Rapid selection of dhfr mutant allele in Plasmodium falciparum isolates after the introduction of sulfadoxine/pyrimethamine in combination with 4-aminoquinolines in Papua New Guinea
Rapid selection of dhfr mutant allele in Plasmodium falciparum isolates after the introduction of sulfadoxine/pyrimethamine in combination with 4-aminoquinolines in Papua New Guinea
复制标题
DOI：
10.1016/j.meegid.2006.02.004
复制
发表时间：
2006-11-01
影响因子：
3.2
通讯作者：
Bjorkman, Anders
中科院分区：
文献类型：
--
作者：
Mita, Toshihiro;Kaneko, Akira;Bjorkman, Anders
为了克服巴布亚新几内亚4-氨基喹啉类药物疗效下降的问题，自2000年以来，磺胺嘧啶/乙胺嘧啶（SP）与4-氨基喹啉类药物联合作为恶性疟疾的一线治疗药物。为了评估这种变化如何影响SP耐药基因多态性，我们确定了等位基因频率的dhfr和dhps在113恶性疟原虫分离株从韦瓦克，东塞皮克的巴布亚新几内亚在2002年和2003年。在dhfr中，双突变体（bar VI下的ACN（RN））是主要等位基因，患病率为91%。我们发现，野生dhfr等位基因的患病率（7%）相比，在东塞皮克相邻地区称为Wosera地区（57%），在1990年至1993年的药物政策改变之前，报告显着下降。在2002年和2003年之间，该等位基因的患病率从15%下降到3%（P = 0.02）。两个不同的微卫星单倍型侧翼dhfr被发现在分离株与dhfr双突变，这表明选择预先存在的SP耐药寄生虫，而不是频繁发生的dhfr突变。在2003年的6个分离株（8%）中鉴定出dhfr/dhps四重突变（dhfr中第VI条下的ACN（RN）和dhps中第AA条下的S（GE））。这种基因型与体内对SP的抗性相关，此前在巴布亚新几内亚尚未报道。这些结果表明，尽管使用SP联合治疗，但对SP耐药的分离株仍被迅速选择，这可能是因为它们对4-氨基喹啉伴侣药物的高水平耐药性。(c)2006 Elsevier B. V.保留所有权利。
To overcome the declining efficacy of the 4-aminoquinolines in Papua New Guinea, sulfadoxine/pyrimethamine (SP) was combined with the 4-aminoquinolines as the first line treatment for falciparum malaria since 2000. To assess how this change had affected SP resistant gene polymorphisms, we determined allele frequencies of dhfr and dhps in 113 Plasmodium falciparum isolates from Wewak, East Sepik of Papua New Guinea in 2002 and 2003. In dhfr, double mutant (ACN (RN) under bar VI) was the predominant allele with a prevalence of 91%. We found a significant decrease of wild dhfr allele prevalence (7%) compared with that reported in the adjacent area of East Sepik called the Wosera region (57%), before the drug policy changed in 1990-1993. Between 2002 and 2003, the prevalence of this allele decreased from 15% to 3% (P = 0.02). Two distinct microsatellite haplotypes flanking dhfr were found in isolates with dhfr double mutant, suggesting the selection of preexisting SP resistant parasites rather than a frequent occurrence of dhfr mutations. The dhfr/dhps quartet mutations (ACN (RN) under bar VI in dhfr and S (GE) under bar AA in dhps) were identified in six of the isolates (8%) from 2003. This genotype, which is associated with in vivo resistance to SP, has not been reported before in Papua New Guinea. These findings suggest that isolates resistant to SP were rapidly selected despite the use of the SP combination therapy, probably because of their preexisting high level of resistance to the 4-aminoquinoline partner drug. (c) 2006 Elsevier B.V. All rights reserved.