Taylor Aimee R, Flegg Jennifer A, Holmes Chris C, Guérin Philippe J, Sibley Carol H, Conrad Melissa D, Dorsey Grant, Rosenthal Philip J
WorldWide Antimalarial Resistance Network, University of Oxford, United Kingdom.
Department of Statistics, University of Oxford, United Kingdom.
Open Forum Infect Dis. 2016 Oct 25;4(1):ofw229. doi: 10.1093/ofid/ofw229. eCollection 2017 Winter.
Altered sensitivity to multiple antimalarial drugs is mediated by polymorphisms in , which encodes the 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 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 N86Y, Y184F, and D1246Y alleles in samples from a longitudinal trial comparing AL and DP to treat uncomplicated 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 N86 and D1246 alleles and decreasing frequency estimates for haplotypes with the mutant 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.
对多种抗疟药物敏感性的改变是由编码多药耐药转运蛋白的基因多态性介导的。在非洲，N86Y和D1246Y多态性已被证明受治疗选择影响，蒿甲醚-本芴醇（AL）和双氢青蒿素-哌喹（DP）分别选择野生型和突变等位基因。然而，对该基因单倍型的研究很少，部分原因是单倍型分析因多克隆感染而变得复杂。
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，用于分析2007年至2012年在乌干达托罗罗进行的一项比较AL和DP治疗非复杂性疟疾的纵向试验样本中多态性的N86Y、Y184F和D1246Y等位基因。我们将估计值与试验组和选择性药物压力的协变量进行回归分析。
年度趋势显示，具有野生型N86和D1246等位基因的单倍型频率估计值增加，而具有突变型86Y等位基因的单倍型频率估计值减少。考虑到上次治疗后的天数，我们发现有证据表明AL选择了具有N86与184F、D1246或两者组合的单倍型，而不选择所有具有86Y的单倍型，并且有证据表明DP仅在与Y184和1246Y组合（单倍型YYY）时选择86Y，而不选择单倍型NFD和NYY。
基于我们的模型，AL选择了几种包含N86的单倍型，而DP的选择是单倍型特异性的，这表明了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，轮换基于青蒿素的抗疟联合治疗方案可能是预防耐药性选择的最佳治疗选择。
