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

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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; Epidemiology; H1N1 subtype; Influenza A virus; Netherlands; Oseltamivir; Signs and symptoms; Surveillance; Viral; Virology..

Fig. (1)

A) Weekly incidence of ILI consultations in Dutch Sentinel Practices during the winter seasons 2007/2008 and 2000/2001, and number of detection of influenza viruses in Dutch Sentinel Practices and non-sentinel surveillance together during winter season 2007/2008. B). Weekly number of detections of influenza A(H1N1) oseltamivir resistant and sensitive viruses from the sentinel and non-sentinel surveillance during the winter season 2007/2008.

Fig. (2)

Neighbor Joining phylogenetic tree inferred with Jukes & Cantor correction of Dutch influenza A(H1N1) virus neuraminidase (nt 171-901) (left figure) and haemagglutinin (nt 184-901) (right figure) sequences. The trees were rooted on the influenza A(H1N1) vaccine strain A/Solomon Islands/3/2006. The trees show evidence for more amino acid variation in the receptor binding site in the haemagglutinin of oseltamivir resistant strains (in bold font) compared to oseltamivir sensitive strains (plain font). Substitution coding: capitals for amino acids and lower case for nucleotide substitutions not leading to an amino acid change. Substitutions indicated on the left side of the trees are valid for all sequences after the indicated node.

Fig. (3)

Percentage of patients for whom the above mentioned symptoms were reported by oseltamivir susceptibility of the influenza A(H1N1) virus and by source of the influenza virus, sentinel or non-sentinel.