Abstract
Emergence of influenza viruses with reduced susceptibility to neuraminidase inhibitors (NAIs) is sporadic, often follows exposure to NAIs, but occasionally occurs in the absence of NAI pressure. The emergence and global spread in 2007/2008 of A(H1N1) influenza viruses showing clinical resistance to oseltamivir due to neuraminidase (NA) H275Y substitution, in the absence of drug pressure, warrants continued vigilance and monitoring for similar viruses. Four World Health Organization (WHO) Collaborating Centres for Reference and Research on Influenza and one WHO Collaborating Centre for the Surveillance, Epidemiology and Control of Influenza (WHO CCs) tested 11,387 viruses collected by WHO-recognized National Influenza Centres (NIC) between May 2012 and May 2013 to determine 50% inhibitory concentration (IC50) data for oseltamivir, zanamivir, peramivir and laninamivir. The data were evaluated using normalized IC50 fold-changes rather than raw IC50 data. Nearly 90% of the 11,387 viruses were from three WHO regions: Western Pacific, the Americas and Europe. Only 0.2% (n=27) showed highly reduced inhibition (HRI) against at least one of the four NAIs, usually oseltamivir, while 0.3% (n=39) showed reduced inhibition (RI). NA sequence data, available from the WHO CCs and from sequence databases (n=3661), were screened for amino acid substitutions associated with reduced NAI susceptibility. Those showing HRI were A(H1N1)pdm09 with NA H275Y (n=18), A(H3N2) with NA E119V (n=3) or NA R292K (n=1) and B/Victoria-lineage with NA H273Y (n=2); amino acid position numbering is A subtype and B type specific. Overall, approximately 99% of circulating viruses tested during the 2012–2013 period were sensitive to all four NAIs. Consequently, these drugs remain an appropriate choice for the treatment and prophylaxis of influenza virus infections.
Highlights
Neuraminidase inhibitors (NAIs) are the most widely used antiviral drugs for the treatment or prophylaxis of influenza
The World Health Organization (WHO)-AVWG was able to perform this global analysis on influenza antiviral susceptibility thanks to National Influenza Centres (NICs) within the WHO Global Influenza Surveillance and Response System (GISRS) fulfilling their Terms of Reference (ToR) by collecting influenza virus positive clinical specimens and sharing a representative proportion of them, or viruses recovered, with the WHO CCs for further detailed characterization (Kitler et al, 2002)
Pooling of IC50 data generated by WHO CCs was possible using methodology based on IC50 fold-change values, developed by the WHO-AVWG, and validated as described in this paper
Summary
Neuraminidase inhibitors (NAIs) are the most widely used antiviral drugs for the treatment or prophylaxis of influenza. The most extreme example was in 2007/2008, when the former seasonal A(H1N1) virus acquired the NA H275Y substitution and spread globally in approximately 12 months (Lackenby et al, 2008; Collins et al, 2009; Dharan et al, 2009; García et al, 2009; Hauge et al, 2009; Hurt et al, 2009; Meijer et al, 2009) This NA substitution conferred HRI by both oseltamivir and peramivir, and was shown in clinical situations to render oseltamivir, the most widely used NAI, significantly less effective for the treatment of this virus infection (Kawai et al, 2009; Dharan et al, 2010). In this paper, which is the first of a series of annual reports, we present the results for viruses collected via GISRS and analysed by five WHO CCs between May 2012 and May 2013 (subsequently referred to as 2012–2013)
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