Baloxavir outperforms oseltamivir, favipiravir, and amantadine in treating lethal influenza A(H5N1) HA clade 2.3.4.4b infection in mice

Abstract Intercontinental spread of highly pathogenic avian influenza A(H5N1) viruses poses significant pandemic risks and necessitates strong protective countermeasures. We evaluated the therapeutic efficacy of the neuraminidase inhibitor oseltamivir, the polymerase inhibitors baloxavir and favipiravir, and an ion-channel blocker amantadine, against severe influenza A(H5N1) infection in mice. Oseltamivir (≥ 100 mg/kg/day for 5 days) provided limited survival benefits and failed to prevent viral neuroinvasion. Baloxavir (≥ 10 mg/kg, 1 dose) fully protected mice, significantly reduced virus respiratory replication, and prevented neuroinvasion. Favipiravir (≥ 100 mg/kg/day for 5 days) provided partial protection, with viral titers being reduced in lungs and brain. Amantadine provided no benefits. Although all drugs inhibited A(H5N1) viruses in vitro, in vivo correlations did not extend beyond baloxavir. Our results indicate that baloxavir is the most reliable treatment to address both respiratory replication and systemic spread of contemporary A(H5N1) viruses in mice and should be considered in pandemic planning.