Resistant influenza A viruses in children treated with oseltarnivir: descriptive study
Resistant influenza A viruses in children treated with oseltarnivir: descriptive study
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DOI：
10.1016/s0140-6736(04)16934-1
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发表时间：
2004-08-28
期刊：
影响因子：
168.9
通讯作者：
Kawaoka, Y
中科院分区：
文献类型：
--
作者：
Kiso, M;Mitamura, K;Kawaoka, Y
背景
奥司他韦是一种有效的流感病毒神经氨酸酶抑制剂。尽管对奥司他韦耐药的病毒出现频率低于对金刚烷胺或金刚乙胺耐药的病毒，但关于儿童临床使用该药物过程中出现的奥司他韦耐药病毒的信息有限。我们的目的是研究一组接受流感治疗的儿童对奥司他韦的耐药性。
方法
我们分析了从50名儿童在使用奥司他韦治疗之前和治疗期间采集的甲型流感病毒（H3N2）。我们对神经氨酸酶和血凝素基因进行了测序，并研究了突变的神经氨酸酶对奥司他韦羧酸盐的敏感性。
结果
我们在9名患者（18%）的病毒中发现了神经氨酸酶突变，其中6名患者在292位（Arg292Lys）发生突变，2名在119位（Glu119Val）发生突变，这些突变已知会导致对神经氨酸酶抑制剂产生耐药性。我们还在1名患者中发现了另一种突变（Asn294Ser）。对奥司他韦羧酸盐的敏感性测试显示，具有Arg292Lys、Glu119Val或Asn294Ser突变的病毒的神经氨酸酶分别比其治疗前的神经氨酸酶耐药性高约10⁴ - 10⁵倍、500倍或300倍。奥司他韦耐药病毒在治疗第4天首次被检测到，并在研究的后续每一天都能检测到。在一些未排出耐药病毒的患者中，即使经过5天的治疗，每毫升仍能检测到超过10³个感染单位的病毒。
解释
在使用奥司他韦治疗流感的儿童中，奥司他韦耐药突变体出现的频率比之前报道的更高。此外，即使经过5天的奥司他韦治疗，儿童仍可能是病毒传播的源头。
Background Oseltamivir is an effective inhibitor of influenza virus neuraminidase. Although viruses resistant to oseltamivir emerge less frequently than those resistant to amantadine or rimantadine, information on oseltamivir-resistant viruses arising during clinical use of the drug in children is limited. Our aim was to investigate oseltamivir resistance in a group of children treated for influenza.Methods We analysed influenza A viruses (H3N2) collected from 50 children before and during treatment with oseltamivir. We sequenced the genes for neuraminidase and haemagglutinin and studied the mutant neuraminidases for their sensitivity to oseltamivir carboxylate.Findings We found neuraminidase mutations in viruses from nine patients (18%), six of whom had mutations at position 292 (Arg292Lys) and two at position 119 (Glu119Val), which are known to confer resistance to neuraminidase inhibitors. We also identified another mutation (Asn294Ser) in one patient. Sensitivity testing to oseltamivir carboxylate revealed that the neuraminidases of viruses that have an Arg292Lys, Glu119Val, or Asn294Ser mutation were about 10(4)-10(5)-fold, 500-fold, or 300-fold more resistant than their pretreatment neuraminidases, respectively. Oseltamivir-resistant viruses were first detected at day 4 of treatment and on each successive day of the study. More than 10(3) infectious units per mL of virus were detected in some of the patients who did not shed drug-resistant viruses, even after 5 days of treatment.Interpretation Oseltamivir-resistant mutants in children being treated for influenza with oseltamivir arise more frequently than previously reported. Furthermore, children can be a source of viral transmission, even after 5 days of treatment with oseltamivir.