Emergence of influenza B viruses with reduced sensitivity to neuraminidase inhibitors.
BACKGROUND
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.


METHODS
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.


METHODS
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.
Hatakeyama
Shuji
S
Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Sugaya
Norio
N
Ito
Mutsumi
M
Yamazaki
Masahiko
M
Ichikawa
Masataka
M
Kimura
Kazuhiro
K
Kiso
Maki
M
Shimizu
Hideaki
H
Kawakami
Chiharu
C
Koike
Kazuhiko
K
Mitamura
Keiko
K
Kawaoka
Yoshihiro
Y
D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D024882:Drug Resistance, Viral / Q000235:genetics; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006388:Hemagglutinins / Q000235:genetics; D006801:Humans; D007223:Infant; D053122:Influenza A Virus, H3N2 Subtype; D053124:Influenza A Virus, H5N1 Subtype; D009981:Influenza B virus / Q000187:drug effects* / Q000235:genetics; D007251:Influenza, Human / Q000188:drug therapy / Q000453:epidemiology / Q000635:transmission / Q000821:virology; D007564:Japan; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000235:genetics; D053139:Oseltamivir / Q000627:therapeutic use; D015995:Prevalence; D012621:Seasons
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D006388:Hemagglutinins; D053139:Oseltamivir; D009439:Neuraminidase