Uhlemann Anne-Catrin, McGready Rose, Ashley Elizabeth A, Brockman Alan, Singhasivanon Pratap, Krishna Sanjeev, White Nicholas J, Nosten Francois, Price Ric N
Centre for Infection, Division of Cellular and Molecular Medicine, St. George's, University of London, London, United Kingdom.
J Infect Dis. 2007 Jan 1;195(1):134-41. doi: 10.1086/509809. Epub 2006 Nov 21.
Increased pfmdr1 copy number is associated with reduced susceptibility to structurally unrelated antimalarial drugs. We assessed how administration of different antimalarial drugs altered pfmdr1 polymorphism in parasites from patients who experienced treatment failure.
In studies conducted on the northwestern border of Thailand, amplifications and single-nucleotide polymorphisms in pfmdr1 were compared before and after antimalarial drug treatment.
Intrahost changes in pfmdr1 copy number were observed in 20% (26/132) of patients with recurrent infections. Among infections that recrudesced after mefloquine-containing regimens, increases in pfmdr1 copy number occurred in 68% (95% confidence interval [CI], 46%-85%), and decreases occurred in 2% (95% CI, 0.4%-11%) of isolates; corresponding proportions after artemether-lumefantrine were 25% (2/8) and 11% (2/19); after quinine, 50% (1/2) and 40% (4/10); and after artemisinins alone, 0% (0/10) and 19% (3/16) of isolates (overall P<.001).
Intrahost selection based on pfmdr1 copy number occurs frequently in parasite populations within individual patients. Amplification confers multidrug resistance but probably imposes a significant fitness cost to the parasites.
pfmdr1基因拷贝数增加与对结构不相关抗疟药物的敏感性降低有关。我们评估了不同抗疟药物的使用如何改变治疗失败患者体内疟原虫的pfmdr1多态性。
在泰国西北边境进行的研究中，比较了抗疟药物治疗前后pfmdr1基因的扩增情况和单核苷酸多态性。
在复发感染的患者中，20%（26/132）观察到宿主内pfmdr1基因拷贝数的变化。在含甲氟喹治疗方案后复发的感染中，68%（95%置信区间[CI]，46%-85%）的分离株pfmdr1基因拷贝数增加，2%（95%CI，0.4%-11%）的分离株减少；蒿甲醚-本芴醇治疗后相应比例分别为25%（2/8）和11%（2/19）；奎宁治疗后分别为50%（1/2）和40%（4/10）；单独使用青蒿素治疗后分别为0%（0/10）和19%（3/16）的分离株（总体P<0.001）。
基于pfmdr1基因拷贝数的宿主内选择在个体患者体内的疟原虫群体中频繁发生。基因扩增赋予多药耐药性，但可能给疟原虫带来显著的适合度代价。
