Kamya Moses R, Nankabirwa Joaniter I, Ebong Chris, Asua Victor, Kiggundu Moses, Orena Stephen, Okitwi Martin, Tukwasibwe Stephen, Agaba Bosco, Kyabayinze Daniel, Opigo Jimmy, Rutazana Damian, Binagwa Benjamin, Mugwanya Edward, Babirye Shakira, Sebikaari Gloria, Condo Patrick M, Appiah Grace, Nsobya Sam L, Conrad Melissa D, Rosenthal Philip J, Moriarty Leah F, Yeka Adoke
Infectious Diseases Research Collaboration, Kampala, Uganda; Department of Medicine, Makerere University, Kampala, Uganda.
Infectious Diseases Research Collaboration, Kampala, Uganda; Department of Medicine, Makerere University, Kampala, Uganda.
Lancet Infect Dis. 2025 Aug 19. doi: 10.1016/S1473-3099(25)00407-4.
Anti-malarial artemisinin-based combination therapies (ACTs) might be losing efficacy in east Africa, with the spread of artemisinin partial resistance and reduced partner drug activity. Our trial aimed to measure the efficacies of artemether-lumefantrine, artesunate-amodiaquine, dihydroartemisinin-piperaquine, and artesunate-pyronaridine in three sites in Uganda.
This randomised, open-label, phase 4 clinical trial was carried out at three sites in the Agago, Arua, and Busia districts of Uganda. Children aged 6 months to 10 years with uncomplicated Plasmodium falciparum malaria were randomly assigned to receive either artemether-lumefantrine (20 mg artemether; 120 mg lumefantrine; twice a day for 3 days) in all sites or dihydroartemisinin-piperaquine (40 mg dihydroartemisinin and 320 mg piperaquine, once a day for 3 days) in Agago, artesunate-amodiaquine (25 mg artesunate and 67·5 mg amodiaquine for children <9 kg or 50 mg artesunate and 135 mg amodiaquine for children ≥9 kg, once a day for 3 days) in Busia; and artesunate-pyronaridine (60 mg artesunate and 180 mg pyronaridine for children >15 kg or 20 mg artesunate and 60 mg pyronaridine for children <15 kg, once a day for 3 days) in Arua, with follow-up to 42 days. Participants were not blinded to group assignments; however, investigators and those assessing outcome were masked. The primary outcome was parasitaemia, assessed by microscopy, either uncorrected or PCR-corrected to distinguish recrudescence from new infection. All participants who received the treatment per protocol and were not lost to follow-up were included in the primary outcome. All participants who were randomly allocated to treatment groups were included in the safety analyses. This study is registered with the Pan African Clinical Trials Registry, number PACTR202301796134887, and is complete.
Between Nov 7, 2022, and March 24, 2023, 808 participants (437 [54%] female) were enrolled and assigned to treatment groups; 15 (2%) were lost to follow-up and 793 (98%) completed follow-up. The uncorrected adequate clinical and parasitological response for artemether-lumefantrine was 87 (51·8%; 95% CI 44·0-59·5) of 168 participants in Arua, 88 (51·8%; 44·0-59·4) of 170 and Busia, and 131 (79·4%; 72·3-85·1) of 165 in Agago. This response for artemether-lumefantrine was lower than that of the other ACTs at all sites: 97 (98·0%; 92·2-99·6) of 99 for dihydroartemisinin-piperaquine in Agago, 95 (99·0%; 93·5-99·9) of 96 for artesunate-amodiaquine in Busia, and 73 (73·7%; 63·8-81·8) of 99 for artesunate-pyronaridine in Arua. PCR-corrected 28-day efficacies were 88 (81·5%; 72·6-88·1) of 108 for artemether-lumefantrine and 95 (100%; 95·2-100·0) of 95 for artesunate-amodiaquine in Busia; 131 (97·0%; 92·1-99·0) of 135 for artemether-lumefantrine and 97 (100%; 95·3-100·0) of 97 for dihydroartemisinin-piperaquine in Agago; and 87 (82·1%; 73·2-88·6) of 106 for artemether-lumefantrine and 73 (92·4%; 83·6-96·9) of 79 for artesunate-pyronaridine in Arua. All regimens were well tolerated. The most common adverse events were upper respiratory tract infection, diarrhoea, and anaemia. None of the reported adverse events were attributed to the study drugs. There were two serious adverse events, both cases of severe malaria in Arua, one in each of the treatment groups. Parasite clearance half-lives were prolonged with parasites carrying the PfK13 Cys469Tyr (median 4·2 h; IQR 3·4-4·9) and Ala675Val (4·9 h; 3·4-5·7) mutations compared with wild-type parasites (2·8 h; 2·3-3·6; p<0·0001).
