Balikagala Betty, Mita Toshihiro, Ikeda Mie, Sakurai Miki, Yatsushiro Shouki, Takahashi Nobuyuki, Tachibana Shin-Ichiro, Auma Mary, Ntege Edward H, Ito Daisuke, Takashima Eizo, Palacpac Nirianne Marie Q, Egwang Thomas G, Onen Joseph Okello, Kataoka Masatoshi, Kimura Eisaku, Horii Toshihiro, Tsuboi Takafumi
Division of Malaria Research, Proteo-Science Center, Ehime University, 3 Bunkyo-cho, Matsuyama, Ehime, 790-8577, Japan.
Department of Molecular and Cellular Parasitology, School of Medicine, Juntendo University, Tokyo, 113-8421, Japan.
Malar J. 2017 Jan 9;16(1):23. doi: 10.1186/s12936-016-1663-1.
Individual drug treatment may select resistant parasites in the human body, a process termed in vivo selection. Some single nucleotide polymorphisms in Plasmodium falciparum chloroquine-resistance transporter (pfcrt) and multidrug resistance gene 1 (pfmdr1) genes have been reportedly selected after artemether-lumefantrine treatment. However, there is a paucity of data regarding in vivo selection of P. falciparum Kelch propeller domain (pfkelch13) polymorphisms, responsible for artemisinin-resistance in Asia, and six putative background mutations for artemisinin resistance; D193Y in ferredoxin, T484I in multiple resistance protein 2, V127M in apicoplast ribosomal protein S10, I356T in pfcrt, V1157L in protein phosphatase and C1484F in phosphoinositide-binding protein.
Artemether-lumefantrine efficacy study with a follow-up period of 28 days was conducted in northern Uganda in 2014. The above-mentioned genotypes were comparatively analysed before drug administration and on days; 3, 7, and 28 days after treatment.
In 61 individuals with successful follow-up, artemether-lumefantrine treatment regimen was very effective with PCR adjusted efficacy of 95.2%. Among 146 isolates obtained before treatment, wild-type alleles were observed in 98.6% of isolates in pfkelch13 and in all isolates in the six putative background genes except I356T in pfcrt, which had 2.4% of isolates as mixed infections. In vivo selection study revealed that all isolates detected in the follow-up period harboured wild type alleles in pfkelch13 and the six background genes.
Mutations in pfkelch13 and the six background genes may not play an important role in the in vivo selection after artemether-lumefantrine treatment in Uganda. Different mechanisms might rather be associated with the existence of parasites after treatment.
个体药物治疗可能会在人体内选择出耐药寄生虫，这一过程称为体内选择。据报道，在蒿甲醚-本芴醇治疗后，恶性疟原虫氯喹抗性转运蛋白（pfcrt）和多药耐药基因1（pfmdr1）基因中的一些单核苷酸多态性被选择出来。然而，关于亚洲青蒿素抗性相关的恶性疟原虫 Kelch 螺旋桨结构域（pfkelch13）多态性以及六种假定的青蒿素抗性背景突变（铁氧化还原蛋白中的 D193Y、多重耐药蛋白2中的 T484I、质体核糖体蛋白 S10中的 V127M、pfcrt中的 I356T、蛋白磷酸酶中的 V1157L 和磷酸肌醇结合蛋白中的 C1484F）的体内选择数据较少。
2014年在乌干达北部进行了为期28天随访的蒿甲醚-本芴醇疗效研究。在给药前以及治疗后第3、7和28天对上述基因型进行了比较分析。
在61例成功随访的个体中，蒿甲醚-本芴醇治疗方案非常有效，PCR校正后的疗效为95.2%。在治疗前获得的146株分离株中，pfkelch13基因中98.6%的分离株以及六个假定背景基因中的所有分离株（除pfcrt中的I356T外，该基因有2.4%的分离株为混合感染）观察到野生型等位基因。体内选择研究表明，随访期间检测到的所有分离株在pfkelch13和六个背景基因中均携带野生型等位基因。
在乌干达，pfkelch13和六个背景基因中的突变可能在蒿甲醚-本芴醇治疗后的体内选择中不起重要作用。治疗后寄生虫的存在可能与不同的机制有关。
