Spillover of Azithromycin Mass Drug Administration and Child Survival: A Secondary Analysis of a Cluster-Randomized Clinical Trial

Abstract

Importance: World Health Organization guidelines on azithromycin mass drug administration for child survival target infants aged 1 to 11 months, although prior studies included those aged 1 to 59 months. The AVENIR trial suggested that infants aged 1 to 11 months have lower mortality if children aged 12 to 59 months in the same household are also included.

Objective: To assess the possibility of a spillover effect by examining the association of azithromycin and mortality among children aged 1 to 11 months in subgroups defined by the presence of a child aged 12 to 59 months in the same household.

Design, setting, and participants: This exploratory secondary analysis of the AVENIR (Azithromycine Pour la Vie des Enfants au Niger: Implementation et Recherche) adaptive cluster-randomized clinical trial was performed in 3000 rural and periurban communities in Niger. AVENIR communities were randomized to 3 arms and followed up for 2 years (November 24, 2020, to July 31, 2023). Study arms consisted of children aged 1 to 59 months receiving azithromycin (child arm); infants aged 1 to 11 months receiving azithromycin with placebo to children aged 12 to 59 months (infant arm); and children aged 1 to 59 months receiving placebo (placebo arm). Participants, investigators, data collectors, and data analysts were masked to randomization.

Intervention: A single 20-mg/kg dose of oral azithromycin or placebo administered by study staff biannually.

Main outcomes and measures: All-cause mortality in infants aged 1 to 11 months (deaths per 1000 person-years) measured through biannual census. Subgroups were defined by the presence of a child aged 12 to 59 months in the household recorded during the census.

Results: After exclusions, 2883 communities and 98 969 infants aged 1 to 11 months were included in the analysis. Among the 23 770 infants in allocation 1 at baseline, mean (SD) age was 6.2 (3.1) months and 11 974 (50.4%) were female. Mortality was 18.5 (95% CI, 16.7-20.4) deaths per 1000 person-years in the child arm, 22.3 (95% CI, 20.0-24.7) in the infant arm, and 23.9 (95% CI, 21.6-26.2) in the placebo arm. The incidence rate ratio comparing mortality in the child and infant arms among children with an older sibling was 0.78 (95% CI, 0.65-0.93) compared with 0.91 (95% CI, 0.73-1.15; P = .26 for interaction) among those without. Comparing the infant and placebo arms, the incidence rate ratio among children with an older sibling was 0.96 (95% CI, 0.81-1.14) compared with 0.90 (95% CI, 0.71-1.12; P = .61 for interaction) among those without.

Conclusions and relevance: In this secondary analysis of a cluster-randomized clinical trial, interaction for the presence of a older sibling was not statistically significant, but results were consistent with lower mortality among infants aged 1 to 11 months living with older, treated children.

Trial registration: ClinicalTrials.gov Identifier: NCT04224987.

Figure 1.. Participant Flow Diagram

Communities were randomized to 1 of 3 arms: biannual azithromycin administration to infants and children aged 1 to 59 months (child arm); biannual azithromycin administration to infants aged 1 to 11 months and placebo administration to children aged 12 to 59 months (infant arm); or biannual administration of placebo to infants and children aged 1 to 59 months (placebo arm). The number of communities is shown for each component of the flow diagram. The total number of communities included in the main trial is shown in the allocation section, whereas for the follow-up section only eligible communities contributing to analyses by census interval and arm are shown. The number of children aged 1 to 11 months is also shown by allocation, census interval (1-4), and arm. As the trial used a dynamic cohort design, communities and children were able to enter, leave, and re-enter the trial in the different intercensus intervals. ^aWe excluded 117 communities after randomization, including 39 with census inaccuracies, 7 refusals, 40 in insecure areas, 2 moved communities, 2 protocol deviations, 1 with only 1 census household, and 26 with no person-time for infants. Only unique children are counted and displayed in the total analysis population.

Figure 2.. Comparison of Child vs Infant Arms

Data are shown for the child arm, with biannual azithromycin administration to infants and children aged 1 to 59 months, and the infant arm, with biannual azithromycin administration to infants aged 1 to 11 months and placebo administration to children aged 12 to 59 months. Mortality incidence rates, incidence rate ratios (IRRs), and incidence rate differences (IRDs) are compared among infants aged 1 to 11 months by treatment arm and presence of an older sibling (12-59 months of age) in the household. IRRs comparing mortality rate by arm and presence of a sibling were estimated using Poisson regression accounting for the adaptation and clustering. IRDs comparing mortality by arm and presence of an older sibling were estimated using G-computation based on the Poisson model. Supportive data are found in eTable 2 in Supplement 2.

Figure 3.. Comparison of Infant vs Placebo Arms

Data are shown for the placebo arm, with biannual administration of placebo to infants and children aged 1 to 59 months, and the infant arm, with biannual azithromycin administration to infants aged 1 to 11 months and placebo administration to children aged 12 to 59 months. Mortality incidence rates, incidence rate ratios (IRRs), and incidence rate differences (IRDs) are compared among infants aged 1 to 11 months by treatment arm and presence of an older sibling (12-59 months of age) in the household. IRRs comparing mortality rate by arm and presence of a sibling were estimated using Poisson regression accounting for the adaptation and clustering. IRDs comparing mortality by arm and presence of an older sibling were estimated using G-computation based on the Poisson model. Supportive data are found in eTable 2 in Supplement 2.