NIHR Global Health Research Group on HIV-associated Fungal Infections 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. 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. 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. 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.