Plasmodium falciparum Polymorphisms Associated with Ex Vivo Drug Susceptibility and Clinical Effectiveness of Artemisinin-Based Combination Therapies in Benin
Plasmodium falciparum Polymorphisms Associated with Ex Vivo Drug Susceptibility and Clinical Effectiveness of Artemisinin-Based Combination Therapies in Benin
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DOI：
10.1128/aac.01790-12
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发表时间：
2014-01-01
影响因子：
4.9
通讯作者：
Houze, Sandrine
中科院分区：
文献类型：
--
作者：
Dahlstroem, Sabina;Aubouy, Agnes;Houze, Sandrine
以青蒿素为基础的综合疗法是治疗疟疾的主要选择，必须密切监测其疗效和敏感性，以避免抗药性。我们评估了恶性疟原虫多态性和离体药物敏感性与临床疗效的关系。2007年在贝宁对参加一项比较蒿甲醚-苯芴醇（n = 96）、固定剂量青蒿琥酯-阿莫地喹（n = 96）和磺胺嘧啶-乙胺嘧啶（n = 48）治疗无并发症疟疾的有效性试验的患者进行了评估。在治疗前和复发感染中分析pfcrt、pfmdr1、pfmrp1、pfdhfr和pfdhps多态性。通过疟原虫乳酸脱氢酶酶联免疫吸附试验（ELISA）测定新鲜基线分离株的药物敏感性。对于去乙基阿莫地喹、本芴醇、甲氟喹和奎宁，大多数菌株的50%抑制浓度（IC50）估计值（50%生长抑制所需的浓度）低于3D7参考克隆，因此被认为是敏感的，而双氢青蒿素和乙胺嘧啶的IC（50）较高。未发现ACT化合物的敏感性与治疗结果之间存在关联。与基线感染相比，在蒿甲醚-苯芴醇复发（复发感染）中观察到pfmdr1 N86等位基因的选择（4/7 [57.1%] vs 36/195 [18.5%]），在青蒿琥酯-阿莫地喹再感染（新发感染）中观察到相反等位基因86 Y的选择（20/22 [90.9%] vs 137/195 [70.3%]）。pfmdr1 N86在本芴醇耐受性中的重要性通过其与本芴醇IC（50）升高的相关性得到强调。N86和Y184之间存在遗传连锁，这与1246Y的低频率一起可能解释了pfmdr1位点选择的区域差异。选择蒿甲醚-苯芴醇和青蒿琥酯-阿莫地喹复发性感染的相反等位基因支持多重一线治疗策略。基于临床、离体、分子和药理学数据的监测是必要的。
Artemisinin-based combination therapies (ACTs) are the main option to treat malaria, and their efficacy and susceptibility must be closely monitored to avoid resistance. We assessed the association of Plasmodium falciparum polymorphisms and ex vivo drug susceptibility with clinical effectiveness. Patients enrolled in an effectiveness trial comparing artemether-lumefantrine (n = 96), fixed-dose artesunate-amodiaquine (n = 96), and sulfadoxine-pyrimethamine (n = 48) for the treatment of uncomplicated malaria 2007 in Benin were assessed. pfcrt, pfmdr1, pfmrp1, pfdhfr, and pfdhps polymorphisms were analyzed pretreatment and in recurrent infections. Drug susceptibility was determined in fresh baseline isolates by Plasmodium lactate dehydrogenase enzyme-linked immunosorbent assay (ELISA). A majority had 50% inhibitory concentration (IC50) estimates (the concentration required for 50% growth inhibition) lower than those of the 3D7 reference clone for desethylamodiaquine, lumefantrine, mefloquine, and quinine and was considered to be susceptible, while dihydroartemisinin and pyrimethamine IC(50)s were higher. No association was found between susceptibility to the ACT compounds and treatment outcome. Selection was observed for the pfmdr1 N86 allele in artemether-lumefantrine recrudescences (recurring infections) (4/7 [57.1%] versus 36/195 [18.5%]), and of the opposite allele, 86Y, in artesunate-amodiaquine reinfections (new infections) (20/22 [90.9%] versus 137/195 [70.3%]) compared to baseline infections. The importance of pfmdr1 N86 in lumefantrine tolerance was emphasized by its association with elevated lumefantrine IC(50)s. Genetic linkage between N86 and Y184 was observed, which together with the low frequency of 1246Y may explain regional differences in selection of pfmdr1 loci. Selection of opposite alleles in artemether-lumefantrine and artesunate-amodiaquine recurrent infections supports the strategy of multiple first-line treatment. Surveillance based on clinical, ex vivo, molecular, and pharmacological data is warranted.