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Monitoring

Monitoring of antiviral resistance among influenza viruses takes place through a number of surveillance initiatives and ad hoc studies. 

The World Health Organisation (WHO) collates data from WHO National Influenza Centres and WHO Collaborating Centres, through the Global Influenza Surveillance and Response System (GISRS). Data from European Union (EU/EEA) countries is collated by the coordinators of Community Network of Reference Laboratories for Human Influenza in Europe (CNRL) under the aegis of the European Centre for Disease Prevention and Control (ECDC).


M2 inhibitors

Monitoring of resistance to the M2 inhibitors is by detection of the well defined resistance mutations, which cause cross-resistance to amantadine and rimantadine.

Both influenza A subtypes currently circulating in the human population, as well as influenza B, are resistant to amantadine and rimantadine.

Resistance of human A(H3N2) viruses emerged in 2002 and subsequently spread worldwide.  The S31N substitution in M2 has been maintained in currently circulating H3N2 viruses.
 

The A(H1N1)pdm09 virus derived its ’resistant’ M gene from the Eurasian lineage of swine viruses, which acquired amantadine resistance in the mid-1980s.
 

Neuraminidase inhibitors

Resistance and altered susceptibility of viruses to the NAIs is monitored by enzyme inhibition assay and/or detection of known mutations.

Prior to 2007, surveillance of viruses from around the world indicated that the occurrence of resistance or reduced susceptibility to oseltamivir and zanamivir among human viruses was low. In Japan, with the highest per capita use of the antivirals, the frequency of detection was less than 1% (Tashiro et al., 2009). 
 

The oseltamivir-resistant seasonal A(H1N1) viruses, with the H275Y substitution in NA, that emerged in 2007 and became the predominant epidemic H1N1 viruses in 2008 spread in the absence of drug pressure (Collins et al., 2009).  The viruses retained susceptibility to zanamivir.  They have since have been replaced by the oseltamivir-sensitive A(H1N1)pdm09 viruses.

Occurrence of oseltamivir resistance due to H275Y among A(H1N1)pdm09 viruses has been mainly sporadic with over 600 cases in 32 countries reported up to October 2011 (with an estimated frequency of less than 1%, depending on country).  There have been a few instances of small clusters of oseltamivir-resistant viruses in immunocompromised patients and healthy adults, indicating the potential of the resistant viruses to transmit from treated to untreated individuals.  Of greater concern as to the more widespread circulation of these viruses has been the local spread of oseltamivir-resistant A(H1N1)pdm09 viruses, with the H275Y substitution, detected in more than 30 individuals in New South Wales, Australia during June to August 2011 (Hurt et al,. 2011).  The viruses retain susceptibility to zanamivir.
 

A cluster (14 cases) of influenza B viruses with reduced susceptibility to oseltamivir and peramivir, associated with an I221V substitution in NA, was reported in the USA, but the clinical significance is unknown (Sleeman et al,. 2011).

WHO summary of influenza antiviral susceptibility surveillance findings, June 2011


References:

Collins, P. J., L. F. Haire, Y. P. Lin, J. Liu, R. J. Russell, P. A. Walker, S. R. Martin, R. S. Daniels, V. Gregory, J. J. Skehel, S. J. Gamblin, and A. J. Hay. 2009. Structural basis for oseltamivir resistance of influenza viruses. Vaccine 27:6317-23.

Hurt, A. C., K. Hardie, N. J. Wilson, Y. M. Deng, M. Osbourn, N. Gehrig, and A. Kelso. 2011. Community transmission of oseltamivir-resistant A(H1N1)pdm09 influenza. N Engl J Med 365:2541-2.

Sleeman, K., T. G. Sheu, Z. Moore, S. Kilpatrick, S. Garg, A. M. Fry, and L. V. Gubareva. 2011. Influenza B viruses with mutation in the neuraminidase active site, North Carolina, USA, 2010-11. Emerg Infect Dis 17:2043-6.

Tashiro, M., J. L. McKimm-Breschkin, T. Saito, A. Klimov, C. Macken, M. Zambon, and F. G. Hayden. 2009. Surveillance for neuraminidase-inhibitor-resistant influenza viruses in Japan, 1996-2007. Antivir Ther 14:751-61.

WHO (2011) Global monitoring of antiviral resistance in currently circulating viruses, November 2011. Weekly Epidemiological Record, 86, 497-501.