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Influenza viruses circulating among humans vary genetically from season to season and even within a season in different regions of the world. Thus, global surveillance for influenza viruses is critical to monitor for antigenic changes in circulating influenza viruses and to inform annual vaccine strain selection. In addition, surveillance is critical to monitor for virus susceptibility to antiviral drugs. Resistance to the adamantane class of drugs (amantadine and rimantadine), caused by substitutions at key amino acid residues in the M2 protein, has been widespread among influenza A viruses [1]. Adamantanes are not effective against currently circulating A(H3N2) viruses and 2009 pandemic influenza A(H1N1) (H1N1pdm09) viruses because of the S31N change in the M2 protein [2, 3]. Resistance to both approved neuraminidase (NA) inhibitors, oseltamivir and zanamivir, has been occasionally reported for all influenza virus A subtypes and influenza B viruses affecting humans [4]; however, widespread global circulation of influenza viruses resistant to an NA inhibitor (NAI) has occurred only once since the initiation of surveillance for NAI resistance in 1999 [5]. Early in the 2007–2008 influenza season, Norway reported the first cluster of seasonal influenza A(H1N1) viruses that carried the oseltamivir resistance–conferring H275Y substitution in the NA [6]. There was no association with prior oseltamivir exposure. Subsequently, during that season, many countries reported an increased prevalence of oseltamivir resistance among seasonal influenza A(H1N1) viruses, although prevalence varied globally [7–9]; previously, the prevalence had been <1%. During the next season (2008–2009), oseltamivir-resistant H275Y variant became the predominant seasonal influenza A(H1N1) viruses in the United States and other countries [10, 11]. During the 2009 pandemic, the oseltamivir-sensitive H1N1pdm09 virus replaced the oseltamivir-resistant seasonal influenza A(H1N1) virus. However, concerns of a repeat of the 2007–2009 phenomenon of rapid emergence and widespread circulation of oseltamivir-resistant viruses have accentuated the importance of ongoing global surveillance for NA inhibitor– resistant influenza viruses as well as the need to broaden therapeutic options. Several investigators have suggested mechanisms that may have contributed to the replacement of the oseltamivirsusceptible seasonal influenza A(H1N1) virus with the oseltamivir-resistant viruses. First, substitutions in the NA, especially those in the active site or its proximity (such as H275Y), can decrease NA function, reducing viral fitness [4]; this was demonstrated for the H275Y substitution. Additional mutations in the NA of the 2008–2009 seasonal influenza A(H1N1) viruses (V234M, R222Q) were identified [12] that appeared to permit more normal NA function compared to H275Y viruses without these “permissive mutations” [13, 14]. Thus, permissive or complementary changes in the NA may have enabled the H275Y viruses to cocirculate with the oseltamivir-susceptible viruses in communities. However, they do not explain why the H275Y resistant viruses out-competed susceptible viruses, especially in the countries where oseltamivir was not widely used. Second, other investigators reasoned that the H275Y substitution beneficially affected the hemagglutinin (HA) and NA functional balance in the seasonal influenza A(H1N1) viruses [15]; thus, the H275Y viruses might replicate better and transmit more efficiently, allowing the H275Y viruses to out-compete oseltamivir-susceptible viruses, even in the absence of drug pressure. Finally, the conventional mechanism for influenza viruses to continuously evolve and escape immune system defenses is antigenic drift in the major surface antigen HA. Although antigenic Received 2 March 2012; accepted 5 March 2012; electronically published 4 May 2012. Correspondence: Alicia M. Fry, MD, MPH, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, 1600 Clifton Ave, MS-A-32, Atlanta, GA 30333 (afry@cdc.gov). The Journal of Infectious Diseases 2012;206:145–7 Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2012. DOI: 10.1093/infdis/jis338

Understanding Influenza Virus Resistance to Antiviral Agents; Early Warning Signs for Wider Community Circulation