BDAA, a yellow fever virus NS4B inhibitor, is effective during therapeutic treatment in a hamster model of yellow fever.

Yellow fever virus (YFV) is a reemerging mosquito-borne flavivirus endemic to South America and Africa. There are no antiviral drugs currently approved for treatment of yellow fever. BDAA, an orally available YFV NS4B inhibitor, has previously shown efficacy against YFV in cell culture and prophylactically in a hamster model of disease. Here, we demonstrated the therapeutic efficacy of BDAA in a hamster model of disease when treatment began as late as 4 days post-infection (dpi). Twice-daily administration of 100 mg/kg BDAA, for a total dose of 200 mg/kg/d, was initiated 4 h pre-infection or 2, 3, or 4 dpi and continued for 7 days. BDAA treatment was effective therapeutically, with significantly improved survival when treatment began as late as 3 dpi and improved serum viremia and serum alanine aminotransferase (ALT) concentrations when treatment began as late as 4 dpi, with a >2 log reduction in serum viremia when treatment was initiated 4 dpi (P = 0.004). Additionally, weight loss and hepatocellular necrosis and apoptosis were reduced in animals receiving BDAA beginning 4 h before or 2 days post-infection. The broad improvement of yellow fever disease parameters in the hamster model with therapeutic BDAA administration strongly supports the clinical potential of BDAA and its analogs as antiviral treatments for yellow fever.