Dataset Information

Effect of Mass Treatment with Azithromycin on Causes of Death in Children in Malawi: Secondary Analysis from the MORDOR Trial.

ABSTRACT: Recent evidence indicates mass drug administration with azithromycin may reduce child mortality. This study uses verbal autopsy (VA) to investigate the causes of individual deaths during the Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance (MORDOR) trial in Malawi. Cluster randomization was performed as part of MORDOR. Biannual household visits were conducted to distribute azithromycin or placebo to children aged 1-59 months and update the census to identify deaths for VA. MORDOR was not powered to investigate mortality effects at individual sites, but the available evidence is presented here for hypothesis generation regarding the mechanism through which azithromycin may reduce child mortality. Automated VA analysis was performed to infer the likely cause of death using two major analysis programs, InterVA and SmartVA. A total of 334 communities were randomized to azithromycin or placebo, with more than 130,000 person-years of follow-up. During the study, there were 1,184 deaths, of which 1,131 were followed up with VA. Mortality was 9% lower in azithromycin-treated communities than in placebo communities (rate ratio 0.91 [95% CI: 0.79-1.05]; P = 0.20). The intention-to-treat analysis by cause using InterVA suggested fewer HIV/AIDS deaths in azithromycin-treated communities (rate ratio 0.70 [95% CI: 0.50-0.97]; P = 0.03) and fewer pneumonia deaths (rate ratio 0.82 [95% CI: 0.60-1.12]; P = 0.22). The use of the SmartVA algorithm suggested fewer diarrhea deaths (rate ratio 0.71 [95% CI: 0.51-1.00]; P = 0.05) and fewer pneumonia deaths (rate ratio 0.58 [95% CI: 0.33-1.00]; P = 0.05). Although this study is not able to provide strong evidence, the data suggest that the mortality reduction during MORDOR in Malawi may have been due to effects on pneumonia and diarrhea or HIV/AIDS mortality.

SUBMITTER: Hart JD

PROVIDER: S-EPMC7470551 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Effect of Mass Treatment with Azithromycin on Causes of Death in Children in Malawi: Secondary Analysis from the MORDOR Trial.

Hart John D JD Kalua Khumbo K Keenan Jeremy D JD Lietman Thomas M TM Bailey Robin L RL

The American journal of tropical medicine and hygiene 20200901 3

Recent evidence indicates mass drug administration with azithromycin may reduce child mortality. This study uses verbal autopsy (VA) to investigate the causes of individual deaths during the Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance (MORDOR) trial in Malawi. Cluster randomization was performed as part of MORDOR. Biannual household visits were conducted to distribute azithromycin or placebo to children aged 1-59 months and update the census to identify deaths for VA. ...[more]

