Detection of influenza viruses resistant to neuraminidase inhibitors in global surveillance during the first 3 years of their use

Abstract

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.

FIG. 1.

Estimated numbers of 5-day treatment courses of oseltamivir administered in 1999 to 2000, 2000 to 2001, and 2001 to 2002 (October to September) in various regions of the world.

FIG. 2.

Box plots of IC₅₀ values (nM), log transformed, for zanamivir (Z) and oseltamivir carboxylate (O) for A/N1 viruses during years 1, 2, and 3 (Y1, Y2, and Y3). Boxes represent the 25th to 75th percentiles, and horizontal lines within the boxes represent the median values.

FIG. 3.

Box plots of IC₅₀ values (nM), log transformed, for zanamivir (Z) and oseltamivir carboxylate (O) for A/N2 viruses during years 1, 2, and 3 (Y1, Y2, and Y3). Boxes represent the 25th to 75th percentiles, and horizontal lines within the boxes represent the median values.

FIG. 4.

Box plots of IC₅₀ values (nM), log transformed, for zanamivir (Z) and oseltamivir carboxylate (O) for B viruses during years 1, 2, and 3 (Y1, Y2, and Y3). Boxes represent the 25th to 75th percentiles, and horizontal lines within the boxes represent the median values.