Enhancement of Favipiravir With Compound X in a Hamster Model of Yellow Fever Virus Infection

Yellow fever virus (YFV) has long been a worldwide health concern, and recent outbreaks in South America and Africa have resulted in significant mortality. There is currently an effective vaccine to prevent infection, but there are no currently developed antiviral drugs to treat patients that have already contracted the disease. Because of this, an effective antiviral is needed to combat unanticipated cases or emergence in areas that have previously been unaffected by this virus. A drug called favipiravir has shown promising results previously. This compound acts as a nucleoside analog to halt the replication of the virus and stop infection. However, the needed dosages of favipiravir are toxic in humans. A separate drug termed "Compound X" has shown potentiator activity by increasing the concentration of the active form of favipiravir in vitro. In this study, we administered suboptimal, non-toxic doses of favipiravir in combination with Compound X to determine this combination treatment's antiviral efficacy against YFV infection in an in-vivo, hamster model. Different doses of favipiravir alone, Compound X alone, a vehicle placebo drug, or both favipiravir and Compound X in tandem were administered twice daily for seven days. Mortality and weight change were recorded for the course of 21 days. Serum was collected on days four and six post infection and analyzed for serum virus titers as well as alanine aminotransferase (ALT) levels indicative of YFV infection. No significant difference was seen in serum viremia or ALT levels in any groups. However, there was a significant difference in weight change and mortality among the groups treated with the combination treatment. The combination treatment of Compound X with favipiravir was more effective than either drug alone at reducing weight loss and overall mortality in the groups treated. These results show promise for the future that these drugs may be used in combination to effectively treat YFV infection while avoiding toxicity in humans.