Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia; WorldWide Antimalarial Resistance Network, Asia-Pacific Regional Centre, Melbourne, VIC, Australia; General and Subspecialty Medicine, Grampians Health Ballarat, Ballarat, VIC, Australia.
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
Lancet Child Adolesc Health. 2024 Nov;8(11):798-808. doi: 10.1016/S2352-4642(24)00210-4. Epub 2024 Sep 24.
Primaquine, the only widely available treatment to prevent relapsing Plasmodium vivax malaria, is produced as 15 mg tablets, and new paediatric formulations are being developed. To inform the optimal primaquine dosing regimen for children, we aimed to determine the efficacy and safety of different primaquine dose strategies in children younger than 15 years.
We undertook a systematic review (Jan 1, 2000-July 26, 2024) for P vivax efficacy studies with at least one treatment group that was administered primaquine over multiple days, that enrolled children younger than 15 years, that followed up patients for at least 28 days, and that had data available for inclusion by June 30, 2022. Patients were excluded if they were aged 15 years or older, presented with severe malaria, received adjunctive antimalarials within 14 days of diagnosis, commenced primaquine more than 7 days after starting schizontocidal treatment, had a protocol violation in the original study, or were missing data on age, sex, or primaquine dose. Available individual patient data were collated and standardised. To evaluate efficacy, the risk of recurrent P vivax parasitaemia between days 7 and 180 was assessed by time-to-event analysis for different total mg/kg primaquine doses (low total dose of ∼3·5 mg/kg and high total dose of ∼7 mg/kg). To evaluate tolerability and safety, the following were assessed by daily mg/kg primaquine dose (low daily dose of ∼0·25 mg/kg, intermediate daily dose of ∼0·5 mg/kg, and high daily dose of ∼1 mg/kg): gastrointestinal symptoms (vomiting, anorexia, or diarrhoea) on days 5-7, haemoglobin decrease of at least 25% to less than 7g/dL (severe haemolysis), absolute change in haemoglobin from day 0 to days 2-3 or days 5-7, and any serious adverse events within 28 days. This study is registered with PROSPERO, CRD42021278085.
In total, 3514 children from 27 studies and 15 countries were included. The cumulative incidence of recurrence by day 180 was 51·4% (95% CI 47·0-55·9) following treatment without primaquine, 16·0% (12·4-20·3) following a low total dose of primaquine, and 10·2% (8·4-12·3) following a high total dose of primaquine. The hazard of recurrent P vivax parasitaemia in children younger than 15 years was reduced following primaquine at low total doses (adjusted hazard ratio [HR] 0·17, 95% CI 0·11-0·25) and high total doses (0·09, 0·07-0·12), compared with no primaquine. In 525 children younger than 5 years, the relative rates of recurrence were also reduced, with an adjusted HR of 0·33 (95% CI 0·18-0·59) for a low total dose and 0·13 (0·08-0·21) for a high total dose of primaquine compared with no primaquine. The rate of recurrence following a high total dose was reduced compared with a low dose in children younger than 15 years (adjusted HR 0·54, 95% CI 0·35-0·85) and children younger than 5 years (0·41, 0·21-0·78). Compared with no primaquine, children treated with any dose of primaquine had a greater risk of gastrointestinal symptoms on days 5-7 after adjustment for confounders, with adjusted risks of 3·9% (95% CI 0-8·6) in children not treated with primaquine, 9·2% (0-18·7) with a low daily dose of primaquine, 6·8% (1·7-12·0) with an intermediate daily dose of primaquine, and 9·6% (4·8-14·3) with a high daily dose of primaquine. In children with 30% or higher glucose-6-phosphate dehydrogenase (G6PD) activity, there were few episodes of severe haemolysis following no primaquine (0·4%, 95% CI 0·1-1·5), a low daily dose (0·0%, 0·0-1·6), an intermediate daily dose (0·5%, 0·1-1·4), or a high daily dose (0·7%, 0·2-1·9). Of 15 possibly drug-related serious adverse events in children, two occurred following a low, four following an intermediate, and nine following a high daily dose of primaquine.
A high total dose of primaquine was highly efficacious in reducing recurrent P vivax parasitaemia in children compared with a low dose, particularly in children younger than 5 years. In children treated with high and intermediate daily primaquine doses compared with low daily doses, there was no increase in gastrointestinal symptoms or haemolysis (in children with 30% or higher G6PD activity), but there were more serious adverse events.
