Bronchopulmonary Function in Response to Azithromycin Treatment for Chronic Lung Disease in HIV-infected Children (BREATHE)

Bronchopulmonary Function in Response to Azithromycin Treatment for Chronic Lung Disease in HIV-infected Children

Bronchopulmonary Function in Response to Azithromycin Treatment for Chronic Lung Disease in HIV-infected Children

Biomedical Research and Training Institute, Zimbabwe, Malawi-Liverpool-Wellcome Trust Clinical Research Programme, University of Tromso, University of Cape Town, University of Oxford

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). . Azithromycin has anti-inflammatory activity and treatment of CLD with this agent may lead to suppression of generalized immune activation. This specific aims of this project are to: Primary objective: 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. Secondary objectives: To investigate the intervention effect on mortality, exacerbations of lung disease, quality of life, morbidity. To investigate adverse events related to azithromycin treatment 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 assess using spirometry and the Forced expiratory volume in the first minute (FEV1) will be the primary outcome. The mean change in FEV1 z-score levels will be compared between trial arms after 12 months of initiation of azithromycin treatment.

Clinical Phase: III Trial Design: Multi-site, individually randomised, double-blinded, placebo-controlled trial of weekly azithromycin for 12 months Trial Participants: Children aged 6-16 years living with HIV and with diagnosis of chronic lung disease. Another 200 children living with HIV but with no chronic lung disease in a comparison arm. Planned Sample Size: 400 cases and 100 in the comparison arm Treatment duration: 12 months Follow up duration: 18 months Planned Trial Period: June 2016-September 2019 Objectives: Primary trial outcome: 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. Secondary trial outcomes: .To investigate the intervention effect on mortality,exacerbations of lung disease, quality of life and morbidity.. .To investigate adverse events related to azithromycin treatment. .-Laboratory sub-studies .To determine the effect of azithromycin therapy on antimicrobial resistance in bacteria colonizing the respiratory tract. .To investigate the diversity and composition of the respiratory microbiome in HIV-infected children with CLD. .To investigate the diversity and composition of the gut microbiome in HIV-infected children with CLD. .To investigate the effect of azithromycin on biomarkers of systemic inflammation in HIV-infected children with CLD. .-Cardiac sub-study: .Describe the cardiac symptoms and echocardiograph findings of HIV-infected children with chronic lung disease. .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. Investigational Medicinal Product(s): Azithromycin and placebo. Formulation:Tablets 250 mg Dose: According to weight bands (30 mg/kg/week): 10-20 kg: 250 mg 20-29 kg: 500 mg 30-39 kg: 750 mg 40-49 kg: 1250 mg Route of Administration:Oral

Azithromycin tablets 250 mg, 30mg/kg/week by mouth, once a week for 12 months. 10-20 kg: 250 mg 20-29 kg: 500 mg 30-39 kg: 750 mg 40-49 kg: 1250 mg

Placebo tablets 250 mg, 30 mg/kg/week by mouth, once a week for 12 months. 10-20 kg: 250 mg 20-29 kg: 500 mg 30-39 kg: 750 mg 40-49 kg: 1250 mg

Prevalence of colonization with macrolide (and multidrug-resistant) Streptococcus pneumoniae, Staphylococcus aureus and Haemophilus influenzae in the two trial arms at 12 months of initiation of treatment with azithromycin

Composition and diversity of the respiratory bacterial microbiome (determined by culture of clinically relevant organisms and sequencing of 16s rRNA gene amplicons)

Composition and diversity of the gut bacterial microbiome (determined by culture of clinically relevant organisms and sequencing of 16s rRNA gene amplicons

Prevalence of right sided cardiac dilatation and dysfunction at 12 and 24 months of initiation of azithromycin therapy by intervention arm

Inclusion Criteria: Diagnosis of chronic lung disease (defined as FEV1 and/or FVC <80% predicted) Age 6-19 years Perinatally-acquired HIV infection the most likely source of transmission On first or second-line ART for at least one year HIV-1 viral load undetectable (as defined by each trial site) A firm home address accessible for visiting and intending to remain there for 24 months Willing to agree to participate in the study and to give samples of blood and sputum HIV status disclosed to child for those aged older than 12 years Exclusion Criteria: Any condition (except HIV) that may prove fatal during the study period (e.g. malignancy, end-stage HIV disease or other conditions deemed likely fatal by the trial physician) Diagnosis of active pulmonary TB Infection with non-tuberculous mycobacteria (NTM) Pregnant or breast-feeding Condition likely to lead to lack of understanding of study procedures or to uncooperative behaviour e.g. neurocognitive disease, developmental delay or psychiatric illness History of prolonged QTc syndrome or current or planned therapy with drugs likely to cause cardiac dysrhythmias Abnormal ECG findings Acute respiratory tract infection during enrolment (patients will be eligible once their acute infection is treated) Creatinine clearance of <30mls/minute ALT more than 2 times the upper limit of normal No defined guardian/stable caregiver No consent/assent from guardian/child

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Jackson C, Rehman AM, McHugh G, Gonzalez-Martinez C, Ngwira LG, Bandason T, Mujuru H, Odland JO, Corbett EL, Ferrand RA, Simms V. Risk factors for sustained virological non-suppression among children and adolescents living with HIV in Zimbabwe and Malawi: a secondary data analysis. BMC Pediatr. 2022 Jun 11;22(1):340. doi: 10.1186/s12887-022-03400-4.

Ferrand RA, McHugh G, Rehman AM, Mujuru H, Simms V, Majonga ED, Nicol MP, Flaegstad T, Gutteberg TJ, Gonzalez-Martinez C, Corbett EL, Rowland-Jones SL, Kranzer K, Weiss HA, Odland JO; BREATHE Trial Group. Effect of Once-Weekly Azithromycin vs Placebo in Children With HIV-Associated Chronic Lung Disease: The BREATHE Randomized Clinical Trial. JAMA Netw Open. 2020 Dec 1;3(12):e2028484. doi: 10.1001/jamanetworkopen.2020.28484.

Rehman AM, Ferrand R, Allen E, Simms V, McHugh G, Weiss HA. Exclusion of enrolled participants in randomised controlled trials: what to do with ineligible participants? BMJ Open. 2020 Dec 2;10(12):e039546. doi: 10.1136/bmjopen-2020-039546.

McHugh G, Rehman AM, Simms V, Gonzalez-Martinez C, Bandason T, Dauya E, Moyo B, Mujuru H, Rylance J, Sovershaeva E, Weiss HA, Kranzer K, Odland J, Ferrand RA; BREATHE Clinical Trial Team. Chronic lung disease in children and adolescents with HIV: a case-control study. Trop Med Int Health. 2020 May;25(5):590-599. doi: 10.1111/tmi.13375. Epub 2020 Feb 10.

Gonzalez-Martinez C, Kranzer K, McHugh G, Corbett EL, Mujuru H, Nicol MP, Rowland-Jones S, Rehman AM, Gutteberg TJ, Flaegstad T, Odland JO, Ferrand RA; BREATHE study team. 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. Trials. 2017 Dec 28;18(1):622. doi: 10.1186/s13063-017-2344-2.