Recovery and stable persistence of chloroquine sensitivity in Plasmodium falciparum parasites after its discontinued use in Northern Uganda
Recovery and stable persistence of chloroquine sensitivity in Plasmodium falciparum parasites after its discontinued use in Northern Uganda
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DOI：
10.1186/s12936-020-03157-0
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发表时间：
2020-02-18
期刊：
影响因子：
3
通讯作者：
Mita, Toshihiro
中科院分区：
文献类型：
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作者：
Balikagala, Betty;Sakurai-Yatsushiro, Miki;Mita, Toshihiro
背景：由于耐药寄生虫在全球传播，在几乎所有流行地区停止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，许多流行病学研究表明，停止使用氯喹导致对氯喹敏感的恶性疟原虫重新出现，这表明在未来的疟疾控制中可能发挥作用。然而，大多数研究都是横断面的，很少有研究着眼于氯喹长期恢复的持久性。本研究通过使用分子和表型方法提供至少6年的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。方法2013 - 2018年在乌干达北部Gulu地区对氯喹（n = 319）和氨苯曲明（n = 335）进行体外药敏试验，该地区自2006年起将氯喹从官方疟疾治疗方案中移除。同时对pfcrt和pfmdr1进行基因分型。结果氯喹耐药（>= 100 nM） 3例（1.3%）。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IC(50)s显著低于携带K76T等位基因的寄生虫（21.4 nM比43.1 nM， p值= 3.9 × 10(-8)）。K76等位基因的患病率从2013年的71%逐渐上升到2018年的100%。结论本研究发现，在乌干达北部地区停用氯喹后，pfcrt K76在该地区的固定存在稳定的氯喹敏感性。在乌干达其他流行地区积累类似的证据，可以为今后可能重新使用氯喹作为治疗或预防疟疾的一种选择开辟渠道。
Background 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. 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. Results 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 IC(50)s to chloroquine than the parasites harbouring K76T alleles (21.4 nM vs. 43.1 nM, p-value = 3.9 x 10(-8)). Prevalence of K76 alleles gradually increased from 71% in 2013 to 100% in 2018. Conclusion 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.