Impact of low level viremia, immune and inflammatory status on the risk of viral failure in HIV infected children and adolescents with chronic lung disease

Background and Objectives Chronic lung disease (CLD) is one of the most manifestations of HIV infection among children even in the era of antiretroviral therapy. Studies across sub-Saharan Africa have shown a high prevalence of CLD characterised by chronic cough, reduced exercise tolerance, hypoxia and reduced lung function. Radiological studies show predominantly small airways disease consistent with constrictive obliterative bronchiolitis (OB), a condition that results from small airways inflammation and fibrosis. HIV results in dysregulated immune activation and also predisposes to infections, which is thought to be the underlying driver for development of CLD. Azithromycin has both anti-inflammatory and antibiotic activity and has een shown to be effective in a number of chronic lung diseases. The overall goal of the BREATHE trial was to investigate whether azithromycin given weekly over 48 weeks improves lung function and reduces the risk of respiratory exacerbations among children aged 6-19 years with HIV takig antiretroviral therapy. In addition the trial investigated the risk of development of antimicrobial resistance and the effect of azithromycin on the respiratory and gut microbiome. The trial also investigated whether azithromycin reduced systemic inflammation. R&D task and groups involved in project implementation The R&D tasks included the conduct of a multi-country Phase III double-blinded placebo-controlled trial of azithromycin compliant with the principles of Good Clinical Practice and monitoring of the safety of the trial drug. In addition, laboratory studies to assess drug resistance and changes in the gut and respiratory microbiome and in systemic inflammatory biomarkers were undertaken. The project was undertaken by a consortium of the following institutions: University of Tromso, Norway Malawi-Liverpool-Wellcome Programme & College of Medicine, Malawi Biomedical Research and Training Institute & University of Zimbabwe, Zimbabwe University of Cape Town, South Africa London School of Hygiene & Tropical Medicine (LSHTM), UK University of Oxford, UK The trial was conducted in Malawi and Zimbabwe, with participants recruited from Queen Elizabeth Hospital Blantyre, and Harare Central Hospital, Harare, respectively. Research teams in both countries undertook eligibility screening, recruitment, follow-up and safety monitoring of participants. Samples for laboratory studies were collected at predefined intervals by the study teams at each trial site. Samples were shipped to Cape Town for studies to investigate antimicrobial resistance and a collaboration between the Universities of Tromso and Cape Town was established to conduct the microbiome studies. Researchers from the University of Oxford established assays in Harare for measurement of biomarkers, using Luminex technology (established through the project). The LSHTM provided oversight on study design, data management and analysis. The trial was managed from the BRTI, where the Chief Investigator (Professor Ferrand) is based. The trial protocol, the Clinical Record Forms and Standard Operating Procedures were all developed locally at the institutions where the trial was implemented. Data management and analysis were performed in the countries that the trial was conducted in (Malawi and Zimbabwe). The trial was commended by the Sponsor and the External Monitoring Agencies for the consistently high standards of practice maintained by the trial. The major finding of the trial was that azithromycin did not show a significant difference in lung function but significantly reduced the risk of acute respiratory exacerbations. Azithromycin was found to be safe and well-tolerated. The trial protocol and main trial findings have been published. Papers are coming continuously together with the PhDs ongoing and finished. Sovarshaevas PhD was the practical result of the Helse Nord funding. The project findings have strong significance and translational value at several levels. To date, paediatric HIV programmes have predominantly focused on delivery of antiretroviral infection, and there has been little focus on comorbidities associated with HIV infection and/or its treatment. It is becoming increasingly apparent that longstanding HIV is associated with multisystem co-morbidities in children, many of which are unrecognised and unaddressed in clinical practice. Th project contributes to increasing the awareness of CLD and more generally the adverse long term effects of HIV infection in children growing up with HIV ,despite antiretroviral therapy. BREATHE is the first project to trial an intervention to address HIV-associated chronic lung disease in children and that it has a role to play in management of CLD. It confirms that azithromycin is a safe and well-tolerated drug. It also contributes to our understanding of the underlying pathogenesis of the condition, including the likely common pathogenic pathways which may contribute to multisystem comorbidities. The trial is particularly complex- it enrolled an age-group that is often excluded from clinical trials. A key contribution of the trial is the learning on the clinical, statistical, ethical challenges associated with research with children and adolescents. The BREATHE project also is a model for a collaborative North-South and South-South effort and how scientific platforms can be used for developing of scientific capacity. Not only was the centre of gravity of the project based in the global South, but the project facilitated a flow of expertise from North to South, South to South and South to North. The findings of the project are being disseminated through a number of channels. A dissemination meeting including academics, clinicians, programmers, policy makers, community-based organisations and donors was held in Harare in November 2020, at which the project findings were presented. Findings have also bene presented at conferences through the course of the project. The main trial results were presented at the CROI 2020 conference (oral presentation) and the findings have also been published in JAMA Network Open. A total of 13 papers have already been published and additional papers are under review, in draft form or in preparation. The findings have also been presented at a CDC/UNIATIS/CHAI webinar. A policy brief is being drafted which will be shared with national and international policy makers including the WHO HIV Department. We anticipate that this will be used to inform the guidelines on management of HIV-associated comorbidities within WHO HIV treatment guidelines. As described above, the project included a number of mechanistic studies which could only be completed once the final samples (at the end of follow-up) had been obtained. These studies have been ongoing and are currently being analysed. These include the impact of azithromycin on biomarkers, the microbiome and drug resistance. In addition, the project also investigated growth and HIV viral load trends, adherence measurement approaches and the impact of azithromycin on cardiac function (as chronic lung disease can result in secondary pulmonary hypertension). Finally, a PhD project around development of Quality of Life measures for children and adolescents was embedded within the BREATHE project and findings of this project are outstanding.