Neuraminidase inhibitor resistance after oseltamivir treatment of acute influenza A and B in children.
BACKGROUND
Oseltamivir, a specific influenza neuraminidase inhibitor, is an effective treatment for seasonal influenza. Emergence of drug-resistant influenza viruses after treatment has been reported, particularly in children in Japan, where the dosing schedule is different from that used throughout the rest of the world. We investigated the emergence of drug-resistant infection in children treated with a tiered weight-based dosing regimen.


METHODS
We analyzed sequential clinical nasopharyngeal samples, obtained before and after tiered weight-based oseltamivir therapy, from children with acute influenza during 2005-2007. We isolated viruses, tested for drug resistance with use of a fluorescence-based neuraminidase inhibition assay, performed neuraminidase gene sequencing, and determined quantitative viral loads.


RESULTS
Sixty-four children (34 with influenza A subtype H3N2, 11 with influenza A subtype H1N1, and 19 with influenza B virus) aged 1-12 years (median age, 3 years, 1 month) were enrolled. By days 4-7 after initiation of treatment, of 64 samples tested, 47 (73.4%) and 26 (40.6%) had virus detectable by reverse-transcriptase polymerase chain reaction and culture, respectively. By days 8-12 after initiation of treatment, of 53 samples tested, 18 (33.9%) and 1 (1.8%) had virus detectable by reverse-transcriptase polymerase chain reaction and culture, respectively. We found no statistically significant differences in the reduction of viral shedding or time to clearance of virus between viral subtypes. Antiviral-resistant viruses were recovered from 3 (27.3%) of 11 children with influenza A subtype H1N1, 1 (2.9%) of 34 children with influenza A subtype H3N2, and 0 (0%) of 19 children with influenza B virus, all of whom were treated with oseltamivir (P = .004). There was no evidence of prolonged illness in children infected with drug-resistant virus.


CONCLUSIONS
Drug resistance emerges at a higher rate in influenza A subtype H1N1 virus than in influenza A subtype H3N2 or influenza B virus after tiered weight-based oseltamivir therapy. Virological surveillance for patterns of drug resistance is essential for determination of antiviral treatment strategies and for composition of pandemic preparedness stockpiles.
Stephenson
Iain
I
Infectious Diseases Unit, Leicester Royal Infirmary, Leicester, UK. iain.stephenson@uhl-tr.nhs.uk
Democratis
Jane
J
Lackenby
Angie
A
McNally
Teresa
T
Smith
James
J
Pareek
Manish
M
Ellis
Joanna
J
Bermingham
Alison
A
Nicholson
Karl
K
Zambon
Maria
M
D000998:Antiviral Agents / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D024882:Drug Resistance, Viral; D005260:Female; D006801:Humans; D007223:Infant; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification; D009980:Influenza A virus / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D009981:Influenza B virus / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D007251:Influenza, Human / Q000188:drug therapy* / Q000821:virology; D008297:Male; D008826:Microbial Sensitivity Tests; D009439:Neuraminidase / Q000235:genetics; D053139:Oseltamivir / Q000627:therapeutic use*; D017422:Sequence Analysis, DNA; D019562:Viral Load; D014764:Viral Proteins / Q000235:genetics
D000998:Antiviral Agents; D014764:Viral Proteins; D053139:Oseltamivir; C487630:NA protein, influenza A virus; C541223:NA protein, influenza B virus; D009439:Neuraminidase