Surveillance for neuraminidase inhibitor resistance among human influenza A and B viruses circulating worldwide from 2004 to 2008
Surveillance for neuraminidase inhibitor resistance among human influenza A and B viruses circulating worldwide from 2004 to 2008
复制标题
DOI：
10.1128/aac.00555-08
复制
发表时间：
2008-09-01
影响因子：
4.9
通讯作者：
Gubareva, Larisa V.
中科院分区：
文献类型：
--
作者：
Sheu, Tiffany G.;Deyde, Varough M.;Gubareva, Larisa V.
采用神经氨酸酶（NA）抑制剂抑制试验监测季节性流感病毒对NA抑制剂的易感性。测定了2004年10月至2008年3月在全球收集的4570种病毒的50%抑制浓度（IC(50)s）。基于平均ic50， A（H3N2）病毒（0.44 nM）比A（H1N1）病毒（0.91 nM）对奥司他韦更敏感。扎那米韦对甲型H1N1流感和甲型H3N2流感的影响则相反：分别为1.06 nM和2.54 nM。乙型流感病毒对奥司他韦（3.42 nM）和扎那米韦（3.87 nM）的敏感性最低。为了识别潜在耐药病毒（异常值），为类型/亚型和药物定义了平均IC50值+ 3个标准差的阈值。对异常值进行序列分析，以确定可能与易感性降低相关的NA变化。在2004年至2007年收集的6种甲型H1N1病毒（H274Y）和1种甲型H3N2病毒（E119V）中发现了奥司他韦耐药的分子标记。一些异常值包含先前报道的突变（例如B型病毒中的I222T），而其他突变（例如B型病毒中的R371K和H274Y以及A型（H3N2）病毒中的H274N）则是新发现的。R371K B病毒对这两种抑制剂均表现出高水平的耐药性（bbb100 nM）。在A（H3N2）扎那米韦耐药异常值中，残留D151处存在显著差异。新发现的NA突变的临床相关性尚不清楚。在正在进行的2007年至2008年流感季节，在美国和其他国家发现携带H274Y突变的甲型H1N1流感病毒对奥司他韦耐药的发生率有所上升。截至2008年3月，美国甲型H1N1流感病毒的耐药率为8.6%（50/579株）。最近从未经治疗的患者中分离出的甲型H1N1流感病毒对奥司他韦的耐药性有所增加，这引起了公共卫生关注，有必要密切监测对NA抑制剂的耐药性。
The surveillance of seasonal influenza virus susceptibility to neuraminidase (NA) inhibitors was conducted using an NA inhibition assay. The 50% inhibitory concentration values (IC(50)s) of 4,570 viruses collected globally from October 2004 to March 2008 were determined. Based on mean IC50s, A( H3N2) viruses (0.44 nM) were more sensitive to oseltamivir than A(H1N1) viruses (0.91 nM). The opposite trend was observed with zanamivir: 1.06 nM for A( H1N1) and 2.54 nM for A( H3N2). Influenza B viruses exhibited the least susceptibility to oseltamivir (3.42 nM) and to zanamivir (3.87 nM). To identify potentially resistant viruses (outliers), a threshold of a mean IC50 value + 3 standard deviations was defined for type/subtype and drug. Sequence analysis of outliers was performed to identify NA changes that might be associated with reduced susceptibility. Molecular markers of oseltamivir resistance were found in six A(H1N1) viruses (H274Y) and one A(H3N2) virus (E119V) collected between 2004 and 2007. Some outliers contained previously reported mutations (e.g., I222T in the B viruses), while other mutations e.g., R371K and H274Y in B viruses and H274N in A(H3N2) viruses were novel. The R371K B virus outlier exhibited high levels of resistance to both inhibitors (> 100 nM). A substantial variance at residue D151 was observed among A(H3N2) zanamivir-resistant outliers. The clinical relevance of newly identified NA mutations is unknown. A rise in the incidence of oseltamivir resistance in A(H1N1) viruses carrying the H274Y mutation was detected in the United States and in other countries in the ongoing 2007 to 2008 season. As of March 2008, the frequency of resistance among A(H1N1) viruses in the United States was 8.6% (50/579 isolates). The recent increase in oseltamivir resistance among A(H1N1) viruses isolated from untreated patients raises public health concerns and necessitates close monitoring of resistance to NA inhibitors.