Selection of Plasmodium falciparum pfcrt and pfmdr1 polymorphisms after treatment with artesunate-amodiaquine fixed dose combination or artemether-lumefantrine in Liberia
Selection of Plasmodium falciparum pfcrt and pfmdr1 polymorphisms after treatment with artesunate-amodiaquine fixed dose combination or artemether-lumefantrine in Liberia
复制标题
DOI：
10.1186/s12936-016-1503-3
复制
发表时间：
2016-09-05
期刊：
影响因子：
3
通讯作者：
Houze, Sandrine
中科院分区：
文献类型：
--
作者：
Otienoburu, Sabina Dahlstrom;Maiga-Ascofare, Oumou;Houze, Sandrine
背景：以青蒿素为基础的联合疗法（ACT）可成功治疗恶性疟原虫单纯性疟疾。然而，耐药性正在蔓延到不同的ACT化合物；青蒿素衍生物和伴生药物。恶性疟原虫与耐药相关的多态性研究可以为追踪耐药和指导治疗政策以及深入了解耐药的发展和传播提供有用的工具。方法：2008-2009年在利比里亚宁巴县进行了一项比较青蒿琥酯-阿莫地喹固定剂量联合用药与蒿甲醚-氨苯曲明固定剂量联合用药治疗疟疾的疗效试验，评估恶性疟原虫分子标志物在选择再感染中的作用。采用PCR-RFLP和焦磷酸测序技术分析了恶性疟原虫pfcrt 76、pfmdr1 86、184和1246以及pfmrp1 876和1466的多态性。结果：宁巴县pfmdr1 1246Y的基线患病率较高（38%）。在青蒿琥酯-阿莫地喹组的再感染中选择Pfmdr1 1246Y和Pfmdr1 86+184+1246单倍型NYY和YYY，在蒿甲醚-甲地喹组的再感染中选择Pfmdr1 K76、Pfmdr1 N86和Pfmdr1单倍型NFD。携带pfmdr1 1246Y的寄生虫在青蒿琥酯-阿莫地喹治疗后可以更早地再感染，携带pfmdr1 N86的寄生虫在蒿甲醚-氨苯曲明治疗后可以在更高浓度的氨苯曲明再感染。结论：虽然治疗非常有效，但再次感染的分子标记选择可能表明寄生虫对当前治疗的敏感性或耐受性降低，应密切监测分子标记的基线流行情况。由于已证明个人药物水平和再感染日期是选择再感染的关键决定因素，因此需要收集和考虑这些数据，以便准确评估抗疟疾治疗的分子标记。
Background: Plasmodium falciparum uncomplicated malaria can successfully be treated with an artemisinin-based combination therapy (ACT). However resistance is spreading to the different ACT compounds; the artemisinin derivative and the partner drug. Studies of P. falciparum polymorphisms associated with drug resistance can provide a useful tool to track resistance and guide treatment policy as well as an in-depth understanding of the development and spread of resistance.Methods: The role of P. falciparum molecular markers in selection of reinfections was assessed in an efficacy trial comparing artesunate-amodiaquine fixed-dose combination with artemether-lumefantrine to treat malaria in Nimba County, Liberia 2008-2009. P. falciparum polymorphisms in pfcrt 76, pfmdr1 86, 184 and 1246, and pfmrp1 876 and 1466 were analysed by PCR-RFLP and pyrosequencing.Results: High baseline prevalence of pfmdr1 1246Y was found in Nimba county (38 %). Pfmdr1 1246Y and pfmdr1 86+184+1246 haplotypes NYY and YYY were selected in reinfections in the artesunate-amodiaquine arm and pfcrt K76, pfmdr1 N86 and pfmdr1 haplotype NFD were selected in artemether-lumefantrine reinfections. Parasites harbouring pfmdr1 1246Y could reinfect earlier after treatment with artesunate-amodiaquine and parasites carrying pfmdr1 N86 could reinfect at higher lumefantrine concentrations in patients treated with artemether-lumefantrine.Conclusions: Although treatment is highly efficacious, selection of molecular markers in reinfections could indicate a decreased sensitivity or tolerance of parasites to the current treatments and the baseline prevalence of molecular markers should be closely monitored. Since individual drug levels and the day of reinfection were demonstrated to be key determinants for selection of reinfections, this data needs to be collected and taken into account for accurate evaluation of molecular markers for anti-malarial treatments.