Abstract
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 HIV-infected children live and where HIV-associated CLD is highly prevalent.
Trial registration
ClinicalTrials.gov, NCT02426112. Registered on 21 April 2015.
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Details
1 Liverpool School of Tropical Medicine, Liverpool, UK (GRID:grid.48004.38) (ISNI:0000 0004 1936 9764); Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre 3, Malawi (GRID:grid.419393.5); College of Medicine, University of Malawi, Department of Paediatrics and Child Health, Blantyre 3, Malawi (GRID:grid.10595.38) (ISNI:0000 0001 2113 2211)
2 London School of Hygiene and Tropical Medicine, Department of Clinical Research, London, UK (GRID:grid.8991.9) (ISNI:0000 0004 0425 469X)
3 Biomedical Research and Training Institute, Harare, Zimbabwe (GRID:grid.418347.d)
4 Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre 3, Malawi (GRID:grid.419393.5); London School of Hygiene and Tropical Medicine, Department of Infectious Disease Epidemiology, London, UK (GRID:grid.8991.9) (ISNI:0000 0004 0425 469X)
5 University of Zimbabwe, Department of Paediatrics, Harare, Zimbabwe (GRID:grid.13001.33) (ISNI:0000 0004 0572 0760)
6 University of Cape Town, Division of Clinical Microbiology, Cape Town, South Africa (GRID:grid.7836.a) (ISNI:0000 0004 1937 1151); National Health Laboratory Service, Johannesburg, South Africa (GRID:grid.416657.7) (ISNI:0000 0004 0630 4574)
7 Old Road Campus, University of Oxford, Nuffield Department of Medicine, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948)
8 London School of Hygiene and Tropical Medicine, MRC Tropical Epidemiology Group, London, UK (GRID:grid.8991.9) (ISNI:0000 0004 0425 469X)
9 University Hospital of North Norway, Department of Microbiology and Infection Control, Tromsø, Norway (GRID:grid.412244.5) (ISNI:0000 0004 4689 5540); Arctic University of Norway, Faculty of Health Sciences, Tromsø, Norway (GRID:grid.10919.30) (ISNI:0000000122595234)
10 Arctic University of Norway, Faculty of Health Sciences, Tromsø, Norway (GRID:grid.10919.30) (ISNI:0000000122595234); University Hospital of North Norway, Department of Paediatrics, Tromsø, Norway (GRID:grid.412244.5) (ISNI:0000 0004 4689 5540)
11 Arctic University of Norway, Faculty of Health Sciences, Tromsø, Norway (GRID:grid.10919.30) (ISNI:0000000122595234); School of Health Systems and Public Health, Faculty of Health Sciences, University of Pretoria, Hatfield, South Africa (GRID:grid.49697.35) (ISNI:0000 0001 2107 2298)
12 Biomedical Research and Training Institute, Harare, Zimbabwe (GRID:grid.418347.d); London School of Hygiene and Tropical Medicine, Department of Infectious Disease Epidemiology, London, UK (GRID:grid.8991.9) (ISNI:0000 0004 0425 469X)