AAC Accepts, published online ahead of print on 14 July 2008
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Antimicrob. Agents Chemother. doi:10.1128/AAC.00555-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Surveillance for neuraminidase inhibitor resistance among human influenza A and B viruses circulating worldwide in 2004-2008

Tiffany G. Sheu, Varough M. Deyde, Margaret Okomo-Adhiambo, Rebecca Garten, Xiyan Xu, Rick Bright, Eboneé Butler, Teresa R. Wallis, Alexander I. Klimov, and Larisa V. Gubareva*

Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, 30333, USA

* To whom correspondence should be addressed. Email: LGubareva{at}cdc.gov.


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Abstract

Surveillance of seasonal influenza virus susceptibility to neuraminidase (NA) inhibitors was conducted using a NA inhibition (NAI) assay. The IC50s of 4570 viruses collected globally from October 2004 to March 2008, were determined. Based on mean IC50s, A(H3N2) viruses (0.44nM) were more sensitive to oseltamivir compared to A(H1N1) viruses (0.91nM). The opposite trend was observed with zanamivir: 1.06nM for A(H1N1) and 2.54nM for A(H3N2). Influenza B viruses exhibited the least susceptibility to oseltamivir (3.42nM) and zanamivir (3.87nM). To identify potentially resistant viruses (outliers), a threshold of IC50 > mean IC50 + 3SD was defined for type/subtype and drug. Sequence analysis of outliers was performed to identify NA changes that might be associated with reduced susceptibility. Molecular markers of oseltamivir-resistance were found in six A(H1N1) viruses (H274Y) and one A(H3N2) virus (E119V) collected from 2004-07. Some outliers contained previously reported mutations (e.g., I222T in B viruses), while others (e.g., R371K and H274Y in B; H274N in N2) were novel. The R371K B outlier exhibited high levels of resistance to both inhibitors (>100nM). A substantial variance at residue D151 was observed among A(H3N2) zanamivir-outliers. The clinical relevance of newly identified NA mutations is unknown.

A rise in the incidence of oseltamivir-resistance in A(H1N1) viruses with the H274Y mutation was detected in the U.S. and other countries in the ongoing 2007-08 season. As of March 2008, the frequency of resistance in U.S. among A(H1N1) viruses was 8.6% (50/579). The recent increase in oseltamivir-resistance among A(H1N1) viruses isolated from untreated patients raises public health concerns and necessitates close monitoring of resistance to NA inhibitors.




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