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Recovery and stable persistence of chloroquine sensitivity in Plasmodium falciparum parasites after its discontinued use in Northern Uganda.
Malaria Journal ( IF 3 ) Pub Date : 2020-02-18 , DOI: 10.1186/s12936-020-03157-0
Betty Balikagala 1 , Miki Sakurai-Yatsushiro 2 , Shin-Ichiro Tachibana 1 , Mie Ikeda 1 , Masato Yamauchi 1 , Osbert T Katuro 3 , Edward H Ntege 4 , Makoto Sekihara 1 , Naoyuki Fukuda 1 , Nobuyuki Takahashi 2 , Shouki Yatsushiro 5 , Toshiyuki Mori 1 , Makoto Hirai 1 , Walter Opio 6 , Paul S Obwoya 6 , Denis A Anywar 7 , Mary A Auma 6 , Nirianne M Q Palacpac 8 , Takafumi Tsuboi 4 , Emmanuel I Odongo-Aginya 7 , Eisaku Kimura 9 , Martin Ogwang 6 , Toshihiro Horii 8 , Toshihiro Mita 1
Affiliation  

Usage of chloroquine was discontinued from the treatment of Plasmodium falciparum infection in almost all endemic regions because of global spread of resistant parasites. Since the first report in Malawi, numerous epidemiological studies have demonstrated that the discontinuance led to re-emergence of chloroquine-susceptible P. falciparum, suggesting a possible role in future malaria control. However, most studies were cross-sectional, with few studies looking at the persistence of chloroquine recovery in long term. This study fills the gap by providing, for a period of at least 6 years, proof of persistent re-emergence/stable recovery of susceptible parasite populations using both molecular and phenotypic methods. Ex vivo drug-susceptibility assays to chloroquine (n = 319) and lumefantrine (n = 335) were performed from 2013 to 2018 in Gulu, Northern Uganda, where chloroquine had been removed from the official malaria treatment regimen since 2006. Genotyping of pfcrt and pfmdr1 was also performed. Chloroquine resistance (≥ 100 nM) was observed in only 3 (1.3%) samples. Average IC50 values for chloroquine were persistently low throughout the study period (17.4–24.9 nM). Parasites harbouring pfcrt K76 alleles showed significantly lower IC50s to chloroquine than the parasites harbouring K76T alleles (21.4 nM vs. 43.1 nM, p-value = 3.9 × 10−8). Prevalence of K76 alleles gradually increased from 71% in 2013 to 100% in 2018. This study found evidence of stable persistence of chloroquine susceptibility with the fixation of pfcrt K76 in Northern Uganda after discontinuation of chloroquine in the region. Accumulation of similar evidence in other endemic areas in Uganda could open channels for possible future re-use of chloroquine as an option for malaria treatment or prevention.

中文翻译:

在乌干达北部停止使用后,恶性疟原虫寄生虫中氯喹敏感性的恢复和稳定持续。

由于抗药性寄生虫在全球范围内的传播,几乎在所有地方性流行地区都不再使用氯喹治疗恶性疟原虫感染。自马拉维的第一份报告以来,大量的流行病学研究表明,停药导致易受氯喹感染的恶性疟原虫再次出现,表明其可能在未来的疟疾控制中发挥作用。但是,大多数研究都是横断面的,很少有研究关注长期氯喹回收的持续性。这项研究通过使用分子和表型方法提供至少6年的时间,证明易感寄生虫种群持续重新出现/稳定恢复的证据,填补了这一空白。从2013年至2018年在古鲁市开展了对氯喹(n = 319)和lumefantrine(n = 335)的离体药物敏感性试验。乌干达北部,自2006年以来已从正式的疟疾治疗方案中删除了氯喹。还对pfcrt和pfmdr1进行了基因分型。仅在3个(1.3%)样品中观察到氯喹抗性(≥100 nM)。在整个研究期间,氯喹的平均IC50值持续较低(17.4-24.9 nM)。携带pfcrt K76等位基因的寄生虫对氯喹的IC50值明显低于携带K76T等位基因的寄生虫(21.4 nM对43.1 nM,p值= 3.9×10-8)。K76等位基因的患病率从2013年的71%逐渐增加到2018年的100%。这项研究发现,在乌干达北部地区停用氯喹后,通过pfcrt K76固定,氯喹敏感性持续稳定存在。
更新日期:2020-02-18
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