PMID: 32342837

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Project description:ImportanceThe MORDOR (Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance) trial demonstrated that mass azithromycin administration reduced mortality by 18% among children aged 1 to 59 months in Niger. The identification of high-risk subgroups to target with this intervention could reduce the risk of antimicrobial resistance.ObjectiveTo evaluate whether distance to the nearest primary health center modifies the effect of azithromycin administration to children aged 1 to 59 months on child mortality.Design, setting, and participantsThe MORDOR cluster randomized trial was conducted from December 1, 2014, to July 31, 2017; this post hoc secondary analysis was conducted in 2023 among 594 clusters (communities or grappes) in the Boboye and Loga departments in Niger. All children aged 1 to 59 months in eligible communities were evaluated.InterventionsBiannual (twice-yearly) administration of a single dose of oral azithromycin or matching placebo over 2 years.Main outcomes and measuresA population-based census was used to monitor mortality and person-time at risk (trial primary outcome). Community distance to a primary health center was calculated as kilometers between the center of each community and the nearest health center. Negative binomial regression was used to evaluate the interaction between distance and the effect of azithromycin on the incidence of all-cause mortality among children aged 1 to 59 months.ResultsBetween December 1, 2014, and July 31, 2017, a total of 594 communities were enrolled, with 76 092 children (mean [SD] age, 31 [2] months; 39 022 [51.3%] male) included at baseline, for a mean (SD) of 128 (91) children per community. Median (IQR) distance to the nearest primary health center was 5.0 (3.2-7.1) km. Over 2 years, 145 693 person-years at risk were monitored and 3615 deaths were recorded. Overall, mortality rates were 27.5 deaths (95% CI, 26.2-28.7 deaths) per 1000 person-years at risk in the placebo arm and 22.5 deaths (95% CI, 21.4-23.5 deaths) per 1000 person-years at risk in the azithromycin arm. For each kilometer increase in distance in the placebo arm, mortality increased by 5% (adjusted incidence rate ratio, 1.05; 95% CI, 1.03-1.07; P < .001). The effect of azithromycin on mortality varied significantly by distance (interaction P = .02). Mortality reduction with azithromycin compared with placebo was 0% at 0 km from the health center (95% CI, -19% to 17%), 4% at 1 km (95% CI, -12% to 17%), 16% at 5 km (95% CI, 7% to 23%), and 28% at 10 km (95% CI, 17% to 38%).Conclusions and relevanceIn this secondary analysis of a cluster randomized trial of mass azithromycin administration for child mortality, children younger than 5 years who lived farthest from health facilities appeared to benefit the most from azithromycin administration. These findings may help guide the allocation of resources to ensure that those with the least access to existing health resources are prioritized in program implementation.Trial registrationClinicalTrials.gov Identifier: NCT02047981.

Project description:BackgroundBiannual azithromycin distribution has been shown to reduce child mortality as well as increase antimicrobial resistance. Targeting distributions to vulnerable subgroups such as malnourished children is one approach to reaching those at the highest risk of mortality while limiting selection for resistance. The objective of this analysis was to assess whether the effect of azithromycin on mortality differs by nutritional status.Methods and findingsA large simple trial randomized communities in Niger to receive biannual distributions of azithromycin or placebo to children 1-59 months old over a 2-year timeframe. In exploratory subgroup analyses, the effect of azithromycin distribution on child mortality was assessed for underweight subgroups using weight-for-age Z-score (WAZ) thresholds of -2 and -3. Modification of the effect of azithromycin on mortality by underweight status was examined on the additive and multiplicative scale. Between December 2014 and August 2017, 27,222 children 1-11 months of age from 593 communities had weight measured at their first study visit. Overall, the average age among included children was 4.7 months (interquartile range [IQR] 3-6), 49.5% were female, 23% had a WAZ < -2, and 10% had a WAZ < -3. This analysis included 523 deaths in communities assigned to azithromycin and 661 deaths in communities assigned to placebo. The mortality rate was lower in communities assigned to azithromycin than placebo overall, with larger reductions among children with lower WAZ: -12.6 deaths per 1,000 person-years (95% CI -18.5 to -6.9, P < 0.001) overall, -17.0 (95% CI -28.0 to -7.0, P = 0.001) among children with WAZ < -2, and -25.6 (95% CI -42.6 to -9.6, P = 0.003) among children with WAZ < -3. No statistically significant evidence of effect modification was demonstrated by WAZ subgroup on either the additive or multiplicative scale (WAZ < -2, additive: 95% CI -6.4 to 16.8, P = 0.34; WAZ < -2, multiplicative: 95% CI 0.8 to 1.4, P = 0.50, WAZ < -3, additive: 95% CI -2.2 to 31.1, P = 0.14; WAZ < -3, multiplicative: 95% CI 0.9 to 1.7, P = 0.26). The estimated number of deaths averted with azithromycin was 388 (95% CI 214 to 574) overall, 116 (95% CI 48 to 192) among children with WAZ < -2, and 76 (95% CI 27 to 127) among children with WAZ < -3. Limitations include the availability of a single weight measurement on only the youngest children and the lack of power to detect small effect sizes with this rare outcome. Despite the trial's large size, formal tests for effect modification did not reach statistical significance at the 95% confidence level.ConclusionsAlthough mortality rates were higher in the underweight subgroups, this study was unable to demonstrate that nutritional status modified the effect of biannual azithromycin distribution on mortality. Even if the effect were greater among underweight children, a nontargeted intervention would result in the greatest absolute number of deaths averted.Trial registrationThe MORDOR trial is registered at clinicaltrials.gov NCT02047981.

