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

Date Published: June 25, 2019

Publisher: Public Library of Science

Author(s): Ahmed M. Arzika, Ramatou Maliki, Nameywa Boubacar, Salissou Kane, Sun Y. Cotter, Elodie Lebas, Catherine Cook, Robin L. Bailey, Sheila K. West, Philip J. Rosenthal, Travis C. Porco, Thomas M. Lietman, Jeremy D. Keenan, Lorenz von Seidlein

Abstract: BackgroundMass 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 findingsIn 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.ConclusionsMass 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 registrationThe trial was registered on (NCT02048007).

Partial Text: Mass azithromycin distributions have lowered childhood mortality in Africa, although the mechanism explaining this effect is unknown. Macrolides Oraux pour Réduire les Décés avec un Oeil sur la Resistance (MORDOR) was a cluster-randomized placebo-controlled trial conducted in Malawi, Niger, and Tanzania that found a 14% reduction in childhood mortality in communities randomized to biannual mass azithromycin distributions targeted to 1- to 59-month-old children. The protective effect of azithromycin distributions was especially high in Niger, where malaria accounts for a large proportion of childhood deaths [1]. Azithromycin has activity against the malarial apicoplast and has demonstrated modest antimalarial activity in vitro and in numerous field studies [2–13]. Thus, the mortality benefit observed with mass azithromycin distributions may be due, in part, to decreased malaria.

Baseline characteristics of the 15 azithromycin-treated communities and 15 placebo-treated communities are shown in Table 1. Communities in the placebo group were on average larger than those in the azithromycin group, with a total of 1,695 children aged 1 to 59 months enumerated in the azithromycin arm and a total of 3,029 children enumerated in the placebo arm at baseline. The age and sex distribution within communities was similar between the 2 groups. All communities received their allocated study medication, and none were lost to follow-up. Across all 4 study visits, study drug was distributed to 78.7% (95% CI 74.9%–82.6%) of eligible children in the azithromycin group and 81.7% (95% CI 78.9%–84.5%) of eligible children in the placebo group (Fig 1).

In this placebo-controlled study, mass azithromycin distributions resulted in a significantly lower prevalence of malaria parasitemia and lower parasite density levels when assessed at 2 annual post-treatment study visits. Hemoglobin levels were slightly greater and the prevalence of anemia slightly lower in azithromycin-treated communities, although neither of these were statistically significant. These results raise the possibility that reductions in malaria may in part explain the childhood mortality benefit of azithromycin.



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