Influenza A(H1N1) Oseltamivir Resistant Viruses in the Netherlands During the Winter 2007/2008

Frederika Dijkstra*, 1, Marcel Jonges 1, 2, Ruud van Beek 2, Gé A Donker 3, François G Schellevis 3, 4, Marion Koopmans 1, 2, Marianne A.B van der Sande 1, 5, Albert D.M.E Osterhaus 2, Charles A.B Boucher 2, Guus F Rimmelzwaan 2, Adam Meijer 1
1 Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
2 Department of Virology, Erasmus Medical Centre (ErasmusMC), Rotterdam, The Netherlands
3 NIVEL, Netherlands Institute for Health Services Research, Utrecht, The Netherlands
4 Department of General Practice/EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands
5 Julius Center for Health Sciences and Primary Care, University Medical Centre, Utrecht, The Netherlands

© Dijkstra et al.; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http: // which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

* Address correspondence to this author at the Centre for Infectious Disease Control, National Institute for Public Health and the Environment, PO box 1 – pb 75, 3720 BA Bilthoven, The Netherlands; Tel: +31 30 2743781; Fax: +31 30 2744409; E-mail:



Antiviral susceptibility surveillance in the Netherlands was intensified after the first reports about the emergence of influenza A(H1N1) oseltamivir resistant viruses in Norway in January, 2008.


Within the existing influenza surveillance an additional questionnaire study was performed to retrospectively assess possible risk factors and establish clinical outcome of all patients with influenza virus A(H1N1) positive specimens. To discriminate resistant and sensitive viruses, fifty percent inhibitory concentrations for the neuramidase inhibitors oseltamivir and zanamivir were determined in a neuraminidase inhibition assay. Mutations previously associated with resistance to neuramidase inhibitors and M2 blockers (amantadine and rimantadine) were searched for by nucleotide sequencing of neuraminidase and M2 genes respectively.


Among 171 patients infected with A(H1N1) viruses an overall prevalence of oseltamivir resistance of 27% (95% CI: 20-34%) was found. None of influenza A(H1N1) oseltamivir resistant viruses tested was resistant against amantadine or zanamivir. Patient characteristics, underlying conditions, influenza vaccination, symptoms, complications, and exposure to oseltamivir and other antivirals did not differ significantly between patients infected with resistant and sensitive A(H1N1) viruses.


In 2007/2008 a large proportion of influenza A(H1N1) viruses resistant to oseltamivir was detected. There were no clinical differences between patients infected with resistant and sensitive A(H1N1) viruses. Continuous monitoring of the antiviral drug sensitivity profile of influenza viruses is justified, preferably using the existing sentinel surveillance, however, complemented with data from the more severe end of the clinical spectrum. In order to act timely on emergencies of public health importance we suggest setting up a surveillance system that can guarantee rapid access to the latter.

Keywords: Drug resistance, Viral, Epidemiology, Influenza A virus, H1N1 subtype, Oseltamivir, Signs and symptoms, Surveillance, Netherlands, Virology..