Characterization of neuraminidase inhibitor-resistant influenza A(H1N1)pdm09 viruses isolated in four seasons during pandemic and post-pandemic periods in Japan

Influenza Other Respir Viruses. 2013 Nov;7(6):1390-9. doi: 10.1111/irv.12132. Epub 2013 Jun 8.


Background/objectives: Japan has the highest frequency of neuraminidase (NA) inhibitor use against influenza in the world. Therefore, Japan could be at high risk of the emergence and spread of NA inhibitor-resistant viruses. The aim of this study was to monitor the emergence of NA inhibitor-resistant viruses and the possibility of human-to-human transmission during four influenza seasons in Japan.

Methods: To monitor antiviral-resistant A(H1N1)pdm09 viruses, we examined viruses isolated in four seasons from the 2008-2009 season through the 2011-2012 season in Japan by allelic discrimination, NA gene sequencing, and NA inhibitor susceptibility.

Results: We found that 157 (1·3%) of 12 026 A(H1N1)pdm09 isolates possessed an H275Y substitution in the NA protein that confers about 400- and 140-fold decreased susceptibility to oseltamivir and peramivir, respectively, compared with 275H wild-type viruses. The detection rate of resistant viruses increased from 1·0% during the pandemic period to 2·0% during the post-pandemic period. The highest detection rate of the resistant viruses was found in patients who were 0-9 years old. Furthermore, among the cases with resistant viruses, the percentage of no known exposure to antiviral drugs increased from 16% during the pandemic period to 44% during the post-pandemic period, implying that suspected human-to-human transmission of the resistant viruses gradually increased in the post-pandemic period.

Conclusions: A(H1N1)pdm09 viruses resistant to oseltamivir and peramivir were sporadically detected in Japan, but they did not spread throughout the community. No viruses resistant to zanamivir and laninamivir were detected.

Keywords: Influenza A(H1N1)pdm09 virus; neuraminidase inhibitor resistant; neuraminidase inhibitor susceptibility.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acids, Carbocyclic
  • Alleles
  • Antiviral Agents / pharmacology*
  • Cyclopentanes / pharmacology
  • Drug Resistance, Viral*
  • Enzyme Inhibitors / pharmacology
  • Genotype
  • Guanidines / pharmacology
  • Humans
  • Influenza A Virus, H1N1 Subtype / drug effects*
  • Influenza A Virus, H1N1 Subtype / genetics
  • Influenza A Virus, H1N1 Subtype / isolation & purification
  • Influenza, Human / epidemiology
  • Influenza, Human / virology*
  • Japan / epidemiology
  • Neuraminidase / antagonists & inhibitors
  • Neuraminidase / genetics*
  • Oseltamivir / pharmacology
  • Pandemics
  • RNA, Viral / genetics
  • Sequence Analysis, DNA
  • Viral Proteins / antagonists & inhibitors
  • Viral Proteins / genetics*


  • Acids, Carbocyclic
  • Antiviral Agents
  • Cyclopentanes
  • Enzyme Inhibitors
  • Guanidines
  • RNA, Viral
  • Viral Proteins
  • Oseltamivir
  • NA protein, influenza A virus
  • Neuraminidase
  • peramivir