Artemether-Lumefantrine and Dihydroartemisinin-Piperaquine Exert Inverse Selective Pressure on Plasmodium Falciparum Drug Sensitivity-Associated Haplotypes in Uganda.
Artemether-Lumefantrine and Dihydroartemisinin-Piperaquine Exert Inverse Selective Pressure on Plasmodium Falciparum Drug Sensitivity-Associated Haplotypes in Uganda.
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DOI：
10.1093/ofid/ofw229
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发表时间：
2017
影响因子：
4.2
通讯作者：
Rosenthal PJ
中科院分区：
文献类型：
--
作者：
Taylor AR;Flegg JA;Holmes CC;Guérin PJ;Sibley CH;Conrad MD;Dorsey G;Rosenthal PJ
对多种抗疟药物敏感性的改变是由编码恶性疟原虫多药耐药转运蛋白的pfmdr 1的多态性介导的。在非洲，N86 Y和D1246 Y多态性已被证明是通过治疗选择的，蒿甲醚-苯芴醇（AL）和双氢青蒿素-哌喹（DP）分别选择野生型和突变型等位基因。然而，对pfmdr 1单倍型的研究很少，部分原因是多克隆感染使单倍型分析变得复杂。我们拟合了一个单倍型频率估计模型，该模型考虑了多克隆感染，从2007年至2012年在乌干达托罗罗进行的一项纵向试验中比较AL和DP治疗无并发症恶性疟原虫疟疾的样本中多态性pfmdr 1 N86 Y，Y184 F和D1246 Y等位基因。我们回归估计试验组和选择性药物压力的协变量。年度趋势显示，增加频率估计的单倍型与野生型pfmdr 1 N86和D1246等位基因和减少频率估计的单倍型与突变pfmdr 1 86 Y等位基因。考虑到自先前治疗以来的天数，我们看到了提示AL选择N86与184 F、D1246或两者组合的单倍型以及针对86 Y的所有单倍型的证据，以及提示DP选择86 Y仅当与Y184和1246 Y（单倍型YYY）组合时以及针对单倍型NFD和NYY的证据。基于我们的模型，AL选择了几个单倍型含有N86，而DP选择是单倍型特异性，证明单倍型分析的重要性。AL和DP对互补单倍型NFD和YYY的反向选择压力表明，轮换青蒿素为基础的抗疟联合方案可能是防止耐药选择的最佳治疗选择。
Altered sensitivity to multiple antimalarial drugs is mediated by polymorphisms in pfmdr1, which encodes the Plasmodium falciparum multidrug resistance transporter. In Africa the N86Y and D1246Y polymorphisms have been shown to be selected by treatment, with artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) selecting for wild-type and mutant alleles, respectively. However, there has been little study of pfmdr1 haplotypes, in part because haplotype analyses are complicated by multiclonal infections. We fit a haplotype frequency estimation model, which accounts for multiclonal infections, to the polymorphic pfmdr1 N86Y, Y184F, and D1246Y alleles in samples from a longitudinal trial comparing AL and DP to treat uncomplicated P falciparum malaria in Tororo, Uganda from 2007 to 2012. We regressed estimates onto covariates of trial arm and selective drug pressure. Yearly trends showed increasing frequency estimates for haplotypes with wild type pfmdr1 N86 and D1246 alleles and decreasing frequency estimates for haplotypes with the mutant pfmdr1 86Y allele. Considering days since prior therapy, we saw evidence suggestive of selection by AL for haplotypes with N86 combined with 184F, D1246, or both, and against all haplotypes with 86Y, and evidence suggestive of selection by DP for 86Y only when combined with Y184 and 1246Y (haplotype YYY) and against haplotypes NFD and NYY. Based on our model, AL selected several haplotypes containing N86, whereas DP selection was haplotype specific, demonstrating the importance of haplotype analyses. Inverse selective pressure of AL and DP on the complementary haplotypes NFD and YYY suggests that rotating artemisinin-based antimalarial combination regimens may be the best treatment option to prevent resistance selection.