Azithromycin versus placebo for the treatment of HIV-associated chronic lung disease in children and adolescents (BREATHE trial) : study protocol for a randomised controlled trial
Kranzer, Katharina; McHugh, Grace; Corbett, Elizabeth L.; Mujuru, Hilda; Nicol, Mark P.; Rowland-Jones, Sarah; Rehman, Andrea M.; Gutteberg, Tore J.; Flaegstad, Trond; Odland, Jon Oyvind; Ferrand, Rashida A.; BREATHE study team
BACKGROUND : Human 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/DESIGN : We 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.
DISCUSSION : 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.