Temporal trends in prevalence of Plasmodium falciparum molecular markers selected for by artemether-lumefantrine treatment in pre-ACT and post-ACT parasites in western Kenya
Temporal trends in prevalence of Plasmodium falciparum molecular markers selected for by artemether-lumefantrine treatment in pre-ACT and post-ACT parasites in western Kenya
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DOI：
10.1016/j.ijpddr.2015.05.005
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发表时间：
2015-12-01
影响因子：
4
通讯作者：
Kamau, Edwin
中科院分区：
文献类型：
--
作者：
Achieng, Angela O.;Muiruri, Peninah;Kamau, Edwin
2006年，蒿甲醚-氨苯曲明（AL）在肯尼亚成为治疗无并发症疟疾的一线药物。研究表明，与基线感染相比，AL在复发性寄生虫中选择pfcrt和pfmdr1基因的snp。与AL选择相关的基因型分别是pfcrt中的K76和pfmdr1中的N86、184F和D1246。为了评估这些基因型在肯尼亚西部的时间变化，对引进AL之前（1995-2003年）和之后（2008-2014年）收集的47株寄生虫分离株进行了分析。此外，还测定了寄生虫单倍型对蒿甲醚和氨芳啶IC50和清除率的相关性。1995 - 2014年收集的寄生虫基因组DNA在Sequenom MassARRAY上进行测序或基于pcr的单碱基扩展分析。对样本子集的IC(50)s进行了测定。从2013年到2014年，有118个样本来自一项疗效试验，其中68个有清除半衰期。数据显示，act前基因型与act后基因型在4个密码子上存在显著差异（χ 2分析，p < 0.0001）。pfcrt K76和N86的患病率分别从1995-1996年的6.4%上升到2014年的93.2%，2002-2003年的0.0%上升到2014年的92.4%。对携带纯K + NFD或T + YYY单倍型等位基因的寄生虫进行分析发现，act前寄生虫携带T + YYY的比例为100.0%，act后寄生虫携带K + NFD的比例为99.3%。lumefantrine IC50与pfmdr1密码子184位点多态性有显著相关（p = 0.04）。基于遗传单倍型谱的寄生虫清除半衰期没有差异。该研究表明，寄生虫基因型发生了显著变化，AL选择的关键分子决定因素几乎达到饱和。这些发现的意义尚不清楚，因为AL仍然非常有效。然而，有必要密切监测寄生虫的基因型、表型和临床动态，以应对肯尼亚西部继续使用AL。由Elsevier Ltd代表澳大利亚寄生虫学学会出版。
Artemether-lumefantrine (AL) became the first-line treatment for uncomplicated malaria in Kenya in 2006. Studies have shown AL selects for SNPs in pfcrt and pfmdr1 genes in recurring parasites compared to the baseline infections. The genotypes associated with AL selection are K76 in pfcrt and N86, 184F and D1246 in pfmdr1. To assess the temporal change of these genotypes in western Kenya, 47 parasite isolates collected before (pre-ACT; 1995-2003) and 745 after (post-ACT; 2008-2014) introduction of AL were analyzed. In addition, the associations of parasite haplotype against the IC50 of artemether and lumefantrine, and clearance rates were determined. Parasite genomic DNA collected between 1995 and 2014 was analyzed by sequencing or PCR-based single-base extension on Sequenom MassARRAY. IC(50)s were determined for a subset of the samples. One hundred eighteen samples from 2013 to 2014 were from an efficacy trial of which 68 had clearance half-lives. Data revealed there were significant differences between pre-ACT and post-ACT genotypes at the four codons (chi-square analysis; p < 0.0001). The prevalence of pfcrt K76 and N86 increased from 6.4% in 1995-1996 to 93.2% in 2014 and 0.0% in 2002-2003 to 92.4% in 2014 respectively. Analysis of parasites carrying pure alleles of K + NFD or T + YYY haplotypes revealed that 100.0% of the pre-ACT parasites carried T + YYY and 99.3% of post-ACT parasites carried K + NFD. There was significant correlation (p = 0.04) between lumefantrine IC50 and polymorphism at pfmdr1 codon 184. There was no difference in parasite clearance half-lives based on genetic haplotype profiles. This study shows there is a significant change in parasite genotype, with key molecular determinants of AL selection almost reaching saturation. The implications of these findings are not clear since AL remains highly efficacious. However, there is need to closely monitor parasite genotypic, phenotypic and clinical dynamics in response to continued use of AL in western Kenya. Published by Elsevier Ltd on behalf of Australian Society for Parasitology.