Baloxavir Treatment Delays Influenza B Virus Transmission in Ferrets and Results in Limited Generation of Drug-Resistant Variants.

Clinical efficacy of the influenza antiviral baloxavir marboxil (baloxavir) is compromised by treatment-emergent variants harboring a polymerase acidic protein I38T (isoleucine-38-threonine) substitution. However, the fitness of I38T-containing influenza B viruses (IBVs) remains inadequately defined. After the pharmacokinetics of the compound were confirmed in ferrets, animals were injected subcutaneously with 8 mg/kg of baloxavir acid (BXA) at 24 h postinoculation with recombinant BXA-sensitive (BXA-, I38) or BXA-resistant (BXA-, I38T) B/Brisbane/60/2008 (Victoria lineage) virus. BXA treatment of donor ferrets reduced virus replication and delayed transmission of the BXA- but not the BXA- IBV. The I38 genotype remained dominant in the BXA--infected animals, even with BXA treatment. In competitive-mixture experiments, no transmission to aerosol contacts was seen from BXA-treated donors coinfected with the BXA- and BXA- B/Brisbane/60/2008 viruses. However, in parallel mixed infections with the B/Phuket/3073/2013 (Yamagata lineage) virus background, BXA treatment failed to block airborne transmission of the BXA- virus, and the I38T genotype generally predominated. Therefore, the relative fitness of BXA- IBVs is complex and dependent on the virus backbone and within-host virus competition. BXA treatment of single-virus-infected ferrets hampers aerosol transmission of the BXA- virus and does not readily generate BXA- variants, whereas mixed infections may result in propagation of BXA- IBVs of the Yamagata lineage. Our findings confirm the antiviral potency of baloxavir against IBVs, while supporting optimization of the dosing regimen to maximize clinical benefit.