Dynamics of Malaria Drug Resistance Patterns in the Amazon Basin Region following Changes in Peruvian National Treatment Policy for Uncomplicated Malaria
Dynamics of Malaria Drug Resistance Patterns in the Amazon Basin Region following Changes in Peruvian National Treatment Policy for Uncomplicated Malaria
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DOI：
10.1128/aac.01677-08
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发表时间：
2009-05-01
影响因子：
4.9
通讯作者：
Udhayakumar, Venkatachalam
中科院分区：
文献类型：
--
作者：
Bacon, David J.;McCollum, Andrea M.;Udhayakumar, Venkatachalam
监测耐药和敏感基因型频率的变化可以促进体内临床试验，以在完全失败发生之前评估药物的疗效。2001年，秘鲁在亚马孙流域将其对单纯性疟疾的国家治疗政策改为青蒿琥酯加甲氟喹综合疗法。我们对1999年收集的分离株和2006 - 2007年收集的分离株进行基因分型，以检测恶性疟原虫二氢叶酸还原酶（Pfdhfr）和二氢蝶酸合酶（Pfdhps）基因、多药耐药基因1（Pfmdr-1）、氯喹（CQ）耐药转运蛋白基因（Pfcrt）和Ca 2 + ATP酶基因（PfATP 6）的突变;这些已被证明分别涉及对磺胺嘧啶-乙胺嘧啶（SP）、MQ、CQ和可能的ART的抗性。还确定了Pfdhfr、Pfdhps、Pfcrt和Pfmdr-1位点周围的微卫星单倍型。从1999年到2006年，高度抗SP的Pfdhfr和Pfdhps基因型显著下降。相反，CQ耐药Pfcrt基因型在同一时期的频率增加。在1999年发现的五种不同的Pfmdr-1等位基因形式中，两种基因型的频率增加，而一种基因型的频率在2006年下降。我们还注意到以前未描述的PfATP 6基因的多态性，以及在此期间的缺失突变的频率增加。此外，微卫星分析表明，耐药Pfdhfr，Pfdhps和Pfcrt基因型都从一个单一的创始人单倍型进化而来，而Pfmdr-1基因型至少从两个独立的单倍型进化而来。重要的是，这项研究表明，秘鲁的三重突变Pfdhps基因型与南美洲其他地区的基因型非常相似。
Monitoring changes in the frequencies of drug-resistant and -sensitive genotypes can facilitate in vivo clinical trials to assess the efficacy of drugs before complete failure occurs. Peru changed its national treatment policy for uncomplicated malaria to artesunate (ART)-plus-mefloquine (MQ) combination therapy in the Amazon basin in 2001. We genotyped isolates collected in 1999 and isolates collected in 2006 to 2007 for mutations in the Plasmodium falciparum dihydrofolate reductase (Pfdhfr) and dihydropteroate synthase (Pfdhps) genes, multidrug resistance gene 1 (Pfmdr-1), the chloroquine (CQ) resistance transporter gene (Pfcrt), and the Ca2+ ATPase gene (PfATP6); these have been shown to be involved in resistance to sulfadoxine-pyrimethamine (SP), MQ, CQ, and possibly ART, respectively. Microsatellite haplotypes around the Pfdhfr, Pfdhps, Pfcrt, and Pfmdr-1 loci were also determined. There was a significant decline in the highly SP resistant Pfdhfr and Pfdhps genotypes from 1999 to 2006. In contrast, a CQ-resistant Pfcrt genotype increased in frequency during the same period. Among five different Pfmdr-1 allelic forms noted in 1999, two genotypes increased in frequency while one genotype decreased by 2006. We also noted previously undescribed polymorphisms in the PfATP6 gene as well as an increase in the frequency of a deletion mutant during this period. In addition, microsatellite analysis revealed that the resistant Pfdhfr, Pfdhps, and Pfcrt genotypes have each evolved from a single founder haplotype, while Pfmdr-1 genotypes have evolved from at least two independent haplotypes. Importantly, this study demonstrates that the Peruvian triple mutant Pfdhps genotypes are very similar to those found in other parts of South America.