The Duration of Protection from Azithromycin Against Malaria, Acute Respiratory, Gastrointestinal, and Skin Infections When Given Alongside Seasonal Malaria Chemoprevention: Secondary Analyses of Data from a Clinical Trial in Houndé, Burkina Faso, and Bougouni, Mali

Abstract

Background Mass drug administration (MDA) with azithromycin (AZ) is being considered as a strategy to promote child survival in sub-Saharan Africa, but the mechanism by which AZ reduces mortality is unclear. To better understand the nature and extent of protection provided by AZ, we explored the profile of protection by time since administration, using data from a household-randomised, placebo-controlled trial in Burkina Faso and Mali. Methods Between 2014 and 2016, 30,977 children aged 3-59 months received seasonal malaria chemoprevention (SMC) with sulphadoxine-pyrimethamine plus amodiaquine and either AZ or placebo monthly, on four occasions each year. Poisson regression with gamma-distributed random effects, accounting for the household randomisation and within-individual clustering of illness episodes, was used to compare incidence of pre-specified outcomes between SMC+AZ versus SMC+placebo groups in fixed time strata post-treatment. The likelihood ratio test was used to assess evidence for a time-treatment group interaction. Results Relative to SMC+placebo, there was no evidence of protection from SMC+AZ against hospital admissions and deaths. Additional protection from SMC+AZ against malaria was confined to the first two weeks post-administration (protective efficacy (PE): 24.2% [95% CI: 17.8%, 30.1%]). Gastroenteritis and pneumonia were reduced by 29.9% [21.7; 37.3%], and 34.3% [14.9; 49.3%], respectively in the first two weeks post-administration. Protection against non-malaria fevers with a skin condition persisted up to 28 days: PE: 46.3% [35.1; 55.6%]). Conclusions The benefits of AZ-MDA are broad-ranging but short-lived. To maximise impact, timing of AZ-MDA must address the challenge of targeting asynchronous morbidity and mortality peaks from different causes.

Malaria Positivity Following a Single Oral Dose of Azithromycin Among Children in Burkina Faso: A Randomized Controlled Trial

“…A trial in Burkina Faso and Mali found SMC + AZ provided additional protection from malaria, but this effect was limited to the rst two weeks post-administration. (19) Concomitant SMC distribution during the trial period may explain the lower than expected malaria prevalence we observed (8% RDT positivity at baseline and follow-up). (20-23) Community-level distribution of AZ could be more effective for malaria control compared to individuallevel as several community based trials have demonstrated that mass AZ distribution reduces malaria parasitemia.…”

“…Gastroenteritis and pneumonia were reduced 30% and 34% respectively in a West African azithromycin trial, suggesting AZ may lower other fever-inducing infections commonly found in sub Saharan Africa. (19,22) There were no other signi cant differences in other adverse events or clinic visits. Administration of azithromycin to preschool aged children appears to be safe and well tolerated.…”

Effect of 3 Days of Oral Azithromycin on Young Children With Acute Diarrhea in Low-Resource Settings

“… 26 Secondary analysis of a trial of the mass administration of seasonal malaria prophylaxis plus azithromycin or placebo 27 showed no evidence of a protective effect of azithromycin on hospitalization and deaths, and protection from infectious illnesses was short-lived (2-4 weeks). 28 A trial in Niger is under way to test the effect of age-based targeting of biannual azithromycin on mortality and antimicrobial resistance in children. 29 …”

Effect of a single dose of oral azithromycin on malaria parasitaemia in children: a randomized controlled trial

“…A household randomized trial of azithromycin versus placebo given alongside seasonal malaria chemoprevention for 3 consecutive years of administration in children aged 2 to 59 months showed no additional effect of azithromycin on malaria parasitaemia in Burkina Faso and Mali [ 21 ]. However, secondary analysis from this trial found a short-term reduction in rapid diagnostic test-confirmed malaria in children receiving azithromycin compared to placebo, confined to approximately 14 days post-treatment [ 22 ]. A study of biannual mass azithromycin distribution in Niger among children aged 1 to 59 months old found a nearly 50% reduction in the odds of malaria parasitaemia in children living in communities receiving azithromycin compared to placebo [ 3 ].…”