Histoplasmosis: a missing piece in the global efforts to end HIV deaths

Histoplasmosis is a leading opportunistic infection and cause of mortality in people with advanced HIV disease. Yet, histoplasmosis is largely neglected in the global HIV response. Previously considered endemic only in the region of the Americas, histoplasmosis is now recognised to be distributed throughout much of sub-Saharan Africa, southeast Asia, and other parts of the world. Making a diagnosis is the greatest challenge. Commercial Histoplasma antigen tests are highly sensitive and specific and provide the best tool for early diagnosis of disseminated histoplasmosis, but global access is extremely scarce, leading to misdiagnosis, inadequate knowledge on the global burden of disease, and ultimately impeding progress towards ending deaths from advanced HIV disease. The number of effective antifungal agents remains limited; current regimens rely on amphotericin B with high efficacy but substantial toxicity, and itraconazole with suboptimal absorption and potency. Latin America's progress towards coordinated surveillance, diagnostic scale-up, and standardised treatment protocols, offer a practical model for other endemic countries seeking to reduce deaths from histoplasmosis. This Review assesses current knowledge in epidemiology, diagnosis, and treatment histoplasmosis, and calls for urgent investment in research and integration of Histoplasma antigen screening into the advanced HIV disease package of care to end the systemic neglect of histoplasmosis within the global HIV response.