Abstract
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 10,641 viruses collected by WHO-recognized National Influenza Centres between May 2013 and May 2014 to determine 50% inhibitory concentration (IC50) data for neuraminidase inhibitors (NAIs) oseltamivir, zanamivir, peramivir and laninamivir. In addition, neuraminidase (NA) sequence data, available from the WHO CCs and from sequence databases (n=3206), were screened for amino acid substitutions associated with reduced NAI susceptibility. Ninety-five per cent of the viruses tested by the WHO CCs were from three WHO regions: Western Pacific, the Americas and Europe. Approximately 2% (n=172) showed highly reduced inhibition (HRI) against at least one of the four NAIs, commonly oseltamivir, while 0.3% (n=32) showed reduced inhibition (RI). Those showing HRI were A(H1N1)pdm09 with NA H275Y (n=169), A(H3N2) with NA E119V (n=1), B/Victoria-lineage with NA E117G (n=1) and B/Yamagata-lineage with NA H273Y (n=1); amino acid position numbering is A subtype and B type specific. Although approximately 98% of circulating viruses tested during the 2013–2014 period were sensitive to all four NAIs, a large community cluster of A(H1N1)pdm09 viruses with the NA H275Y substitution from patients with no previous exposure to antivirals was detected in Hokkaido, Japan. Significant numbers of A(H1N1)pdm09 NA H275Y viruses were also detected in China and the United States: phylogenetic analyses showed that the Chinese viruses were similar to those from Japan, while the United States viruses clustered separately from those of the Hokkaido outbreak, indicative of multiple resistance-emergence events. Consequently, global surveillance of influenza antiviral susceptibility should be continued from a public health perspective.
Highlights
The first class of influenza antiviral drugs to be approved, the adamantanes, continue to be ineffective for the treatment of influenza due to resistance conferred by a S31N amino acid substitution in the M2 protein of virtually all currently circulating A(H1N1)pdm09 and A(H3N2) viruses
The neuraminidase inhibitor (NAI) class of influenza antivirals first came to market in 1999 and encompasses four compounds e oseltamivir (Tamiflu®), zanamivir (Relenza®), peramivir (Rapivab®) and laninamivir (Inavir®) - that differ in their chemical structure, bioavailability and mode of administration
From phylogenetic analyses of these variants over the last five years, we identified an early 2014 cluster of six Japanese viruses with NA D197N substitution that had identical HA and NA sequences, further suggesting that these viruses can spread in the community (Supplementary Fig. S1)
Summary
The first class of influenza antiviral drugs to be approved, the adamantanes (namely amantadine and rimantadine), continue to be ineffective for the treatment of influenza due to resistance conferred by a S31N amino acid substitution in the M2 protein of virtually all currently circulating A(H1N1)pdm and A(H3N2) viruses. Other influenza antivirals that target other viral proteins or host factors, such as nitazoxanide, favipiravir and fludase, are currently in late-phase clinical trials but as yet have not been approved for use in patients with uncomplicated influenza infections As such there remains a strong reliance on the NAIs, oseltamivir, for the treatment of severely ill patients. Clusters of A(H1N1)pdm viruses containing NA H275Y substitution have been detected at a local level (Hurt et al, 2011; Takashita et al, 2015a) Two of these clusters, in Hokkaido, Japan and Pennsylvania, USA were described in our last annual report of NAI susceptibility for the 2013e14 period (Takashita et al, 2015b). The presence of other permissive amino acid substitutions are thought to restore the usual deteriorating effect of the NA H275Y substitution on viral fitness (Butler et al, 2014; Abed et al, 2015)
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