Resistance in influenza viruses
The Department of Virology at the Norwegian Institute of Public Health (NIPH) functions as a WHO National Influenza Centre
(NIC) and the Ministry of Health designated national reference laboratory for influenza. In the latter function lies also the
obligation to monitor and assess the occurrence of resistance. In addition to national monitoring, a selection of influenza viruses
that is shipped by European NICs to the WHO Collaborating Centre in the United Kingdom is also tested for antiviral
Background
Two classes of antiviral drugs are being used against influenza virus infection. M2 blockers inhibit replication of influenza type
A viruses, while the more recently developed neuraminidase inhibitors (NIs) inhibit the replication of both type A and B.
Historically, resistance has been known to develop quite easily against the M2 blockers, and increasing proportions of resistant
viruses have been observed, particularly of subtype A(H3N2) (1). The more recently developed NIs initially seemed to be much
less affected by resistance development and resistant mutants in general have seemed less viable. However, an oseltamivir
resistant seasonal A(H1N1) virus variant, carrying the neuraminidase mutation H275Y, emerged in 2007 (2,3) and within a year
reached almost total predominance among seasonal viruses of this subtype. This global emergence of resistance was discovered
first through analysis of viruses from Norwegian influenza surveillance, and it took place with no association to recorded
In early 2009, a novel influenza A(H1N1) virus entered the human population and caused an influenza pandemic. To date the
H1N1pdm virus is uniformly resistant to M2 blockers but with very few exceptions they remain fully susceptible to the
neuraminidase inhibitors oseltamivir and zanamivir. During the early months of 2011, a variant H1N1pdm virus with mildly
reduced oseltamivir and zanamivir sensitivity due to a S247N neuraminidase mutation has been detected in more than 30% of
samples from northern Australia. When combined with the H275Y mutation, as detected in an oseltamivir-treated patient, the
dual S247N+H275Y mutant shows unusually strong oseltamivir resistance (4).
Surveillance findings
In Norway, Victoria lineage B was the dominating strain in circulation during the 2010/11 season. The circulation of
A(H1N1)pdm virus developed at a parallel, but lower level, varying between one-fifth and one-third of the virus detections. A(H3N2) and type B Yamagata-lineage viruses have been encountered only sporadically this season. The uniformly oseltamivir
resistant former seasonal A(H1N1) viruses seem to have been displaced during the pandemic; only a very few former seasonal
A(H1N1) viruses have been detected globally during the influenza season 2010/11, none of them in Western Europe.
Findings from Norwegian surveillance are summarised in Table 60. So far, the H1N1pdm viruses analysed have been 100%
susceptible to the neuramidase inhibitors in the phenotypic assay (MUNANA), but 100% resistant to M2 blockers. Four
H1N1pdm viruses had a mixed 275H/Y genotype. The H275Y substitution is commonly associated with oseltamivir resistance.
The virus yield in these four samples was however too low to confirm a decrease in sensitivity to oseltamivir with a phenotypic
assay. The few recent A(H3N2) viruses that have been analysed remain resistant to the M2 blocker adamantine, but susceptible
to the neuramidase inhibitors oseltamivir and zanamivir. All analysed influenza B viruses are susceptible to both oseltamivir and
zanamivir. The findings for M2 blocker resistance is largely in accordance with the global patterns, with H3N2 and H1N1pdm
viruses generally being resistant. Fortunately, H1N1pdm viruses resistant to NIs are rare and mostly associated with treated,
long-term carriers. However, the possibility of community spread of oseltamivir-resistant H1N1pdm virus still remains a
concern, particularly given that data from animal studies suggest that the fitness of the H275Y variant may not be significantly
TABLE 60. Norwegian influenza viruses resistant to M2 blockers (adamantanes) and the NIs oseltamivir and zanamivir during
the influenza seasons 2005/06 through 2010/11. Two screening tools were used to determine oseltamivir/zanamivir resistance:
sequence analysis of viral genes or a neuraminidase inhibition assay.
2007/08 0% (n=112) 100% (n=2) 68% (n=272)
2009-pand*100% (n=258) 100% (n=2) 0% (n=884)
2010/11* 100% (n=54) 100% (n=10) 1.6%** (n=244) 0% (n=1) 0% (n=30) 0% (n=2)
* During influenza season 2009/10 and 2010/11all A(H1N1) tested were pdmH1. ** A(H1N1)pdm with the mutation 275Y in mixture commonly associated
with oseltamivir resistance. ND=Not determined.
References
1. Hungnes O. Dudman SG. Resistance in influenza viruses (Article in Norwegian) Tidsskr Nor Laegeforen. 2008 Nov 20;128(22):2601-6.
2. Lackenby A. Hungnes O. Dudman SG. Meijer A. Paget WJ. Hay AJ. et al. Emergence of resistance to oseltamivir among influenza A(H1N1) viruses in
3. Hauge SH. Dudman S. Borgen K. Lackenby A. Hungnes O. Oseltamivir-resistant influenza viruses A (H1N1). Norway. 2007-08. Emerg Infect Dis. 2009
4. Meijer A. Lackenby A. Hay A. Zambon M. Influenza antiviral susceptibility monitoring activities in relation to national antiviral stockpiles in Europe during
the winter 2006/2007 season. Euro Surveill. 2007 Apr 1;12(4):E3-4
Anette Kilander, Susanne Dudman, Olav Hungnes, Department of Virology, Norwegian Institute of Public Health, Oslo.
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Resistance in influenza viruses