PDF(Pubmed)
Abstract：
BACKGROUND: Plasmodium falciparum is an apicomplexan parasite responsible for lethal cases of malaria. According to WHO recommendations, P falciparum cases are treated with artemisinin-based combination therapy including dihydroartemisinin-piperaquine. However, the emergence of resistant parasites against dihydroartemisinin-piperaquine was reported in southeast Asia in 2008 and, a few years later, suspected in South America.
METHODS: To characterise resistance emergence, a treatment efficacy study was performed on the reported patients infected with P falciparum and treated with dihydroartemisinin-piperaquine in French Guiana (n=6, 2016-18). Contemporary isolates collected in French Guiana were genotyped for P falciparum chloroquine resistance transporter (pfCRT; n=845) and pfpm2 and pfpm3 copy number (n=231), phenotyped using the in vitro piperaquine survival assay (n=86), and analysed through genomic studies (n=50). Additional samples from five Amazonian countries and one outside the region were genotyped (n=1440).
RESULTS: In field isolates, 40 (47%) of 86 (95% CI 35·9-57·1) were resistant to piperaquine in vitro; these phenotypes were more associated with pfCRTC350R (ie, Cys350Arg) and pfpm2 and pfpm3 amplifications (Dunn test, p<0·001). Those markers were also associated with dihydroartemisinin-piperaquine treatment failure (n=3 [50%] of 6). A high prevalence of piperaquine resistance markers was observed in Suriname in 19 (83%) of 35 isolates and in Guyana in 579 (73%) of 791 isolates. The pfCRTC350R mutation emerged before pfpm2 and pfpm3 amplification in a temporal sequence different from southeast Asia, and in the absence of artemisinin partial resistance, suggesting a geographically distinctive epistatic relationship between these genetic markers.
CONCLUSIONS: The high prevalence of piperaquine resistance markers in parasite populations of the Guianas, and the risk of associated therapeutic failures calls for caution on dihydroartemisinin-piperaquine use in the region. Furthermore, greater attention should be given to potential differences in genotype to phenotype mapping across genetically distinct parasite populations from different continents.
BACKGROUND: Pan American Health Organization and WHO, French Ministry for Research, European Commission, Santé publique France, Agence Nationale de la Recherche, Fundação de Amparo à Pesquisa do Estado do Amazonas, Ministry of Health of Brazil, Oswaldo Cruz Foundation, and National Institutes of Health.
UNASSIGNED: For the French and Portuguese translations of the abstract see Supplementary Materials section.
METHODS: To characterise resistance emergence, a treatment efficacy study was performed on the reported patients infected with P falciparum and treated with dihydroartemisinin-piperaquine in French Guiana (n=6, 2016-18). Contemporary isolates collected in French Guiana were genotyped for P falciparum chloroquine resistance transporter (pfCRT; n=845) and pfpm2 and pfpm3 copy number (n=231), phenotyped using the in vitro piperaquine survival assay (n=86), and analysed through genomic studies (n=50). Additional samples from five Amazonian countries and one outside the region were genotyped (n=1440).
RESULTS: In field isolates, 40 (47%) of 86 (95% CI 35·9-57·1) were resistant to piperaquine in vitro; these phenotypes were more associated with pfCRTC350R (ie, Cys350Arg) and pfpm2 and pfpm3 amplifications (Dunn test, p<0·001). Those markers were also associated with dihydroartemisinin-piperaquine treatment failure (n=3 [50%] of 6). A high prevalence of piperaquine resistance markers was observed in Suriname in 19 (83%) of 35 isolates and in Guyana in 579 (73%) of 791 isolates. The pfCRTC350R mutation emerged before pfpm2 and pfpm3 amplification in a temporal sequence different from southeast Asia, and in the absence of artemisinin partial resistance, suggesting a geographically distinctive epistatic relationship between these genetic markers.
CONCLUSIONS: The high prevalence of piperaquine resistance markers in parasite populations of the Guianas, and the risk of associated therapeutic failures calls for caution on dihydroartemisinin-piperaquine use in the region. Furthermore, greater attention should be given to potential differences in genotype to phenotype mapping across genetically distinct parasite populations from different continents.
BACKGROUND: Pan American Health Organization and WHO, French Ministry for Research, European Commission, Santé publique France, Agence Nationale de la Recherche, Fundação de Amparo à Pesquisa do Estado do Amazonas, Ministry of Health of Brazil, Oswaldo Cruz Foundation, and National Institutes of Health.
