Oseltamivir-Resistant Pandemic (H1N1) 2009, Japan | CDC EID

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Volume 17, Number 3–March 2011
Research
Monitoring and Characterization of Oseltamivir-Resistant Pandemic (H1N1) 2009 Virus, Japan, 2009–2010
Makoto Ujike, Miho Ejima, Akane Anraku, Kozue Shimabukuro, Masatsugu Obuchi, Noriko Kishida, Xu Hong, Emi Takashita, Seiichiro Fujisaki, Kazuyo Yamashita, Hiroshi Horikawa, Yumiko Kato, Akio Oguchi, Nobuyuki Fujita, Masato Tashiro, Takato Odagiri, and the Influenza Virus Surveillance Group of Japan1

Author affiliations: National Institute of Infectious Diseases, Tokyo, Japan (M. Ujike, M. Ejima, A. Anraku, K. Shimabukuro, M. Obuchi, N. Kishida, X. Hong, E. Takashita, S. Fujisaki, K. Yamashita, M. Tashiro, T. Odagiri); and National Institute of Technology and Evaluation,

Suggested citation for this article

Abstract
To monitor and characterize oseltamivir-resistant (OR) pandemic (H1N1) 2009 virus with the H275Y mutation, we analyzed 4,307 clinical specimens from Japan by neuraminidase (NA) sequencing or inhibition assay; 61 OR pandemic (H1N1) 2009 viruses were detected. NA inhibition assay and M2 sequencing indicated that OR pandemic (H1N1) 2009 virus was resistant to M2 inhibitors, but sensitive to zanamivir. Full-genome sequencing showed OR and oseltamivir-sensitive (OS) viruses had high sequence similarity, indicating that domestic OR virus was derived from OS pandemic (H1N1) 2009 virus. Hemagglutination inhibition test demonstrated that OR and OS pandemic (H1N1) 2009 viruses were antigenically similar to the A/California/7/2009 vaccine strain. Of 61 case-patients with OR viruses, 45 received oseltamivir as treatment, and 10 received it as prophylaxis, which suggests that most cases emerged sporadically from OS pandemic (H1N1) 2009, due to selective pressure. No evidence of sustained spread of OR pandemic (H1N1) 2009 was found in Japan; however, 2 suspected incidents of human-to-human transmission were reported.
In March and early April of 2009, a new swine-origin A/H1N1 influenza virus, now called pandemic (H1N1) 2009, emerged in Mexico and the United States and spread rapidly (1–3). On June 11, 2009, the World Health Organization (WHO) declared a phase-6 pandemic alert, indicating a global pandemic. The earliest virus isolates were sensitive to the neuraminidase inhibitors (NAIs) zanamivir and oseltamivir, but resistant to M2 inhibitors, such as amantadine and rimantadine (1,3–5). Thus, the NAIs have been used globally for treatment and prophylaxis of pandemic (H1N1) 2009 virus inflection.

Oseltamivir-resistant (OR) pandemic (H1N1) 2009 was first detected in Japan, Denmark, and Hong Kong during May–June 2009 and has since been sporadically identified around the world (6–8). The OR pandemic (H1N1) 2009 viruses have a specific NA mutation, a histidine-to-tyrosine substitution at amino acid position 275 (N1 numbering, H275Y), that confers resistance to oseltamivir. In a report of 39 OR pandemic (H1N1) 2009 cases (as of October 22, 2009), 16 were associated with treatment, 13 were associated with postexposure prophylaxis, 3 were in NAI-untreated patients, and 7 were of unknown association (8). Preliminary global NAI surveillance showed 190 OR pandemic (H1N1) 2009 infections among >15,000 clinical specimens; thus, the global frequency of OR pandemic (H1N1) 2009 was <1.5% (as of January 8, 2010) (9). These reports indicated that human-to-human transmission of OR pandemic (H1N1) 2009 was limited but that oseltamivir treatment and prophylaxis could lead to emergence of OR pandemic (H1N1) 2009 virus. A report for 1997–2007 showed that Japan accounted for ≈70% of the world's oseltamivir consumption (10). From August 2009 to March 2010, 9.76 million doses of oseltamivir were supplied in Japan, ≈2.3× that of the 2008–09 seasons (data from Chugai Co. Ltd, Tokyo, Japan). Thus, Japan is a high-risk environment for the development of OR pandemic (H1N1) 2009 virus because of drug use pressure. The emergence of such resistance is alarming, because OR seasonal influenza A (H1N1) viruses can rapidly spread worldwide once they acquire the capacity for human-to-human transmission (11–15). Additionally, in the 2009–10 season in Japan, almost all cases of influenza were caused by pandemic (H1N1) 2009 viruses (Figure 1). Thus, close surveillance must be maintained to detect pandemic (H1N1) 2009 and changes in its transmissibility and genetic and antigenic characteristics. We monitored and characterized 4,307 clinical specimens collected in Japan during May 2009–February 2010 from patients with OR pandemic (H1N1) 2009 by NA sequencing, NAI assay, or both. Of them, we found 61 OR pandemic (H1N1) 2009 viruses with the H275Y mutation. full-text: Oseltamivir-Resistant Pandemic (H1N1) 2009, Japan | CDC EID


Suggested Citation for this Article
Ujike M, Ejima M, Anraku A, Shimabukuro K, Obuchi M, Noriko Kishida N, et al. Monitoring and characterization of oseltamivir-resistant pandemic (H1N1) 2009 virus, Japan, 2009–2010 Emerg Infect Dis [serial on the Internet]. 2011 Mar [date cited]. http://www.cdc.gov/EID/content/17/3/470.htm


DOI: 10.3201/eid1703.101188



1Members of the Influenza Virus Surveillance Group of Japan are listed at the end of this article.


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Takato Odagiri, Center for Influenza Virus Research, National Institute of Infectious Diseases, 4-7-1,Gakuen, Musashi-murayama, Tokyo 208-0011, Japan; email: todagiri@nih.go.jp