Artemether-lumefantrine was associated with a higher risk of recurrent malaria than other antimalarial combinations tested, and K13 mutations were associated with delayed parasite clearance. Changes in first-line therapy for uncomplicated malaria must be considered in response to suboptimal efficacy of artemether-lumefantrine.
US President's Malaria Initiative, US Agency for International Development, through the Uganda Malaria Reduction Activity and the National Institutes of Health (AI075045 and AI117001).
For the Swahili translation of the abstract see Supplementary Materials section.
随着青蒿素部分耐药性的传播以及辅助药物活性的降低，基于青蒿素的抗疟联合疗法（ACTs）在东非可能正失去疗效。我们的试验旨在测定蒿甲醚-本芴醇、青蒿琥酯-阿莫地喹、双氢青蒿素-哌喹和青蒿琥酯-咯萘啶在乌干达三个地点的疗效。
这项随机、开放标签的4期临床试验在乌干达阿加戈、阿鲁阿和布西亚地区的三个地点进行。年龄在6个月至10岁之间的单纯性恶性疟原虫疟疾患儿被随机分配，在所有地点接受蒿甲醚-本芴醇（20毫克蒿甲醚；120毫克本芴醇；每日两次，共3天）治疗，在阿加戈接受双氢青蒿素-哌喹（40毫克双氢青蒿素和320毫克哌喹，每日一次，共3天）治疗，在布西亚接受青蒿琥酯-阿莫地喹（体重<9千克的儿童用25毫克青蒿琥酯和67.5毫克阿莫地喹，或体重≥9千克的儿童用50毫克青蒿琥酯和135毫克阿莫地喹，每日一次，共3天）治疗；在阿鲁阿接受青蒿琥酯-咯萘啶（体重>15千克的儿童用60毫克青蒿琥酯和180毫克咯萘啶，或体重<15千克的儿童用20毫克青蒿琥酯和60毫克咯萘啶，每日一次，共3天）治疗，随访42天。参与者不了解分组情况；然而，研究人员和评估结果的人员是盲法的。主要结局是通过显微镜检查评估的寄生虫血症，未校正或经PCR校正以区分复发与新感染。所有按方案接受治疗且未失访的参与者均纳入主要结局。所有随机分配到治疗组的参与者均纳入安全性分析。本研究已在泛非临床试验注册中心注册，注册号为PACTR202301796134887，且已完成。
在2022年11月7日至2023年3月24日期间，808名参与者（43�[54%]为女性）入组并被分配到治疗组；15名（2%）失访，793名（98%）完成随访。在阿鲁阿，168名参与者中蒿甲醚-本芴醇未校正的充分临床和寄生虫学反应为87名（51.8%；95%CI 44.0-59.5），在布西亚170名参与者中为88名（51.8%；44.0-59.4），在阿加戈165名参与者中为131名（79.4%；72.3-85.1）。在所有地点，蒿甲醚-本芴醇的这种反应均低于其他ACTs：在阿加戈，双氢青蒿素-哌喹99名参与者中有97名（98.0%；92.2-99.6），在布西亚，青蒿琥酯-阿莫地喹96名参与者中有95名（99.0%；93.5-99.9），在阿鲁阿，青蒿琥酯-咯萘啶99名参与者中有73名（�.7%；63.8-81.8）。在布西亚，蒿甲醚-本芴醇经PCR校正的28天疗效为108名中有88名（81.5%；72.6-88.1），青蒿琥酯-阿莫地喹95名中有95名（100%；95.2-100.0）；在阿加戈，蒿甲醚-本芴醇135名中有131名（97.0%；92.1-99.0），双氢青蒿素-哌喹97名中有97名（100%；95.3-100.0）；在阿鲁阿，蒿甲醚-本芴醇106名中有87名（82.1%；73.2-88.6）青蒿琥酯-咯萘啶79名中有73名（92.4%；83.6-96.9）。所有治疗方案耐受性良好。最常见的不良事件是上呼吸道感染、腹泻和贫血。报告的不良事件均未归因于研究药物。有两起严重不良事件，均发生在阿鲁阿的严重疟疾病例中，每个治疗组各有一例。与野生型寄生虫（2.8小时；2.3-3.6小时；p<0.0001）相比，携带PfK13 Cys469Tyr（中位数4.2小时；IQR 3.4-4.9小时）和Ala675Val（4.9小时；3.4-5.7小时）突变的寄生虫的寄生虫清除半衰期延长。
与其他测试的抗疟联合疗法相比，蒿甲醚-本芴醇复发性疟疾风险更高，且K13突变与寄生虫清除延迟有关。鉴于蒿甲醚-本芴醇疗效欠佳，必须考虑改变单纯性疟疾的一线治疗方案。
美国总统疟疾倡议、美国国际开发署，通过乌干达疟疾减少活动和美国国立卫生研究院（AI075045和AI117001）。
摘要的斯瓦希里语翻译见补充材料部分。
