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BRONCHOPULMONARY FUNCTION IN RESPONSE TO AZITHROMYCIN TREATMENT FOR CHRONOC LUNG DISEASE IN HIV-INFECTED CHILDREN (BREATHE PROJECT)

Funder:                        Medical Research Council of Norway

Award Period:           September 2015-September 2019

Goal:                             To improve symptoms and lung function in HIV-infected children whose HIV infection is optimally controlled with ART through adjuvant treatment with azithromycin

Principal Investigator:            Dr Rashida Ferrand

Project Coordinator:                Ms Ethel Dauya

Data Manager:                            Ms Tsitsi Bandason

Collaborators:             BRTI; Harare Central Hospital, Ministry of Health and Child Welfare AIDS and TB Unit; London School of Hygiene and Tropical Medicine, UK; Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Malawi; University of Oxford, UK; University of Captetown

Aim

To investigate whether adjuvant treatment with azithromycin results in improvement in lung function in HIV-infected children with chronic lung disease, who are stable on antiretroviral therapy. In addition, the trial will investigate the intervention effect on mortality, exacerbations of lung disease, morbidity and adverse events related to azithromycin treatment .

Objectives

  1. To investigate the intervention effect on exacerbations of lung disease and morbidity
  2. To investigate adverse events related to azithromycin treatment
  3. To determine the effect of azithromycin therapy on antimicrobial resistance in bacteria colonizing the respiratory tract.
  4. To investigate the diversity and composition of the respiratory and gut microbiome in HIV-infected children with and without CLD, and by trial arm.
  5. To investigate the levels of biomarkers between those with and without CLD and the effect of azithromycin on biomarkers of systemic inflammation in HIV-infected children with CLD.
  6. Describe the cardiac symptoms and echocardiograph findings of HIV-infected children with chronic lung disease, who are stable on antiretroviral therapy.
  7. Determine the prevalence of right-sided cardiac dysfunction and/or pulmonary hypertension in HIV-infected children with chronic lung disease, who are stable on antiretroviral therapy, determined by echocardiography at baseline.
  8. To investigate whether adjuvant treatment with azithromycin results in improvement in right-sided cardiac function and/or pulmonary hypertension in HIV-infected children with chronic lung disease, who are stable on ARV, determined by echocardiography at 12 months.

Background

Chronic pulmonary disease (CLD) is the most common manifestation of HIV/AIDS among children, accounting for more than 50% of HIV-associated mortality. Recently, a novel form of CLD, affecting more than 30% of African HIV-infected older children was described by Ferrand et al in Zimbabwe, high-resolution CT scanning findings showed predominantly small airways disease consistent with constrictive obliterative bronchiolitis (OB). OB is a life-threatening condition that results from small airways inflammation and fibrosis, can progress to hypoxic respiratory failure and cor pulmonale, and may impair lung growth in children. The aetiology of OB is incompletely understood but is thought to be due to an interaction of immune-mediated mechanisms and processes such as infection or ischaemia, leading to tissue injury followed by aberrant fibro-proliferative remodelling in the small airways. HIV infection results in chronic systemic immune activation and this is believed to be a key mechanism of pathogenesis of several chronic complications of HIV and may also predispose to CLD. Azithromycin has anti-inflammatory activity and treatment of CLD with this agent may lead to suppression of generalized immune activation.

Methodology

BREATHE is a multi-site, individually randomised, double-blinded, placebo-controlled trial of weekly azithromycin given to HIV infected children who are stable on antiretroviral therapy but have a chronic lung disease.

In total, 400 children aged 6-16 years, living with HIV and diagnosed with CLD will be enrolled at Harare Children´s Hospital in Harare (Zimbabwe) and Queen Elizabeth Central Hospital in Blantyre (Malawi). These will receive weekly treatment with azithromycin or placebo during 12 months. Another 100 children (50 per site) living with HIV but with no CLD will be enrolled as a comparison group for laboratory sub-studies.

Lung function will be assessed using spirometry and the Forced Expiratory Volume in the first second (FEV1) will be the primary outcome. The mean FEV1 z-score will be compared between trial arms 12 months after initiation of azithromycin treatment.

Results will help in the evidence-based management of these patients and will give insight of the pathogenesis of CLD. Results will be disseminated to relevant national and international stakeholders and for publication in peer review journals.

Outcomes

  1. Comparison by trial arms, the mean (sd) Forced Expiratory Volume in one second z score (FEV1z) after 12 months of initiation of the trial drug
  2. Time to death and first acute exacerbation
  3. Number of hospitalizations, exacerbations and mild, moderate and severe adverse events by 12 and 18 months after azithromycin initiation
  4. Incidence of blood stream infections due to Salmonella typhi and non-typhi and gastroenteritis episodes in the 12 months after treatment initiation
  5. Prevalence of colonization with macrolide (and multidrug-resistant) Streptococcus pneumoniae, Staphylococcus aureus and Haemophilus influenzae in the two trial arms at 12 months after initiation of therapy with azithromycin
  6. Composition and diversity of the respiratory bacterial microbiome gut bacterial microbiome (determined by culture of clinically relevant organisms and sequencing of 16s rRNA gene amplicons) at 12 months by trial arm AND between those with and without CLD at baseline
  7. Association between biomarker levels and FEV1 z-score; Comparison of levels of biomarkers of systemic and pulmonary inflammation between the two trial arms at 12 and 18 months after initiation of therapy with azithromycin
  8. Baseline echocardiographic parameters and prevalence of right sided cardiac dilatation and dysfunction
  9. Prevalence of right sided cardiac dilatation and dysfunction at 12 months after initiation of therapy with azithromycin between the two trial arms
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