NIHR Global Health Research Group on HIV-associated Fungal Infections

Invasive fungal infections are a growing global threat to human health, affecting >150 million people and accounting for up to 1.5 million deaths per year. However, this burden is under-appreciated and medical mycology is chronically underfunded. Research into improvements in diagnosis and treatment and implementation of this research are essential to reduce death and disability. Four HIV-associated fungal infections - cryptococcal meningitis, talaromycosis, Pneumocystis jirovecii pneumonia (PCP), and histoplasmosis - are responsible for 250,000 deaths per year, and up to 20% of all HIV-associated mortality. The WHO has recognized that HIV deaths cannot be further reduced until these major complications of advanced HIV disease are effectively addressed. This proposal brings together a team of leading researchers, clinians, NGO partners (MSF and DNDi), and community and patient representatives, to improve the diagnosis and treatment of these HIV-associated fungal infections and ensure that these improvements are made widely available to the underserved populations most commonly affected in Africa (DRC, Mozambique, Guinea, Malawi, Botswana, South Africa), and SE Asia (Vietnam). Specifically, our partnership will: 1) Implement improved treatment for cryptococcal meningitis, building on the results of 2 landmark trials, ACTA and AMBITION-cm, completed by partners in this consortium, demonstrating improved survival with regimens that are practical and affordable in resource-limited settings. 2) Optimize the screen-and-treat strategy, to identify and treat early cryptococcal disease, before it becomes clinically apparent, in Africa. Semi-quantitative tests will be evaluated for cryptococcal antigen screening, and the PK of pre-emptive treatment with modified-release flucytosine determined. Screening will be evaluated to prevent talaromycosis, cryptococcosis, and histoplasmosis in SE Asia, and histoplasmosis and emergomycosis in Africa. The cost-effectiveness of pre-emptive therapies for cryptococcosis, and of combined screening for the 3 major fungal infections prevalent in SE Asia will be modelled. 3) Initiate a programme of earlier-stage, laboratory-based work on PCP, and develop a clinical cohort and sample bio-bank as a resource to develop and test novel diagnostic tests for PCP, which constitutes the major barrier to reducing PCP deaths. 4) Support a comprehensive training and capacity strengthening programme in clinical (epidemiology, health economics and/or public health), and laboratory research, and including 3 laboratory, MSc, 2 taught MSc and 3 PhD places. Training will be enabled by a recent strategic UK-African partnership based at the University of Cape Town (UCT) between the MRC Centre for Medical Mycology and UCT, and will build on our extensive experience of training and capacity strengthening within existing multinational projects. Our goal is to train and mentor clinicians and researchers who will help drive and develop this partnership beyond the initial 4-year period. Our partnership will be equitable, with leadership shared across the work packages, insights from qualitative research, guidance from a community advisory board, and priorities set at initial meetings led by LMIC partners. In addition to the direct impact of the work, we will liaise with national, regional, and international bodies (MoHs, MSF and other major NGOs, UNITAID, WHO) in order to effectively scale the results and impact of our work.