Malaria Research and Training Centre, Faculty of Pharmacy, Medicine, and Dentistry, University of Science, Techniques, and Technologies of Bamako, Bamako, Mali.
Global Health Group, Malaria Elimination Initiative, University of California, San Francisco, CA, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
Lancet Infect Dis. 2018 Jun;18(6):627-639. doi: 10.1016/S1473-3099(18)30044-6. Epub 2018 Feb 6.
Primaquine and methylene blue are gametocytocidal compounds that could prevent Plasmodium falciparum transmission to mosquitoes. We aimed to assess the efficacy and safety of primaquine and methylene blue in preventing human to mosquito transmission of P falciparum among glucose-6-phosphate dehydrogenase (G6PD)-normal, gametocytaemic male participants.
This was a phase 2, single-blind, randomised controlled trial done at the Clinical Research Centre of the Malaria Research and Training Centre (MRTC) of the University of Bamako (Bamako, Mali). We enrolled male participants aged 5-50 years with asymptomatic P falciparum malaria. G6PD-normal participants with gametocytes detected by blood smear were randomised 1:1:1:1 in block sizes of eight, using a sealed-envelope design, to receive either sulfadoxine-pyrimethamine and amodiaquine, sulfadoxine-pyrimethamine and amodiaquine plus a single dose of 0·25 mg/kg primaquine, dihydroartemisinin-piperaquine, or dihydroartemisinin-piperaquine plus 15 mg/kg per day methylene blue for 3 days. Laboratory staff, investigators, and insectary technicians were masked to the treatment group and gametocyte density of study participants. The study pharmacist and treating physician were not masked. Participants could request unmasking. The primary efficacy endpoint, analysed in all infected patients with at least one infectivity measure before and after treatment, was median within-person percentage change in mosquito infectivity 2 and 7 days after treatment, assessed by membrane feeding. This study is registered with ClinicalTrials.gov, number NCT02831023.
Between June 27, 2016, and Nov 1, 2016, 80 participants were enrolled and assigned to the sulfadoxine-pyrimethamine and amodiaquine (n=20), sulfadoxine-pyrimethamine and amodiaquine plus primaquine (n=20), dihydroartemisinin-piperaquine (n=20), or dihydroartemisinin-piperaquine plus methylene blue (n=20) groups. Among participants infectious at baseline (54 [68%] of 80), those in the sulfadoxine-pyrimethamine and amodiaquine plus primaquine group (n=19) had a median 100% (IQR 100 to 100) within-person reduction in mosquito infectivity on day 2, a larger reduction than was noted with sulfadoxine-pyrimethamine and amodiaquine alone (n=12; -10·2%, IQR -143·9 to 56·6; p<0·0001). The dihydroartemisinin-piperaquine plus methylene blue (n=11) group had a median 100% (IQR 100 to 100) within-person reduction in mosquito infectivity on day 2, a larger reduction than was noted with dihydroartemisinin-piperaquine alone (n=12; -6·0%, IQR -126·1 to 86·9; p<0·0001). Haemoglobin changes were similar between gametocytocidal arms and their respective controls. After exclusion of blue urine, adverse events were similar across all groups (59 [74%] of 80 participants had 162 adverse events overall, 145 [90%] of which were mild).
Adding a single dose of 0·25 mg/kg primaquine to sulfadoxine-pyrimethamine and amodiaquine or 3 days of 15 mg/kg per day methylene blue to dihydroartemisinin-piperaquine was highly efficacious for preventing P falciparum transmission. Both primaquine and methylene blue were well tolerated.
Bill & Melinda Gates Foundation, European Research Council.
伯氨喹啉和亚甲蓝是可杀灭配子体的化合物，能够防止恶性疟原虫传播给蚊子。我们旨在评估伯氨喹啉和亚甲蓝在预防葡萄糖-6-磷酸脱氢酶（G6PD）正常的配子体血症男性参与者中恶性疟原虫向蚊子传播的效果和安全性。
这是一项在马里疟疾研究和培训中心临床研究中心（巴马科，马里）进行的 2 期、单盲、随机对照试验。我们招募了年龄在 5-50 岁之间、无症状恶性疟原虫感染的男性参与者。通过血涂片检测到配子体的 G6PD 正常参与者，按照 8 人一组的大小，采用密封信封设计，随机分为 1：1：1：1 四组，分别接受磺胺多辛-乙胺嘧啶和阿莫地喹、磺胺多辛-乙胺嘧啶和阿莫地喹加单次 0.25mg/kg 伯氨喹啉、双氢青蒿素-哌喹或双氢青蒿素-哌喹加 3 天 15mg/kg/天亚甲蓝治疗。实验室工作人员、研究人员和昆虫学技术员对治疗组和研究参与者的配子体密度进行了盲法处理。研究药剂师和治疗医生未进行盲法处理。参与者可要求揭盲。主要疗效终点为治疗前后至少有一项感染性测量的感染患者的中位个体内蚊子感染性百分比变化，通过膜喂食进行评估。本研究在 ClinicalTrials.gov 注册，编号为 NCT02831023。
在 2016 年 6 月 27 日至 2016 年 11 月 1 日期间，共招募了 80 名参与者，并分为磺胺多辛-乙胺嘧啶和阿莫地喹组（n=20）、磺胺多辛-乙胺嘧啶和阿莫地喹加伯氨喹啉组（n=20）、双氢青蒿素-哌喹组（n=20）和双氢青蒿素-哌喹加亚甲蓝组（n=20）。在基线时具有传染性的参与者中（80 名中的 54 名，68%），磺胺多辛-乙胺嘧啶和阿莫地喹加伯氨喹啉组（n=19）在第 2 天的蚊子感染性中位个体内降低了 100%（IQR 100 至 100），降幅大于磺胺多辛-乙胺嘧啶和阿莫地喹单独治疗组（n=12；-10.2%，IQR-143.9 至 56.6；p<0.0001）。双氢青蒿素-哌喹加亚甲蓝组（n=11）在第 2 天的蚊子感染性中位个体内降低了 100%（IQR 100 至 100），降幅大于双氢青蒿素-哌喹单独治疗组（n=12；-6.0%，IQR-126.1 至 86.9；p<0.0001）。配子体杀灭组与各自对照组的血红蛋白变化相似。排除蓝尿后，所有组的不良事件相似（80 名参与者共发生 162 起不良事件，其中 145 起[90%]为轻度不良事件）。
磺胺多辛-乙胺嘧啶和阿莫地喹加单次 0.25mg/kg 伯氨喹啉或双氢青蒿素-哌喹加 3 天 15mg/kg/天亚甲蓝治疗可显著预防恶性疟原虫传播。伯氨喹啉和亚甲蓝均具有良好的耐受性。
比尔及梅琳达·盖茨基金会、欧洲研究理事会。