Project description:The MORDOR study, a masked, community-level randomized clinical trial conducted in Niger, Malawi and Tanzania (2015 to 2017), showed that biannual administration of single-dose azithromycin to preschool children reduced all-cause mortality. We sought to evaluate its impact on causes of death in children aged 1-59 months in Tanzania. A random sampling of 614 communities was conducted in Kilosa District, Tanzania, with simple random assignment of communities to receive either azithromycin or placebo. In these communities, a census was carried out every 6 months and children aged 1-59 months received biannual (every 6 months), single-dose azithromycin (~20mg/kg) or placebo depending on community assignment, over a 2-year period. Mortality was determined at the time of the biannual census. For child deaths, a verbal autopsy was performed to ascertain the cause using a standardized diagnostic classification. A total of 190- (0.58 /100 person-years) and 200 deaths (0.59/100 person-years) were reported in the azithromycin and placebo arms, respectively. Malaria, pneumonia and diarrhea, accounted for 71% and 68% of deaths in the respective arms. Overall, the mortality was not different by treatment arm, nor were the distribution of causes of death after adjusting for community clustering. The cause-specific mortality for diarrhea/pneumonia was no different over time. In children aged 1-5 months, 32 deaths occurred in the placebo arm and 25 deaths occurred in the azithromycin arm; 20 (62.5%) deaths in the placebo- and 10 (40%) in the azithromycin arm were attributed to diarrhea or pneumonia. Neither differences in the number of deaths nor the diarrhea/pneumonia attribution was statistically significant after adjusting for community clustering. In conclusion, azithromycin was not associated with a significant decline in deaths by specific causes compared to placebo. The non-significant lower rates of diarrhea or pneumonia in children <6 months who received azithromycin merit further investigation in high-mortality settings. Trial registration: NCT02048007.

Project description:ImportanceBecause transmission of ocular strains of Chlamydia trachomatis is greatest among preschool-aged children, limiting azithromycin distributions to this age group may conserve resources and result in less antimicrobial resistance, which is a potential advantage in areas with hypoendemic trachoma and limited resources.ObjectiveTo determine the efficacy of mass azithromycin distributions to preschool-aged children as a strategy for trachoma elimination in areas with hypoendemic disease.Design, setting, and participantsIn this cluster randomized clinical trial performed from November 23, 2014, until July 31, 2017, thirty rural communities in Niger were randomized at a 1:1 ratio to biannual mass distributions of either azithromycin or placebo to children aged 1 to 59 months. Participants and study personnel were masked to treatment allocation. Data analyses for trachoma outcomes were performed from October 19, 2021, through June 10, 2022.InterventionsEvery 6 months, a single dose of either oral azithromycin (20 mg/kg using height-based approximation for children who could stand or weight calculation for small children) or oral placebo was provided to all children aged 1 to 59 months.Main outcomes and measuresTrachoma was a prespecified outcome of the trial, assessed as the community-level prevalence of trachomatous inflammation-follicular and trachomatous inflammation-intense through masked grading of conjunctival photographs from a random sample of 40 children per community each year during the 2-year study period. A secondary outcome was the seroprevalence of antibodies to C trachomatis antigens.ResultsAt baseline, 4726 children in 30 communities were included; 1695 children were enrolled in 15 azithromycin communities and 3031 children were enrolled in 15 placebo communities (mean [SD] proportions of boys, 51.8% [4.7%] vs 52.0% [4.2%]; mean [SD] age, 30.8 [2.8] vs 30.6 [2.6] months). The mean coverage of study drug for the 4 treatments was 79% (95% CI, 75%-83%) in the azithromycin group and 82% (95% CI, 79%-85%) in the placebo group. The mean prevalence of trachomatous inflammation-follicular at baseline was 1.9% (95% CI, 0.5%-3.5%) in the azithromycin group and 0.9% (95% CI, 0-1.9%) in the placebo group. At 24 months, trachomatous inflammation-follicular prevalence was 0.2% (95% CI, 0-0.5%) in the azithromycin group and 0.8% (95% CI, 0.2%-1.6%) in the placebo group (incidence rate ratio adjusted for baseline: 0.18 [95% CI, 0.01-1.20]; permutation P = .07).Conclusions and relevanceThe findings of this trial do not show that biannual mass azithromycin distributions to preschool-aged children were more effective than placebo, although the underlying prevalence of trachoma was low. The sustained absence of trachoma even in the placebo group suggests that trachoma may have been eliminated as a public health problem in this part of Niger.Trial registrationClinicalTrials.gov Identifier: NCT02048007.

