Molecular markers for failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparum malaria
Molecular markers for failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparum malaria
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DOI：
10.1086/338566
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发表时间：
2002-02-01
影响因子：
6.4
通讯作者：
Plowe, CV
中科院分区：
文献类型：
--
作者：
Kublin, JG;Dzinjalamala, FK;Plowe, CV
尚未实施监测抗磺胺嘧啶-乙胺嘧啶恶性疟原虫的分子测定，因为赋予抗药性的寄生虫突变的遗传和统计复杂性及其与治疗结果的关系。本研究分析了治疗前二氢叶酸还原酶（DHFR）和二氢蝶酸合酶（DHPS）基因型和治疗结果在双盲，安慰剂对照试验磺胺嘧啶乙胺嘧啶和氯丙胍氨苯砜治疗无并发症恶性疟原虫疟疾。使用多元逻辑回归来识别预测治疗失败的突变，并识别相互作用和混杂因素。由具有3个DHFR突变和2个DHPS突变（“五重突变体”）的寄生虫引起的感染与磺胺嘧啶-乙胺嘧啶治疗失败相关，但与氯丙胍-氨苯砜治疗失败无关。一个DHFR突变（Arg-59）和一个DHPS突变（Glu-540）的存在准确地预测了五重突变体的存在。如果这一模型在其他人群中得到验证，最终将有可能使用分子标记来监测非洲抗叶酸剂耐药的恶性疟原虫疟疾。
Molecular assays for monitoring sulfadoxine-pyrimethamine-resistant Plasmodium falciparum have not been implemented because of the genetic and statistical complexity of the parasite mutations that confer resistance and their relation to treatment outcomes. This study analyzed pretreatment dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) genotypes and treatment outcomes in a double-blind, placebo-controlled trial of sulfadoxine-pyrimethamine and chlorproguanildapsone treatment for uncomplicated P. falciparum malaria. Multiple logistic regression was used to identify mutations that were predictive of treatment failure and to identify interactions and confounding factors. Infections caused by parasites with 3 DHFR mutations and 2 DHPS mutations (the "quintuple mutant") were associated with sulfadoxine-pyrimethamine treatment failure but not with chlorproguanil-dapsone treatment failure. The presence of a single DHFR mutation (Arg-59) with a single DHPS mutation (Glu-540) accurately predicted the presence of the quintuple mutant. If this model is validated in other populations, it will finally be possible to use molecular markers for surveillance of antifolate-resistant P. falciparum malaria in Africa.