Surveillance for neuraminidase-inhibitor-resistant influenza viruses in Japan, 1996–2007

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Abstract
Background: High usage of the neuraminidase inhibitor (NAI) oseltamivir in Japan since 2003 led the Neuraminidase Inhibitor Susceptibility Network to assess the susceptibility of community isolates of influenza viruses to oseltamivir and zanamivir. Methods: Isolates were tested by the enzyme inhibition assay and by neuraminidase (NA) sequence analysis. Results: Among 1,141 A(H3N2) viruses and 171 type B viruses collected in Japan during the 2003–2004 season, 3 (0.3%) A(H3N2) isolates showed high 50% inhibitory concentrations (IC50) to oseltamivir. Each possessed a known resistance NA mutation at R292K or E119V. During the 2004–2005 season, no resistance was found among 567 influenza A(H3N2) or 60 A(H1N1) isolates, but 1 of 58 influenza B isolates had an NAI resistance mutation (D197N). Sequence analysis found that 4 (3%) of 132 A(H1N1) viruses from 2005–2006 had known NA resistance mutations (all H274Y), but no additional resistant isolates were detected from that or the subsequent 2006–2007 season. Concurrent testing of a selection of 500 influenza B viruses from 2000 to 2006 showed significant variations between seasons in both oseltamivir and zanamivir IC50 values, but no persistent increases over this period. Conclusions: Our findings suggested possible low-level transmission of resistant variants from oseltamivir-treated patients in several seasons in Japan but no sustained reductions in NAI susceptibility or consistently increased frequency of detecting resistant variants for any strain or subtype, despite high levels of drug use. In particular, although oseltamivir-resistant A(H1N1) viruses with the H274Y mutation spread globally in 2007–2008, we found little evidence for increasing levels of resistant A(H1N1) variants in Japan in preceding years.