Award Title: NIHR Global Health Research Group on HIV-associated Fungal Infections
Funder: Department of Health and Social Care

Abstract: 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. _x000D_
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:_x000D_
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. _x000D_
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. _x000D_
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. _x000D_
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._x000D_
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.

Lay Abstract: Invasive fungal infections are a major threat to human health, but their importance is under-recognized. Research into improved diagnosis and treatment and their implementation are essential to reduce death and disability but have been chronically underfunded. Four fungal infections most frequently seen in people living with HIV - cryptococcal meningitis, talaromycosis, Pneumocystis jiroveci pneumonia (PCP), and histoplasmosis - are responsible for approximately 250,000 deaths per year, accounting for up to 20% of all HIV-associated mortality. The WHO has recognized that HIV deaths cannot be significantly reduced until these major complications of advanced HIV disease are addressed. _x000D_
_x000D_
This proposal brings together a team of leading researchers, clinical leaders, and NGO partners (Medecin-Sans-Frontiers and DNDi), as well as civil society 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 commonly affected in LMICs in Africa (DRC, Mozambique, Guinea, Malawi, Botswana, South Africa), and SE Asia (Vietnam). We will implement early diagnosis and improved treatment for cryptococcal meningitis, building on the results of 2 landmark trials conducted by members of the consortium, demonstrating improved survival with regimens that are practical and affordable in resource-limited settings. Novel diagnostic and treatment strategies proven in cryptococcal disease will be evaluated in talaromycosis, a leading cause of HIV-associated fungal infection in SE Asia. Studies will test ways to optimize screening programmes for early manifestations of cryptococcosis, talaromycosis, and histoplasmosis, in order to identify and treat these infections before they become life-threatening. We will also initiate laboratory work and develop a clinical cohort in order to develop novel diagnostic tests for PJP, which constitutes the major roadblock to reducing PJP deaths. Promising diagnostic and therapeutic interventions will be subjected to health economic analysis and used to leverage future funding for definitive trials._x000D_
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Priorities and detailed work packages will be defined in liaison with policy makers, clinicians, and patient and civil society representatives. In addition to the impact of the work in the countries where the studies will take place, our track records of partnerships with global and regional bodies (Ministries of Health, WHO, the Global Fund, PEPFAR, UNITAID, Southern African HIV Clinicians Society, MSF, other major NGOs, and civil society organisations) will enable the results of our work to be scaled for impact on a regional and global scale._x000D_
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A pivotal component of the proposal is a comprehensive training and capacity strengthening programme in clinical research (with courses in epidemiology, health economics and public health), and in mycology, enabled by a recent strategic UK-African partnership between the MRC Centre for Medical Mycology and University of Cape Town (UCT). The training will build on our extensive experience of training and capacity strengthening within existing multinational projects, providing unique opportunities for young African and Asian clinicians and scientists to build careers in medical mycology. Our goal is to build an international coalition of clinicians and researchers who will continue to drive and develop this programme beyond the initial 4-year period.

Research Activity Codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.4 POPULATION SCREENING;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);6.1 PHARMACEUTICALS
Health Categories: INFECTION