title: Virological response after 6 week triple-drug regimens for hepatitis C: a proof-of-concept phase 2A cohort study.
abstract: BACKGROUND
  Direct-acting antiviral drugs have a high cure rate and favourable tolerability for patients with hepatitis C virus (HCV). Shorter courses could improve affordability and adherence. Sofosbuvir and ledipasvir with ribavirin have high efficacy when taken for 8 weeks but not for 6 weeks. We assessed whether the addition of a third direct-acting antiviral drug to sofosbuvir and ledipasvir would allow a shorter treatment duration.
  
  
  METHODS
  In this single-centre, open-label, phase 2A trial, we sequentially enrolled treatment-naive patients with HCV genotype 1 infection into three treatment groups: 12 weeks of sofosbuvir and ledipasvir; 6 weeks of sofosbuvir, ledipasvir, and GS-9669; or 6 weeks of sofosbuvir, ledipasvir, and GS-9451. Patients and investigators were not masked to treatment assignment. The primary endpoint was the propotion of patients with sustained viral response at 12 weeks after treatment completion (SVR12), assessed by serum HCV RNA concentrations lower than 43 IU/mL (the lower limit of quantification). We did an intention-to-treat analysis for the primary endpoint and adverse events. This study is registered with ClinicalTrials.gov, number NCT01805882.
  
  
  RESULTS
  Between Jan 11, 2013, and Dec 17, 2013, we enrolled 60 patients, and sequentially assigned them into three groups of 20. We noted an SVR12 in all 20 patients (100%, 95% CI 83-100) allocated to sofosbuvir and ledipasvir for 12 weeks; in 19 (95%, 75-100) of the 20 patients allocated to sofosbuvir, ledipasvir, and GS-9669 for 6 weeks (one patient relapsed 2 weeks after completion of treatment); and in 19 (95%, 75-100%) of the 20 patients allocated to sofosbuvir, ledipasvir, and GS-9451 for 6 weeks (one patient was lost to follow-up after reaching sustained viral response at 4 weeks). Most adverse events were mild and no patients discontinued treatment. Two serious adverse events occurred (pain after a post-treatment liver biopsy and vertigo), both unrelated to study drugs.
  
  
  CONCLUSIONS
  In this small proof-of-concept study, two different three-drug regimens that were given for 6 weeks resulted in high cure rates for HCV infection with excellent tolerability. Addition of a third potent direct-acting antiviral drug can reduce the duration of treatment required to achieve sustained viral response in patients with chronic HCV genotype 1 infection without cirrhosis.
  
  
  BACKGROUND
  National Institute of Allergy and Infectious Diseases (NIAID), National Cancer Institute and Clinical Center Intramural Program, German Research Foundation, National Institutes of Health, Gilead Sciences.
authors.affiliation: Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, Bethesda, MD, USA; Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Kohli
authors.affiliation: Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA; Department of Medicine, Dalhousie University, Halifax, NS, Canada.
authors.forename: Anuoluwapo
authors.initials: A
authors.lastname: Osinusi
authors.affiliation: Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Zayani
authors.initials: Z
authors.lastname: Sims
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MD, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Nelson
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MD, USA.
authors.forename: Eric G
authors.initials: EG
authors.lastname: Meissner
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MD, USA; Department of Medicine, Dalhousie University, Halifax, NS, Canada.
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Barrett
authors.affiliation: Institute of Biostatistics and Mathematical Modeling, Johann Wolfgang Goethe University, Frankfurt, Germany.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Bon
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MD, USA.
authors.forename: Miriam M
authors.initials: MM
authors.lastname: Marti
authors.affiliation: Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Silk
authors.affiliation: Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: Colleen
authors.initials: C
authors.lastname: Kotb
authors.affiliation: Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: Chloe
authors.initials: C
authors.lastname: Gross
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MD, USA.
authors.forename: Tim A
authors.initials: TA
authors.lastname: Jolley
authors.affiliation: Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Sreetha
authors.initials: S
authors.lastname: Sidharthan
authors.affiliation: Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Tess
authors.initials: T
authors.lastname: Petersen
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MD, USA.
authors.forename: Kerry
authors.initials: K
authors.lastname: Townsend
authors.affiliation: Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: D'Andrea
authors.initials: D
authors.lastname: Egerson
authors.affiliation: Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: Rama
authors.initials: R
authors.lastname: Kapoor
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MD, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Spurlin
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MD, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Sneller
authors.affiliation: Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MD, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Proschan
authors.affiliation: Institute of Biostatistics and Mathematical Modeling, Johann Wolfgang Goethe University, Frankfurt, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Herrmann
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MD, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Kwan
authors.affiliation: Unity Health Care, Washington DC, USA.
authors.forename: Gebeyehu
authors.initials: G
authors.lastname: Teferi
authors.affiliation: Division of Infectious Diseases, Institute of Human Virology, University of Maryland, MD, USA.
authors.forename: Rohit
authors.initials: R
authors.lastname: Talwani
authors.affiliation: Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA; The National Cancer Institute, National Institutes of Health, MD, USA.
authors.forename: Gabbie
authors.initials: G
authors.lastname: Diaz
authors.affiliation: Laboratory of Pathology, National Cancer Institute, MD, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Kleiner
authors.affiliation: Center for Interventional Oncology, Radiology and Imaging Sciences, NIH Clinical Center and National Cancer Institute, MD, USA.
authors.forename: Brad J
authors.initials: BJ
authors.lastname: Wood
authors.affiliation: Unity Health Care, Washington DC, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Chavez
authors.affiliation: Unity Health Care, Washington DC, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Abbott
authors.affiliation: Gilead Sciences, CA, USA.
authors.forename: William T
authors.initials: WT
authors.lastname: Symonds
authors.affiliation: Gilead Sciences, CA, USA.
authors.forename: G Mani
authors.initials: GM
authors.lastname: Subramanian
authors.affiliation: Gilead Sciences, CA, USA.
authors.forename: Phillip S
authors.initials: PS
authors.lastname: Pang
authors.affiliation: Gilead Sciences, CA, USA.
authors.forename: John
authors.initials: J
authors.lastname: McHutchison
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MD, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Polis
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MD, USA.
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Fauci
authors.affiliation: Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Masur
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MD, USA. Electronic address: skottilil@niaid.nih.gov.
authors.forename: Shyam
authors.initials: S
authors.lastname: Kottilil
mesh_terms: D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use*; D015331:Cohort Studies; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D005449:Fluorenes / Q000627:therapeutic use*; D005663:Furans / Q000627:therapeutic use*; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D057194:Intention to Treat Analysis; D008297:Male; D008875:Middle Aged; D011804:Quinolines / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood*; D012254:Ribavirin / Q000627:therapeutic use*; D000069474:Sofosbuvir; D013876:Thiophenes / Q000627:therapeutic use*; D016896:Treatment Outcome; D014542:Uridine Monophosphate / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D005449:Fluorenes; D005663:Furans; C573362:GS-9451; C582393:GS-9669; D011804:Quinolines; D012367:RNA, Viral; D013876:Thiophenes; C586541:ledipasvir; D012254:Ribavirin; D014542:Uridine Monophosphate; D000069474:Sofosbuvir