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Background: Biannual mass azithromycin administration to preschool children reduces all-cause mortality, but the mechanism for the effect is not understood. Azithromycin has activity against malaria parasites, and malaria is a leading cause of child mortality in the Sahel. The effect of biannual versus annual azithromycin distribution for trachoma control on serological response to merozoite surface protein 1 (MSP-119), a surrogate for malaria incidence, was evaluated among children in Niger. Methods: Markers of malaria exposure were measured in two arms of a factorial randomized controlled trial designed to evaluate targeted biannual azithromycin distribution to children under 12 years of age compared to annual azithromycin to the entire community for trachoma control (N = 12 communities per arm). Communities were treated for 36 months (6 versus 3 distributions). Dried blood spots were collected at 36 months among children ages 1-5 years, and MSP-119 antibody levels were assessed using a bead-based multiplex assay to measure malaria seroprevalence. Results: Antibody results were available for 991 children. MSP-119 seropositivity was 62.7% in the biannual distribution arm compared to 68.7% in the annual arm (prevalence ratio 0.91, 95% CI 0.83 to 1.00). Mean semi-quantitative antibody levels were lower in the biannual distribution arm compared to the annual arm (mean difference – 0.39, 95% CI – 0.05 to – 0.72). Conclusions: Targeted biannual azithromycin distribution was associated with lower malaria seroprevalence compared to that in a population that received annual distribution. Trial Registration Clinicaltrials.gov NCT00792922.
Ethical approval was obtained from the Committee on Human Research at the University of California, San Francisco and the Comité d’Ethique du Niger. Verbal informed consent was obtained from local chiefs of each study community and from the parent or guardian of each study participant. CDC staff did not have contact with study personnel or access to personal identifying information and were determined to not be engaged in human subjects research. PRET was a series of community-randomized trials in Niger, The Gambia, and Tanzania designed to assess mass azithromycin distribution strategies for trachoma control (clinicaltrials.gov {“type”:”clinical-trial”,”attrs”:{“text”:”NCT00792922″,”term_id”:”NCT00792922″}}NCT00792922). In the present report, data from the Niger trial only were included [26–28]. The Niger trial was a 2 × 2 factorial trial of standard versus enhanced coverage and annual versus biannual distribution of azithromycin for trachoma control. In Niger, communities were randomized to one of four arms in a 1:1:1:1 fashion: (1) annual treatment of all individuals in the community with a treatment coverage target of 80%; (2) annual treatment of all individuals in the community with an enhanced treatment coverage target of 90%; (3) biannual treatment of children aged 12 and under with a treatment coverage target of 80%; or (4) biannual treatment of children aged 12 and under with an enhanced treatment coverage target of 90%. Communities were randomized by stratified block randomization within each Centre de Santé Intégrée (CSI) by high or low trachoma prevalence, as previously described [26]. The present report is restricted only to the enhanced coverage arms, as dried blood spots for antibody tested were only collected in these arms. The remainder of this report is, therefore, focused only on the enhanced distribution study arms. Communities were eligible for inclusion in the study if they had a population between 250 and 600 at the most recent government census (done in 2001 with population sizes in 2010 estimated based on projected population growth) and clinical trachoma prevalence of at least 10% at the time of the census. Study communities were located in Matamèye District, Zinder Region and were treated from May 2010 until May 2013. This region is situated in the Sahel and has highly seasonal malaria incidence, with peak transmission shortly after the peak in rainfall, typically in September [29, 30]. At the time of the study, there was no seasonal malaria chemoprevention programme in this region, although a bed net distribution programme was active. Annual distributions occurred in June/July, at the beginning of the high transmission season. In the biannual distribution arm, communities were additionally treated in December/January, during the low transmission season. Data for the present analysis was collected in September 2013. Prior to each MDA, a door-to-door enumerative census was undertaken in all study communities, which formed the sampling frame for treatment and evaluation. In all