Baloxavir susceptibility of seasonal influenza viruses during the first seven seasons of clinical use in Japan, 2017/18 to 2023/24

Emi Takashita; Seiichiro Fujisaki; Hiroko Morita; Shiho Nagata; Hideka Miura; Noriko Kishida; Kazuya Nakamura; Masayuki Shirakura; Aya Sato; Miki Akimoto; Hiromi Sugawara; Keiko Mitamura; Takashi Abe; Masataka Ichikawa; Masahiko Yamazaki; Shinji Watanabe; Takato Odagiri; Hideki Hasegawa; the Influenza Virus Surveillance Group of Japan

doi:10.2807/1560-7917.ES.2026.31.1.2500336

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Baloxavir susceptibility of seasonal influenza viruses during the first seven seasons of clinical use in Japan, 2017/18 to 2023/24
Emi Takashita^1,* , Seiichiro Fujisaki^1,* , Hiroko Morita¹ , Shiho Nagata¹ , Hideka Miura¹ , Noriko Kishida¹ , Kazuya Nakamura¹ , Masayuki Shirakura¹ , Aya Sato¹ , Miki Akimoto¹ , Hiromi Sugawara¹ , Keiko Mitamura² , Takashi Abe³ , Masataka Ichikawa⁴ , Masahiko Yamazaki⁵ , Shinji Watanabe¹ , Takato Odagiri¹ , Hideki Hasegawa¹ , the Influenza Virus Surveillance Group of Japan⁶
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Affiliations: ¹ Influenza Research Center, National Institute of Infectious Diseases, Japan Institute for Health Security, Tokyo, Japan ² Eiju General Hospital, Tokyo, Japan ³ Abe Children’s Clinic, Kanagawa, Japan ⁴ Ichikawa Children’s Clinic, Kanagawa, Japan ⁵ Zama Children’s Clinic, Kanagawa, Japan ⁶ The members of the group are listed under Collaborators. ^* These authors contributed equally to this work and share first authorship.

Correspondence:
Emi Takashita
takashita.e jihs.go.jp
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The Influenza Virus Surveillance Group of Japan: Rika Komagome, Asami Ohnishi, Kyohei Saka, Tomoko Takahashi, Mie Sasaki, Minako Ato, Youko Fujiya, Naomi Ogawa, Nozomi Saito, Miyako Kon, Hiromi Kita, Asaka Okubo, Yuki Wakabayashi, Akira Wakatsuki, Hiroyuki Tsukagoshi, Noriko Hamamoto, Yasuo Kaburagi, Hitomi Yahata, Tomofumi Seno, Mami Nagashima, Sumi Watanabe, Kohei Shimizu, Chie Akaboshi, Yumiko Nagasawa, Ikuyo Kiuchi, Miho Kitazume, Michiko Takeuchi, Erina Miyajima, Asaka Ikegaya, Hirosato Ehara, Ryota Akaike, Takahisa Shimada, Nao Kobashi, Nobushige Sakai, Masahiro Nishioka, Keisuke Futamura, Yoshihiro Yasui, Takuya Yano, Asa Tanino, Yoshihiro Tanabe, Kazuko Nakagawa, Saeko Morikawa, Hiromi Fukuda, Tomohiro Oshibe, Ai Mori, Ryutaro Murayama, Saya Yamamoto, Shiho Nagase, Masaki Nishikawa, Arisa Izumi, Yurie Kanba, Akiyoshi Baba, Yukie Shimazu, Yasutsugu Kawahara, Yayoi Orita, Mizuki Yamamoto, Yukari Tsuchida, Sayako Yoshida, Wataru Satou, Yuri Kondo, Michihiko Miyamoto, Sonoko Izumida, Ukyo Osoegawa, Yumika Takaki, Eisuke Tokuoka, Mayumi Kadoguchi, Toru Hayashi, Nami Tsuru, Yuka Hamada, Noriyuki Maeshiro

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Citation style for this article: Takashita Emi, Fujisaki Seiichiro, Morita Hiroko, Nagata Shiho, Miura Hideka, Kishida Noriko, Nakamura Kazuya, Shirakura Masayuki, Sato Aya, Akimoto Miki, Sugawara Hiromi, Mitamura Keiko, Abe Takashi, Ichikawa Masataka, Yamazaki Masahiko, Watanabe Shinji, Odagiri Takato, Hasegawa Hideki, the Influenza Virus Surveillance Group of Japan. Baloxavir susceptibility of seasonal influenza viruses during the first seven seasons of clinical use in Japan, 2017/18 to 2023/24. Euro Surveill. 2026;31(1):pii=2500336. https://doi.org/10.2807/1560-7917.ES.2026.31.1.2500336 Received: 14 May 2025; Accepted: 04 Sept 2025

Abstract

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.

This work is licensed under a Creative Commons Attribution 4.0 International License.

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Baloxavir susceptibility of seasonal influenza viruses during the first seven seasons of clinical use in Japan, 2017/18 to 2023/24

Citation style for this article: <a href="/search?value1=Emi+Takashita&option1=author&noRedirect=true" class="nonDisambigAuthorLink">Takashita Emi</a>, <a href="/search?value1=Seiichiro+Fujisaki&option1=author&noRedirect=true" class="nonDisambigAuthorLink">Fujisaki Seiichiro</a>, <a href="/search?value1=Hiroko+Morita&option1=author&noRedirect=true" class="nonDisambigAuthorLink">Morita Hiroko</a>, <a href="/search?value1=Shiho+Nagata&option1=author&noRedirect=true" class="nonDisambigAuthorLink">Nagata Shiho</a>, <a href="/search?value1=Hideka+Miura&option1=author&noRedirect=true" class="nonDisambigAuthorLink">Miura Hideka</a>, <a href="/search?value1=Noriko+Kishida&option1=author&noRedirect=true" class="nonDisambigAuthorLink">Kishida Noriko</a>, <a href="/search?value1=Kazuya+Nakamura&option1=author&noRedirect=true" class="nonDisambigAuthorLink">Nakamura Kazuya</a>, <a href="/search?value1=Masayuki+Shirakura&option1=author&noRedirect=true" class="nonDisambigAuthorLink">Shirakura Masayuki</a>, <a href="/search?value1=Aya+Sato&option1=author&noRedirect=true" class="nonDisambigAuthorLink">Sato Aya</a>, <a href="/search?value1=Miki+Akimoto&option1=author&noRedirect=true" class="nonDisambigAuthorLink">Akimoto Miki</a>, <a href="/search?value1=Hiromi+Sugawara&option1=author&noRedirect=true" class="nonDisambigAuthorLink">Sugawara Hiromi</a>, <a href="/search?value1=Keiko+Mitamura&option1=author&noRedirect=true" class="nonDisambigAuthorLink">Mitamura Keiko</a>, <a href="/search?value1=Takashi+Abe&option1=author&noRedirect=true" class="nonDisambigAuthorLink">Abe Takashi</a>, <a href="/search?value1=Masataka+Ichikawa&option1=author&noRedirect=true" class="nonDisambigAuthorLink">Ichikawa Masataka</a>, <a href="/search?value1=Masahiko+Yamazaki&option1=author&noRedirect=true" class="nonDisambigAuthorLink">Yamazaki Masahiko</a>, <a href="/search?value1=Shinji+Watanabe&option1=author&noRedirect=true" class="nonDisambigAuthorLink">Watanabe Shinji</a>, <a href="/search?value1=Takato+Odagiri&option1=author&noRedirect=true" class="nonDisambigAuthorLink">Odagiri Takato</a>, <a href="/search?value1=Hideki+Hasegawa&option1=author&noRedirect=true" class="nonDisambigAuthorLink">Hasegawa Hideki</a>, <a href="/search?value1=the+Influenza+Virus+Surveillance+Group+of+Japan&option1=author&noRedirect=true" class="nonDisambigAuthorLink">the Influenza Virus Surveillance Group of Japan</a>. Baloxavir susceptibility of seasonal influenza viruses during the first seven seasons of clinical use in Japan, 2017/18 to 2023/24. <a href="/content/ecdc">Euro Surveill.</a> 2026;31(1):pii=2500336. <a href="https://doi.org/10.2807/1560-7917.ES.2026.31.1.2500336" title="doi link" target="_blank">https://doi.org/10.2807/1560-7917.ES.2026.31.1.2500336</a> Received: 14 May 2025;   Accepted: 04 Sept 2025

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Baloxavir susceptibility of seasonal influenza viruses during the first seven seasons of clinical use in Japan, 2017/18 to 2023/24

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