Favipiravir (T-705) Inhibits Junín Virus Infection and Reduces Mortality in a Guinea Pig Model of Argentine Hemorrhagic Fever

Brian B. Gowen, Terry L. Juelich, Eric J. Sefing, Trevor Brasel, Jennifer K. Smith, Lihong Zhang, Bersabeh Tigabu, Terence E. Hill, Tatyana Yun, Colette Pietzsch, Yousuke Furuta, Alexander Freiberg

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Background:Junín virus (JUNV), the etiologic agent of Argentine hemorrhagic fever (AHF), is classified by the NIAID and CDC as a Category A priority pathogen. Presently, antiviral therapy for AHF is limited to immune plasma, which is readily available only in the endemic regions of Argentina. T-705 (favipiravir) is a broadly active small molecule RNA-dependent RNA polymerase inhibitor presently in clinical evaluation for the treatment of influenza. We have previously reported on the in vitro activity of favipiravir against several strains of JUNV and other pathogenic New World arenaviruses.Methodology/Principal Findings:To evaluate the efficacy of favipiravir in vivo, guinea pigs were challenged with the pathogenic Romero strain of JUNV, and then treated twice daily for two weeks with oral or intraperitoneal (i.p.) favipiravir (300 mg/kg/day) starting 1-2 days post-infection. Although only 20% of animals treated orally with favipiravir survived the lethal challenge dose, those that succumbed survived considerably longer than guinea pigs treated with placebo. Consistent with pharmacokinetic analysis that showed greater plasma levels of favipiravir in animals dosed by i.p. injection, i.p. treatment resulted in a substantially higher level of protection (78% survival). Survival in guinea pigs treated with ribavirin was in the range of 33-40%. Favipiravir treatment resulted in undetectable levels of serum and tissue viral titers and prevented the prominent thrombocytopenia and leucopenia observed in placebo-treated animals during the acute phase of infection.Conclusions/Significance:The remarkable protection afforded by i.p. favipiravir intervention beginning 2 days after challenge is the highest ever reported for a small molecule antiviral in the difficult to treat guinea pig JUNV challenge model. These findings support the continued development of favipiravir as a promising antiviral against JUNV and other related arenaviruses.

Original languageEnglish (US)
Article numbere2614
JournalPLoS Neglected Tropical Diseases
Volume7
Issue number12
DOIs
StatePublished - 2013

Fingerprint

Virus Diseases
Guinea Pigs
Fever
Mortality
Viruses
Antiviral Agents
New World Arenaviruses
National Institute of Allergy and Infectious Diseases (U.S.)
Arenavirus
Placebos
RNA Replicase
favipiravir
Ribavirin
Argentina
Leukopenia
Therapeutics
Centers for Disease Control and Prevention (U.S.)
Infection
Intraperitoneal Injections
Thrombocytopenia

ASJC Scopus subject areas

  • Infectious Diseases
  • Public Health, Environmental and Occupational Health
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Favipiravir (T-705) Inhibits Junín Virus Infection and Reduces Mortality in a Guinea Pig Model of Argentine Hemorrhagic Fever. / Gowen, Brian B.; Juelich, Terry L.; Sefing, Eric J.; Brasel, Trevor; Smith, Jennifer K.; Zhang, Lihong; Tigabu, Bersabeh; Hill, Terence E.; Yun, Tatyana; Pietzsch, Colette; Furuta, Yousuke; Freiberg, Alexander.

In: PLoS Neglected Tropical Diseases, Vol. 7, No. 12, e2614, 2013.