UNASSIGNED: For the French and Portuguese translations of the abstract see Supplementary Materials section.
摘要：
背景：恶性疟原虫是一种导致疟疾致死病例的顶复虫寄生虫。根据世卫组织的建议，恶性疟原虫病例采用基于青蒿素的联合治疗，包括双氢青蒿素-哌喹。然而,2008年在东南亚报道了对双氢青蒿素-哌喹的抗性寄生虫的出现，几年后,怀疑在南美。
方法：为了表征抗性出现，在法属圭亚那,对报告的感染恶性疟原虫并接受双氢青蒿素-哌喹治疗的患者进行了治疗疗效研究(n=6,2016-18).对在法属圭亚那收集的当代分离株进行了恶性疟原虫氯喹抗性转运蛋白（pfCRT；n=845）和pfpm2和pfpm3拷贝数（n=231）的基因分型，使用体外哌喹存活测定法(n=86)进行表型分析，并通过基因组研究进行分析(n=50)。对来自五个亚马逊国家和该地区以外的一个国家的其他样本进行了基因分型（n=1440）。
结果：在现场分离物中，86例（95％CI35·9-57·1）中有40例（47％）在体外对哌喹具有抗性；这些表型与pfCRTC350R更相关（即，Cys350Arg)和pfpm2和pfpm3扩增(邓恩试验，p<0·001)。这些标记也与双氢青蒿素-哌喹治疗失败有关(n=3[6的50%])。在苏里南的35个分离株中的19个（83％）和圭亚那的791个分离株中的579个（73％）中观察到哌喹抗性标记的高流行率。pfCRTC350R突变出现在pfpm2和pfpm3扩增之前，时间序列不同于东南亚。在没有青蒿素部分耐药性的情况下，表明这些遗传标记之间存在地理上独特的上位性关系。
结论：在圭亚那的寄生虫种群中，哌喹抗性标记的高患病率，相关治疗失败的风险要求该地区谨慎使用双氢青蒿素-哌喹。此外，在不同大陆遗传上不同的寄生虫种群中,应更多地注意基因型与表型图谱的潜在差异.
背景：泛美卫生组织和世界卫生组织，法国研究部,EuropeanCommission,SantépubliqueFrance,国家机构，亚马逊基金会，巴西卫生部,奥斯瓦尔多·克鲁兹基金会,和美国国立卫生研究院。
■有关摘要的法语和葡萄牙语翻译，请参见补充材料部分。
方法：为了表征抗性出现，在法属圭亚那,对报告的感染恶性疟原虫并接受双氢青蒿素-哌喹治疗的患者进行了治疗疗效研究(n=6,2016-18).对在法属圭亚那收集的当代分离株进行了恶性疟原虫氯喹抗性转运蛋白（pfCRT；n=845）和pfpm2和pfpm3拷贝数（n=231）的基因分型，使用体外哌喹存活测定法(n=86)进行表型分析，并通过基因组研究进行分析(n=50)。对来自五个亚马逊国家和该地区以外的一个国家的其他样本进行了基因分型（n=1440）。
结果：在现场分离物中，86例（95％CI35·9-57·1）中有40例（47％）在体外对哌喹具有抗性；这些表型与pfCRTC350R更相关（即，Cys350Arg)和pfpm2和pfpm3扩增(邓恩试验，p<0·001)。这些标记也与双氢青蒿素-哌喹治疗失败有关(n=3[6的50%])。在苏里南的35个分离株中的19个（83％）和圭亚那的791个分离株中的579个（73％）中观察到哌喹抗性标记的高流行率。pfCRTC350R突变出现在pfpm2和pfpm3扩增之前，时间序列不同于东南亚。在没有青蒿素部分耐药性的情况下，表明这些遗传标记之间存在地理上独特的上位性关系。
结论：在圭亚那的寄生虫种群中，哌喹抗性标记的高患病率，相关治疗失败的风险要求该地区谨慎使用双氢青蒿素-哌喹。此外，在不同大陆遗传上不同的寄生虫种群中,应更多地注意基因型与表型图谱的潜在差异.
背景：泛美卫生组织和世界卫生组织，法国研究部,EuropeanCommission,SantépubliqueFrance,国家机构，亚马逊基金会，巴西卫生部,奥斯瓦尔多·克鲁兹基金会,和美国国立卫生研究院。
■有关摘要的法语和葡萄牙语翻译，请参见补充材料部分。
