title: Virologic response following combined ledipasvir and sofosbuvir administration in patients with HCV genotype 1 and HIV co-infection.
abstract: OBJECTIVE
  There is an unmet need for interferon- and ribavirin-free treatment for chronic hepatitis C virus (HCV) infection in patients co-infected with human immunodeficiency virus (HIV).
  
  
  OBJECTIVE
  To evaluate the rates of sustained virologic response (SVR) and adverse events in previously untreated patients with HCV genotype 1 and HIV co-infection following a 12-week treatment of the fixed-dose combination of ledipasvir and sofosbuvir.
  
  
  METHODS
  Open-label, single-center, phase 2b pilot study of previously untreated, noncirrhotic patients with HCV genotype 1 and HIV co-infection conducted at the Clinical Research Center of the National Institutes of Health, Bethesda, Maryland, from June 2013 to September 2014. Patients included those receiving antiretroviral therapy with HIV RNA values of 50 copies/mL or fewer and a CD4 T-lymphocyte count of 100 cells/mL or greater or patients with untreated HIV infection with a CD4 T-lymphocyte count of 500 cells/mL or greater. Serial measurements of safety parameters, virologic and host immune correlates, and adherence were performed.
  
  
  METHODS
  Fifty patients with HCV genotype 1 never before treated for HCV were prescribed a fixed-dose combination of ledipasvir (90 mg) and sofosbuvir (400 mg) once daily for 12 weeks.
  
  
  METHODS
  The primary study outcome was the proportion of patients with sustained viral response (plasma HCV RNA level <12 IU/mL) 12 weeks after end of treatment.
  
  
  RESULTS
  Forty-nine of 50 participants (98% [95% CI, 89% to 100%]) achieved SVR 12 weeks after end of treatment, whereas 1 patient experienced relapse at week 4 following treatment. In the patient with relapse, deep sequencing revealed a resistance associated mutation in the NS5A region conferring resistance to NS5A inhibitors, such as ledipasvir. The most common adverse events were nasal congestion (16% of patients) and myalgia (14%). There were no discontinuations or serious adverse events attributable to study drug.
  
  
  CONCLUSIONS
  In this open-label, uncontrolled, pilot study enrolling patients co-infected with HCV genotype 1 and HIV, administration of an oral combination of ledipasvir and sofosbuvir for 12 weeks was associated with high rates of SVR after treatment completion. Larger studies that also include patients with cirrhosis and lower CD4 T-cell counts are required to understand if the results of this study generalize to all patients co-infected with HCV and HIV.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier:NCT01878799.
authors.affiliation: Division of Infectious Diseases, Institute of Human Virology, University of Maryland, Baltimore2Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland3Gilead Sciences Inc, F.
authors.forename: Anu
authors.initials: A
authors.lastname: Osinusi
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Kerry
authors.initials: K
authors.lastname: Townsend
authors.affiliation: Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, Bethesda, Maryland5Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc (formerly SAIC-Frederick, Inc), Frederick Nationa.
authors.forename: Anita
authors.initials: A
authors.lastname: Kohli
authors.affiliation: Division of Infectious Diseases, Institute of Human Virology, University of Maryland, Baltimore2Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Amy
authors.initials: A
authors.lastname: Nelson
authors.affiliation: Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, Bethesda, Maryland.
authors.forename: Cassie
authors.initials: C
authors.lastname: Seamon
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland6Department of Microbiology and Immunology, Medical University of South Carolina College of Medicine, Charleston.
authors.forename: Eric G
authors.initials: EG
authors.lastname: Meissner
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: Division of Infectious Diseases, Institute of Human Virology, University of Maryland, Baltimore5Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc (formerly SAIC-Frederick, Inc), Frederick National Laborato.
authors.forename: Rachel
authors.initials: R
authors.lastname: Silk
authors.affiliation: Division of Infectious Diseases, Institute of Human Virology, University of Maryland, Baltimore5Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc (formerly SAIC-Frederick, Inc), Frederick National Laborato.
authors.forename: Chloe
authors.initials: C
authors.lastname: Gross
authors.affiliation: Division of Infectious Diseases, Institute of Human Virology, University of Maryland, Baltimore5Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc (formerly SAIC-Frederick, Inc), Frederick National Laborato.
authors.forename: Angie
authors.initials: A
authors.lastname: Price
authors.affiliation: Division of Infectious Diseases, Institute of Human Virology, University of Maryland, Baltimore.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Sajadi
authors.affiliation: Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, Bethesda, Maryland.
authors.forename: Sreetha
authors.initials: S
authors.lastname: Sidharthan
authors.affiliation: Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, Bethesda, Maryland.
authors.forename: Zayani
authors.initials: Z
authors.lastname: Sims
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: Unity Health Care Inc, Washington, DC.
authors.forename: John
authors.initials: J
authors.lastname: Hogan
authors.affiliation: Unity Health Care Inc, Washington, DC.
authors.forename: Gebeyehu
authors.initials: G
authors.lastname: Teferi
authors.affiliation: Division of Infectious Diseases, Institute of Human Virology, University of Maryland, Baltimore.
authors.forename: Rohit
authors.initials: R
authors.lastname: Talwani
authors.affiliation: Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Michael
authors.initials: M
authors.lastname: Proschan
authors.affiliation: Family and Medical Counseling Services, Washington, DC.
authors.forename: Veronica
authors.initials: V
authors.lastname: Jenkins
authors.affiliation: Department of Pathology, National Cancer Institute, Rockville, Maryland.
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, Bethesda, Maryland.
authors.forename: Brad J
authors.initials: BJ
authors.lastname: Wood
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: Phillip S
authors.initials: PS
authors.lastname: Pang
authors.affiliation: Gilead Sciences Inc, Foster City, California.
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
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, Bethesda, Maryland.
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Fauci
authors.affiliation: Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, Bethesda, Maryland.
authors.forename: Henry
authors.initials: H
authors.lastname: Masur
authors.affiliation: Division of Infectious Diseases, Institute of Human Virology, University of Maryland, Baltimore2Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Shyam
authors.initials: S
authors.lastname: Kottilil
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D060085:Coinfection; D004359:Drug Therapy, Combination; D005260:Female; D005449:Fluorenes / Q000009:adverse effects / Q000627:therapeutic use*; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy*; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D063806:Myalgia / Q000139:chemically induced; D012367:RNA, Viral; D000069474:Sofosbuvir; D016896:Treatment Outcome; D014542:Uridine Monophosphate / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D005449:Fluorenes; D012367:RNA, Viral; C586541:ledipasvir; D014542:Uridine Monophosphate; D000069474:Sofosbuvir