title: Efficacy of the Combination of Sofosbuvir, Velpatasvir, and the NS3/4A Protease Inhibitor GS-9857 in Treatment-Naïve or Previously Treated Patients With Hepatitis C Virus Genotype 1 or 3 Infections.
abstract: We performed a phase 2 trial of the efficacy and safety of 4, 6, and 8 weeks of sofosbuvir, given in combination with the NS5A inhibitor velpatasvir and the NS3/4A protease inhibitor GS-9857, in patients with hepatitis C virus (HCV) infection.
  
  
  
  We enrolled 161 treatment-naïve or previously treated patients infected with HCV genotypes 1 or 3 with or without compensated cirrhosis at 2 centers in New Zealand, from September 2014 through March 2015. All patients received sofosbuvir (400 mg) and velpatasvir (100 mg) plus GS-9857 (100 mg) once daily. The primary efficacy end point was sustained virologic response at 12 weeks after therapy (SVR12). The duration of therapy was determined by baseline patient characteristics: 4 or 6 weeks for treatment-naïve patients without cirrhosis, 6 weeks for treatment-naïve patients with cirrhosis, and 6 or 8 weeks for treatment-experienced patients with or without cirrhosis.
  
  
  
  Four weeks of sofosbuvir, velpatasvir, and GS-9857 produced an SVR12 in 4 of 15 (27%) treatment-naïve patients with HCV genotype 1 without cirrhosis. Six weeks of this combination produced a SVR12 in 14 of 15 (93%) treatment-naïve patients with HCV genotype 1 without cirrhosis, in 13 of 15 (87%) treatment-naïve genotype 1 patients with cirrhosis, in 15 of 18 (83%) treatment-naïve patients with HCV genotype 3 with cirrhosis, and in 20 of 30 (67%) patients with HCV genotype 1 who had failed an all-oral regimen of 2 or more direct-acting antiviral agents. Eight weeks of the drug combination produced an SVR12 in 17 of 17 (100%) patients with HCV genotype 1, in 19 of 19 (100%) patients with HCV genotype 3 and cirrhosis who had failed pegylated interferon plus ribavirin, in 25 of 28 (89%) patients with HCV genotype 1 who had failed protease inhibitor-based triple therapy, and in 4 of 4 (100%) patients with HCV genotype 3 who had failed an all-oral regimen of ≥2 direct-acting antiviral agents. The most common reported adverse events were headache, nausea, and fatigue.
  
  
  
  Eight weeks of treatment with the combination of sofosbuvir, velpatasvir, and GS-9857 produced an SVR12 in most treatment-naïve or previously treated patients with HCV genotype 1 or 3 infections, including those with compensated cirrhosis. ClinicalTrials.gov, Number: NCT02202980.
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: Auckland Clinical Studies, Ltd, Auckland, New Zealand.
authors.forename: Christian
authors.initials: C
authors.lastname: Schwabe
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: Yin
authors.initials: Y
authors.lastname: Yang
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: Luisa M
authors.initials: LM
authors.lastname: Stamm
authors.affiliation: Gilead Sciences, Inc, Foster City, California.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Brainard
authors.affiliation: Gilead Sciences, Inc, Foster City, California.
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.affiliation: Gastroenterology Department, Christchurch Hospital, and University of Otago, Christchurch, New Zealand.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Stedman
mesh_terms: D000328:Adult; D000368:Aged; D000621:Aminoisobutyric Acids; D000998:Antiviral Agents / Q000008:administration & dosage*; D002219:Carbamates / Q000008:administration & dosage*; D003521:Cyclopropanes; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage*; D006801:Humans; D047029:Lactams, Macrocyclic; D007930:Leucine / Q000031:analogs & derivatives; D008103:Liver Cirrhosis / Q000821:virology; D047028:Macrocyclic Compounds / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D009520:New Zealand; D011392:Proline / Q000031:analogs & derivatives; D011480:Protease Inhibitors / Q000008:administration & dosage*; D011810:Quinoxalines; D057057:Serine Proteases; D000069474:Sofosbuvir / Q000008:administration & dosage*; D013449:Sulfonamides / Q000008:administration & dosage*; D000072230:Sustained Virologic Response; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors; D055815:Young Adult; D001562:Benzimidazoles; D001578:Benzopyrans
chemical_list: D000621:Aminoisobutyric Acids; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D006576:Heterocyclic Compounds, 4 or More Rings; D047029:Lactams, Macrocyclic; D007930:Leucine; D047028:Macrocyclic Compounds; D011392:Proline; D011480:Protease Inhibitors; D011810:Quinoxalines; D057057:Serine Proteases; D000069474:Sofosbuvir; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C000619503:voxilaprevir; C000614516:NS3-4A serine protease, Hepatitis C virus; C000604171:velpatasvir; D001562:Benzimidazoles; D001578:Benzopyrans
keywords: Clinical Trial; Difficult to Treat; LEPTON; Time of Treatment