3. A(H1N1)pdm09 viruses showing RI or HRI
Of 5152 A(H1N1)pdm09 viruses tested, 175 (3%) showed RI or
HRI by one or more of the NAIs (Fig. 2 and Table 1), of which the
NA amino acid substitution H275Y was present in 169 of those.
Twelve of the 169 H275Y variants harboured a mixed population
of H275Y variant virus and H275 wild type virus. One H275Y variant
with an additional NA I223R substitution was detected in Japan
from a hospitalised patient treated with peramivir; this dual substitution
has been reported previously by the United States, in a
child after prolonged treatment with oseltamivir (Nguyen et al.,
2010). The timing of specimen collection and geographic distribution
of the 169 H275Y variant viruses are shown in Fig. 3. The
H275Y variants were detected between weeks 24/2013 and 15/
2014 (Fig. 3A), with 112 (66%) detected in the Western Pacific
region, 56 (33%) in the Americas and one (1%) in Europe, from 10
countries in total (Fig. 3B). The NA H275Y substitution conferred151- to 2212-fold higher oseltamivir IC50 values and 87- to 2045-
fold higher peramivir IC50 values compared to wild type viruses,
but had little or no effect on zanamivir or laninamivir susceptibility
(Table 1). The H275Y/H mixed variants showed 5.4- to 584-fold
higher oseltamivir IC50 values and 4.8- to 599-fold higher peramivir
IC50 values, depending on the proportion of the H275Y variant
in the mixed population. The H275Y/I223R variant showed HRI
with very high increases in oseltamivir (10,739-fold) and peramivir