The Carter Center, Niamey, Niger.
Francis I Proctor Foundation, University of California, San Francisco, San Francisco, California, United States of America.
PLoS Med. 2019 Jun 25;16(6):e1002835. doi: 10.1371/journal.pmed.1002835. eCollection 2019 Jun.
Mass azithromycin distributions have been shown to reduce mortality in preschool children, although the factors mediating this mortality reduction are not clear. This study was performed to determine whether mass distribution of azithromycin, which has modest antimalarial activity, reduces the community burden of malaria.
In a cluster-randomized trial conducted from 23 November 2014 until 31 July 2017, 30 rural communities in Niger were randomized to 2 years of biannual mass distributions of either azithromycin (20 mg/kg oral suspension) or placebo to children aged 1 to 59 months. Participants, field staff, and investigators were masked to treatment allocation. The primary malaria outcome was the community prevalence of parasitemia on thick blood smear, assessed in a random sample of children from each community at study visits 12 and 24 months after randomization. Analyses were performed in an intention-to-treat fashion. At the baseline visit, a total of 1,695 children were enumerated in the 15 azithromycin communities, and 3,029 children were enumerated in the 15 placebo communities. No communities were lost to follow-up. The mean prevalence of malaria parasitemia at baseline was 8.9% (95% CI 5.1%-15.7%; 52 of 552 children across all communities) in the azithromycin-treated group and 6.7% (95% CI 4.0%-12.6%; 36 of 542 children across all communities) in the placebo-treated group. In the prespecified primary analysis, parasitemia was lower in the azithromycin-treated group at month 12 (mean prevalence 8.8%, 95% CI 5.1%-14.3%; 51 of 551 children across all communities) and month 24 (mean 3.5%, 95% CI 1.9%-5.5%; 21 of 567 children across all communities) than it was in the placebo-treated group at month 12 (mean 15.3%, 95% CI 10.8%-20.6%; 81 of 548 children across all communities) and month 24 (mean 4.8%, 95% CI 3.3%-6.4%; 28 of 592 children across all communities) (P = 0.02). Communities treated with azithromycin had approximately half the odds of parasitemia compared to those treated with placebo (odds ratio [OR] 0.54, 95% CI 0.30 to 0.97). Parasite density was lower in the azithromycin group than the placebo group at 12 and 24 months (square root-transformed outcome; density estimates were 7,540 parasites/μl lower [95% CI -350 to -12,550 parasites/μl; P = 0.02] at a mean parasite density of 17,000, as was observed in the placebo arm). No significant difference in hemoglobin was observed between the 2 treatment groups at 12 and 24 months (mean 0.34 g/dL higher in the azithromycin arm, 95% CI -0.06 to 0.75 g/dL; P = 0.10). No serious adverse events were reported in either group, and among children aged 1 to 5 months, the most commonly reported nonserious adverse events (i.e., diarrhea, vomiting, and rash) were less common in the azithromycin-treated communities. Limitations of the trial include the timing of the treatments and monitoring visits, both of which took place before the peak malaria season, as well as the uncertain generalizability to areas with different malaria transmission dynamics.
Mass azithromycin distributions were associated with a reduced prevalence of malaria parasitemia in this trial, suggesting one possible mechanism for the mortality benefit observed with this intervention.
The trial was registered on ClinicalTrials.gov (NCT02048007).
大规模阿奇霉素分发已被证明可降低学龄前儿童的死亡率，尽管介导这种死亡率降低的因素尚不清楚。本研究旨在确定大规模分发具有适度抗疟活性的阿奇霉素是否可以减轻疟疾的社区负担。
在 2014 年 11 月 23 日至 2017 年 7 月 31 日进行的一项整群随机试验中，尼日尔的 30 个农村社区被随机分为两组，每组 2 年，每 6 个月接受一次阿奇霉素（20mg/kg 口服混悬液）或安慰剂治疗，对象为 1 至 59 个月的儿童。参与者、现场工作人员和研究人员对治疗分配情况进行了盲法处理。主要疟疾结局是在随机选择的每个社区的儿童中，在随机分组后 12 个月和 24 个月时，通过厚血涂片评估社区中疟原虫血症的流行率。分析采用意向治疗方法进行。在基线检查时，在阿奇霉素治疗组的 15 个社区中共有 1695 名儿童被计数，在安慰剂治疗组的 15 个社区中共有 3029 名儿童被计数。没有社区失访。在阿奇霉素治疗组和安慰剂治疗组中，基线时疟原虫血症的平均流行率分别为 8.9%（95%CI 5.1%-15.7%；552 名儿童中有 52 名）和 6.7%（95%CI 4.0%-12.6%；542 名儿童中有 36 名）。在预先指定的主要分析中，在第 12 个月（平均流行率 8.8%，95%CI 5.1%-14.3%；551 名儿童中有 51 名）和第 24 个月（平均流行率 3.5%，95%CI 1.9%-5.5%；567 名儿童中有 21 名）时，阿奇霉素治疗组的疟原虫血症低于安慰剂治疗组，第 12 个月（平均流行率 15.3%，95%CI 10.8%-20.6%；548 名儿童中有 81 名）和第 24 个月（平均流行率 4.8%，95%CI 3.3%-6.4%；592 名儿童中有 28 名）（P=0.02）。与安慰剂治疗组相比，接受阿奇霉素治疗的社区发生疟原虫血症的可能性约为其一半（优势比[OR]0.54，95%CI 0.30 至 0.97）。与安慰剂组相比，阿奇霉素组在第 12 个月和第 24 个月时的寄生虫密度较低（平方根转换结局；在安慰剂组观察到的平均寄生虫密度为 17000 时，寄生虫密度估计值分别低 7540 个/μl[95%CI -350 至 -12550 个/μl；P=0.02]）。在第 12 个月和第 24 个月时，两组血红蛋白均无显著差异（阿奇霉素组平均高 0.34g/dL，95%CI 0.06 至 0.75g/dL；P=0.10）。两组均未报告严重不良事件，在 1 至 5 个月的儿童中，报告的最常见非严重不良事件（即腹泻、呕吐和皮疹）在阿奇霉素治疗社区中较少见。该试验的局限性包括治疗和监测访视的时间安排，两者均在疟疾高发季节之前进行，以及这种干预措施对疟疾传播动力学不同的地区的推广应用尚不确定。
在本试验中，大规模分发阿奇霉素与降低疟疾疟原虫血症的流行率有关，这表明这种干预措施可能存在降低死亡率的机制。
该试验在 ClinicalTrials.gov（NCT02048007）上注册。
