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Detection of Influenza Viruses Resistant to Neuraminidase Inhibitors in Global Surveillance during the First 3 Years of Their Use

University of Michigan School of Public Health, Ann Arbor, Michigan,¹ CSIRO Molecular and Health Technologies, Parkville, Australia,² Los Alamos National Laboratory, Los Alamos, New Mexico,³ WHO Collaborating Centre for Reference & Research on Influenza, Melbourne, Australia,⁴ WHO Collaborating Center for Reference & Research on Influenza, National Institute for Medical Research, Mill Hill, London, United Kingdom,⁵ WHO Collaborating Center for Surveillance, Epidemiology and Control of Influenza, Influenza Branch, Centers for Disease Control and Prevention, Atlanta, Georgia,⁶ WHO Collaborating Center for Reference & Research on Influenza, National Institute of Infectious Diseases, Tokyo, Japan,⁷ WHO Collaborating Center for the Studies on the Ecology of Influenza in Animals and Birds, St. Jude Children's Research Hospital, Memphis, Tennessee,⁸ Universit é Claude Bernard, Lyon, France,⁹ University of Virginia School of Medicine, Charlottesville, Virginia,¹⁰ Health Protection Agency, Colindale, London, United Kingdom,¹¹

Received 12 October 2005/ Returned for modification 6 January 2006/ Accepted 20 April 2006

Emergence of influenza viruses with reduced susceptibility to neuraminidase inhibitors (NAIs) develops at a low level following drug treatment, and person-to-person transmission of resistant virus has not been recognized to date. The Neuraminidase Inhibitor Susceptibility Network (NISN) was established to follow susceptibility of isolates and occurrence of NAI resistance at a population level in various parts of the world. Isolates from the WHO influenza collaborating centers were screened for susceptibilities to oseltamivir and zanamivir by a chemiluminescent enzyme inhibition assay, and those considered potentially resistant were analyzed by sequence analysis of the neuraminidase genes. During the first 3 years of NAI use (1999 to 2002), 2,287 isolates were tested. Among them, eight (0.33%) viruses had a >10-fold decrease in susceptibility to oseltamivir, one (0.22%) in 1999 to 2000, three (0.36%) in 2000 to 2001, and four (0.41%) in 2001 to 2002. Six had unique changes in the neuraminidase gene compared to neuraminidases of the same subtype in the influenza sequence database. Although only one of the mutations had previously been recognized in persons receiving NAIs, none were from patients who were known to have received the drugs. During the 3 years preceding NAI use, no resistant variants were detected among 1,054 viruses. Drug use was relatively stable during the period, except for an approximate 10-fold increase in oseltamivir use in Japan during the third year. The frequency of variants with decreased sensitivity to the NAIs did not increase significantly during this period, but continued surveillance is required, especially in regions with higher NAI use.

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