Clinical and pharmacological determinants of the therapeutic response to dihydroartemisinin-piperaquine for drug-resistant malaria
Clinical and pharmacological determinants of the therapeutic response to dihydroartemisinin-piperaquine for drug-resistant malaria
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DOI：
10.1128/aac.00486-07
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发表时间：
2007-11-01
影响因子：
4.9
通讯作者：
Tjitra, E.
中科院分区：
文献类型：
--
作者：
Price, R. N.;Hasugian, A. R.;Tjitra, E.
双氢青蒿素哌喹（DHP）是治疗耐药性疟疾的一种重要的新疗法，尽管对该组合的药代动力学研究有限。在印度尼西亚巴布亚，我们评估了 DHP 对单纯性疟疾的治疗效果的决定因素。在第7天和第28天测量血浆哌喹浓度，并使用生存分析计算第42天寄生虫学失败的累积风险。在可评估人群的 598 名患者中，342 名患者感染了恶性疟原虫，83 名患者感染了间日疟原虫，173 名患者同时感染了两种疟原虫。恶性疟原虫未经调整的累积复发风险为 7.0%（95% 置信区间 [Cl]：4.6 至 9.4%），活体疟原虫为 8.9%（95% CI：6.0 至 12%）。校正再感染后，恶性疟原虫复发的风险为 1.1%（95% CI：0.1 至 2.1%）。寄生虫学失败的主要决定因素是血浆哌喹浓度。尽管儿童的总剂量（毫克/千克体重）比成人高 9%（P < 0.001），但 15 岁以下儿童中 38%（21/56）和成人中 22%（31/140）的浓度在第 7 天低于 30 ng/ml（P = 0.04）。哌喹水平低于 30 ng/ml 的患者更有可能出现恶性疟原虫复发（风险比 [HR] = 6.6 [95% CI：1.9 至 231；P = 0.003）或间日疟原虫复发（HR = 9.0 [95% CI：2.3 至 351；P = 0.001）。第 7 天哌喹的血浆浓度是 DHP 治疗反应的主要决定因素。儿童血浆哌喹浓度较低和失败率较高表明该年龄组可能需要调整剂量。
Dihydroartemisinin-piperaquine (DHP) is an important new treatment for drug-resistant malaria, although pharmacokinetic studies on the combination are limited. In Papua, Indonesia, we assessed determinants of the therapeutic efficacy of DHP for uncomplicated malaria. Plasma piperaquine concentrations were measured on day 7 and day 28, and the cumulative risk of parasitological failure at day 42 was calculated using survival analysis. Of the 598 patients in the evaluable population 342 had infections with Plasmodium falciparum, 83 with Plasmodium vivax, and 173 with a mixture of both species. The unadjusted cumulative risks of recurrence were 7.0% (95% confidence interval [Cl]: 4.6 to 9.4%) for P. falciparum and 8.9% (95% CI: 6.0 to 12%) for P. vivar. After correcting for reinfections the risk of recrudescence with P. falciparum was 1.1% (95% CI: 0.1 to 2.1%). The major determinant of parasitological failure was the plasma piperaquine concentration. A concentration below 30 ng/ml on day 7 was observed in 38% (21/56) of children less than 15 years old and 22% (31/140) of adults (P = 0.04), even though the overall dose (mg per kg of body weight) in children was 9% higher than that in adults (P < 0.001). Patients with piperaquine levels below 30 ng/ml were more likely to have a recurrence with P. falciparum (hazard ratio [HR] = 6.6 [95% Cl: 1.9 to 231; P = 0.003) or P. vivax (HR = 9.0 [95% CI: 2.3 to 351; P = 0.001). The plasma concentration of piperaquine on day 7 was the major determinant of the therapeutic response to DHP. Lower plasma piperaquine concentrations and higher failure rates in children suggest that dose revision may be warranted in this age group.