Resistant influenza A viruses in children treated with oseltamivir: descriptive study.
BACKGROUND
Oseltamivir is an effective inhibitor of influenza virus neuraminidase. Although viruses resistant to oseltamivir emerge less frequently than those resistant to amantadine or rimantadine, information on oseltamivir-resistant viruses arising during clinical use of the drug in children is limited. Our aim was to investigate oseltamivir resistance in a group of children treated for influenza.


METHODS
We analysed influenza A viruses (H3N2) collected from 50 children before and during treatment with oseltamivir. We sequenced the genes for neuraminidase and haemagglutinin and studied the mutant neuraminidases for their sensitivity to oseltamivir carboxylate.


RESULTS
We found neuraminidase mutations in viruses from nine patients (18%), six of whom had mutations at position 292 (Arg292Lys) and two at position 119 (Glu119Val), which are known to confer resistance to neuraminidase inhibitors. We also identified another mutation (Asn294Ser) in one patient. Sensitivity testing to oseltamivir carboxylate revealed that the neuraminidases of viruses that have an Arg292Lys, Glu119Val, or Asn294Ser mutation were about 10(4)-10(5)-fold, 500-fold, or 300-fold more resistant than their pretreatment neuraminidases, respectively. Oseltamivir-resistant viruses were first detected at day 4 of treatment and on each successive day of the study. More than 10(3) infectious units per mL of virus were detected in some of the patients who did not shed drug-resistant viruses, even after 5 days of treatment.


CONCLUSIONS
Oseltamivir-resistant mutants in children being treated for influenza with oseltamivir arise more frequently than previously reported. Furthermore, children can be a source of viral transmission, even after 5 days of treatment with oseltamivir.
Kiso
Maki
M
Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Mitamura
Keiko
K
Sakai-Tagawa
Yuko
Y
Shiraishi
Kyoko
K
Kawakami
Chiharu
C
Kimura
Kazuhiro
K
Hayden
Frederick G
FG
Sugaya
Norio
N
Kawaoka
Yoshihiro
Y
D000081:Acetamides / Q000627:therapeutic use*; D000293:Adolescent; D019943:Amino Acid Substitution; D002648:Child; D002675:Child, Preschool; D024882:Drug Resistance, Viral / Q000235:genetics*; D006389:Hemagglutinins, Viral / Q000235:genetics; D006801:Humans; D007223:Infant; D009980:Influenza A virus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D007251:Influenza, Human / Q000188:drug therapy* / Q000821:virology*; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000235:genetics; D053139:Oseltamivir; D017354:Point Mutation
D000081:Acetamides; D006389:Hemagglutinins, Viral; D053139:Oseltamivir; D009439:Neuraminidase