苏丹青蒿素联合疗法后恶性疟原虫耐药基因的演变

Evolution of Plasmodium falciparum drug resistance genes following artemisinin combination therapy in Sudan.

作者信息

Bakhiet Amani M A, Abdelraheem Mohamed H, Kheir Amani, Omer Samia, Gismelseed Linda, Abdel-Muhsin Abdel-Muhsin A, Naiem Ahmed, Al Hosni Ahmed, Al Dhuhli Amani, Al Rubkhi Maymona, Al-Hamidhi Salama, Gadalla Amal, Mukhtar Moawia, Sultan Ali A, Babiker Hamza A

机构信息

Department of Biochemistry, Faculty of Medicine and Health Sciences, Sultan Qaboos University, Al Khoudh, Oman.

Sudan Academy of Sciences, Department of Epidemiology and Molecular Biology, Khartoum, Sudan.

出版信息

Trans R Soc Trop Med Hyg. 2019 Nov 1;113(11):693-700. doi: 10.1093/trstmh/trz059.

DOI:10.1093/trstmh/trz059

PMID:31369106

Abstract

BACKGROUND

Malaria control efforts in Sudan rely heavily on case management. In 2004, health authorities adopted artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria. However, some recent surveys have reported ACT failure and a prevalent irrational malaria treatment practice. Here we examine whether the widespread use of ACT and failure to adhere to national guidelines have led to the evolution of drug resistance genes.

METHODS

We genotyped known drug resistance markers (Pfcrt, Pfmdr-1, Pfdhfr, Pfdhps, Pfk13 propeller) and their flanking microsatellites among Plasmodium falciparum isolates obtained between 2009 and 2016 in different geographical regions in Sudan. Data were then compared with published findings pre-ACT (1992-2003).

RESULTS

A high prevalence of Pfcrt76T, Pfmdr-1-86Y, Pfdhfr51I, Pfdhfr108N, Pfdhps37G was observed in all regions, while no Pfk13 mutations were detected. Compared with pre-ACT data, Pfcrt-76T and Pfmdr-1-86Y have decayed, while Pfdhfr-51I, Pfdhfr-108N and Pfdhps-437G strengthened. Haplotypes Pfcrt-CVIET, Pfmdr-1-NFSND/YFSND, Pfdhfr-ICNI and Pfdhps-SGKAA predominated in all sites. Microsatellites flanking drug resistance genes showed lower diversity than neutral ones, signifying high ACT pressure/selection.

CONCLUSIONS

Evaluation of P. falciparum drug resistance genes in Sudan matches the drug deployment pattern. Regular monitoring of these genes, coupled with clinical response, should be considered to combat the spread of ACT resistance.

摘要

背景

苏丹的疟疾防控工作严重依赖病例管理。2004年，卫生当局采用以青蒿素为基础的联合疗法（ACTs）治疗非复杂性疟疾。然而，最近的一些调查报道了ACT治疗失败以及普遍存在的不合理疟疾治疗做法。在此，我们研究ACT的广泛使用和未遵守国家指南是否导致了耐药基因的演变。

方法

我们对2009年至2016年期间在苏丹不同地理区域获得的恶性疟原虫分离株中的已知耐药标记（Pfcrt、Pfmdr-1、Pfdhfr、Pfdhps、Pfk13螺旋桨）及其侧翼微卫星进行基因分型。然后将数据与ACT应用前（1992 - 2003年）已发表的研究结果进行比较。

结果

在所有地区均观察到Pfcrt76T、Pfmdr-1-86Y、Pfdhfr51I、Pfdhfr108N、Pfdhps37G的高流行率，而未检测到Pfk13突变。与ACT应用前的数据相比，Pfcrt-76T和Pfmdr-1-86Y有所衰减，而Pfdhfr-51I、Pfdhfr-108N和Pfdhps-437G有所增强。单倍型Pfcrt-CVIET、Pfmdr-1-NFSND/YFSND、Pfdhfr-ICNI和Pfdhps-SGKAA在所有地点均占主导地位。耐药基因侧翼的微卫星显示出比中性微卫星更低的多样性，表明存在较高的ACT压力/选择。