Can pretreatment screening for dhps and dhfr point mutations in Plasmodium falciparum infections be used to predict sulfadoxine-pyrimethamine treatment failure?
Can pretreatment screening for dhps and dhfr point mutations in Plasmodium falciparum infections be used to predict sulfadoxine-pyrimethamine treatment failure?
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DOI：
10.1016/s0035-9203(01)90250-0
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发表时间：
2001-05-01
影响因子：
2.2
通讯作者：
Warhurst, DC
中科院分区：
文献类型：
--
作者：
Omar, SA;Adagu, IS;Warhurst, DC
本研究探讨了磺胺嘧啶-乙胺嘧啶（S-P）化疗后疟疾治疗失败与治疗前恶性疟原虫二氢蝶酸合酶（dhps）和二氢叶酸还原酶（dhfr）基因（与体外S和P抗性相关）突变之间的关系。在肯尼亚，1997-98年，全流行区的38名疟疾患者和流行区的21名疟疾患者参加了该试验。在这两个地区，观察到dhfr任何突变的病例中分别有76%和75%发生药物失败（阳性预测值分别为76%和75%：P = 0.003和0.008），并且与dhfr Asn-108存在相同的相关性。在完全流行区，所有dhfr基因突变的发生都预示着药物治疗失败。在疫源地仅发现3例，但治疗均失败。仅在疫源地，8例dhps突变≥ 1的病例中有7例（88%）和所有dhps Gly-437等位基因的出现预测了失败。在合并的位点中，dhps突变和dhfr突变之间的关联被注意到，与结果无关。虽然这使得组合dhfr和dhps突变与失败的关系更加难以解释，但它仍然支持作用于两个基因的S-P选择。在完全流行的网站，治疗成功率随着年龄的增长。在这个部位，获得性免疫可能掩盖了dhps突变的影响，因为磺胺嘧啶的治疗效果不如乙胺嘧啶。
This study examines the relationship between malaria treatment failure after sulfadoxine-pyrimethamine (S-P) chemotherapy and presence of mutations in the Plasmodium falciparum dihydropteroate synthase (dhps) and dihydrofolate reductase (dhfr) genes (associated with resistance in vitro to S and P) before treatment. In Kenya, 38 malaria patients in a holoendemic area, and 21 in an epidemic area, participated in the trial in 1997-98. In the 2 areas, drug failure occurred in 76% and 75% of cases where any mutation in dhfr was seen (positive predictive values 76% and 75%: P = 0.003 and 0.008) and an identical association was seen with dhfr Asn-108. In the holoendemic area all occurrences of, 2 mutations in dhfr predicted drug failure. Only 3 instances were seen in the epidemic focus, but treatment failed in all. Only in the epidemic focus, 7 (88%) of 8 occurrences of greater than or equal to 1 mutations in dhps, and all occurrences of the Gly-437 allele of dhps, predicted failure. Association between mutations in dhps and mutations in dhfr was noted in the combined sites, irrespective of outcome. Although this makes the relationship of combined dhfr and dhps mutations to failure more difficult to interpret, it nevertheless supports S-P selection acting on both genes. In the holoendemic site, treatment success increased with age. In this location, acquired immunity may mask the impact of mutations in dhps, since sulfadoxine is a less effective treatment than pyrimethamine.