A neglected epidemic: fungal infections in HIV/AIDS Darius Armstrong-James 1 , Graeme Meintjes 2 , and Gordon D. Brown 2, 3 1 Imperial Fungal Diseases Group, Imperial College London, Department of Infectious Diseases and Immunity, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK 2 Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, 7925 Cape Town, South Africa 3 Aberdeen Fungal Group, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK Invasive fungal infections (IFIs) are a major cause of HIV- related mortality globally. Despite widespread rollout of combined antiretroviral therapy, there are still up to 1 million deaths annually from IFIs, accounting for 50% of all AIDS-related death. A historic failure to focus efforts on the IFIs that kill so many HIV patients has led to fundamental flaws in the management of advanced HIV infection. This review, based on the EMBO AIDS-Related Mycoses Workshop in Cape Town in July 2013, sum- marizes the current state of the-art in AIDS-related mycoses, and the key action points required to improve outcomes from these devastating infections. Fungal infections and HIV/AIDS Invasive fungal infections (IFIs) have rapidly emerged as a global threat to health owing to an increasing population of immunocompromised individuals and our dynamic interface with natural ecosystems [1]. The global HIV pandemic is now a major driver for mortality from fungal diseases worldwide [2]. Although combined antiretroviral therapy (cART) has dramatically changed the face of the HIV epidemic, many patients still present to clinical services with advanced HIV-related immunosuppression, particularly in developing countries. A failure to ade- quately address the IFIs that affect such patients has become a primary driver for AIDS-related death world- wide (Table 1). In July 2013, leading researchers from around the world working at the interface of HIV and IFIs met at the EMBO AIDS-Related Mycoses Conference in Cape Town, South Africa, to address these issues. In this review we summarise the major topics discussed: the epidemiological interaction between HIV and fungal infec- tions; the immunopathogenesis and clinical aspects of fungal infection in the context of HIV/AIDS; and key knowledge gaps that need to be addressed to reduce the unacceptably high mortality. A formal position statement produced at the conference also accompanies this article [3]. Common fungal infections in HIV and their global impact Since the first cases of AIDS were identified in San Fran- cisco and New York in the early 1980s, opportunistic fungal infections have been a primary driver for mortality from HIV infection. Although Pneumocystis pneumonia (PCP) was initially responsible for over 70% of the first 400 recorded deaths from HIV/AIDS, cryptococcal meningitis (CM) now accounts for the majority of worldwide deaths from HIV-related fungal infection (Table 1) [4,5]. Further- more, the ongoing HIV pandemic has led to the emergence of further opportunistic infections in the context of endemic mycoses. Cryptococcosis CM is a devastating infection associated with a high case fatality rate, primarily associated with advanced HIV dis- ease (typically a CD4 T cell count < 100 cells/mm 3 ) [5,6] and caused by the basidiomycete Cryptococcus neoformans. Infection is acquired by inhalation, and a failure to control latent infection in alveolar macrophages as a consequence of HIV infection leads to systemic dissemination with death from meningoencephalitis and raised intracranial pressure [5]. The majority of HIV-related CM occurs in sub- Saharan Africa; an epidemiological study published in 2009 suggested that there are 720 000 cases per annum in this region, and approximately 950 000 cases globally per annum [5]. There are an estimated 120 000 cases per annum in South and Southeast Asia, 7800 cases in North America, 6500 cases in North Africa and the Middle East, 500 cases in Western and Central Europe, and 100 cases in Oceania. As a consequence of these infections, there are 625 000 deaths due to CM globally per annum. Case fatal- ity rates among treated patients vary widely, from approxi- mately 9% in developed countries to 70% in sub-Saharan Africa, reflecting differences in time to diagnosis and ther- apy used. In addition, cryptococcal immune reconstitution inflammatory syndrome (IRIS) has emerged as a major problem and a significant contributor to mortality. We urgently need better global surveillance to accurately define the evolving disease burden of CM. Amphotericin B and flucytosine are the cornerstone of antifungal therapy for CM. Recent studies have sought to determine optimal treatment regimens that can be used in developing countries, where amphotericin B is difficult to administer owing to its intravenous formulation, toxicity, Review 0966-842X/$ – see front matter ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tim.2014.01.001 Corresponding author: Armstrong-James, D. (d.armstrong@imperial.ac.uk). Keywords: HIV; fungal infection; immunity; AIDS; mycoses. 120 Trends in Microbiology, March 2014, Vol. 22, No. 3