Oseltamivir-Resistant Influenza Viruses, Japan | CDC EID

EID Journal Home > Volume 16, Number 6–June 2010

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 Odagiri, 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); and National Institute of Technology and Evaluation, Tokyo (H. Horikawa, Y. Kato, N. Fujita)

Suggested citation for this article

Abstract
To monitor oseltamivir-resistant influenza viruses A (H1N1) (ORVs) with H275Y in neuraminidase (NA) in Japan during 2 influenza seasons, we analyzed 3,216 clinical samples by NA sequencing and/or NA inhibition assay. The total frequency of ORVs was 2.6% (45/1,734) during the 2007–08 season and 99.7% (1,477/1,482) during the 2008–09 season, indicating a marked increase in ORVs in Japan during 1 influenza season. The NA gene of ORVs in the 2007–08 season fell into 2 distinct lineages by D354G substitution, whereas that of ORVs in the 2008–09 season fell into 1 lineage. NA inhibition assay and M2 sequencing showed that almost all the ORVs were sensitive to zanamivir and amantadine. The hemagglutination inhibition test showed that ORVs were antigenetically similar to the 2008–09 vaccine strain A/Brisbane/59/2007. Our data indicate that the current vaccine or zanamivir and amantadine are effective against recent ORVs, but continuous surveillance remains necessary.
Influenza A and B viruses are major pathogens that represent a threat to public health with subsequent economic losses worldwide (1). Vaccination is the primary method for prevention; antiviral drugs are used mainly for prophylaxis and therapy. Currently, 2 classes of drugs, matrix 2 (M2) blockers and neuraminidase inhibitors (NAIs) are available, but M2 blockers such as amantadine and rimantadine are not commonly used because of the rapid generation of resistance and lack of efficacy against influenza B virus (2–4). The NAIs zanamivir and oseltamivir are widely used because of effects against influenza A and B viruses and a low frequency of resistance. NAI virus surveillance studies by several groups have demonstrated that <1% of viruses tested show naturally occurring resistance to oseltamivir as of 2007 (5–10), indicating limited human-to-human transmission of these viruses.

At the beginning of the 2007–08 influenza season, however, detection of a substantially increased number of oseltamivir-resistant influenza viruses A (H1N1) (ORVs) was reported, mainly in countries in Europe where the prevalence varies, with the highest levels in Norway (67%) and France (47%) (11–14). These viruses showed a specific NA mutation with a histidine-to-tyrosine substitution at the aa 275 position (N1 numbering, H275Y), conferring high-level resistance to oseltamivir. Most of these ORVs were isolated from NAI-untreated patients and retained similar ability of human-to-human transmission to oseltamivir-sensitive influenza viruses A (H1N1) (OSVs) (10,15). In response to public health concerns about ORVs, the World Health Organization (WHO) directed Global Influenza Surveillance Network laboratories to intensify NAI surveillance and announced regularly updated summaries of ORV data collected from each laboratory on its website (16). This site reported that the global frequency increased from 16% (October 2007–March 2008) to 44% (April 2008–September 2008) to 95% (October 2008–January 2009), indicating that ORVs have spread rapidly around the world.

Japan has the highest annual level of oseltamivir usage per capita in the world, comprising >70% of world consumption (10). Such high use of oseltamivir has raised concerns about emergence of OSVs with increased resistance to this drug. Moreover, in Japan, 2 recent influenza seasons were dominated by influenza viruses A (H1N1) (Figure 1). If a high prevalence of ORVs is observed, primary selection of oseltamivir treatment for influenza patients should be reconsidered. Thus, monitoring ORVs is a serious public health issue.

To estimate the frequency of ORVs and characterize these viruses, we analyzed 1,734 clinical samples isolated from the 2007–08 season and 1,482 isolates from the 2008–09 season by NA sequencing and/or NAI inhibition assay. The total frequencies were 2.6% in the 2007–08 season and 99.7% in the 2008–09 season, indicating that ORVs increased dramatically in Japan.

open here to see the full-text:
Oseltamivir-Resistant Influenza Viruses, Japan | CDC EID