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.
Bibliographical noteFunding Information:
We thank all laboratories, mostly NICs of the WHO GISRS ( http://www.who.int/influenza/gisrs_laboratory/national_influenza_centres/list/en/ ), which contributed to this global analysis by submitting influenza virus positive samples (clinical specimens or virus isolates) to WHO CCs for detailed characterisation. We gratefully acknowledge the authors, originating and submitting laboratories of the 372 sequences unique to the GISAID database, additional to those of the 2826 sequences submitted to the GISAID database by the authors of this paper and the 233 sequences imported by GISAID from public databases ( Supplementary Table 3 ), and the 230 sequences retrieved from NCBI-IVR, that were included in this global analysis. The London WHO CC is funded by the British Medical Research Council through programme U117512723 . The Melbourne WHO CC is supported by the Australian Government, Department of Health. The Tokyo WHO CC is supported by Grants-in-Aid for Emerging and Re-emerging Infectious Diseases from the Ministry of Health, Labour and Welfare, Japan - Japan.
- Antiviral resistance
- Global analysis
- Influenza virus
- Neuraminidase inhibitors
- Normalization using fold-change data