Pfmdr1 copy number and arteminisin derivatives combination therapy failure in falciparum malaria in Cambodia.
Pfmdr1 copy number and arteminisin derivatives combination therapy failure in falciparum malaria in Cambodia.
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DOI：
10.1186/1475-2875-8-11
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发表时间：
2009-01-12
期刊：
影响因子：
3
通讯作者：
Ariey F
中科院分区：
文献类型：
--
作者：
Lim P;Alker AP;Khim N;Shah NK;Incardona S;Doung S;Yi P;Bouth DM;Bouchier C;Puijalon OM;Meshnick SR;Wongsrichanalai C;Fandeur T;Le Bras J;Ringwald P;Ariey F
2000年，柬埔寨将青蒿琥酯和甲氟喹联合作为治疗恶性疟原虫疟疾的国家一线药物。然而，最近在泰柬边境进行的临床试验表明，青蒿琥酯-甲氟喹和蒿甲醚-氨苯曲明的疗效都在下降。由于pfmdr1调节对甲氟喹和青蒿素衍生物的敏感性，本研究的目的是评估pfmdr1拷贝数、对单个药物的体外敏感性和联合治疗失败之间的联系。在柬埔寨西北部的两项体内疗效研究中，收集了恶性疟原虫感染患者的血液样本：2002年和2003年，在Sampovloun， 135名患者接受了蒿甲醚-甲氟曲明（AL组）治疗，2003年和2004年，在Sampovloun和Veal Veng， 140名患者接受了青蒿琥酯-甲氟喹（AM组）治疗。入组时，检测体外IC50，并通过实时PCR对菌株进行pfmdr1拷贝数的基因分型。分析了AM组115株和AL组109株的pfmdr1拷贝数。pfmdr1拷贝数增加的寄生虫对甲氟喹、氨芳汀和青蒿琥酯的体外敏感性显著降低。pfmdr1多态性与体外易感性之间没有关联。在接受AM治疗的患者中，临床和寄生虫学反应充分的患者的平均pfmdr1拷贝数低于治疗晚期失败的患者（n = 112, p < 0.001）。这在AL治疗的患者中没有观察到（n = 96, p = 0.364）。pfmdr1基因存在3个或更多拷贝与甲氟喹治疗患者的复发相关（风险比(HR) = 7.80 [95%CI: 2.09-29.10], N = 115）， p = 0.002)，但与蒿甲醚-甲氟喹治疗患者的复发无关（HR = 1.03 [95%CI: 0.24-4.44], N = 109, p = 0.969）。本研究表明，pfmdr1拷贝数是泰柬边境地区恶性疟疾AM治疗失败的分子标志物。然而，尽管pfmdr1拷贝数与氟苯曲明的IC50增加有关，但与该地区AL治疗失败无关，这表明在柬埔寨AL治疗失败中涉及其他分子机制。
The combination of artesunate and mefloquine was introduced as the national first-line treatment for Plasmodium falciparum malaria in Cambodia in 2000. However, recent clinical trials performed at the Thai-Cambodian border have pointed to the declining efficacy of both artesunate-mefloquine and artemether-lumefantrine. Since pfmdr1 modulates susceptibility to mefloquine and artemisinin derivatives, the aim of this study was to assess the link between pfmdr1 copy number, in vitro susceptibility to individual drugs and treatment failure to combination therapy. Blood samples were collected from P. falciparum-infected patients enrolled in two in vivo efficacy studies in north-western Cambodia: 135 patients were treated with artemether-lumefantrine (AL group) in Sampovloun in 2002 and 2003, and 140 patients with artesunate-mefloquine (AM group) in Sampovloun and Veal Veng in 2003 and 2004. At enrollment, the in vitro IC50 was tested and the strains were genotyped for pfmdr1 copy number by real-time PCR. The pfmdr1 copy number was analysed for 115 isolates in the AM group, and for 109 isolates in the AL group. Parasites with increased pfmdr1 copy number had significantly reduced in vitro susceptibility to mefloquine, lumefantrine and artesunate. There was no association between pfmdr1 polymorphisms and in vitro susceptibilities. In the patients treated with AM, the mean pfmdr1copy number was lower in subjects with adequate clinical and parasitological response compared to those who experienced late treatment failure (n = 112, p < 0.001). This was not observed in the patients treated with AL (n = 96, p = 0.364). The presence of three or more copies of pfmdr1 were associated with recrudescence in artesunate-mefloquine treated patients (hazard ratio (HR) = 7.80 [95%CI: 2.09–29.10], N = 115), p = 0.002) but not with recrudescence in artemether-lumefantrine treated patients (HR = 1.03 [95%CI: 0.24–4.44], N = 109, p = 0.969). This study shows that pfmdr1 copy number is a molecular marker of AM treatment failure in falciparum malaria on the Thai-Cambodian border. However, while it is associated with increased IC50 for lumefantrine, pfmdr1 copy number is not associated with AL treatment failure in the area, suggesting involvement of other molecular mechanisms in AL treatment failures in Cambodia.
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影响因子：
6.4
作者：
Uhlemann, Anne-Catrin;McGready, Rose;Price, Ric N.
通讯作者：
Price, Ric N.
DOI：
10.4269/ajtmh.1963.12.840
发表时间：
1963-01-01
影响因子：
3.3
作者：
EYLES, DE;HOO, CC;SANDOSHAM, AA
通讯作者：
SANDOSHAM, AA
影响因子：
4.9
作者：
Price, RN;Cassar, C;Krishna, S
通讯作者：
Krishna, S
DOI：
10.1016/s0035-9203(99)90120-7
发表时间：
1999-07-01
影响因子：
2.2
作者：
Snounou, G;Zhu, XP;Viriyakosol, S
通讯作者：
Viriyakosol, S
DOI：
10.4269/ajtmh.2007.76.641
发表时间：
2007-04-01
影响因子：
3.3
作者：
Alker, Alisa P.;Lim, Pharath;Meshnick, Steven R.
通讯作者：
Meshnick, Steven R.