Project description:ImportanceMass azithromycin distributions may decrease childhood mortality, although the causal pathway is unclear. The potential for antibiotics to function as growth promoters may explain some of the mortality benefit.ObjectiveTo investigate whether biannual mass azithromycin distributions are associated with increased childhood growth.Design, setting, and participantsThis cluster-randomized trial was performed from December 2014 until March 2020 among 30 rural communities in Boboye and Loga departments in Niger, Africa, with populations from 200 to 2000 individuals. Communities were randomized in a 1:1 ratio to biannual mass distributions of azithromycin or placebo for children ages 1 to 59 months. Participants, field-workers, and study personnel were masked to treatment allocation. Height and weight changes from baseline to follow-up at 4 years were compared between groups. Data were analyzed from June through November 2021.InterventionsParticipants received azithromycin at 20 mg/kg using height-based approximation or by weight for children unable to stand every 6 months at the participants' households. Placebo contained the vehicle of the azithromycin suspension.Main outcomes and measuresLongitudinal anthropometric assessments were performed on a random sample of children before the first treatment and then annually for 5 years. Height and weight were the prespecified primary outcomes.ResultsAmong 3936 children enrolled from 30 communities, baseline characteristics were similar between 1299 children in the azithromycin group and 2637 children in the placebo group (mean 48.2% [95% CI, 45.5% to 50.8%] girls vs 48.0% [95% CI, 45.7% to 50.3%] girls; mean age, 30.8 months [95% CI, 29.5 to 32.0 months] vs 30.6 months [95% CI, 29.2 to 31.6 months]). Baseline anthropometric assessments were performed among 2230 children, including 985 children in the azithromycin group and 1245 children in the placebo group, of whom follow-up measurements were available for 789 children (80.1%) and 1063 children (85.4%), respectively. At the prespecified 4-year follow-up visit, children in the azithromycin group gained a mean 6.7 cm (95% CI, 6.5 to 6.8 cm) in height and 1.7 kg (95% CI, 1.7 to 1.8 kg) in weight per year and children in the placebo group gained a mean 6.6 cm (95% CI, 6.4 to 6.7 cm) in height and 1.7 kg (95% CI, 1.7 to 1.8 kg) in weight per year. Height at 4 years was not statistically significantly different between groups when adjusted for baseline height (0.08 cm [95% CI, -0.12 to 0.28 cm] greater in the azithromycin group; P = .45), and neither was weight when adjusted for height and baseline weight (0.02 kg [95% CI, -0.10 to 0.06 kg] less in the azithromycin group; P = .64). However, among children in the shortest quartile of baseline height, azithromycin was associated with a 0.4 cm (95% CI, 0.1 to 0.7 cm) increase in height compared with placebo.Conclusions and relevanceThis study did not find evidence of an association between mass azithromycin distributions and childhood growth, although subgroup analysis suggested some benefit for the shortest children. These findings suggest that the mortality benefit of mass azithromycin distributions is unlikely to be due solely to growth promotion.Trial registrationClinicalTrials.gov Identifier: NCT02048007.

Dataset Information

Effect of Mass Treatment with Azithromycin on Causes of Death in Children in Malawi: Secondary Analysis from the MORDOR Trial.

Publications

Effect of Mass Treatment with Azithromycin on Causes of Death in Children in Malawi: Secondary Analysis from the MORDOR Trial.

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