Molecular markers of in vivo Plasmodium vivax resistance to amodiaquine plus sulfadoxine-pyrimethamine:: Mutations in pvdhfr and pvmdr1
Molecular markers of in vivo Plasmodium vivax resistance to amodiaquine plus sulfadoxine-pyrimethamine:: Mutations in pvdhfr and pvmdr1
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DOI：
10.1086/589882
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发表时间：
2008-08-01
影响因子：
6.4
通讯作者：
Genton, Blaise
中科院分区：
文献类型：
--
作者：
Marfurt, Jutta;de Monbrison, Frederique;Genton, Blaise
背景资料。间日疟原虫对磺胺类药物抗性的分子标记已有报道。然而，关于参与4-氨基喹啉类药物耐药性产生的分子相关因素及其与体内治疗反应的相关性的数据很少。在巴布亚新几内亚(PNG)接受阿莫地喹(AQ)联合SP治疗的94例患者中，我们检测了pvdhfr(F57L/I、S58R、T61M、S117T/N和I173F/L)和pvmdr1(Y976F和F1076L)突变。然后我们调查了寄生虫基因和治疗反应之间的关系。治疗失败率达13%。Pvdhfr F57L、S58R、T61M、S117T/N和pvmdr1 Y976F的多态频率分别为60%、67%、20%、40%和39%。单个突变pvdhfr 57与Tf的相关性最强(优势比[OR]，9.04；P=0.01)。四重突变pvdhfr 57L+58R+61M+117T和pvmdr1突变976F的联合存在是预测TF的最佳因素(OR，8.56；P=0.01)。不同部位转铁率的差异反映在各自寄生虫的遗传耐药谱上。本研究在pvmdr1中发现了一个新的分子标记，它与体内对AQ+SP的反应有关。我们建议在使用这些药物的国家监测间日疟原虫对AQ+SP的耐药性的适当标记集。
Background. Molecular markers for sulfadoxine-pyrimethamine (SP) resistance in Plasmodium vivax have been reported. However, data on the molecular correlates involved in the development of resistance to 4-aminoquinolines and their association with the in vivo treatment response are scarce.Methods. We assessed pvdhfr (F57L/I, S58R, T61M, S117T/N, and I173F/L) and pvmdr1 (Y976F and F1076L) mutations in 94 patients who received amodiaquine (AQ) plus SP in Papua New Guinea (PNG). We then investigated the association between parasite genotype and treatment response.Results. The treatment failure (TF) rate reached 13%. Polymorphisms in pvdhfr F57L, S58R, T61M, and S117T/N and in pvmdr1 Y976F were detected in 60%, 67%, 20%, 40%, and 39% of the samples, respectively. The single mutant pvdhfr 57 showed the strongest association with TF (odds ratio [OR], 9.04; P = .01). The combined presence of the quadruple mutant pvdhfr 57L + 58R + 61M + 117T and pvmdr1 mutation 976F was the best predictor of TF (OR, 8.56; P = .01). The difference in TF rates between sites was reflected in the genetic drug-resistance profile of the respective parasites.Conclusions. The present study identified a new molecular marker in pvmdr1 that is associated with the in vivo response to AQ + SP. We suggest suitable marker sets with which to monitor P. vivax resistance against AQ + SP in countries where these drugs are used.