Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2014-2015

Abstract

The World Health Organization (WHO) Collaborating Centres for Reference and Research on Influenza (WHO CCs) tested 13,312 viruses collected by WHO recognized National Influenza Centres between May 2014 and May 2015 to determine 50% inhibitory concentration (IC50) data for neuraminidase inhibitors (NAIs) oseltamivir, zanamivir, peramivir and laninamivir. Ninety-four per cent of the viruses tested by the WHO CCs were from three WHO regions: Western Pacific, the Americas and Europe. Approximately 0.5% (n = 68) of viruses showed either highly reduced inhibition (HRI) or reduced inhibition (RI) (n = 56) against at least one of the four NAIs. Of the twelve viruses with HRI, six were A(H1N1)pdm09 viruses, three were A(H3N2) viruses and three were B/Yamagata-lineage viruses. The overall frequency of viruses with RI or HRI by the NAIs was lower than that observed in 2013-14 (1.9%), but similar to the 2012-13 period (0.6%). Based on the current analysis, the NAIs remain an appropriate choice for the treatment and prophylaxis of influenza virus infections.

Keywords: Antiviral resistance; Global analysis; Influenza virus; Neuraminidase inhibitors; Oseltamivir; Reduced susceptibility.

Fig. 1

Influenza viruses collected and tested for phenotypic neuraminidase inhibitor (NAI) susceptibility during 2014–2015. 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

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; D, B/Yamagata-lineage) and neuraminidase inhibitor (labelled on the X-axis: oseltamivir, zanamivir, peramivir, laninamivir). Panel C also contains B/Yamagata-lineage haemagglutinin:B/Victoria-lineage neuraminidase reassortants, of which the one with amino acid substitution is indicated with an asterisk (*) in the peramivir column. The boxes indicate the 25–75 percentile and the whiskers stretch to the lowest and highest value within 1.5 times 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 World Health Organization Antiviral Working Group recommended thresholds for normal inhibition (NI) (A viruses <10-fold; B viruses <5-fold), reduced inhibition (RI) (A viruses 10- to 100-fold; B viruses 5- to 50-fold), and highly reduced inhibition (HRI) (A viruses >100-fold; B viruses >50-fold). For RI and HRI viruses that have been sequenced the determined NA amino acid substitutions are shown; amino acid position numbering is A subtype and B type specific. All viruses were tested for susceptibility to oseltamivir and zanamivir but not all, including some variants, were tested against peramivir and laninamivir.

Fig. 3

A) Proportions of viruses showing RI or HRI by neuraminidase inhibitors over the 2012–2015 period. B) Number of viruses tested in NA inhibition assays. Data compiled from the global studies reporting on viruses isolated during 2012–13 (Meijer et al., 2014), 2013–14 (Takashita et al., 2015b) and 2014–15 (this study).