Artemether-Lumefantrine versus Dihydroartemisinin-Piperaquine for Treatment of Uncomplicated Plasmodium falciparum Malaria in Children Aged Less than 15 Years in Guinea-Bissau – An Open-Label Non-Inferiority Randomised Clinical Trial

BackgroundArtemether-lumefantrine (AL) was introduced for treatment of uncomplicated malaria in Guinea-Bissau in 2008. Malaria then resurged and recurrent malaria after treatment with AL and stock-outs of AL were common. This study therefore aimed to assess the efficacy of AL and identify an alternative second line antimalarial. Dihydroartemisinin-piperaquine (DP) was chosen as it has been shown to be safe and efficacious and to reduce the incidence of recurrent malaria.Methods and FindingsIn a multicentre randomised open-label non-inferiority clinical trial, AL or DP were given over 3 days to children aged 6 months-15 years with uncomplicated P. falciparum mono-infection. Intake was observed and AL was given with milk. Children were seen on days 0, 1, 2 and 3 and then weekly days 7–42. Recurring P. falciparum were classified as recrudescence or new infections by genotyping. Between November 2012 and July 2015, 312 children were randomised to AL (n = 155) or DP (n = 157). The day 42 PCR adjusted per protocol adequate clinical and parasitological responses were 95% and 100% in the AL and DP groups respectively, Mantel-Haenszel weighted odds ratio (OR) 0.22 (95% CI 0–0.68), p = 0.022. In a modified intention to treat analysis in which treatment failures day 0 and reinfections were also considered as treatment failures adequate clinical and parasitological responses were 94% and 97% (OR 0.42 [95% CI, 0.13–1.38], p = 0.15). Parasite clearance and symptom resolution were similar with both treatments.ConclusionsBoth treatments achieved the WHO recommended efficacy for antimalarials about to be adopted as policy. DP was not inferior to AL for treatment of uncomplicated P. falciparum malaria in Guinea-Bissau.Trial RegistrationClinicalTrials.gov NTC01704508

背景：青蒿素哌喹复方（Artemether-lumefantrine，AL）于2008年在几内亚比绍被引入用于治疗无并发症疟疾。此后疟疾疫情出现反弹，使用AL治疗后复发的疟疾病例以及AL药物缺货的情况十分常见。因此本研究旨在评估AL的临床疗效，并筛选可替代的二线抗疟药物。二氢青蒿素哌喹复方（Dihydroartemisinin-piperaquine，DP）被选为候选药物，因其已被证实安全有效，且可降低疟疾复发率。

方法与结果：本研究为多中心、随机、开放标签的非劣效性临床试验，将6月龄至15岁、确诊为单纯恶性疟原虫（Plasmodium falciparum）单一感染的无并发症疟疾患儿随机分为两组，分别给予3天疗程的AL或DP治疗，给药过程需全程观察服药依从性，且AL需与牛奶同服。研究分别在第0、1、2、3天对患儿进行随访，随后在第7至42天每周随访一次。通过基因分型技术，将检出的复发性恶性疟原虫感染区分为虫株复燃与新发感染。2012年11月至2015年7月期间，共312名患儿完成随机分组，其中AL组155例，DP组157例。按方案修正后的第42天PCR校正充足临床和寄生虫学应答率（adequate clinical and parasitological responses, ACPR）在AL组与DP组分别为95%与100%，Mantel-Haenszel加权比值比（odds ratio, OR）为0.22（95%置信区间confidence interval, CI：0~0.68），p=0.022。在改良意向治疗分析中，将第0天的治疗失败病例以及再感染病例均纳入治疗失败统计范畴，此时两组的ACPR分别为94%与97%（OR=0.42，95%CI：0.13~1.38，p=0.15）。两种治疗方案的寄生虫清除速率与症状缓解效果相当。

结论：两种治疗方案均达到了世界卫生组织（World Health Organization, WHO）推荐的拟纳入公共卫生政策的抗疟药物疗效标准。在几内亚比绍，DP治疗无并发症恶性疟原虫感染的疗效非劣于AL。

试验注册：ClinicalTrials.gov 编号：NTC01704508