title: Ledipasvir and sofosbuvir for hepatitis C genotype 4: a proof-of-concept, single-centre, open-label phase 2a cohort study.
abstract: BACKGROUND
  Worldwide, although predominantly in low-income countries in the Middle East and Africa, up to 13% of hepatitis C virus (HCV) infections are caused by HCV genotype 4. For patients with HCV genotype 1, the combination of ledipasvir and sofosbuvir has been shown to cure high proportions of patients with excellent tolerability, but this regimen has not been assessed for the treatment of HCV genotype 4. We assessed the efficacy, safety, and tolerability of 12 weeks of combination therapy with ledipasvir and sofosbuvir for patients with chronic HCV genotype 4 infections.
  
  
  METHODS
  In this single-centre, open-label cohort, phase 2a trial, patients with HCV genotype 4 who were treatment naive or interferon treatment experienced (HIV-negative) were sequentially enrolled at the Clinical Center of the National Institutes of Health, Bethesda, MD, USA. We gave patients 12 weeks of ledipasvir (90 mg) and sofosbuvir (400 mg) as a single combination tablet once per day. The primary efficacy endpoint was sustained viral response at 12 weeks (SVR12), as measured by the proportion of patients with HCV RNA concentrations less than the lower limit of quantification (COBAS TaqMan HCV test, version 1.0, 43 IU/mL). The primary safety endpoint was the frequency and severity of adverse events. We did our analyses on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT01805882.
  
  
  RESULTS
  Between Sept 16, 2013, and Nov 2, 2014, we recruited 21 patients. 20 (95%) of 21 patients completed 12 weeks of treatment and achieved SVR12 (95% CI 76-100), including seven patients with cirrhosis. One patient was non-adherent to study drugs and withdrew from the study, but was included in the intention-to-treat analysis. No patients discontinued treatment because of adverse events and no grade 3 or 4 adverse events occurred that were related to study medications. The most common adverse events were diarrhoea (two patients), fatigue (three patients), nausea (two patients), and upper respiratory infections (two patients).
  
  
  CONCLUSIONS
  Ledipasvir and sofosbuvir treatment for 12 weeks was well tolerated by patients with HCV genotype 4 and resulted in 100% SVR for all patients who received all 12 weeks of study drugs, irrespective of previous treatment status and underlying liver fibrosis. This is the first report of a single-pill, all-oral, interferon-free, ribavirin-free treatment for patients with HCV genotype 4.
  
  
  BACKGROUND
  NIAID, National Cancer Institute and Clinical Center Intramural Program. The study was also supported in part by a Cooperative Research and Development Agreement between NIH and 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 (formerly SAIC-Frederick), Frederick National Laboratory for Cancer Research, MD, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Kohli
authors.affiliation: Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research (formerly SAIC-Frederick), Frederick National Laboratory for Cancer Research, MD, USA.
authors.forename: Rama
authors.initials: R
authors.lastname: Kapoor
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: Institute of Human Virology, University of Maryland, Baltimore, MD, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Nelson
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: INOVA Fairfax Hospital, Fairfax, VA, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Lam
authors.affiliation: Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research (formerly SAIC-Frederick), Frederick National Laboratory for Cancer Research, MD, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Silk
authors.affiliation: Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research (formerly SAIC-Frederick), Frederick National Laboratory for Cancer Research, MD, USA.
authors.forename: Colleen
authors.initials: C
authors.lastname: Kotb
authors.affiliation: Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research (formerly SAIC-Frederick), Frederick National Laboratory for Cancer Research, MD, USA.
authors.forename: Chloe
authors.initials: C
authors.lastname: Gross
authors.affiliation: Unity Health Care, Washington, DC, USA.
authors.forename: Gebeyehu
authors.initials: G
authors.lastname: Teferi
authors.affiliation: Unity Health Care, Washington, DC, USA.
authors.forename: Kate
authors.initials: K
authors.lastname: Sugarman
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Phillip S
authors.initials: PS
authors.lastname: Pang
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Anu
authors.initials: A
authors.lastname: Osinusi
authors.affiliation: Collaborative Clinical Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Polis
authors.affiliation: Division of Hepatology, Thomas E Starlz Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Vinod
authors.initials: V
authors.lastname: Rustgi
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: Institute of Human Virology, University of Maryland, Baltimore, MD, USA. Electronic address: skottilil@niaid.nih.gov.
authors.forename: Shyam
authors.initials: S
authors.lastname: Kottilil
mesh_terms: D000368:Aged; D001562:Benzimidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D004279:DNA, Viral / Q000097:blood*; D004338:Drug Combinations; D005260:Female; D005449:Fluorenes / Q000009:adverse effects / Q000627:therapeutic use*; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000069474:Sofosbuvir / Q000009:adverse effects / Q000627:therapeutic use*; D019562:Viral Load
chemical_list: D001562:Benzimidazoles; D004279:DNA, Viral; D004338:Drug Combinations; D005449:Fluorenes; C586541:ledipasvir; D000069474:Sofosbuvir