title: Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 in Patients With Genotype 1 Hepatitis C Virus Infection in an Open-Label, Phase 2 Trial.
abstract: The best regimen to re-treat patients who do not respond to direct-acting antivirals (DAAs) and the feasibility of further shortening regimens is unclear. We assessed the efficacy and safety of the combination of the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the NS3/4A protease inhibitor GS-9857 in patients with hepatitis C virus genotype 1 infection.
  
  
  
  We performed an open-label trial at 32 sites in the United States and at 2 sites in New Zealand of 197 patients with genotype 1 hepatitis C virus infection, with or without compensated cirrhosis, who were treatment-naive or were treated previously with a DAA. Between March 2, 2015, and September 1, 2015, patients received sofosbuvir-velpatasvir (400 mg/100 mg in a fixed-dose combination) plus GS-9857 (100 mg) once daily for 6-12 weeks, plus ribavirin for 1 treatment group consisting of treatment-naive patients with cirrhosis. The primary end point was sustained virologic response 12 weeks after treatment (SVR12).
  
  
  
  Among treatment-naive patients without cirrhosis, 71% (24 of 34; 95% confidence interval [CI], 53-85) achieved SVR12 after 6 weeks of treatment and 100% (36 of 36; 95% CI, 90%-100%) achieved SVR12 after 8 weeks of treatment. Among treatment-naive patients with cirrhosis, 94% (31 of 33; 95% CI, 80-99) achieved SVR12 after 8 weeks of treatment and 81% (25 of 31; 95% CI, 63-93) achieved SVR12 after 8 weeks of treatment with ribavirin. Among DAA-experienced patients treated for 12 weeks, 100% without cirrhosis (31 of 31; 95% CI, 89-100) and 100% with cirrhosis (32 of 32; 95% CI, 89-100) achieved SVR12. The most common adverse events were headache, diarrhea, fatigue, and nausea. One patient (<1%) discontinued treatment because of adverse events.
  
  
  
  In a phase 2 open-label trial, we found 8 weeks of treatment with sofosbuvir-velpatasvir plus GS-9857 to be safe and effective in treatment-naive patients; 12 weeks was safe and effective in patients previously treated with DAAs. The combination was safe and effective in patients with or without compensated cirrhosis. Clinicaltrials.gov no: NCT02378935.
authors.affiliation: Texas Liver Institute, University of Texas Health Sciences Center, San Antonio, Texas. Electronic address: lawitz@txliver.com.
authors.forename: Eric
authors.initials: E
authors.lastname: Lawitz
authors.affiliation: Rush University Medical Center, Chicago, Illinois.
authors.forename: Nancy
authors.initials: N
authors.lastname: Reau
authors.affiliation: Orlando Immunology Center, Orlando, Florida.
authors.forename: Federico
authors.initials: F
authors.lastname: Hinestrosa
authors.affiliation: University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Mordechai
authors.initials: M
authors.lastname: Rabinovitz
authors.affiliation: Schiff Center for Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Eugene
authors.initials: E
authors.lastname: Schiff
authors.affiliation: Gastrointestinal Specialists of Georgia, Marietta, Georgia.
authors.forename: Aasim
authors.initials: A
authors.lastname: Sheikh
authors.affiliation: GastroOne, Germantown, Tennessee.
authors.forename: Ziad
authors.initials: Z
authors.lastname: Younes
authors.affiliation: Quality Medical Research Center, Nashville, Tennessee.
authors.forename: Robert
authors.initials: R
authors.lastname: Herring
authors.affiliation: University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: K Rajender
authors.initials: KR
authors.lastname: Reddy
authors.affiliation: Sinai Medical Center, Los Angeles, California.
authors.forename: Tram
authors.initials: T
authors.lastname: Tran
authors.affiliation: Medical Associates Research Group, Inc, San Diego, California.
authors.forename: Michael
authors.initials: M
authors.lastname: Bennett
authors.affiliation: Infectious Disease Care, Hillsborough, New Jersey.
authors.forename: Ronald
authors.initials: R
authors.lastname: Nahass
authors.affiliation: Gilead Sciences, Foster City, California.
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Yang
authors.affiliation: Gilead Sciences, Foster City, California.
authors.forename: Sophia
authors.initials: S
authors.lastname: Lu
authors.affiliation: Gilead Sciences, Foster City, California.
authors.forename: Hadas
authors.initials: H
authors.lastname: Dvory-Sobol
authors.affiliation: Gilead Sciences, Foster City, California.
authors.forename: Luisa M
authors.initials: LM
authors.lastname: Stamm
authors.affiliation: Gilead Sciences, Foster City, California.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Brainard
authors.affiliation: Gilead Sciences, Foster City, California.
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.affiliation: Atlanta Medical Center, Atlanta, Georgia.
authors.forename: Brian
authors.initials: B
authors.lastname: Pearlman
authors.affiliation: The Liver Institute of Virginia, Richmond, Virginia.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Shiffman
authors.affiliation: Southwest CARE Center, Santa Fe, New Mexico.
authors.forename: Trevor
authors.initials: T
authors.lastname: Hawkins
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Michael
authors.initials: M
authors.lastname: Curry
authors.affiliation: Mount Sinai Beth Israel, New York, New York.
authors.forename: Ira
authors.initials: I
authors.lastname: Jacobson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000621:Aminoisobutyric Acids; D000998:Antiviral Agents / Q000627:therapeutic use*; D002219:Carbamates / Q000627:therapeutic use*; D003521:Cyclopropanes; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000627:therapeutic use*; D006801:Humans; D047029:Lactams, Macrocyclic; D007930:Leucine / Q000031:analogs & derivatives; D047028:Macrocyclic Compounds / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011392:Proline / Q000031:analogs & derivatives; D011810:Quinoxalines; D012254:Ribavirin / Q000627:therapeutic use; D057057:Serine Proteases; D000069474:Sofosbuvir / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*; D016896:Treatment Outcome; 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; D004338:Drug Combinations; D006576:Heterocyclic Compounds, 4 or More Rings; D047029:Lactams, Macrocyclic; D007930:Leucine; D047028:Macrocyclic Compounds; D011392:Proline; D011810:Quinoxalines; D012254:Ribavirin; 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: Direct-Acting Antiviral Agent; NS3/4A; NS5A; NS5B