Favipiravir (T-705) protects against peracute Rift Valley fever virus infection and reduces delayed-onset neurologic disease observed with ribavirin treatment.
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.
Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, UT, USA; Institute for Antiviral Research, Utah State University, Logan, UT, USA.
Dionna
D
Scharton
Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, UT, USA; Institute for Antiviral Research, Utah State University, Logan, UT, USA.
Kevin W
KW
Bailey
Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, UT, USA; Institute for Antiviral Research, Utah State University, Logan, UT, USA.
Zachary
Z
Vest
Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, UT, USA; Institute for Antiviral Research, Utah State University, Logan, UT, USA.
Jonna B
JB
Westover
Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, UT, USA; Institute for Antiviral Research, Utah State University, Logan, UT, USA.
Yohichi
Y
Kumaki
Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, UT, USA; School of Veterinary Medicine, Utah State University, Logan, UT, USA; Utah Veterinary Diagnostic Laboratory, Logan, UT, USA.
Arnaud
A
Van Wettere
Toyama Chemical Co., Ltd., Toyama, Japan.
Yousuke
Y
Furuta
Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, UT, USA; Institute for Antiviral Research, Utah State University, Logan, UT, USA; School of Veterinary Medicine, Utah State University, Logan, UT, USA. Electronic address: brian.gowen@usu.edu.
Brian B
BB
Gowen
D000577:Amides / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D020805:Central Nervous System Viral Diseases / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000821:virology*; D006224:Cricetinae; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D008826:Microbial Sensitivity Tests; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D012295:Rift Valley Fever / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000821:virology*; D012296:Rift Valley fever virus / Q000187:drug effects* / Q000201:enzymology*; D019562:Viral Load
D000577:Amides; D000998:Antiviral Agents; D011719:Pyrazines; C462182:favipiravir
Bunyavirus; Favipiravir (T-705); Phlebovirus; Ribavirin; Rift Valley fever virus