Abstract
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.
Highlights
Human immunodeficiency virus (HIV)-related chronic lung disease (CLD) among children is associated with substantial morbidity, despite antiretroviral therapy
The 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 HIVinfected children live and where HIV-associated CLD is highly prevalent
No association was observed between abnormal lung function, antiretroviral therapy (ART) use or duration or CD4 count, suggesting that this form of HIV-related chronic lung disease may not be responsive to ART
Summary
The massive scale-up of ART programmes globally has resulted in a dramatic improvement in survival, such that increasing numbers of children perinatally infected with HIV, many of whom would have died in early childhood without HIV treatment, are reaching adolescence. We postulate that azithromycin is a strong candidate as a therapeutic agent for HIV-associated chronic lung disease, given its broadspectrum antibiotic activity and its anti-inflammatory and immunomodulatory properties, as well as demonstrated activity in similar chronic lung diseases and a good safety profile and tolerability. In this trial, we will investigate the effect of azithromycin on lung function as well as on acute exacerbations and other infections, and the trial will provide insight into the pathogenesis of this condition.
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