Neuraminidase inhibitor resistance after oseltamivir treatment of acute influenza A and B in children

Iain Stephenson*, Jane Democratis, Angie Lackenby, Teresa McNally, James Smith, Manish Pareek, Joanna Ellis, Alison Bermingham, Karl Nicholson, Maria Zambon

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

150 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)389-396
Number of pages8
JournalClinical Infectious Diseases
Volume48
Issue number4
DOIs
Publication statusPublished - 15 Feb 2009

Bibliographical note

Funding Information:
Potential conflicts of interest. I.S. has received research funding from Hoffman LaRoche, Novartis Vaccines, European Union, and UK Medical Research Council and has received speaker and consultancy fees from Hoffman LaRoche, Novartis Vaccines, GlaxoSmithKline, and Biocryst Pharmaceuticals. J.D. has received grant support from the British Medical Association (Joan Dawkins award). A.L. has received support for attendance at meetings from Hoffman LaRoche. K.N. has received research funding from Novartis Vaccines, Wyeth, UK Medical Research Council, Health Technology Assessment, GlaxoSmithKline, and Baxter and speaker and consultancy fees from Novartis Vaccines, GlaxoSmithKline, and Baxter. J.S. is an employee of Hoffman LaRoche. All other authors: no conflicts.

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