title: Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial.
abstract: BACKGROUND
  Interferon-based treatment is not suitable for many patients with hepatitis C virus (HCV) infection because of contraindications such as psychiatric illness, and a high burden of adverse events. We assessed the efficacy and safety of an interferon-free regimen--a fixed-dose combination of the nucleotide polymerase inhibitor sofosbuvir (400 mg) and the HCV NS5A inhibitor ledipasvir (90 mg), with and without ribavirin--in patients with genotype-1 hepatitis C infection who were treatment-naive or previously treated with a protease-inhibitor regimen.
  
  
  METHODS
  For this open-label study, we enrolled 100 adult patients (>18 years) with HCV infection at a centre in the USA between Nov 2, 2012, and Dec 21, 2012. In cohort A, we used a computer-generated sequence to randomly assign (1:1:1; stratified by HCV genotype [1a vs 1b]) 60 non-cirrhotic, treatment-naive patients to receive sofosbuvir plus ledipasvir for 8 weeks (group 1), sofosbuvir plus ledipasvir and ribavirin for 8 weeks (group 2), or sofosbuvir plus ledipasvir for 12 weeks (group 3). In cohort B, we randomly allocated (1:1; stratified by genotype and presence or absence of cirrhosis) 40 patients who previously had virological failure after receiving a protease inhibitor regimen to receive sofosbuvir plus ledipasvir for 12 weeks (group 4) or sofosbuvir plus ledipasvir and ribavirin for 12 weeks (group 5). 22 (55%) of 40 patients in cohort B had compensated cirrhosis. The primary endpoint was sustained virological response 12 weeks after treatment (SVR12), analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01329978.
  
  
  RESULTS
  In cohort A, SVR12 was achieved by 19 (95%) of 20 patients (95% CI 75-100) in group 1, by 21 (100%) of 21 patients (84-100) in group 2, and by 18 (95%) of 19 patients (74-100) in group 3. In cohort B, SVR12 was achieved by 18 (95%) of 19 patients (74-100) in group 4 and by all 21 (100%) of 21 patients (84-100) in group 5. Two patients had viral relapse; one patient was lost to follow-up after achieving sustained virological response 8 weeks after treatment. The most common adverse events were nausea, anaemia, upper respiratory tract infection, and headache. One patient in group five had a serious adverse event of anaemia, thought to be related to ribavirin treatment.
  
  
  CONCLUSIONS
  These findings suggest that the fixed-dose combination of sofosbuvir-ledipasvir alone or with ribavirin has the potential to cure most patients with genotype-1 HCV, irrespective of treatment history or the presence of compensated cirrhosis. Further clinical trials are needed to establish the best treatment duration and to further assess the contribution of ribavirin.
  
  
  BACKGROUND
  Gilead Sciences.
authors.affiliation: Texas Liver Institute and the University of Texas Health Science Center, San Antonio, TX, USA. Electronic address: lawitz@txliver.com.
authors.forename: Eric
authors.initials: E
authors.lastname: Lawitz
authors.affiliation: Texas Liver Institute and the University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Fred F
authors.initials: FF
authors.lastname: Poordad
authors.affiliation: Gilead Sciences Inc, Foster City, CA, USA.
authors.forename: Phillip S
authors.initials: PS
authors.lastname: Pang
authors.affiliation: Gilead Sciences Inc, Foster City, CA, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Hyland
authors.affiliation: Gilead Sciences Inc, Foster City, CA, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Ding
authors.affiliation: Gilead Sciences Inc, Foster City, CA, USA.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Mo
authors.affiliation: Gilead Sciences Inc, Foster City, CA, USA.
authors.forename: William T
authors.initials: WT
authors.lastname: Symonds
authors.affiliation: Gilead Sciences Inc, Foster City, CA, USA.
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.affiliation: Texas Liver Institute and the University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Fernando E
authors.initials: FE
authors.lastname: Membreno
mesh_terms: D000998:Antiviral Agents / Q000008:administration & dosage*; D001562:Benzimidazoles / Q000008:administration & dosage; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005260:Female; D005449:Fluorenes / Q000008:administration & dosage; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D011480:Protease Inhibitors / Q000627:therapeutic use*; D012367:RNA, Viral / Q000378:metabolism; D012254:Ribavirin / Q000008:administration & dosage*; D000069474:Sofosbuvir; D016896:Treatment Outcome; D014542:Uridine Monophosphate / Q000008:administration & dosage / Q000031:analogs & derivatives*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D004338:Drug Combinations; D005449:Fluorenes; D011480:Protease Inhibitors; D012367:RNA, Viral; D012254:Ribavirin; D000069474:Sofosbuvir; D014542:Uridine Monophosphate; D017361:Viral Nonstructural Proteins; C586541:ledipasvir; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase