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Volume 16, Number 6—June 2010

Research

Oseltamivir-Resistant Influenza Viruses A (H1N1) during 2007–2009 Influenza Seasons, Japan

Makoto Ujike, Kozue Shimabukuro, Kiku Mochizuki, Masatsugu Obuchi, Tsutomu Kageyama, Masayuki Shirakura, Noriko Kishida, Kazuyo Yamashita, Hiroshi Horikawa, Yumiko Kato, Nobuyuki Fujita, Masato Tashiro, Takato OdagiriComments to Author , and the Working Group for Influenza Virus Surveillance in Japan1
Author affiliations: National Institute of Infectious Diseases, Tokyo, Japan (M. Ujike, K. Shimabukuro, K. Mochizuki, M. Obuchi, T. Kageyama, M. Shirakura, N. Kishida, K. Yamashita, M. Tashiro, T. Odagiri); National Institute of Technology and Evaluation, Tokyo (H. Horikawa, Y. Kato, N. Fujita); 1Members of the Working Group for Influenza Virus Surveillance in Japan are listed at the end of this article.

Main Article

Table 1

Influenza virus A (H1N1) outliers to oseltamivir and/or zanamivir, Japan*

Strain
Sequence change(s)

Clinical specimen
Curve fit‡
IC50, nmol/L
D151
H275
Q136
D151
Oseltamivir
Zanamivir
Oseltamivir outlier
A/YAMAGATA/28/2008 D/E† H Q NA Normal 0.55 0.60
Zanamivir outlier candidates
A/TOTTORI/16/2008 D H K NA Normal 0.08 41.89
A/TOTTORI/60/2008 D Y Q NA Normal 113.86 3.64
A/KOBE/31/2008 D Y Q NA Type A 26.05 2.75
A/KOBE/32/2008 D Y Q NA Type A 135.85 3.56
A/MIE/13/2008 D/G H Q D Type A 0.18 14.80
A/YOKOHAMA/75/2007 D/G H Q NA Type A 0.13 6.53
A/HAMAMATSU/33/2008 D/G H Q NA Type A 0.13 6.15
A/TOCHIGI/30/2008 D/G H Q NA Type A 0.13 4.32
A/YOKOHAMA/74/2007 D/G H Q NA Type A 0.12 2.81
A/HIROSHIMA/92/2007 D/G H Q NA Type B 0.07 NA
A/MIE/9/2008 D/G H Q D Type B 0.08 NA
A/MIE/1/2008 D/G H Q D Type B 0.16 NA
A/MIE/14/2008 D/G H Q D Type B 0.08 NA
A/YAMAGATA/60/2008 D/G H Q NA Type B 0.19 NA
A/SAPPORO/64/2008 D/G Y Q NA Type B 147.90 NA
A/TOTTORI/44/2008 D/G Y Q NA Normal§ 180.06 84.42
A/HIROSHIMA/44/2008 D/N Y Q NA Type A 239.23 2.26
A/YOKOHAMA/79/2008 D/N Y Q NA Type A 167.66 2.28
A/HIROSHIMA/46/2008 D/N Y Q NA Type A 190.35 2.40
A/HIROSHIMA/45/2008 D/N Y Q NA Type A 169.92 3.34
A/MIE/1/2009 D/N Y Q NA Type A 231.78 3.55
A/HIROSHIMA/47/2008 D/N Y Q NA Type A 106.19 4.24
A/YOKOHAMA/96/2008
D/V
Y
Q

NA
Type B
126.50
NA
Zanamivir sensitive
A/MIE/18/2008 D/E¶ H Q D Normal 0.35 1.06
A/MIE/21/2008 D/N H Q D Normal 0.22 1.18
IC50 mean of sensitive viruses 0.10 ± 0.05 0.40 ± 0.26
Cutoff IC50 values (UQ +5.0 IQR) 0.40 1.99

*IC50, drug concentrations required to inhibit neurominidase activity by 50%; UQ, upper quartile; IQR, interquartile range; NA, not available. Oseltamivir-resistant viruses with H275Y were excluded from overall population in statistical analysis of oseltamivir.
†Mixture of D151 and D151 variants.
‡Curve fit patterns were evaluated based on Figure 3, panels C (Type A) and D (Type B). Although the viruses with D151D/G tend to generate both patterns from repeat testing for the same samples, type B was selected in this case.
§Although A/TOTTORI/44/2008 showed mixed population of D151D/G, it tended to show a normal curve fit (Figure 3, panel B).
¶The IC50 values of most viruses with D151D/E tend to be higher than mean IC50 values but do not exceed the cutoff value.

Main Article

1Members of the Working Group for Influenza Virus Surveillance in Japan: Hideki Nagano (Hokkaido Institute of Public Health), Masayuki Kikuchi (Sapporo City Institute of Public Health), Masaki Takahashi (Research Institute for Environmental Sciences and Public Health of Iwate Prefecture), Yuki Sato (Miyagi Prefectural Institute of Public Health and Environment), Masanori Katsumi (Sendai City Institute of Public Health), Hiroyuki Saito (Akita Research Center for Public Health and Environment), Katsumi Mizuta (Yamagata Prefectural Institute of Public Health), Syoko Hirose (Fukushima Prefectural Institute of Public Health), Setsuko Fukaya (Ibaraki Prefectural Institute of Public Health), Asumi Hirata(Tochigi Prefectural Institute of Public Health and Environmental Science), Hiroyuki Tsukagoshi (Gunma Prefectural Institute of Public Health and Environmental Sciences), Yuka Uno (Saitama City Institute of Health Science and Research), Hiromi Maru (Chiba Prefectural Institute of Public Health), Hajime Yokoi (Chiba City Institute of Health and Environment), Mami Nagashima (Tokyo Metropolitan Institute of Public Health), Sumi Watanabe (Kanagawa Prefectural Institute of Public Health), Hideaki Shimizu (Kawasaki City Institute of Public Health), Sumiko Ueda (Sagamihara City Laboratory of Public Health), Chika Hirokawa (Niigata Prefectural Institute of Public Health and Environmental Sciences), Gen Kobayashi and Yoko Miyajima (Niigata City Institute of Public Health and Environment), Sanae Kuramoto and Hiroe Kodama (Ishikawa Prefectural Institute of Public Health and Environmental Science), Masako Nakamura (Fukui Prefectural Institute of Public Health), Hiroyoshi Asakawa (Yamanashi Institute for Public Health), Seiko Sawatari (Gifu Prefectural Institute of Health and Enviromental Sciences), Yasunori Tanaka (Gifu Municipal Institute of Public Health), Yoshinobu Miwa (Shizuoka Institute of Environment and Hygiene), Shinobu Ide (Shizuoka City Institute of Environmental Sciences and Public Health), Yoshinori Kohno and Ryu Hibino (Hamamatsu City Health Environment Research Center), Mami Hata (Aichi Prefectural Institute of Public Health), Noriko Goto (Nagoya City Public Health Research Institute), Takuya Yano (Mie Prefecture Health and Environment Research Institute), Fumie Matsumoto (Shiga Prefectural Institute of Public Health), Tohru Ishizaki (Kyoto Prefectural Institute of Public Health and Environment), Satoshi Hiroi (Osaka Prefectural Institute of Public Health), Hideyuki Kubo (Osaka City Institute of Public Health and Environmental Sciences), Kiyoko Uchino (Sakai City Institute of Public Health), Tomohiro Oshibe (Hyogo Prefectural Institute of Public Health and Consumer Sciences), Ai Mori and Tomoko Suga (Kobe Institute of Health), Yoshiteru Kitahori (Nara Prefectural Institute for Hygiene and Environment), Fumio Terasoma (Wakayama Prefectural Research Center of Environment and Public Health), Yoshiaki Kimura and Naomi Matsumoto (Tottori Prefectural Institute of Public Health and Environmental Science), Tamaki Omura (Shimane Prefectural Institute of Public Health and Environmental Science), Shinichi Takao (Center for Public Health and Environment, Hiroshima Prefectural Technology Research Institute), Katsuhiko Abe (Hiroshima City Institute of Public Health), Yumiko Kawakami (Tokushima Prefectural Centre for Public Health and Environmental Sciences), Ootsuka Yuka (Ehime Prefecture Institute of Public Health and Environmental Science), Daisuke Kawamoto (Fukuoka City Institute for Hygiene and the Environment), Takayuki Hirano and Hisato Masumoto (Saga Prefectural Institute of Public Health and Pharmaceutical Research), Manabu Hirano and Akinori Yamaguchi (Nagasaki Prefectural Institute for Environment Research and Public Health), Seiya Harada and Koichi Nishimura (Kumamoto Prefectural Institute of Public Health and Environmental Science), Miki Kato (Oita Prefectural Institute of Health and Environment), Miho Miura (Miyazaki Prefectural Institute for Public Health and Environment), Kanji Ishitani and Akihide Kamimura (Kagoshima Prefectural Institute for Environmental Research and Pubulic Health), Katsuya Taira (Okinawa Prefectural Institute of Health and Environment), Mitsutaka Kuzuya (Okayama Prefectural Institute for Environmental Science and Public Health), Shoichi Toda (Yamaguchi Prefectural Institute of Public Health and Environment), Chiharu Kawakami (Yokohama City Institute of Health), Mayumi Konno (Kyoto City Institute of Health and Environmental Sciences), Hiroya Komoda (Kagawa Prefectural Research Institute for Environmental Sciences and Public Health), Tae Taniwaki (Kochi Public Health and Sanitation Institute), Toshitaka Minegishi (Saitama Institute of Public Health), Rika Tsutsui (Aomori Prefectural Institute of Public Health and Environment), Shizuko Kasuo (Nagano Environmental Conservation Research Institute), Yuichiro Okamura (Nagano City Health Center), Eiji Horimoto (Toyama Institute of Health), Nobuyuki Sera (Fukuoka Institute of Health and Environmental Sciences), and Hiromi Yoshikawa (Kitakyushu City Institute of Environmental Sciences)

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