Biannual mass azithromycin distributions and malaria parasitemia in pre-school children in Niger: A cluster-randomized, placebo-controlled trial

Abstract

Background: 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.

Methods and findings: 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.

Conclusions: 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.

Trial registration: The trial was registered on ClinicalTrials.gov (NCT02048007).

Conflict of interest statement

I have read the journal's policy and the authors of this manuscript have the following competing interests: TML has received a research grant from the Bill & Melinda Gates Foundation for this project and from the National Institutes of Health and private foundations for unrelated projects. The other authors have declared that no competing interests exist.

Figures

Fig 1. Trial flow.

Communities were selected from the same pool of communities as the parent MORDOR trial; communities were excluded before randomization if not in the desired population range (i.e., 200–2,000 people) or if not required to reach the targeted sample size. A census was conducted approximately every 6 months. A random sample of children was selected at months 0, 12, and 24 for monitoring. Children excluded from analysis had thick smears that were missing or unreadable. MORDOR, Macrolides Oraux pour Réduire les Décés avec un Oeil sur la Resistance.

Fig 2. MORDOR study area.

MORDOR was conducted in Boboye and Loga departments, Dosso region, Niger. Each point represents a community, with azithromycin-treated communities in blue and placebo-treated communities in orange. The 30 communities enrolled in the present study (darker markers) were randomly selected from the same pool of communities as the main MORDOR trial (lighter markers). Base maps of the Loga and Boboye departments were taken from the Humanitarian Data Exchange (https://data.humdata.org). MORDOR, Macrolides Oraux pour Réduire les Décés avec un Oeil sur la Resistance.

Fig 3. Timing of examination visits and treatment.

The x-axis depicts calendar time during the trial, and the y-axis shows each community as a discrete row. Examinations and treatment visits were typically conducted over a several-day period; the vertical lines represent the median date of the examination (black) or treatment (blue for azithromycin, orange for placebo).

Fig 4. Community-specific malaria parasitemia prevalence among 1- to 59-month-old children at the 3 annual monitoring visits.

Each thin line represents a community, and the thick lines represent the mean prevalence of parasitemia in each trial arm.