Medicines for Malaria Venture, Bill & Melinda Gates Foundation, and Australian National Health and Medical Research Council.
目前唯一广泛应用于预防间日疟复发的药物是 15 毫克片剂的伯氨喹，而新的儿科制剂正在研发中。为了确定儿童使用伯氨喹的最佳剂量方案，我们旨在确定不同剂量的伯氨喹在年龄小于 15 岁的儿童中的疗效和安全性。
我们进行了一项系统评价（2000 年 1 月 1 日至 2024 年 7 月 26 日），包括至少有一个治疗组接受了多天的伯氨喹治疗、纳入了年龄小于 15 岁的儿童、随访时间至少 28 天、并在 2022 年 6 月 30 日之前获得了可纳入的数据的间日疟疗效研究。如果患者年龄为 15 岁或以上、患有严重疟疾、在诊断后 14 天内接受了辅助抗疟药物、在开始裂殖体治疗后超过 7 天开始使用伯氨喹、在原始研究中存在方案违规或缺少年龄、性别或伯氨喹剂量的相关数据，则将其排除在外。对可用的个体患者数据进行了整理和标准化。为了评估疗效，我们通过时间至事件分析评估了不同总 mg/kg 伯氨喹剂量（低总剂量约 3.5 mg/kg 和高总剂量约 7 mg/kg）之间第 7 至 180 天的复发性间日疟寄生虫血症的风险。为了评估耐受性和安全性，我们评估了每日 mg/kg 伯氨喹剂量（低日剂量约 0.25 mg/kg、中日剂量约 0.5 mg/kg 和高日剂量约 1 mg/kg）的以下方面：第 5-7 天的胃肠道症状（呕吐、厌食或腹泻）、血红蛋白下降至少 25%至低于 7g/dL（严重溶血）、第 0 天至第 2-3 天或第 5-7 天的血红蛋白绝对变化，以及 28 天内的任何严重不良事件。本研究在 PROSPERO 注册，注册号为 CRD42021278085。
共有来自 15 个国家的 27 项研究的 3514 名儿童被纳入研究。未使用伯氨喹治疗的患者中，180 天的累积复发率为 51.4%（95%CI，47.0-55.9），低总剂量伯氨喹治疗组为 16.0%（12.4-20.3），高总剂量伯氨喹治疗组为 10.2%（8.4-12.3）。与未使用伯氨喹相比，年龄小于 15 岁的儿童使用低总剂量（调整后的危害比[HR]，0.17；95%CI，0.11-0.25）和高总剂量（0.09；0.07-0.12）的伯氨喹后，间日疟寄生虫血症的发生风险降低。在 525 名年龄小于 5 岁的儿童中，低总剂量和高总剂量的复发相对率也有所降低，调整后的 HR 分别为 0.33（95%CI，0.18-0.59）和 0.13（0.08-0.21）。与低总剂量相比，年龄小于 15 岁（调整后的 HR，0.54；95%CI，0.35-0.85）和年龄小于 5 岁（0.41；0.21-0.78）的儿童使用高总剂量的伯氨喹后，复发风险降低。与未使用伯氨喹相比，使用任何剂量伯氨喹的儿童在调整混杂因素后，第 5-7 天的胃肠道症状风险更高，未使用伯氨喹的儿童的调整风险为 3.9%（95%CI，0-8.6），低日剂量的为 9.2%（0-18.7），中日剂量的为 6.8%（1.7-12.0），高日剂量的为 9.6%（4.8-14.3）。在葡萄糖-6-磷酸脱氢酶（G6PD）活性为 30%或更高的儿童中，未使用伯氨喹（0.4%，95%CI，0.1-1.5）、低日剂量（0.0%，0.0-1.6）、中日剂量（0.5%，0.1-1.4）或高日剂量（0.7%，0.2-1.9）的患者中，严重溶血的发生率很少。在 15 例可能与药物相关的严重不良事件中，有 2 例发生在低剂量组，4 例发生在中剂量组，9 例发生在高剂量组。
与低剂量相比，高总剂量的伯氨喹在降低儿童间日疟寄生虫血症的复发方面非常有效，尤其是在年龄小于 5 岁的儿童中。与低日剂量相比，使用高日剂量和中日剂量的伯氨喹的儿童中，胃肠道症状或溶血没有增加（在 G6PD 活性为 30%或更高的儿童中），但严重不良事件更多。
药品专利池、比尔及梅琳达·盖茨基金会和澳大利亚国家卫生与医学研究理事会。
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