Ed Rybicki 🇿🇲🇿🇦🇬🇧🍷🚀 (@edrybicki.bsky.social)

Baloxavir susceptibility of seasonal influenza viruses during the first seven seasons of clinical use in Japan, 2017/18 to 2023/24 BACKGROUND: Baloxavir marboxil, a cap-dependent endonuclease inhibitor, was approved in Japan in February 2018 for treatment of influenza A and B infections, making Japan the first country to introduce its clinical use. AIM: We aimed to assess baloxavir susceptibility among seasonal influenza viruses in Japan during the first seven seasons of clinical use, from 2017/18 to 2023/24. METHODS: We conducted nationwide surveillance on 3,671 influenza viruses using phenotypic and genotypic assays to evaluate baloxavir susceptibility and identify amino acid substitutions in the polymerase acidic (PA) protein associated with reduced susceptibility. RESULTS: Overall, 1.7% of tested viruses exhibited reduced susceptibility to baloxavir. Influenza A(H3N2) viruses showed the highest frequency (3.6%), followed by influenza A(H1N1)pdm09 (0.9%); no influenza B viruses exhibited reduced susceptibility. Key PA substitutions included E23K, Y24C, I38M/N/S/T/V and E199G/K. Viruses with reduced susceptibility were detected in both treated and untreated individuals. Reduced susceptibility was most frequent during the 2018/19 (4.6%) and 2022/23 (3.2%) seasons, both dominated by A(H3N2) viruses. Notably, the 2018/19 season coincided with peak baloxavir supply to medical institutions, while subsequent seasons with lower antiviral use showed a lower proportion of reduced-susceptibility viruses. CONCLUSION: Our findings suggest a possible association between the extent of baloxavir use and the emergence of resistance and highlight how circulating subtypes shape seasonal susceptibility profiles. Although reduced susceptibility to baloxavir remains relatively rare, emergence of transmissible virus variants emphasises the need for continued phenotypic and genotypic surveillance to guide treatment strategies, support public health preparedness, and prevent the spread of resistant viruses. https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2026.31.1.2500336