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-randomized, 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 sulfadoxine-pyrimethamine plus amodiaquine and either AZ or placebo monthly, on 4 occasions each year. Poisson regression with gamma-distributed random effects, accounting for the household randomization and within-individual clustering of illness episodes, was used to compare incidence of prespecified 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 2 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 2 weeks postadministration. Protection against nonmalaria 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 maximize impact, timing of AZ-MDA must address the challenge of targeting asynchronous morbidity and mortality peaks from different causes.

Keywords: Azithromycin; Sahel; child mortality; duration of protection; seasonal malaria chemoprevention.

Figure 1.

Protective efficacy of azithromycin against the primary outcome (deaths and hospital admissions) by time since most recent seasonal malaria chemoprevention (SMC) course. Protective Efficacy (%) was calculated as (1—Incidence Rate Ratio) X 100. Incidence Rate was calculated as the total number of events divided by total person-years at risk. For each time stratum, incidence rate was calculated as number of events divided by person-years at risk. Rate ratios compare SMC+Azithromycin versus SMC+placebo groups. Poisson regression models, with a gamma distributed random effect to account for the household randomisation and within-individual clustering of morbidity episodes. Models were adjusted for study country only. Red squares are point estimates, solid vertical lines indicate 95% confidence intervals. Dashed horizontal line indicates no protective efficacy of azithromycin.

Figure 2.

Protective efficacy of azithromycin against predefined secondary outcomes by time since most recent SMC course: (A) RDT-confirmed clinical malaria; (B) Gastroenteritis; (C) Acute lower respiratory tract infections; and (D) Non-malaria fevers with a skin condition. For each time stratum, incidence rate was calculated as number of events divided by person-years at risk. Rate ratios compare SMC+Azithromycin versus SMC+placebo groups. Poisson regression models, with a gamma distributed random effect to account for the household randomisation and within-individual clustering of morbidity episodes. Models were adjusted for study country only. Red squares are point estimates, solid vertical lines indicate 95% confidence intervals. Dashed horizontal line indicates no protective efficacy of azithromycin. For clarity of presentation the Y-axis is truncated at -100 for ALRI. The lower limit of the CIs for 29–35 days and >35 days extend to –156% and -188%, respectively. Abbreviations: ALRI, acute lower respiratory tract infections; AZ, azithromycin; RDT, rapid diagnosic test; SMC seasonal malaria chemoprevention.