The role of Seasonal Malaria Chemoprevention in the effect of Azithromycin on Child Mortality: A Secondary Analysis of the CHAT Cluster Randomized Clinical Trial.

Objective: Mass treatment with azithromycin (AZ) and administration of seasonal malaria chemoprevention (SMC) are both effective in reducing mortality among children under 5. However, it is not clear whether the benefit of AZ for mortality varies in the presence of routine SMC administration. The objective of this study was to examine whether the effect of mass AZ distribution on all-cause mortality among children less than 5 years of age varies with SMC administration season or SMC coverage. Methods: This was a secondary analysis of the Community Health with Azithromycin Trial (CHAT), a cluster randomized placebo-controlled trial of 341 communities in the Nouna District of Burkina Faso. Communities randomized to intervention received treatment with twice yearly mass AZ while control communities receive placebo. All communities received SMC as standard-of-care. SMC administration and coverage data were provided from National Malaria Control Program. SMC administration season was defined as the period during and immediately following SMC (July-December) versus the months of no SMC (January-June). SMC coverage was assessed as proportion of the population covered and by whether it was below or above a threshold of 80%. We used Poisson regression models with person-time at risk used as an offset and robust standard error to analyze mortality rates by treatment group and SMC subgroups and assessed interaction on both the multiplicative and additive scales. Results: Mortality was higher in SMC seasons for both arms, with a mortality rate of 10.3 per 1,000 person-years (95% CI: 9.0 to 11.6) in SMC seasons and 7.9 (95% CI: 6.9 to 9.0) in non-SMC seasons. Compared to placebo, the mortality rate in AZ clusters was 0.77 (95% CI: 0.60 to 0.98) during SMC season, while it was 0.89 (95% CI: 0.68 to 1.15) during the non-SMC seasons. The effect of AZ compared to placebo in clusters with <80% SMC coverage was 0.73 95%CI (0.56 to 0.96) and in clusters with ≥80% SMC coverage, it was 1.0 95%CI (0.59 to 1.69). The interaction between AZ and SMC season or coverage was not statistically significant on the additive or multiplicative scales. Conclusion: While our findings did not reach statistical significance, they raise the question of whether prioritizing MDA AZ during high transmission periods or in regions with low SMC coverage could be beneficial. Further research is needed to determine if targeting these periods or areas could lead to greater reductions in child mortality. Trial Registration: ClinicalTrials.gov Identifier: NCT03676764.