Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, California, USA.
Department of Medicine, University of California, San Francisco, California, USA.
Antimicrob Agents Chemother. 2017 Nov 22;61(12). doi: 10.1128/AAC.01516-17. Print 2017 Dec.
Dihydroartemisinin-piperaquine (DP) has demonstrated excellent efficacy for the treatment and prevention of malaria in Uganda. However, resistance to both components of this regimen has emerged in Southeast Asia. The efficacy of artemether-lumefantrine, the first-line regimen to treat malaria in Uganda, has also been excellent, but continued pressure may select for parasites with decreased sensitivity to lumefantrine. To gain insight into current drug sensitivity patterns, sensitivities were assessed and genotypes previously associated with altered drug sensitivity were characterized for 58 isolates collected in Tororo, Uganda, from subjects presenting in 2016 with malaria from the community or as part of a clinical trial comparing DP chemoprevention regimens. Compared to community isolates, those from trial subjects had lower sensitivities to the aminoquinolines chloroquine, monodesethyl amodiaquine, and piperaquine and greater sensitivities to lumefantrine and mefloquine, an observation consistent with DP selection pressure. Compared to results for isolates from 2010 to 2013, the sensitivities of 2016 community isolates to chloroquine, amodiaquine, and piperaquine improved (geometric mean 50% inhibitory concentrations [IC] = 248, 76.9, and 19.1 nM in 2010 to 2013 and 33.4, 14.9, and 7.5 nM in 2016, respectively [ < 0.001 for all comparisons]), the sensitivity to lumefantrine decreased (IC = 3.0 nM in 2010 to 2013 and 5.4 nM in 2016 [ < 0.001]), and the sensitivity to dihydroartemisinin was unchanged (IC = 1.4 nM). These changes were accompanied by decreased prevalence of transporter mutations associated with aminoquinoline resistance and low prevalence of polymorphisms recently associated with resistance to artemisinins or piperaquine. Antimalarial drug sensitivities are changing in Uganda, but novel genotypes associated with DP treatment failure in Asia are not prevalent.
二氢青蒿素-哌喹（DP）已被证明对乌干达的疟疾治疗和预防具有极好的疗效。然而，这种方案的两种成分在东南亚都出现了耐药性。青蒿琥酯-咯萘啶，乌干达治疗疟疾的一线方案，疗效也非常好，但持续的压力可能会选择对咯萘啶敏感性降低的寄生虫。为了深入了解当前的药物敏感性模式，评估了敏感性，并对 2016 年在乌干达托罗罗收集的 58 株分离株的基因型进行了特征分析，这些分离株来自社区就诊的疟疾患者或作为比较 DP 化学预防方案的临床试验的一部分。与社区分离株相比，来自试验对象的分离株对氨基喹啉类药物氯喹、单去乙基阿莫地喹和哌喹的敏感性较低，对咯萘啶和甲氟喹的敏感性较高，这一观察结果与 DP 的选择压力一致。与 2010 年至 2013 年分离株的结果相比，2016 年社区分离株对氯喹、阿莫地喹和哌喹的敏感性有所提高（2010 年至 2013 年几何平均 50%抑制浓度[IC]分别为 248、76.9 和 19.1 nM，2016 年分别为 33.4、14.9 和 7.5 nM[所有比较均 < 0.001]），对咯萘啶的敏感性降低（2010 年至 2013 年 IC 为 3.0 nM，2016 年为 5.4 nM[<0.001]），对二氢青蒿素的敏感性不变（IC 为 1.4 nM）。这些变化伴随着与氨基喹啉类耐药相关的转运体突变的流行率降低，以及与青蒿素类或哌喹类耐药相关的新突变的低流行率。乌干达的抗疟药物敏感性正在发生变化，但与亚洲 DP 治疗失败相关的新型基因型并不流行。