Research output: Contribution to journalArticle

Gowen, BB, Juelich, TL, Sefing, EJ, Brasel, T, Smith, JK, Zhang, L, Tigabu, B, Hill, TE, Yun, T, Pietzsch, C, Furuta, Y & Freiberg, A 2013, 'Favipiravir (T-705) Inhibits Junín Virus Infection and Reduces Mortality in a Guinea Pig Model of Argentine Hemorrhagic Fever', PLoS Neglected Tropical Diseases, vol. 7, no. 12, e2614. https://doi.org/10.1371/journal.pntd.0002614
Gowen, Brian B. ; Juelich, Terry L. ; Sefing, Eric J. ; Brasel, Trevor ; Smith, Jennifer K. ; Zhang, Lihong ; Tigabu, Bersabeh ; Hill, Terence E. ; Yun, Tatyana ; Pietzsch, Colette ; Furuta, Yousuke ; Freiberg, Alexander. / Favipiravir (T-705) Inhibits Junín Virus Infection and Reduces Mortality in a Guinea Pig Model of Argentine Hemorrhagic Fever. In: PLoS Neglected Tropical Diseases. 2013 ; Vol. 7, No. 12.
@article{b5150325e960435c87bfed58cb58268f,
title = "Favipiravir (T-705) Inhibits Jun{\'i}n Virus Infection and Reduces Mortality in a Guinea Pig Model of Argentine Hemorrhagic Fever",
abstract = "Background:Jun{\'i}n virus (JUNV), the etiologic agent of Argentine hemorrhagic fever (AHF), is classified by the NIAID and CDC as a Category A priority pathogen. Presently, antiviral therapy for AHF is limited to immune plasma, which is readily available only in the endemic regions of Argentina. T-705 (favipiravir) is a broadly active small molecule RNA-dependent RNA polymerase inhibitor presently in clinical evaluation for the treatment of influenza. We have previously reported on the in vitro activity of favipiravir against several strains of JUNV and other pathogenic New World arenaviruses.Methodology/Principal Findings:To evaluate the efficacy of favipiravir in vivo, guinea pigs were challenged with the pathogenic Romero strain of JUNV, and then treated twice daily for two weeks with oral or intraperitoneal (i.p.) favipiravir (300 mg/kg/day) starting 1-2 days post-infection. Although only 20{\%} of animals treated orally with favipiravir survived the lethal challenge dose, those that succumbed survived considerably longer than guinea pigs treated with placebo. Consistent with pharmacokinetic analysis that showed greater plasma levels of favipiravir in animals dosed by i.p. injection, i.p. treatment resulted in a substantially higher level of protection (78{\%} survival). Survival in guinea pigs treated with ribavirin was in the range of 33-40{\%}. Favipiravir treatment resulted in undetectable levels of serum and tissue viral titers and prevented the prominent thrombocytopenia and leucopenia observed in placebo-treated animals during the acute phase of infection.Conclusions/Significance:The remarkable protection afforded by i.p. favipiravir intervention beginning 2 days after challenge is the highest ever reported for a small molecule antiviral in the difficult to treat guinea pig JUNV challenge model. These findings support the continued development of favipiravir as a promising antiviral against JUNV and other related arenaviruses.",
author = "Gowen, {Brian B.} and Juelich, {Terry L.} and Sefing, {Eric J.} and Trevor Brasel and Smith, {Jennifer K.} and Lihong Zhang and Bersabeh Tigabu and Hill, {Terence E.} and Tatyana Yun and Colette Pietzsch and Yousuke Furuta and Alexander Freiberg",
year = "2013",
doi = "10.1371/journal.pntd.0002614",
language = "English (US)",
volume = "7",
journal = "PLoS Neglected Tropical Diseases",
issn = "1935-2727",
publisher = "Public Library of Science",
number = "12",

}

TY - JOUR

T1 - Favipiravir (T-705) Inhibits Junín Virus Infection and Reduces Mortality in a Guinea Pig Model of Argentine Hemorrhagic Fever

AU - Gowen, Brian B.

AU - Juelich, Terry L.

AU - Sefing, Eric J.

AU - Brasel, Trevor

AU - Smith, Jennifer K.

AU - Zhang, Lihong

AU - Tigabu, Bersabeh

AU - Hill, Terence E.

