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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

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.

	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.