communities included in this report, each MDA occurred over a 1-to-4-day period: up to three follow-up visits occurred after the initial MDA day in an attempt to achieve coverage of 90% or greater. In the annual MDA arm, communities received a total of three rounds of MDA distributed via a door-to-door program to all individuals, regardless of age. In the biannual MDA communities, children aged 6 months to 12 years received a total of six rounds of door-to-door MDA; no one over the age of 12 was treated in these communities. During each MDA, all eligible participants were offered a single dose of directly observed oral azithromycin (20 mg/kg up to a maximum dose of 1 g in adults). Children under 6 months of age or those with macrolide allergy were offered topical tetracycline ointment (1%) for 6 weeks. In the annual treatment arm, pregnant women were offered tetracycline ointment. In each study community, a random sample of 50 children aged 0 to 5 years were selected to have samples collected. Dried blood spots were only collected in children age 1 to 5 years of age due to the presence of maternal antibodies. Blood samples were collected via finger or heel stick in September 2013. Dried blood spots based on the most recent census [31] were analysed for antibody response to a portion of the P. falciparum antigen MSP-119 using a multiplex bead array assay on a Luminex 200 platform. Results were reported as the median fluorescence intensity (MFI) minus background (MFI-BG), where background is the signal from beads with buffer only. The seropositivity cutoff was MFI-BG ≥ 1758 as determined by receiver operator characteristic curve analysis using a positive panel of serum from individuals with malaria slides positive for P. falciparum and a negative panel of serum from US-residents who had never travelled to a malaria-endemic region. Blood samples from the children who contributed dried blood spots were also tested for P. falciparum infection using microscopy. Thick blood smears were stained with 3% Giemsa, and each slide was read by two experienced microscopists at the Zinder Regional Hospital. Discrepancies were adjudicated by a third reader. Microscopists determined the presence or absence of P. falciparum parasites and counted the number of asexual parasites per 200 white blood cells (assuming a white blood cell count of 8000/μl). Each child’s tympanic temperature was assessed at the time of blood collection. Clinically symptomatic malaria was defined as a blood slide positive for P. falciparum accompanied by tympanic temperature ≥ 38.5 °C. The geometric mean of the two parasite densities was used for analysis. Haemoglobin concentration was measured for all children (HemoCue AB, Ängelholm, Sweden). The trial was powered for the primary trachoma outcome [26]. An a priori sample size calculation was not performed for this non-prespecified secondary outcome. All analyses were conducted as intention-to-treat. Descriptive statistics were calculated by study arm with medians and interquartile ranges (IQR) or proportions. A log10 transformations of MFI-BG (as a semi-quantitative indicator of antibody levels) and parasite density was used for analysis. Parasite prevalence, clinically symptomatic malaria prevalence, and seroprevalence of MSP-119-specific antibodies and corresponding binomial 95% confidence intervals (CI) were calculated at the community level. Prevalence ratios (PR) for the association between malaria infection and MSP-119 seropositivity were calculated using generalized linear mixed models with a binomial distribution and log link with a random effect for the study community to account for clustering within communities, and adjusted for age and gender [32, 33]. To assess the difference in seropositivity to MSP-1 by study arm, generalized linear mixed model with a binomial distribution and log link were used to estimate risk ratios, with a random effect for study community. To assess differences in quantitative antibody levels, a log10 transformation of the MSP-1 MFI-BG values was used. Generalized linear mixed models with a Gaussian distribution and identity link were used to estimate the mean difference in antibody level between study arms, with a random effect for study community. Differences in the age-seroprevalence and semi-quantitative antibody curves were evaluated to assess differences in short- and long-term malaria exposure in a generalized linear model with binomial (seropositivity) or Gaussian (MFI-BG) distribution, with a study arm by age category interaction term, with age treated as a continuous variable. All analyses were conducted in R (version 3.4.3, The R Foundation for Statistical Computing, Vienna, Austria).
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