Failure of miltefosine treatment for visceral leishmaniasis in children and men in South-East Asia.
Failure of miltefosine treatment for visceral leishmaniasis in children and men in South-East Asia.
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DOI：
10.1371/journal.pone.0100220
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Boelaert M
中科院分区：
文献类型：
--
作者：
Ostyn B;Hasker E;Dorlo TP;Rijal S;Sundar S;Dujardin JC;Boelaert M
在印度和尼泊尔随访12个月的米替膦治疗内脏利什曼病（VL）患者的高复发率。确定印度和尼泊尔近期接受标准剂量米替福新治疗的VL患者复发的流行病学和临床风险因素。在印度比哈尔邦Muzaffarpur区的3家初级卫生中心和1家参考中心以及尼泊尔东南部的2家地区医院和1家大学医院进行的前瞻性观察性研究; 2009年至2011年期间根据黑热病消除项目的现行治疗指南诊断为VL并接受米替福新治疗的所有知情同意患者的记录。我们比较了78例复发病例与775例无复发记录的患者的临床记录。男性患者的复发率是男性患者的2倍（IRR 2.14，95% CI 1.27-3.61），15岁以下年龄组的发生率是25岁以上年龄组的2 - 3倍（10 - 14岁：IRR 2.53; 95% CI 1.37-4.65; 2 - 9岁：IRR 3.19; 95% CI 1.77-5.77）。早期VL发作史或诊断时的特定临床特征（如症状持续时间或脾脏大小）不是复发的预测因素。年轻和男性与米替福新治疗后VL复发风险增加相关，表明复发机制主要与宿主相关，即免疫因素和/或药物暴露（药代动力学）。观察到的米替福新疗效降低可能是由于与早期临床试验相比，纳入了更年轻的患者，而不是由于寄生虫对米替福新的易感性降低。我们的研究结果强调了在儿童中进行适当的临床试验的重要性，包括药代动力学，以确定该年龄组新药的安全性，有效性，药物暴露和治疗反应。
High frequency of relapse in miltefosine-treated visceral leishmaniasis (VL) patients in India and Nepal followed up for twelve months. To identify epidemiological and clinical risk factors for relapse of VL in patients recently treated with standard dosing of miltefosine in India and Nepal. Prospective observational study in three Primary Health Centers and one reference center in Muzaffarpur district, Bihar, India; and two zonal hospitals and a university hospital in South-east Nepal; records of all consenting patients diagnosed with VL and treated with miltefosine according to the current treatment guidelines of the Kala azar elimination program between 2009 and 2011. We compared the clinical records of 78 cases of relapse with those of 775 patients who had no record of subsequent relapse. Relapse was 2 times more common amongst male patients (IRR 2.14, 95% CI 1.27–3.61), and 2 to 3 times more frequent in the age groups below 15 compared to the over 25 year olds (age 10 to 14: IRR 2.53; 95% CI 1.37–4.65 and Age 2 to 9: IRR 3.19; 95% CI 1.77–5.77). History of earlier VL episodes, or specific clinical features at time of diagnosis such as duration of symptoms or spleen size were no predictors of relapse. Young age and male gender were associated with increased risk of VL relapse after miltefosine, suggesting that the mechanism of relapse is mainly host-related i.e. immunological factors and/or drug exposure (pharmacokinetics). The observed decrease in efficacy of miltefosine may be explained by the inclusion of younger patients compared to the earlier clinical trials, rather than by a decreased susceptibility of the parasite to miltefosine. Our findings highlight the importance of proper clinical trials in children, including pharmacokinetics, to determine the safety, efficacy, drug exposure and therapeutic response of new drugs in this age group.
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