenterology, Centre Hospitalier Universitaire Limoges, U850 INSERM, Université de Limoges, Limoges, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Loustaud-Ratti
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D005449:Fluorenes / Q000008:administration & dosage / Q000627:therapeutic use*; D005602:France; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000187:drug effects* / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood; D000069474:Sofosbuvir / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D005449:Fluorenes; D012367:RNA, Viral; C586541:ledipasvir; D000069474:Sofosbuvir