Treatment of Chronic Lung Disease in HIV-infected Children in Africa. A multisite controlled trial of weekly azithromycin treatment.

BREATHE is a Phase III clinical trial investigating the impact of adjuvant azithromycin on lung function and morbidity in children and adolescents with HIV-associated chronic lung disease (HCLD) taking antiretroviral therapy (ART) in Southern Africa. The underlying hypothesis is that HCLD occurs as a sequelae of chronic immune activation and/or repeated or respiratory tract infections associated with HIV infection, and that , and azithromycin (which has both antibiotic and immunomodulatory properties) will improve lung function and lower the risk of respiratory infections. An individually-randomised double-blind placebo-controlled trial of weekly azithromycin for 48 weeks was conducted in Malawi and Zimbabwe. The primary outcome was mean difference in forced expiratory volume [FEV1], a measure of lung function, measured at the end of the intervention period. Clinical (secondary outcomes) included acute respiratory exacerbations (ARE), hospitalisations, change in weight and mortality. Sub-studies were embedded in the project to investigate antimicrobial resistance associated with azithromycin use and to understand the mechanistic pathways to understand the effect of azithromycin specifically whether azithromycin treatment reduced systemic inflammation and how it affects the respiratory and gut microbiome. The project partners are Malawi-Liverpool-Wellcome Trust Programme, the Biomedical Research and Training Institute (BRTI), Harare, the London School of Hygiene and Tropical Medicine (LSHTM), the University of Cape Town (UCT), the University of Oxford (UoO) and the University of Tromso (UiT). Project findings of 350 older HIV infected children (6-19 years) with CLD (defined as those with forced expiratory Volume in one second (FEV1)-a measure of airflow obstruction)and taking antiretroviral therapy for >6 months were randomised and followed up for 12 months. Biomarkers of inflammation and antibiotic resistance profiles by arm were studied. The trial was completed in August 2018, with a total of 347 participants recruited. There was no significant difference in FEV1 Z-score between trial arms, but azithromycin resulted in a significant reduction in the rate of acute respiratory exacerbations. The rate of hospitalisations was also much lower in the azithromycin than in the placebo arm. The adherence to medication was generally good, and as expected better adherence was associated with intervention effect. Individuals with HCLD were more likely to have colonisation by common respiratory pathogens (such as Streptococcus pneumoniae or Moraxhella catarrhalis) than an age- and sex- matched group of children with HIV without HCLD. Studies are underway to explore the impact of azithromycin on development of antimicrobial resistance and as well as on systemic immune activation. The trial findings contribute to management of chronic lung disease-this is the first trial to address HCLD in children and the findings have directly translatable potential in terms of informing treatment guidelines. Further analyses are underway to investigate what subgroups may benefit the most from azithromycin use. More broadly, the BREATHE project raises awareness of the growing burden of chronic co-morbidities in children growing up with HIV infection in the era of ART. It underscores the need to focus not only on delivery of ART and achieving viral suppression, but the need to screen for, diagnose and manage chronic comorbidities within paediatric HIV programmes. The BREATHE project has contributed to the understanding of the pathogenesis of chronic lung disease. The pathogenic pathways defined in BREATHE may provide a template for considering the underlying mechanisms to understand other HIV-associated comorbidities. In addition, the project will aim to the address an important question about the risk and persistence of resistance to azithromycin which the project has provided a platform for strengthening research capacity at different levels. The project has supported 6 doctoral (PhD) students across the consortium institutions, and 2 post-doctoral scientists. In addition, 6 MSc, 4 BSc and 2 MB BS student projects were embedded within BREATHE.

The trial is the first trial to address HIV-associated chronic lung disease in children and demonstrates that azithromycin reduced the risk of acute respiratory exacerbations in children with chronic lung disease. The project raises awareness of the growing burden of chronic co-morbidities in HIV infected children. The pathogenic pathways defined in BREATHE may provide a template for considering the underlying mechanisms to understand other HIV-associated comorbidities. The project has provided a model for developing collaboration with flow of expertise and experience across the partner institutions. Finally, public engagement and engagement with stakeholders to ensure timely dissemination and translation of findings to policy impact has been ongoing through social media, policy briefs, meetings with stakeholders, presentation at conferences and in peer-reviewed journals.

This proposal focuses on a major new disease: chronic lung disease (CLD) in older children with perinatal HIV-infection. Worldwide, >600,000 children are growing up in HIV care. These children are well integrated. Recently we have shown that CLD affects the small airways (most likely obliterative bronchiolitis) of >30%, leading to pronounced exertional desaturation and cough. Progression and acute exacerbations of CLD are the major cause of death. Evidence-based clinical guidelines are currently lacking.Our central component is a therapeutic individually-randomised placebo-controlled clinical trial of once weekly azithromycin, with the outcome (change in forced expiratory volume [FEV1]) measured after 12 months of therapy. Immunological and bacteriological substudies will allow investigation of the extent to which abnormal lung function (PFT), and response to treatment, are associated with systemic and pulmonary inflammation, and abnormal microbiome. 400 older HIV infected children (6-19 years) with CLD (abnormal PFT for age & height) on antiretroviral therapy for >6 months will be randomised and followed up for 18 months with PFT, induced sputum and blood sampling. Multiplex PCR and 16s rRNA amplification will be used to investigate the composition and diversity of the respiratory microbiome, comparing children with and without CLD (200 controls), and by randomisation arm. Biomarkers of systematic inflammation and pulmonary functional immunoassays will be investigated six monthly, our hypothesis being that small airways inflammation and fibrosis is driven by systemic inflammation and aberrant pulmonary immune function, and that response to azithromycin will be associated with normalisation of these indices together with normalisation of the respiratory microbiome. The primary outcome is to compare between randomisation arms (azithromycin once weekly versus control) the change in lung function from baseline to 12 months.