Department of Medical Parasitology and Infection Biology, University of Basel, Basel, Switzerland.
Lao Tropical and Public Health Institute, Vientiane, Laos.
Lancet Infect Dis. 2018 Jul;18(7):729-737. doi: 10.1016/S1473-3099(18)30220-2. Epub 2018 Apr 16.
Albendazole and mebendazole are commonly used to control hookworm, but have shortcomings in their efficacy profiles. We assessed whether triple drug therapy (TDT) with albendazole, pyrantel pamoate, and oxantel pamoate was more effective than the co-administration of two drugs for the treatment of hookworm infections.
A randomised, single-blind trial was done from Sept 27 until Nov 17, 2017, in Laos. Children (6-15 years) from six schools were invited to participate. Hookworm-positive children were randomly assigned (2:2:1:1) by a computer stratified list (block sizes of six and 12) to TDT with albendazole (400 mg), pyrantel pamoate (20 mg/kg), and oxantel pamoate (20 mg/kg); albendazole plus oxantel pamoate; pyrantel pamoate plus oxantel pamoate; or mebendazole (500 mg) combined with both pyrantel pamoate and oxantel pamoate (used as proof of concept to compare the two TDTs). Two stool samples were collected at baseline and follow-up (17-30 days after treatment) and analysed with the Kato-Katz method. The primary outcome was the proportion of hookworm egg-negative children at follow-up in all Kato-Katz slides (cure rate [CR]) in the TDT with albendazole, pyrantel pamoate, and oxantel pamoate group compared with the albendazole plus oxantel pamoate and pyrantel pamoate plus oxantel pamoate groups. Secondary outcomes were tolerability 3 h and 24 h after treatment, egg reduction rates (ERRs) against hookworm, and efficacy against concomitant soil-transmitted helminth infections. Participating children and field and laboratory technicians were masked to treatment allocation. All children with follow-up data were included in the primary analysis. This trial is registered with ClinicalTrials.gov, number NCT03278431.
1529 children were assessed for eligibility, of whom 533 provided complete baseline data and 414 provided complete outcome data. The CR was higher for the TDT albendazole, pyrantel pamoate, and oxantel pamoate (116 [84%] of 138) than with albendazole plus oxantel pamoate (73 [53%] of 138; odds ratio 4·7, 95% CI 2·7-8·3; p<0·0001) and pyrantel pamoate plus oxantel pamoate (36 [52%] of 69; 4·8, 2·5-9·3; p<0·0001). The geometric ERR of the TDT albendazole, pyrantel pamoate, and oxantel pamoate (99·9%) was higher than that for albendazole plus oxantel pamoate (99·0%; difference in ERR 0·9 percentage points, 95% CI 0·5-1·4), and pyrantel pamoate plus oxantel pamoate (99·2%; 0·7 percentage points, 0·3-1·3). Adverse events were reported by six (1%) children 3 h and none 24 h after treatment, without any difference across treatment groups.
TDT with albendazole, pyrantel pamoate, and oxantel pamoate could make a difference, in particular in the context of soil-transmitted helminth elimination. Pyrantel pamoate might be a useful alternative to prevent benzimidazole resistance; however, larger trials are needed to confirm this finding.
Swiss National Science Foundation.
阿苯达唑和甲苯达唑常用于控制钩虫，但在疗效方面存在缺陷。我们评估了用阿苯达唑、双羟萘酸噻嘧啶和奥苯达唑三联疗法（TDT）治疗钩虫感染是否比两种药物联合治疗更有效。
这项随机、单盲试验于 2017 年 9 月 27 日至 11 月 17 日在老挝进行。来自六所学校的儿童（6-15 岁）受邀参加。钩虫阳性儿童按计算机分层列表（6 个和 12 个块大小）随机分为两组（2:2:1:1）：TDT 用阿苯达唑（400mg）、双羟萘酸噻嘧啶（20mg/kg）和奥苯达唑（20mg/kg）；阿苯达唑加奥苯达唑；双羟萘酸噻嘧啶加奥苯达唑；或甲苯达唑（500mg）联合双羟萘酸噻嘧啶和奥苯达唑（用于证明概念，比较两种 TDT）。在基线和随访（治疗后 17-30 天）时采集两份粪便样本，并采用加藤厚涂片法进行分析。主要结局是阿苯达唑、双羟萘酸噻嘧啶和奥苯达唑 TDT 组与阿苯达唑加奥苯达唑和双羟萘酸噻嘧啶加奥苯达唑组相比，在所有加藤厚涂片上（治愈率[CR]）钩虫阴性儿童的比例。次要结局是治疗后 3 小时和 24 小时的耐受性、钩虫的虫卵减少率（ERR）和对同时存在的土壤传播性蠕虫感染的疗效。参与试验的儿童、现场和实验室技术人员对治疗分配进行了盲法处理。所有有随访数据的儿童均纳入主要分析。这项试验在 ClinicalTrials.gov 上注册，编号为 NCT03278431。
对 1529 名儿童进行了资格评估，其中 533 名提供了完整的基线数据，414 名提供了完整的结局数据。阿苯达唑、双羟萘酸噻嘧啶和奥苯达唑 TDT（138 例中的 116 例，84%）的 CR 高于阿苯达唑加奥苯达唑（138 例中的 73 例，53%；比值比 4.7，95%CI 2.7-8.3；p<0.0001）和双羟萘酸噻嘧啶加奥苯达唑（69 例中的 36 例，52%；4.8，2.5-9.3；p<0.0001）。阿苯达唑、双羟萘酸噻嘧啶和奥苯达唑 TDT（99.9%）的几何 ERR 高于阿苯达唑加奥苯达唑（99.0%；ERR 差异 0.9 个百分点，95%CI 0.5-1.4）和双羟萘酸噻嘧啶加奥苯达唑（99.2%；0.7 个百分点，0.3-1.3）。6 名（1%）儿童在治疗后 3 小时报告了不良反应，无 1 名儿童在 24 小时后报告了不良反应，各组之间没有差异。
用阿苯达唑、双羟萘酸噻嘧啶和奥苯达唑的 TDT 可能会有所不同，特别是在土壤传播性蠕虫消除的背景下。双羟萘酸噻嘧啶可能是预防苯并咪唑耐药的一种有用替代品；然而，还需要更大规模的试验来证实这一发现。
瑞士国家科学基金会。
