Oseltamivir-resistant influenza A(H1N1)pdm09 influenza virus in Dutch travellers returning from Spain, August 2012Archived

Meijer A, Jonges M, van Beek P, Swaan C, Osterhaus A, Daniels RS, Hurt AC, Koopmans MP. Oseltamivir-resistant influenza A(H1N1)pdm09 virus in Dutch travellers returning from Spain, August 2012. Euro Surveill. 2012;17(36):pii=20266.

In this article, the authors describe two Dutch cases of influenza A(H1N1)pdm09 with the H275Y neuraminidase (NA) substitution (associated with oseltamivir resistance), who are highly likely to have acquired infection during travel to the Catalonian coast of Spain. The cases were investigated exhaustively and no clear epidemiological links between the cases were identified, but direct sequencing of viruses from clinical specimens for both cases showed identical nucleotide sequences for partial sections of the haemagglutinin (HA), neraminidase (NA), matrix and PB2 genes. Neither case have any history of being exposed to oseltamivir treatment.

Further comparison of HA and NA gene sequences with those collated by the public sequence databases GISAID and GenBank, showed genetic similarities between these two cases and another oseltamivir-resistant virus containing the H275Y NA substitution (influenza A/Perth/33/2012), which was isolated in 2012 from a case returning from holiday in Bali, Indonesia. Some similarities in the NA gene sequences were also observed when compared with a 2011 Australian cluster of oseltamivir-resistant viruses. The majority of such resistant strains have been isolated during periods of high influenza A(H1N1)pdm09 activity, but the authors suggest that detection of these two Dutch cases outside of the normal influenza season implies that there may be ongoing low-level circulation of an oseltamivir-resistant A(H1N1)pdm09 virus. Given that an A(H1N1) influenza virus with the same H275Y NA substitution emerged in Europe during the 2007/2008 influenza season and became rapidly dominant during the European Autumn/Winter, detection of these cases early in the influenza season warrants further close monitoring.

ECDC Comment (7 September 2012):

Antiviral susceptibility is a key area for influenza surveillance as it can affect patient management, prevention of outbreaks and pandemic preparedness. The early identification of resistant strains and subsequent active surveillance is very important in informing both clinical management of patients and public health preparedness for the pending epidemic season. These findings are unusual in that they seem to suggest community transmission of oseltamivir resistant strains at a time of year when circulation of influenza in Europe is known to be sporadic. [1]

Oseltamivir resistant A(H1N1)pdm09 influenza viruses are commonly observed in hospitals, but almost always in the context of the drug being used in treatment, often of patients with severe underlying disease. The resistance generally affects the ability of the viruses to replicate and transmit and therefore they do not easily predominate over susceptible viruses. Influenza A(H1N1)pdm09 with the H275Y mutation without any known exposure to oseltamivir are much rarer but have previously been observed , for example in the UK in 2010/2011[2] and in Australia in 2011[3]. On these occasions, the mutant did not become the dominant A(H1N1)pdm09 virus.

In contrast a seasonal A(H1N1) virus with the H275YNA mutation which emerged in Europe during the 2007/2008 influenza season did, however, become rapidly dominant first in Europe and globally, although the clinical effect (as measured by influenza-like illness and acute respiratory infection) was thought to remain consistent with normal seasonal activity.[4] To date, most resistant viruses have been few in number and have not transmitted effectively.[5] The reasons for the apparent dominance of the 2007/2008 virus are not fully understood although they are thought to have occurred independently of drug use.[4,6]

During the 2011/2012 season A(H1N1)pdm09 activity was low in Europe, with the predominant circulating virus subtype (98% of sentinel influenza type A viruses sub-typed) being A(H3N2).[1] No oseltamivir resistant strains of influenza A(H1N1)pdm09 have to date been reported to either the TESSy or EUROFLU surveillance systems during the 2011/2012 season by week 34/2012. As such, the isolation of these two cases of oseltamivir-resistant influenza A(H1N1)pdm09 does not at this time pose a significant threat to human health in Europe.

Further data on antiviral susceptibility of circulating viruses will now be required especially as we move into the European season. What cannot be known yet is whether these A(H1N1)pdm09 viruses will vanish like those in Australia and the UK or predominate as happened with the old seasonal A(H1N1) in 2007/8. What findings there are from the 2007/2008 experience suggest that while individual cases of resistant strains directly follow from use of oseltamivir the predominance of resistant viruses has occurred independently of antiviral drug use.[5] Whether a resistant strain becomes dominant is therefore not explained solely by exposure to antiviral drugs, and although it is difficult to predict which strain may dominate the forthcoming influenza season, there is no data at present that would support changes to the recommendations for antiviral treatment by national authorities. However the emergence of antiviral resistance is a situation that will need careful, early and timely monitoring this season in Europe as well as globally.

The identification of these two cases of influenza A(H1N1)pdm09 with the H275Y NA substitution supports the role of ongoing public health efforts to monitor antiviral susceptibility of circulating influenza strains. Surveillance of influenza strains through laboratory testing is established through international networks which rely on active engagement with clinicians. Insight from the Southern hemisphere (where the current epidemic season is reaching its conclusion) and further monitoring as activity increases in the Northern hemisphere, will be paramount in informing the ongoing surveillance of this and other influenza A viruses.