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Key Points Question What is the effect of weekly azithromycin on morbidity in children with HIV-associated chronic lung disease? Findings In this randomized clinical trial that included 347 children aged 6 to 19 years, azithromycin did not improve lung function. The rate of acute respiratory exacerbations was 12.1 events per 100 person-years in the azithromycin group and 24.7 events per 100 person-years in the control group; the hospitalization rate was 1.3 events per 100 person-years in the azithromycin group and 7.1 events per 100 person-years in the placebo group. Meaning These findings suggest that prophylactic azithromycin has no effect on lung function in children with HIV-associated chronic lung disease but it is associated with a lower rate of acute respiratory exacerbations.

BackgroundHuman immunodeficiency virus (HIV)-related chronic lung disease (CLD) among children is associated with substantial morbidity, despite antiretroviral therapy. This may be a consequence of repeated respiratory tract infections and/or dysregulated immune activation that accompanies HIV infection. Macrolides have anti-inflammatory and antimicrobial properties, and we hypothesised that azithromycin would reduce decline in lung function and morbidity through preventing respiratory tract infections and controlling systemic inflammation.Methods/designWe are conducting a multicentre (Malawi and Zimbabwe), double-blind, randomised controlled trial of a 12-month course of weekly azithromycin versus placebo. The primary outcome is the mean change in forced expiratory volume in 1 second (FEV1) z-score at 12 months. Participants are followed up to 18 months to explore the durability of effect. Secondary outcomes are FEV1 z-score at 18 months, time to death, time to first acute respiratory exacerbation, number of exacerbations, number of hospitalisations, weight for age z-score at 12 and 18 months, number of adverse events, number of malaria episodes, number of bloodstream Salmonella typhi infections and number of gastroenteritis episodes. Participants will be followed up 3-monthly, and lung function will be assessed every 6 months. Laboratory substudies will be done to investigate the impact of azithromycin on systemic inflammation and on development of antimicrobial resistance as well as impact on the nasopharyngeal, lung and gut microbiome.DiscussionThe results of this trial will be of clinical relevance because there are no established guidelines on the treatment and management of HIV-associated CLD in children in sub-Saharan Africa, where 80% of the world’s HIV-infected children live and where HIV-associated CLD is highly prevalent.Trial registrationClinicalTrials.gov, NCT02426112. Registered on 21 April 2015.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-017-2344-2) contains supplementary material, which is available to authorized users.