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Emergence of Influenza B Viruses With Reduced Sensitivity to Neuraminidase Inhibitors.
Hatakeyama, Shuji MD, PhD; Sugaya, Norio MD; Ito, Mutsumi DVM; Yamazaki, Masahiko MD; Ichikawa, Masataka MD; Kimura, Kazuhiro MD, PhD; Kiso, Maki DVM; Shimizu, Hideaki; Kawakami, Chiharu; Koike, Kazuhiko MD, PhD; Mitamura, Keiko MD; Kawaoka, Yoshihiro DVM, PhD
[Article] JAMA. 297(13):1435-1442, April 4, 2007.

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Context: Very little is known about the frequency of generation and transmissibility of influenza B viruses with reduced sensitivity to neuraminidase inhibitors. Furthermore, transmission of resistant virus, whether influenza A or B, has not been recognized to date.

Objective: To assess the prevalence and transmissibility of influenza B viruses with reduced sensitivity to neuraminidase inhibitors.

Design, Setting, and Patients: Investigation of the neuraminidase inhibitor sensitivity of influenza B isolates from 74 children before and after oseltamivir therapy and from 348 untreated patients with influenza (including 66 adults) seen at 4 community hospitals in Japan during the 2004-2005 influenza season. Four hundred twenty-two viruses from untreated patients and 74 samples from patients after oseltamivir therapy were analyzed.

Main Outcome Measure: Sialidase inhibition assay was used to test the drug sensitivities of influenza B viruses. The neuraminidase and hemagglutinin genes of viruses showing reduced sensitivity to neuraminidase inhibitors were sequenced to identify mutations that have the potential to confer reduced sensitivity to these drugs.

Results: In 1 (1.4%) of the 74 children who had received oseltamivir, we identified a variant with reduced drug sensitivity possessing a Gly402Ser neuraminidase substitution. We also identified variants with reduced sensitivity carrying an Asp198Asn, Ile222Thr, or Ser250Gly mutation in 7 (1.7%) of the 422 viruses from untreated patients. Review of the clinical and viral genetic information available on these 7 patients indicated that 4 were likely infected in a community setting, while the remaining 3 were probably infected through contact with siblings shedding the mutant viruses.

Conclusions: In this population, influenza B viruses with reduced sensitivity to neuraminidase inhibitors do not arise as frequently as resistant influenza A viruses. However, they appear to be transmitted within communities and families, requiring continued close monitoring.