Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, 1600 Clifton road NE, Mail Stop D-67 Atlanta, GA, 30333, USA.
Malar J. 2010 Aug 30;9:247. doi: 10.1186/1475-2875-9-247.
Mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes of Plasmodium falciparum are associated with resistance to anti-folate drugs, most notably sulphadoxine-pyrimethamine (SP). Molecular studies document the prevalence of these mutations in parasite populations across the African continent. However, there is no systematic review examining the collective epidemiological significance of these studies. This meta-analysis attempts to: 1) summarize genotype frequency data that are critical for molecular surveillance of anti-folate resistance and 2) identify the specific challenges facing the development of future molecular databases.
This review consists of 220 studies published prior to 2009 that report the frequency of select dhfr and dhps mutations in 31 African countries. Maps were created to summarize the location and prevalence of the highly resistant dhfr triple mutant (N51I, C59R, S108N) genotype and dhps double mutant (A437G and K540E) genotype in Africa. A hierarchical mixed effects logistic regression was used to examine the influence of various factors on reported mutant genotype frequency. These factors include: year and location of study, age and clinical status of sampled population, and reporting conventions for mixed genotype data.
A database consisting of dhfr and dhps mutant genotype frequencies from all African studies that met selection criteria was created for this analysis. The map illustrates particularly high prevalence of both the dhfr triple and dhps double mutant genotypes along the Kenya-Tanzania border and Malawi. The regression model shows a statistically significant increase in the prevalence of both the dhfr triple and dhps double mutant genotypes in Africa.
Increasing prevalence of the dhfr triple mutant and dhps double mutant genotypes in Africa are consistent with the loss of efficacy of SP for treatment of clinical malaria in most parts of this continent. Continued assessment of the effectiveness of SP for the treatment of clinical malaria and intermittent preventive treatment in pregnancy is needed. The creation of a centralized resistance data network, such as the one proposed by the WorldWide Antimalarial Resistance Network (WWARN), will become a valuable resource for planning timely actions to combat drug resistant malaria.
恶性疟原虫二氢叶酸还原酶（dhfr）和二氢蝶酸合成酶（dhps）基因突变与抗叶酸药物的耐药性有关，其中最显著的是磺胺多辛-乙胺嘧啶（SP）。分子研究记录了这些突变在整个非洲大陆寄生虫种群中的流行情况。然而，目前还没有系统的综述来检查这些研究的集体流行病学意义。本荟萃分析试图：1）总结对叶酸类药物耐药性分子监测至关重要的基因型频率数据，2）确定未来分子数据库发展所面临的具体挑战。
本综述包括 2009 年前发表的 220 项研究，报告了 31 个非洲国家中选定的 dhfr 和 dhps 突变的频率。绘制地图以总结非洲高度耐药 dhfr 三联突变体（N51I、C59R、S108N）基因型和 dhps 双突变体（A437G 和 K540E）基因型的位置和流行情况。采用分层混合效应逻辑回归分析了各种因素对报告的突变基因型频率的影响。这些因素包括：研究的年份和地点、采样人群的年龄和临床状况、以及混合基因型数据的报告惯例。
创建了一个包含符合选择标准的所有非洲研究的 dhfr 和 dhps 突变基因型频率的数据库，用于本分析。地图显示，肯尼亚-坦桑尼亚边境和马拉维地区 dhfr 三联和 dhps 双突变基因型的流行率特别高。回归模型显示，非洲 dhfr 三联和 dhps 双突变基因型的流行率均呈统计学显著增加。
非洲 dhfr 三联突变体和 dhps 双突变体基因型的流行率不断增加，这与 SP 治疗该大陆大部分地区临床疟疾的疗效丧失一致。需要继续评估 SP 治疗临床疟疾和间歇性预防治疗妊娠的效果。建立一个集中的耐药数据网络，如世界疟疾耐药网络（WWARN）所提议的那样，将成为计划及时采取行动对抗耐药性疟疾的宝贵资源。
