Therapeutic effects of favipiravir against severe fever with thrombocytopenia syndrome virus infection in a lethal mouse model: Dose-efficacy studies upon oral administration

PLoS One. 2018 Oct 26;13(10):e0206416. doi: 10.1371/journal.pone.0206416. eCollection 2018.

Abstract

Severe fever with thrombocytopenia syndrome (SFTS), caused by SFTS virus (SFTSV), is a viral hemorrhagic fever with a high case fatality rate. Favipiravir was reported to be effective in the treatment of SFTSV infection in vivo in type I interferon receptor knockout (IFNAR-/-) mice at treatment dosages of both 60 mg/kg/day and 300 mg/kg/day for a duration of 5 days. In this study, the efficacy of favipiravir at dosages of 120 mg/kg/day and 200 mg/kg/day against SFTSV infection in an IFNAR-/- mouse infection model was investigated. IFNAR-/- mice were subcutaneously infected with SFTSV at a 1.0 × 10(6) 50% tissue culture infectious dose followed by twice daily administration of favipiravir, comprising a total dose of either 120 mg/kg/day or 200 mg/kg/day. The treatment was initiated either immediately post infection or at predesignated time points post infection. Neutralizing antibodies in the convalescent-phase mouse sera was examined by the pseudotyped VSV system. All mice treated with favipiravir at dosages of 120 mg/kg/day or 200 mg/kg/day survived when the treatment was initiated at no later than 4 days post infection. A decrease in body weight of mice was observed when the treatment was initiated at 3-4 days post infection. Furthermore, all control mice died. The body weight of mice did not decrease when treatment with favipiravir was initiated immediately post infection at dosages of 120 mg/kg/day and 200 mg/kg/day. Neutralizing antibodies were detected in the convalescent-phase mouse sera. Similar to the literature-reported peritoneal administration of favipiravir at 300 mg/kg/day, the oral administration of favipiravir at dosages of 120 mg/kg/day and 200 mg/kg/day to IFNAR-/- mice infected with SFTSV was effective.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Amides / administration & dosage*
  • Amides / pharmacology*
  • Amides / therapeutic use
  • Animals
  • Antibodies, Neutralizing / blood
  • Antibodies, Neutralizing / immunology
  • Chlorocebus aethiops
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Mice
  • Phlebotomus Fever / drug therapy*
  • Phlebovirus / drug effects
  • Phlebovirus / immunology
  • Phlebovirus / physiology*
  • Pyrazines / administration & dosage*
  • Pyrazines / pharmacology*
  • Pyrazines / therapeutic use
  • Vero Cells

Substances

  • Amides
  • Antibodies, Neutralizing
  • Pyrazines
  • favipiravir

Supplementary concepts

  • SFTS phlebovirus

Grant support

This research was partially supported by Grants-in-Aid from the Ministry of Health, Labour, and Welfare of Japan (H25-Shinko-Shitei-009) (M.Sa.), AMED under Grant Number JP18fk0108002 (M.Sa.) and JP18fk0108072 (M.Sa.), and JSPS KAKENHI Grant Number JP15K08510 (H.T.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.