Considerable progress has been made in access to HIV testing and treatment globally, with 79% of people living with HIV aware of their status and 62% receiving treatment in 2018. Expanding the testing and treatment of HIV has led to a decline in HIV-associated mortality globally by 33% between 2010 and 2018. Nevertheless, an estimated 770,000 people died from HIV-related illness in 2018 (1). Global progress has been mirrored in Latin America and the Caribbean, where an estimated 79% of people living with HIV knew their status and 61% were receiving treatment in 2018. Despite this progress, the number of people dying from HIV-associated causes declined by only 19% from 2010 to 2018 (41,000 in 2018). Further, more than 30% of the people newly diagnosed with HIV in Latin America and the Caribbean present to care with advanced HIV disease (initial CD4 cell count less than 200 cells/mm3), with little to no progress compared with 2016 (1). For Latin America and the Caribbean to reach the regional target of fewer than 19,000 people dying annually from HIV-related causes, national programs need to enhance their capacity to diagnose HIV earlier, offer antiretroviral therapy with rapid initiation to everyone living with HIV regardless of their immune status and address the most common causes of illness and death among people living with HIV (2).
Globally, leading causes of mortality among adults with advanced HIV disease include tuberculosis (TB), severe bacterial infections, cryptococcal meningitis, toxoplasmosis, and Pneumocystis jirovecii pneumonia. Among children, TB, severe bacterial infections, Pneumocystis jirovecii pneumonia, diarrheal diseases, malnutrition, and wasting are the leading causes of death (3). In Latin America and the Caribbean, in addition to TB (2), fungal infections are a major contributor to mortality, especially histoplasmosis, cryptococcal meningitis, and Pneumocystis jirovecii pneumonia; recent estimates suggest that the burden of histoplasmosis is equivalent in incidence and even higher in deaths compared with TB among people living with HIV in Latin America (4–6).
Histoplasmosis has a high endemicity in certain areas of the Americas (7). Although most frequently diagnosed in the Americas, it is also diagnosed in certain countries of Asia (China, India, Indonesia, Japan, Malaysia, Singapore, Thailand, and Viet Nam) and Africa (Central African Republic, Congo, Côte d’Ivoire, Democratic Republic of the Congo, Gambia, Guinea Bissau, Liberia, Senegal, South Africa, and Uganda) (8). Among people living with HIV, the most frequent clinical presentation of this disease is disseminated histoplasmosis. Symptoms of disseminated histoplasmosis are nonspecific and may be indistinguishable from those of other infectious diseases, especially TB, thus complicating diagnosis and treatment (9). Most histoplasmosis reports come from the Region of the Americas, and each year there are up to 15,600 new cases and 4,500 deaths among people living with HIV (4).
Although recent technological advances have improved the diagnostic accuracy of fungal diseases, these technologies are not yet widely available. Conventional laboratory methods such as culture and histopathology that are used for diagnosing histoplasmosis have several limitations; these include the need for complex laboratory infrastructure (Biosafety Level 3 laboratory), limited laboratory staff with mycology training, delays of several weeks for final diagnosis, and variable diagnostic sensitivity (10). Antibody tests are less sensitive for immunocompromised people, with sensitivity ranging between 38% and 70%, and not usually helpful for diagnosing disseminated histoplasmosis among people living with HIV (10). Although the detection of circulating Histoplasma antigens in urine by enzyme-linked immunosorbent assay (ELISA) has proven highly sensitive (95%) for diagnosing disseminated histoplasmosis, testing is hampered by the limited availability of commercial in vitro diagnostic kits and poor local distribution (10). In summary, lack of access to appropriate antifungal therapies, in vitro diagnostics for rapid detection of histoplasmosis and the co-occurrence of other infectious diseases, especially TB, may affect clinical outcomes and underlie the high mortality of disseminated histoplasmosis among people living with HIV (11, 12).
Recognizing the importance of addressing late HIV diagnosis and deploying differentiated packages of care for people living with HIV with advanced HIV disease, the WHO has recently published guidance documents and recommendations for managing advanced HIV disease and rapidly initiating antiretroviral therapy (3) and updated guidelines for diagnosing, preventing, and managing cryptococcal disease among adults, adolescents, and children living with HIV (13). WHO’s consolidated guidelines for managing advanced HIV disease do not include histoplasmosis but acknowledge its higher burden in Latin America. In 2019, WHO’s updated Model List of Essential In Vitro Diagnostics included Histoplasma antigen testing, and the List of Essential Medicines included new effective antifungal agents (14, 15). Guidelines for managing advanced HIV disease were developed before the availability and inclusion of Histoplasma antigen assays and antifungal medicines in the WHO Model List of Essential In Vitro Diagnostics. These new opportunities, together with updated data on the burden of histoplasmosis among people living with HIV, provide the rationale for producing this WHO guidance for diagnosing and managing disseminated histoplasmosis among people living with HIV.
2.1. Objectives
The objectives of these guidelines are to provide updated, evidence-informed recommendations as well as additional clinical and implementation guidance for a public health approach to diagnosing and managing disseminated histoplasmosis and disseminated histoplasmosis and TB coinfection among people living with HIV. The recommendations contained in these guidelines and provision of technical cooperation for their implementation is expected to improve the capacity to diagnose and treat histoplasmosis throughout regions that are endemic for this disease.
2.2. Target audience
The target audience for these guidelines includes HIV program managers, policy-makers, national treatment advisory boards, implementing partners, and health-care professionals providing care for people living with HIV in resource-limited settings, especially in countries with a high burden of histoplasmosis. These guidelines were initially developed for Latin America and the Caribbean. Nevertheless, the recommendations apply globally.
2.3. Guiding principles
The following principles have informed the development of these guidelines:
The guidelines are based on a public health approach to scaling up the use of antiretroviral therapy along the continuum of HIV prevention, care, and treatment.
Detecting HIV infection early and rapidly initiating antiretroviral therapy, regardless of CD4 count or immune status (“treat all”), are the most important strategies to reduce the incidence of opportunistic infections.
Early and rapid diagnosis and prompt initiation of optimal antifungal treatment are essential to improving survival among people living with HIV who have histoplasmosis.
People should be promptly referred for HIV testing and care after being diagnosed with histoplasmosis to facilitate prompt HIV diagnosis, linkage to care and uptake of antiretroviral therapy.
The implementation of the recommendations in these guidelines should be informed by local context, including HIV epidemiology, the burden of histoplasmosis, the prevalence of other comorbidities, access to laboratory services and availability of specific assays, access to antifungal medicines for treatment, the organization and capacity of the health system, and the anticipated cost-effectiveness.
Annex 1 summarizes the methods for developing these guidelines.
