Tumwebaze Patrick, Conrad Melissa D, Walakira Andrew, LeClair Norbert, Byaruhanga Oswald, Nakazibwe Christine, Kozak Benjamin, Bloome Jessica, Okiring Jaffer, Kakuru Abel, Bigira Victor, Kapisi James, Legac Jennifer, Gut Jiri, Cooper Roland A, Kamya Moses R, Havlir Diane V, Dorsey Grant, Greenhouse Bryan, Nsobya Samuel L, Rosenthal Philip J
Infectious Diseases Research Collaboration, Kampala, Uganda.
Department of Medicine, University of California, San Francisco, California, USA.
Antimicrob Agents Chemother. 2015;59(6):3018-30. doi: 10.1128/AAC.05141-14. Epub 2015 Mar 9.
Changing treatment practices may be selecting for changes in the drug sensitivity of malaria parasites. We characterized ex vivo drug sensitivity and parasite polymorphisms associated with sensitivity in 459 Plasmodium falciparum samples obtained from subjects enrolled in two clinical trials in Tororo, Uganda, from 2010 to 2013. Sensitivities to chloroquine and monodesethylamodiaquine varied widely; sensitivities to quinine, dihydroartemisinin, lumefantrine, and piperaquine were generally good. Associations between ex vivo drug sensitivity and parasite polymorphisms included decreased chloroquine and monodesethylamodiaquine sensitivity and increased lumefantrine and piperaquine sensitivity with pfcrt 76T, as well as increased lumefantrine sensitivity with pfmdr1 86Y, Y184, and 1246Y. Over time, ex vivo sensitivity decreased for lumefantrine and piperaquine and increased for chloroquine, the prevalences of pfcrt K76 and pfmdr1 N86 and D1246 increased, and the prevalences of pfdhfr and pfdhps polymorphisms associated with antifolate resistance were unchanged. In recurrent infections, recent prior treatment with artemether-lumefantrine was associated with decreased ex vivo lumefantrine sensitivity and increased prevalence of pfcrt K76 and pfmdr1 N86, 184F, and D1246. In children assigned chemoprevention with monthly dihydroartemisinin-piperaquine with documented circulating piperaquine, breakthrough infections had increased the prevalence of pfmdr1 86Y and 1246Y compared to untreated controls. The noted impacts of therapy and chemoprevention on parasite polymorphisms remained significant in multivariate analysis correcting for calendar time. Overall, changes in parasite sensitivity were consistent with altered selective pressures due to changing treatment practices in Uganda. These changes may threaten the antimalarial treatment and preventive efficacies of artemether-lumefantrine and dihydroartemisinin-piperaquine, respectively.
治疗方法的改变可能会促使疟原虫的药物敏感性发生变化。我们对2010年至2013年在乌干达托罗罗的两项临床试验中招募的受试者所提供的459份恶性疟原虫样本的体外药物敏感性以及与敏感性相关的寄生虫多态性进行了特征分析。对氯喹和单去乙基氨喹的敏感性差异很大；对奎宁、双氢青蒿素、本芴醇和哌喹的敏感性总体良好。体外药物敏感性与寄生虫多态性之间的关联包括：携带pfcrt 76T时，氯喹和单去乙基氨喹敏感性降低，本芴醇和哌喹敏感性增加；携带pfmdr1 86Y、Y184和1246Y时，本芴醇敏感性增加。随着时间的推移，本芴醇和哌喹的体外敏感性降低，氯喹的体外敏感性增加，pfcrt K76以及pfmdr1 N86和D1246的流行率增加，而与抗叶酸耐药性相关的pfdhfr和pfdhps多态性的流行率未变。在复发性感染中，近期接受蒿甲醚-本芴醇治疗与体外本芴醇敏感性降低以及pfcrt K76和pfmdr1 N86、184F和D1246流行率增加有关。在被指定接受每月一次双氢青蒿素-哌喹化学预防且有记录显示哌喹在体内循环的儿童中，与未治疗的对照组相比，突破性感染使pfmdr1 86Y和1246Y的流行率增加。在对日历时间进行校正的多变量分析中，所指出的治疗和化学预防对寄生虫多态性的影响仍然显著。总体而言，寄生虫敏感性的变化与乌干达治疗方法改变导致的选择压力变化一致。这些变化可能分别威胁到蒿甲醚-本芴醇和双氢青蒿素-哌喹的抗疟治疗和预防效果。
