title: Evaluation of the Activity of Lamivudine and Zidovudine against Ebola Virus.
abstract: In the fall of 2014, an international news agency reported that patients suffering from Ebola virus disease (EVD) in Liberia were treated successfully with lamivudine, an antiviral drug used to treat human immunodeficiency virus-1 and hepatitis B virus infections. According to the report, 13 out of 15 patients treated with lamivudine survived and were declared free from Ebola virus disease. In this study, the anti-Ebola virus (EBOV) activity of lamivudine and another antiretroviral, zidovudine, were evaluated in a diverse set of cell lines against two variants of wild-type EBOV. Variable assay parameters were assessed to include different multiplicities of infection, lengths of inoculation times, and durations of dosing. At a multiplicity of infection of 1, lamivudine and zidovudine had no effect on EBOV propagation in Vero E6, Hep G2, or HeLa cells, or in primary human monocyte-derived macrophages. At a multiplicity of infection of 0.1, zidovudine demonstrated limited anti-EBOV activity in Huh 7 cells. Under certain conditions, lamivudine had low anti-EBOV activity at the maximum concentration tested (320 μM). However, lamivudine never achieved greater than 30% viral inhibition, and the activity was not consistently reproducible. Combination of lamivudine and zidovudine showed no synergistic antiviral activity. Independently, a set of in vitro experiments testing lamivudine and zidovudine for antiviral activity against an Ebola-enhanced green fluorescent protein reporter virus was performed at the Centers for Disease Control and Prevention. No antiviral activity was observed for either compound. A study evaluating the efficacy of lamivudine in a guinea pig model of EVD found no survival benefit. This lack of benefit was observed despite plasma lamivudine concentrations in guinea pig of about 4 μg/ml obtained in a separately conducted pharmacokinetics study. These studies found no evidence to support the therapeutic use of lamivudine for the treatment of EVD.
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Yu
authors.initials: Y
authors.lastname: Cong
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Julie
authors.identifier: http://orcid.org/0000-0002-9856-4183
authors.initials: J
authors.lastname: Dyall
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Brit J
authors.initials: BJ
authors.lastname: Hart
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Lisa Evans
authors.initials: LE
authors.lastname: DeWald
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Johnson
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Elena
authors.initials: E
authors.lastname: Postnikova
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Huanying
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Robin
authors.initials: R
authors.lastname: Gross
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Oscar
authors.initials: O
authors.lastname: Rojas
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Isis
authors.initials: I
authors.lastname: Alexander
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Nicole
authors.initials: N
authors.lastname: Josleyn
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Tengfei
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Julia
authors.initials: J
authors.lastname: Michelotti
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Janosko
authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, United States of America.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Glass
authors.affiliation: Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
authors.forename: Mike
authors.initials: M
authors.lastname: Flint
authors.affiliation: Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
authors.forename: Laura K
authors.initials: LK
authors.lastname: McMullan
authors.affiliation: Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
authors.forename: Christina F
authors.initials: CF
authors.lastname: Spiropoulou
authors.affiliation: The National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Tim
authors.initials: T
authors.lastname: Mierzwa
authors.affiliation: The National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Rajarshi
authors.initials: R
authors.lastname: Guha
authors.affiliation: The National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Shinn
authors.affiliation: The National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Sam
authors.initials: S
authors.lastname: Michael
authors.affiliation: The National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Carleen
authors.initials: C
authors.lastname: Klumpp-Thomas
authors.affiliation: The National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Crystal
authors.initials: C
authors.lastname: McKnight
authors.affiliation: The National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Craig
authors.initials: C
authors.lastname: Thomas
authors.affiliation: Office of Biodefense, Research Resources & Translational Research, Division of Microbiology & Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Eakin
authors.affiliation: SRI International, Menlo Park, California, United States of America.
authors.forename: Kathleen G
authors.initials: KG
authors.lastname: O'Loughlin
authors.affiliation: SRI International, Menlo Park, California, United States of America.
authors.forename: Carol E
authors.initials: CE
authors.lastname: Green
authors.affiliation: SRI International, Menlo Park, California, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Catz
authors.affiliation: SRI International, Menlo Park, California, United States of America.
authors.forename: Jon C
authors.initials: JC
authors.lastname: Mirsalis
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Anna N
authors.initials: AN
authors.lastname: Honko
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Gene G
authors.initials: GG
authors.lastname: Olinger
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Bennett
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Holbrook
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Hensley
authors.affiliation: Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland, United States of America.|Emerging Viral Pathogens Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Jahrling
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D029043:Ebolavirus / Q000187:drug effects* / Q000302:isolation & purification; D006168:Guinea Pigs; D006367:HeLa Cells; D019142:Hemorrhagic Fever, Ebola / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology*; D008264:Macrophages; D010865:Pilot Projects; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D019259:Lamivudine; D015215:Zidovudine