Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors and status of novel antivirals, 2016-2017

Abstract

A total of 13672 viruses, collected by World Health Organization recognised National Influenza Centres between May 2016 and May 2017, were assessed for neuraminidase inhibitor susceptibility by four WHO Collaborating Centres for Reference and Research on Influenza and one WHO Collaborating Centre for the Surveillance Epidemiology and Control of Influenza. The 50% inhibitory concentration (IC₅₀) was determined for oseltamivir and zanamivir for all viruses, and for peramivir and laninamivir in a subset (n = 8457). Of the viruses tested, 94% were obtained from the Western Pacific, Americas and European WHO regions, while limited viruses were available from the Eastern Mediterranean, African and South East Asian regions. Reduced inhibition (RI) by one or more neuraminidase inhibitor was exhibited by 0.2% of viruses tested (n = 32). The frequency of viruses with RI has remained low since this global analysis began (2015/16: 0.8%, 2014/15: 0.5%; 2013/14: 1.9%; 2012/13: 0.6%) but 2016/17 has the lowest frequency observed to date. Analysis of 13581 neuraminidase sequences retrieved from public databases, of which 5243 sequences were from viruses not included in the phenotypic analyses, identified 58 further viruses (29 without phenotypic analyses) with amino acid substitutions associated with RI by at least one neuraminidase inhibitor. Bringing the total proportion to 0.5% (90/18915). This 2016/17 analysis demonstrates that neuraminidase inhibitors remain suitable for treatment and prophylaxis of influenza virus infections, but continued monitoring is important. An expansion of surveillance testing is paramount since several novel influenza antivirals are in late stage clinical trials with some resistance already having been identified.

Keywords: Influenza; Inhibitor; Neuraminidase; Resistance; Surveillance; Susceptibility.

Fig. 1

Influenza viruses collected and tested for phenotypic neuraminidase inhibitor (NAI) susceptibility during 2016–2017. A) Week of specimen collection and virus type/subtype/lineage; for specimens tested, peaks in specimen collection during the Southern Hemisphere winter and during the Northern Hemisphere winter were observed. B) Number of viruses tested for phenotypic susceptibility to the four NAIs by World Health Organization region. B/Yamagata-lineage haemagglutinin:B/Victoria-lineage neuraminidase reassortants are shown separately.

Fig. 2

Comparison of NAI susceptibility surveillance over five seasons. A) Number of viruses tested in neuraminidase inhibition assays over the 2012–2017 period. B) Proportion of viruses showing RI or HRI by NAIs over the 2012–2017 period. Data compiled from the global studies reporting on viruses isolated during 2012–13 (Meijer et al., 2014), 2013–14 (Takashita et al., 2015), 2014–15 (Hurt et al., 2016), 2015–16 Gubareva et al., 2017a) and 2016–17 (current study). B/Yamagata-lineage haemagglutinin:B/Victoria-lineage neuraminidase reassortants are included in the proportion and number of B/Victoria-lineage viruses.

Fig. 3

Column-scatter plots of log-transformed 50% inhibitory concentration (IC₅₀) fold-change values. Data are presented by virus subtype or lineage [A) A(H1N1)pdm09; B) A(H3N2); C) B/Victoria-lineage; and D) B/Yamagata-lineage] and NAI (labelled on the X-axis: oseltamivir, zanamivir, peramivir, laninamivir). Panel C) also contains B/Yamagata-lineage haemagglutinin:B/Victoria-lineage neuraminidase reassortants. The boxes indicate the 25–75 percentile and the whiskers stretch to the lowest and highest values within 1.5 times of the interquartile region value from both the 25 and 75 percentile values respectively (Tukey's definition). The Y-axes have been split into 3 compartments according to the thresholds recommended by the World Health Organization Expert Working Group of GISRS for normal inhibition (NI) (type A viruses <10-fold; type B viruses <5-fold), reduced inhibition (RI) (type A viruses 10- to 100-fold; type B viruses 5- to 50-fold), and highly reduced inhibition (HRI) (type A viruses >100-fold; type B viruses >50-fold). NA amino acid substitutions are shown for viruses displaying RI or HRI that have been sequenced; amino acid position numbering is A subtype- and B lineage-specific. All viruses were tested for susceptibility to oseltamivir and zanamivir but only a subset were tested against peramivir and laninamivir.