title: Efficacy of nucleotide polymerase inhibitor sofosbuvir plus the NS5A inhibitor ledipasvir or the NS5B non-nucleoside inhibitor GS-9669 against HCV genotype 1 infection.
abstract: OBJECTIVE
  We evaluated an all-oral regimen comprising the nucleotide polymerase inhibitor sofosbuvir (SOF) with the NS5A inhibitor ledipasvir (LDV) or the NS5B non-nucleoside inhibitor GS-9669 in patients with genotype 1 hepatitis C virus (HCV) infection.
  
  
  METHODS
  A total of 113 patients were enrolled. Sofosbuvir (400 mg once daily) and LDV (90 mg once daily) plus ribavirin (RBV) were given for 12 weeks to treatment-naïve (TN) patients (n = 25) and those who did not respond to previous therapy (prior null responders, n = 9). Sofosbuvir and GS-9669 (500 mg once daily) plus RBV were given for 12 weeks to TN patients (n = 25) and prior null responders (n = 10). Additionally, prior null responders with cirrhosis were randomly assigned to groups given a fixed-dose combination of SOF and LDV, with RBV (n = 9) or without RBV (n = 10). Finally, a group of TN patients received SOF, LDV, and RBV for 6 weeks (n = 25). The primary efficacy end point was sustained virologic response 12 weeks after therapy (SVR12).
  
  
  RESULTS
  SVR12 was achieved by 25 of 25 (100%) TN patients receiving SOF, LDV, and RBV and 23 of 25 (92%) of those receiving SOF, GS-9669, and RBV. Of TN patients receiving 6 weeks of SOF, LDV, and RBV, 17 of 25 (68%) achieved SVR12. All noncirrhotic prior null responders receiving 12 weeks of SOF along with another direct-acting antiviral agent plus RBV achieved SVR12-9 of 9 (100%) of those receiving SOF, LDV, and RBV and 10 of 10 (100%) of those receiving SOF, GS-9669, and RBV. Among cirrhotic prior null responders, SVR12 was achieved by 9 (100%) of those receiving SOF, LDV, and RBV and 7 (70%) of those receiving SOF and LDVD without RBV. The most common reported adverse events were headache, fatigue, and nausea.
  
  
  CONCLUSIONS
  The combination of SOF and a second direct-acting antiviral agent is highly effective in TN patients with HCV genotype 1 infection and in patients that did not respond to previous treatment. ClinicalTrials.gov ID NCT01260350.
authors.affiliation: New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand. Electronic address: edgane@adhb.govt.nz.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Gane
authors.affiliation: Gastroenterology Department, Christchurch Hospital and University of Otago, Christchurch, New Zealand.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Stedman
authors.affiliation: Gilead Sciences, Inc, Foster City, California.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Hyland
authors.affiliation: Gilead Sciences, Inc, Foster City, California.
authors.forename: Xiao
authors.initials: X
authors.lastname: Ding
authors.affiliation: Gilead Sciences, Inc, Foster City, California.
authors.forename: Evguenia
authors.initials: E
authors.lastname: Svarovskaia
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: William T
authors.initials: WT
authors.lastname: Symonds
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: Phillip S
authors.initials: PS
authors.lastname: Pang
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use; D001562:Benzimidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D005221:Fatigue / Q000453:epidemiology; D005260:Female; D005449:Fluorenes / Q000009:adverse effects / Q000627:therapeutic use*; D005663:Furans / Q000009:adverse effects / Q000627:therapeutic use*; D005838:Genotype; D006261:Headache / Q000453:epidemiology; D016174:Hepacivirus / Q000235:genetics*; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000453:epidemiology; D000069474:Sofosbuvir; D013876:Thiophenes / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D014542:Uridine Monophosphate / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D005449:Fluorenes; D005663:Furans; D000069474:Sofosbuvir; D013876:Thiophenes; D014542:Uridine Monophosphate; D017361:Viral Nonstructural Proteins; C582393:GS-9669; C586541:ledipasvir; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: Clinical Trial; DAA; Drug; Liver Cirrhosis