INFLUENZA (41): NEURAMINIDASE MUTATION
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Date: Fri 9 Jun 2011
Source: Eurosurveillance, Volume 16, Issue 23 [abridged; edited]
<http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19884>
Increased detection in Australia and Singapore of a novel influenza
A(H1N1)2009 variant with reduced oseltamivir and zanamivir sensitivity
due to a S247N neuraminidase mutation
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By: Hurt AC, Lee RT, Leang SK, Cui L, Deng YM, Phuah SP, Caldwell N,
Freeman K, Komadina N, Smith D, Speers D, Kelso A, Lin RT, Maurer-
Stroh S, Barr IG. Euro Surveill. 2011;16(23):pii=19884. Available
online:
<http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19884>
Summary
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A novel influenza A(H1N1)2009 variant with mildly reduced oseltamivir
and zanamivir sensitivity has been detected in more than 10 percent of
community specimens in Singapore and more than 30 percent of samples
from northern Australia during the early months of 2011. The variant,
which has also been detected in other regions of the Asia-Pacific,
contains a S247N neuraminidase mutation. When combined with the H275Y
mutation, as detected in an oseltamivir-treated patient, the dual
S247N+H275Y mutant had extremely high oseltamivir resistance.
Introduction
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The emergence and global spread in 2007/08 of an
oseltamivir-resistant seasonal influenza A(H1N1) variant containing a
histidine to tyrosine substitution (H275Y) in the neuraminidase (NA),
demonstrated the potential for drug-resistant influenza viruses to
arise and spread within the community in the absence of drug-selective
pressure [1]. Since the start of the 2009 pandemic, the
oseltamivir-resistant H275Y variant has only been detected on rare
occasions in pandemic influenza A(H1N1)2009 community specimens (<1
percent), although recent reports have suggested that this frequency
may be increasing [2]. Other NA mutations in influenza A(H1N1)2009
viruses have been reported to confer mildly reduced oseltamivir and/or
zanamivir sensitivity, such as substitutions at the isoleucine residue
at position 223 (N1 numbering), but the detection of these mutants has
been very rare and has occurred mostly in isolated cases of
immunocompromised individuals under long-term NA inhibitor (NAI)
treatment [3,4].
Here we report the identification and increased rate of detection in
community samples of a novel influenza A(H1N1)2009 variant with
reduced oseltamivir and zanamivir sensitivity. The variant contained a
serine to asparagine mutation at residue 247 (S247N) of the NA, and
has been detected in recent community specimens from Australia, Brunei
and Singapore. Although the mutation has been described before in a
small number of seasonal influenza A(H1N1) and highly pathogenic
influenza A(H5N1) viruses with reduced NAI sensitivity [5,6], it has
not previously been reported in influenza A(H1N1)2009 viruses, and has
not occurred in any strains at the frequencies that are described
here.
[Readers are referred to the original text at the source URL for a
detailed account of the methods, experimental data and the literatures
cited]
Discussion
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Previous studies have reported the effect of the S247N mutation on
NAI sensitivity in N1 neuraminidases. The levels of oseltamivir and
zanamivir sensitivity reported for the S247N mutation in a
pre-pandemic seasonal influenza A(H1N1) virus were similar to those
reported here for the mutation in influenza A(H1N1)2009 strains [5].
However a greater reduction in oseltamivir sensitivity was reported
for a highly pathogenic influenza A(H5N1) strain with a S247N mutation
compared to the influenza A(H1N1)2009 strains reported here (24-fold
vs 6-fold reduction compared to their respective wildtypes) [6]. The
same study also reported on an influenza A(H5N1) virus with the S247N
and 2 additional mutations, I223L and K150N (N1 numbering). This
triple mutant virus had a greater reduction in oseltamivir sensitivity
compared to the S247N mutation alone (77-fold vs 24-fold reduction),
further demonstrating that mutations at other key residues such as
I223, in combination with S247N, can cumulatively decrease NAI
sensitivity. Given that a number of studies have recently reported
I223 mutations conferring NAI resistance in influenza A(H1N1)2009
strains [3,4,9,10], and that data from the United Kingdom show an
increased frequency of H275Y mutants in community samples [2], the
likelihood of mutation combinations S247N+I223X and S247N+H275Y is
considerably increased if the S247N influenza A(H1N1)2009 variant
continues to spread.
Pharmacokinetic data would suggest that the maximum drug levels
achieved via the recommended dose easily exceed the observed IC50
values of the S247N mutant [11], and therefore the variant is unlikely
to be clinically resistant. However, it is noteworthy that recent
clinical studies have demonstrated a reduced oseltamivir efficacy for
normal influenza B viruses [12] which have IC50 values only 6-fold
higher than that of the S247N influenza A(H1N1)2009 variants (mean
oseltamivir IC50 plus-or-minus SD for influenza B viruses from 2010
and 2011: 15.5 nM plus-or-minus11.3 (n=557)). Data from Singapore and
Darwin demonstrate that the S247N variant is able to circulate widely
and therefore does not appear to have compromised viral fitness or
transmissibility. If the S247N variant spreads globally, the greatest
concern is that other NA mutations which may have previously caused
only mild reductions in NAI susceptibility (e.g., mutations at the
I223 residue) could instead cumulatively decrease NAI sensitivity to
levels that may be clinically significant and affect treatment
efficacy. Laboratories should consider screening currently circulating
specimens and isolates for the S247N NA mutation to determine whether
the variant is spreading into other regions.
--
Communicated by:
HealthMap alerts via ProMED-mail
<promed@promedmail.org>
[The authors point out that although the maximum drug levels achieved
via the currently recommended doses employed clinically exceed the
observed IC50 values for the S247N mutant, it is likely that
cumulative mutations in the neuraminidase gene may enhance resistance
progressively and continued surveillance is desirable. - Mod.CP]
[see also:
2009
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Influenza pandemic (H1N1) 2009 (31): drug resistance 20090815.2900
2007
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Avian influenza, human (15): Egypt, drug resistance 20070119.0253
Avian influenza, human (15): Egypt, drug resistance 20070118.0238
2005
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Influenza viruses, drug resistance (06) 20051016.3021
Influenza viruses, drug resistance (05) 20051015.3014
Influenza viruses, drug resistance (04) 20051015.2999
Influenza viruses, drug resistance (03) 20051007.2924
Influenza viruses, drug resistance (02): RFI 20051001.2878
Influenza viruses, drug resistance 20050930.2863
2004
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Avian influenza A (H5N1) virus, drug resistance (02) 20040127.0316
Avian influenza A (H5N1) virus, drug resistance 20040125.0298]
.................................................sb/cp/ejp/dk
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