Tashiro Masato, McKimm-Breschkin Jennifer L, Saito Takehiko, Klimov Alexander, Macken Catherine, Zambon Maria, Hayden Frederick G
WHO Collaborating Center for Reference & Research on Influenza, National Institute of Infectious Diseases, Tokyo, Japan.
Antivir Ther. 2009;14(6):751-61. doi: 10.3851/IMP1194.
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.
Isolates were tested by the enzyme inhibition assay and by neuraminidase (NA) sequence analysis.
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 (IC(50)) 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 IC(50) values, but no persistent increases over this period.
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.
自2003年以来，日本对神经氨酸酶抑制剂（NAI）奥司他韦的大量使用促使神经氨酸酶抑制剂敏感性监测网络对社区中分离出的流感病毒对奥司他韦和扎那米韦的敏感性进行评估。
通过酶抑制试验和神经氨酸酶（NA）序列分析对分离株进行检测。
在2003 - 2004年季节从日本收集的1141株A（H3N2）病毒和171株B型病毒中，3株（0.3%）A（H3N2）分离株对奥司他韦表现出高50%抑制浓度（IC50）。每株都在R292K或E119V处存在已知的耐药NA突变。在2004 - 2005年季节，在567株甲型流感病毒（H3N2）或60株甲型流感病毒（H1N1）分离株中未发现耐药情况，但在58株乙型流感病毒分离株中有1株存在NAI耐药突变（D197N）。序列分析发现，2005 - 2006年的132株甲型流感病毒（H1N1）中有4株（3%）存在已知的NA耐药突变（均为H274Y），但在该季节或随后的2006 - 2007年季节未检测到其他耐药分离株。对2000年至2006年选取的500株乙型流感病毒进行的同步检测显示，奥司他韦和扎那米韦的IC50值在不同季节之间存在显著差异，但在此期间没有持续升高。
我们的研究结果表明，在日本的几个季节中，可能存在来自接受奥司他韦治疗患者的耐药变异株的低水平传播，尽管药物使用量很高，但未发现NAI敏感性持续降低或任何毒株或亚型检测到耐药变异株的频率持续增加。特别是，尽管带有H274Y突变的对奥司他韦耐药的甲型流感病毒（H1N1）在2007 - 2008年全球传播，但我们几乎没有发现前几年日本耐药甲型流感病毒（H1N1）变异株水平增加的证据。
