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

Summary

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: 1. 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. 2. Secondary objectives: 1. To investigate the intervention effect on mortality, exacerbations of lung disease, quality of life, morbidity. 2. 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.

Timeline

Start

2016-06

Primary completion

2018-09

Completion

2019-08

Publications

• Mushunje PK, Sovershaeva E, Olwagen CP, Madhi S, Odland JO, Ferrand RA, Nicol MP, Abotsi RE, Dube FS. Weekly azithromycin for 48 weeks impacts nasopharyngeal microbial prevalence and Streptococcus pneumoniae serotypes in children with HIV-associated chronic lung disease. Sci Rep. 2025 Nov 7;15(1):39175. doi: 10.1038/s41598-025-23693-6.
• Madanhire T, McHugh G, Simms V, Ngwira L, Gonzalez-Martinez C, Semphere R, Moyo B, Calderwood C, Nicol M, Bandason T, Odland JO, Rehman AM, Ferrand RA. Longitudinal lung function trajectories in response to azithromycin therapy for chronic lung disease in children with HIV infection: a secondary analysis of the BREATHE trial. BMC Pulm Med. 2024 Jul 12;24(1):339. doi: 10.1186/s12890-024-03155-x.
• Mushunje PK, Dube FS, Olwagen C, Madhi S, Odland JO, Ferrand RA, Nicol MP, Abotsi RE; BREATHE study team. Characterization of bacterial and viral pathogens in the respiratory tract of children with HIV-associated chronic lung disease: a case-control study. BMC Infect Dis. 2024 Jun 26;24(1):637. doi: 10.1186/s12879-024-09540-5.
• Ngwira LG, Maheswaran H, Verstraete J, Petrou S, Niessen L, Smith SC. Psychometric performance of the Chichewa versions of the EQ-5D-Y-3L and EQ-5D-Y-5L among healthy and sick children and adolescents in Malawi. J Patient Rep Outcomes. 2023 Mar 9;7(1):22. doi: 10.1186/s41687-023-00560-4.
• Rehman AM, Simms V, McHugh G, Mujuru H, Ngwira LG, Semphere R, Moyo B, Bandason T, Odland JO, Ferrand RA. Adherence to additional medication for management of HIV-associated comorbidities among older children and adolescents taking antiretroviral therapy. PLoS One. 2022 Jun 15;17(6):e0269229. doi: 10.1371/journal.pone.0269229. eCollection 2022.
• 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.

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