AU - Yun, Tatyana

AU - Pietzsch, Colette

AU - Furuta, Yousuke

AU - Freiberg, Alexander

PY - 2013

Y1 - 2013

N2 - Background:Junín virus (JUNV), the etiologic agent of Argentine hemorrhagic fever (AHF), is classified by the NIAID and CDC as a Category A priority pathogen. Presently, antiviral therapy for AHF is limited to immune plasma, which is readily available only in the endemic regions of Argentina. T-705 (favipiravir) is a broadly active small molecule RNA-dependent RNA polymerase inhibitor presently in clinical evaluation for the treatment of influenza. We have previously reported on the in vitro activity of favipiravir against several strains of JUNV and other pathogenic New World arenaviruses.Methodology/Principal Findings:To evaluate the efficacy of favipiravir in vivo, guinea pigs were challenged with the pathogenic Romero strain of JUNV, and then treated twice daily for two weeks with oral or intraperitoneal (i.p.) favipiravir (300 mg/kg/day) starting 1-2 days post-infection. Although only 20% of animals treated orally with favipiravir survived the lethal challenge dose, those that succumbed survived considerably longer than guinea pigs treated with placebo. Consistent with pharmacokinetic analysis that showed greater plasma levels of favipiravir in animals dosed by i.p. injection, i.p. treatment resulted in a substantially higher level of protection (78% survival). Survival in guinea pigs treated with ribavirin was in the range of 33-40%. Favipiravir treatment resulted in undetectable levels of serum and tissue viral titers and prevented the prominent thrombocytopenia and leucopenia observed in placebo-treated animals during the acute phase of infection.Conclusions/Significance:The remarkable protection afforded by i.p. favipiravir intervention beginning 2 days after challenge is the highest ever reported for a small molecule antiviral in the difficult to treat guinea pig JUNV challenge model. These findings support the continued development of favipiravir as a promising antiviral against JUNV and other related arenaviruses.

AB - Background:Junín virus (JUNV), the etiologic agent of Argentine hemorrhagic fever (AHF), is classified by the NIAID and CDC as a Category A priority pathogen. Presently, antiviral therapy for AHF is limited to immune plasma, which is readily available only in the endemic regions of Argentina. T-705 (favipiravir) is a broadly active small molecule RNA-dependent RNA polymerase inhibitor presently in clinical evaluation for the treatment of influenza. We have previously reported on the in vitro activity of favipiravir against several strains of JUNV and other pathogenic New World arenaviruses.Methodology/Principal Findings:To evaluate the efficacy of favipiravir in vivo, guinea pigs were challenged with the pathogenic Romero strain of JUNV, and then treated twice daily for two weeks with oral or intraperitoneal (i.p.) favipiravir (300 mg/kg/day) starting 1-2 days post-infection. Although only 20% of animals treated orally with favipiravir survived the lethal challenge dose, those that succumbed survived considerably longer than guinea pigs treated with placebo. Consistent with pharmacokinetic analysis that showed greater plasma levels of favipiravir in animals dosed by i.p. injection, i.p. treatment resulted in a substantially higher level of protection (78% survival). Survival in guinea pigs treated with ribavirin was in the range of 33-40%. Favipiravir treatment resulted in undetectable levels of serum and tissue viral titers and prevented the prominent thrombocytopenia and leucopenia observed in placebo-treated animals during the acute phase of infection.Conclusions/Significance:The remarkable protection afforded by i.p. favipiravir intervention beginning 2 days after challenge is the highest ever reported for a small molecule antiviral in the difficult to treat guinea pig JUNV challenge model. These findings support the continued development of favipiravir as a promising antiviral against JUNV and other related arenaviruses.

UR - http://www.scopus.com/inward/record.url?scp=84892749776&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84892749776&partnerID=8YFLogxK

U2 - 10.1371/journal.pntd.0002614

DO - 10.1371/journal.pntd.0002614

M3 - Article

VL - 7

JO - PLoS Neglected Tropical Diseases

JF - PLoS Neglected Tropical Diseases

SN - 1935-2727

IS - 12

M1 - e2614

ER -