安哥拉恶性疟原虫药物耐药性标志物的历史趋势和新监测。
Historical trends and new surveillance of Plasmodium falciparum drug resistance markers in Angola.
机构信息
Department of Biology, Stanford University, Stanford, CA, 94305, USA.
Department of Pediatrics, Infectious Disease, Stanford University School of Medicine, Stanford, CA, 94305, USA.
出版信息
Malar J. 2021 Apr 7;20(1):175. doi: 10.1186/s12936-021-03713-2.
BACKGROUND
Plasmodium falciparum resistance to chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) has historically posed a major threat to malaria control throughout the world. The country of Angola officially replaced CQ with artemisinin-based combination therapy (ACT) as a first-line treatment in 2006, but malaria cases and deaths have recently been rising. Many classic resistance mutations are relevant for the efficacy of currently available drugs, making it important to continue monitoring their frequency in Angola.
METHODS
Plasmodium falciparum DNA was sampled from the blood of 50 hospital patients in Cabinda, Angola from October-December of 2018. Each infection was genotyped for 13 alleles in the genes crt, mdr1, dhps, dhfr, and kelch13, which are collectively involved in resistance to six common anti-malarials. To compare frequency patterns over time, P. falciparum genotype data were also collated from studies published from across Angola in the last two decades.
RESULTS
The two most important alleles for CQ resistance, crt 76T and mdr1 86Y, were found at respective frequencies of 71.4% and 6.5%. Historical data suggest that mdr1 N86 has been steadily replacing 86Y throughout Angola in the last decade, while the frequency of crt 76T has been more variable across studies. Over a third of new samples from Cabinda were 'quintuple mutants' for SP resistance in dhfr/dhps, with a sixth mutation at dhps A581G present at 9.6% frequency. The markers dhfr 51I, dhfr 108N, and dhps 437G have been nearly fixed in Angola since the early 2000s, whereas dhfr 59R may have risen to high frequency more recently. Finally, no non-synonymous polymorphisms were detected in kelch13, which is involved in artemisinin resistance in Southeast Asia.
CONCLUSIONS
Genetic markers of P. falciparum resistance to CQ are likely declining in frequency in Angola, consistent with the official discontinuation of CQ in 2006. The high frequency of multiple genetic markers of SP resistance is consistent with the continued public and private use of SP. In the future, more complete haplotype data from mdr1, dhfr, and dhps will be critical for understanding the changing efficacy of multiple anti-malarial drugs. These data can be used to support effective drug policy decisions in Angola.
背景
历史上，恶性疟原虫对氯喹（CQ）和磺胺多辛-乙胺嘧啶（SP）的耐药性对全球疟疾控制构成了重大威胁。安哥拉于 2006 年正式将青蒿素为基础的联合疗法（ACT）作为一线治疗药物取代 CQ，但最近疟疾病例和死亡人数一直在上升。许多经典的耐药突变与目前可用药物的疗效相关，因此继续监测安哥拉这些突变的频率非常重要。
方法
2018 年 10 月至 12 月，从安哥拉卡宾达的 50 名住院患者的血液中采集恶性疟原虫 DNA。对每个感染的 crt、mdr1、dhps、dhfr 和 kelch13 基因中的 13 个等位基因进行基因分型，这些基因共同参与对六种常见抗疟药物的耐药性。为了比较随时间变化的频率模式，还整理了过去二十年在安哥拉各地发表的研究中恶性疟原虫基因型数据。
结果
发现对 CQ 耐药性最重要的两个等位基因，crt76T 和 mdr186Y，分别出现频率为 71.4%和 6.5%。历史数据表明，mdr1N86 在过去十年中一直在安哥拉取代 86Y，而 crt76T 的频率在不同研究中则更为多变。卡宾达的三分之一以上新样本对 SP 耐药性的 dhfr/dhps 呈“五重突变”，dhpsA581G 第六个突变的出现频率为 9.6%。自 21 世纪初以来，dhfr51I、dhfr108N 和 dhps437G 在安哥拉几乎已固定，而 dhfr59R 最近可能频率升高。最后，kelch13 未检测到非同义多态性，kelch13 参与了东南亚的青蒿素耐药性。
结论
恶性疟原虫对 CQ 耐药性的遗传标记在安哥拉的频率可能正在下降，这与 2006 年 CQ 的正式停用一致。SP 耐药性的多个遗传标记的高频率与 SP 的持续公共和私人使用一致。在未来，来自 mdr1、dhfr 和 dhps 的更完整的单倍型数据对于了解多种抗疟药物的疗效变化至关重要。这些数据可用于支持安哥拉有效的药物政策决策。
Zotero 插件