Favipiravir (T-705) protects against peracute Rift Valley fever virus infection and reduces delayed-onset neurologic disease observed with ribavirin treatment

Antiviral Res. 2014 Apr;104:84-92. doi: 10.1016/j.antiviral.2014.01.016. Epub 2014 Jan 31.

Abstract

Rift Valley fever is a zoonotic, arthropod-borne disease that affects livestock and humans. The etiologic agent, Rift Valley fever virus (RVFV; Bunyaviridae, Phlebovirus) is primarily transmitted through mosquito bites, but can also be transmitted by exposure to infectious aerosols. There are presently no licensed vaccines or therapeutics to prevent or treat severe RVFV infection in humans. We have previously reported on the activity of favipiravir (T-705) against the MP-12 vaccine strain of RVFV and other bunyaviruses in cell culture. In addition, efficacy has also been documented in mouse and hamster models of infection with the related Punta Toro virus. Here, hamsters challenged with the highly pathogenic ZH501 strain of RVFV were used to evaluate the activity of favipiravir against lethal infection. Subcutaneous RVFV challenge resulted in substantial serum and tissue viral loads and caused severe disease and mortality within 2-3 days of infection. Oral favipiravir (200 mg/kg/day) prevented mortality in 60% or greater of hamsters challenged with RVFV when administered within 1 or 6h post-exposure and reduced RVFV titers in serum and tissues relative to the time of treatment initiation. In contrast, although ribavirin (75 mg/kg/day) was effective at protecting animals from the peracute RVFV disease, most ultimately succumbed from a delayed-onset neurologic disease associated with high RVFV burden observed in the brain in moribund animals. When combined, T-705 and ribavirin treatment started 24 h post-infection significantly improved survival outcome and reduced serum and tissue virus titers compared to monotherapy. Our findings demonstrate significant post-RVFV exposure efficacy with favipiravir against both peracute disease and delayed-onset neuroinvasion, and suggest added benefit when combined with ribavirin.

Keywords: Bunyavirus; Favipiravir (T-705); Phlebovirus; Ribavirin; Rift Valley fever virus.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amides / pharmacology*
  • Amides / therapeutic use
  • Animals
  • Antiviral Agents / pharmacology*
  • Antiviral Agents / therapeutic use
  • Cell Line
  • Central Nervous System Viral Diseases / drug therapy
  • Central Nervous System Viral Diseases / mortality
  • Central Nervous System Viral Diseases / pathology
  • Central Nervous System Viral Diseases / virology*
  • Cricetinae
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Female
  • Microbial Sensitivity Tests
  • Pyrazines / pharmacology*
  • Pyrazines / therapeutic use
  • Rift Valley Fever / drug therapy
  • Rift Valley Fever / mortality
  • Rift Valley Fever / pathology
  • Rift Valley Fever / virology*
  • Rift Valley fever virus / drug effects*
  • Rift Valley fever virus / enzymology*
  • Viral Load

Substances

  • Amides
  • Antiviral Agents
  • Pyrazines
  • favipiravir