Implementation challenges include: (1) access to rapid diagnostics; (2) access to optimal antifungal medicines; and (3) educating and training health-care providers.
4.1. Access to rapid diagnostics
Since early diagnosis and timely treatment initiation are key to improving mortality from histoplasmosis, countries need to give priority to access to high-quality in vitro diagnostics for rapid detection of Histoplasma antigen (17, 18, 21, 22). The WHO Model List of Essential In Vitro Diagnostics recently included immunoassays for Histoplasma antigen detection for implementation in clinical laboratory settings (14). Lateral flow assay–based rapid diagnostic tests for Histoplasma antigen will soon be available and provide additional opportunities to rapidly diagnose histoplasmosis at the point of care (49). Price negotiation and pooled procurement mechanisms should be used to improve access, especially for countries highly endemic for histoplasmosis. For Latin America and the Caribbean, the Pan American Health Organization (PAHO) Regional Revolving Fund for Strategic Public Health Supplies is one source of potential support. Implementing this recommendation implies taking appropriate steps to guarantee adequate availability of antigen testing in health facilities managing advanced HIV disease. Kit distribution and costs should be monitored to ensure that tests are accessible.
4.2. Access to optimal antifungal medicines
The WHO Model List of Essential Medicines (15) includes optimal antifungal medicines for treating people with histoplasmosis (conventional and liposomal amphotericin B and itraconazole). Nevertheless, these drugs are not widely available in many of the countries with a high burden of histoplasmosis, and the cost of treatment is extremely high, especially for liposomal amphotericin B. Barriers to accessing antifungal medications for treating histoplasmosis may be overcome by:
increasing advocacy for drug price reduction, expanding the coverage of global access price initiatives, both in terms of scope (such as including histoplasmosis in the current access price of liposomal amphotericin B for leishmaniasis and cryptococcal meningitis) and eligible countries and promoting generic production, especially for amphotericin B;
carrying out quality assurance of available generic formulations;
ensuring national registration of all antifungal drugs and including them in national essential medicine lists based on the WHO Model List of Essential Medicines;
procuring medicines through joint regional procurement mechanisms such as the PAHO Strategic Fund;
ensuring adequate supply chains at the national level; and
developing proper drug forecasting and monitoring systems.
4.3. Educating and training health-care providers
Health-care providers need to have a low threshold for suspecting histoplasmosis among people living with HIV with advanced HIV disease and be trained in differential diagnoses with TB and other systemic fungal infections. Greater efforts need to be made to educate health-care providers and to provide policy guidance at the national level on managing histoplasmosis among people living with HIV. Effectively implementing guidelines also requires supportive supervision systems and prescribing decision-making aids.
4.4. Disseminating, adapting, and implementing the guidelines
These guidelines are available as a web-based product for dissemination and supported by peer-reviewed publications of the systematic reviews on which these recommendations are based. Although these guidelines were initially developed with a focus for the Americas, the recommendations in these guidelines apply globally, and as such will be integrated in the next edition of the WHO consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. These consolidated guidelines are planned to be reviewed and updated every 2–3 years.
WHO and PAHO will work closely with national health ministries and implementing partners to plan for rapidly disseminating, adapting, and implementing the recommendations. Key steps in dissemination include: presenting the recommendations at international conferences, workshops to support country adaptation, rapidly developing adaptation tools to assist countries in setting priorities among limited resources to facilitate full implementation over time, and carrying out briefings and joint planning for dissemination with international and national implementing partners. The policy uptake of the recommendations in national guidelines will be evaluated regularly.
4.5. Research needs
The following research questions emerge from the Guideline Development Group discussions and the evidence reviews:
What is the antigen detection performance outside the context of advanced HIV disease?
Among people with advanced HIV disease, can Histoplasma antigen detection be used as a screening approach for histoplasmosis?
Can antigen detection performance be increased by designing new antibodies through significant support in developing basic science on Histoplasma capsulatum?
Will a Histoplasma interferon-gamma release assay be useful to screen for latent histoplasmosis in advanced HIV disease, prevent histoplasmosis-associated immune reconstitution inflammatory syndrome and help to reduce the time to antiretroviral therapy initiation among people recently diagnosed with HIV?
Can antigen detection screening studies inform about the true burden of histoplasmosis from a global perspective?
Will recently developed Histoplasma antigen detection by lateral flow become the standard diagnostic method for disseminated histoplasmosis among hospitalized people with histoplasmosis, as an outpatient screening tool or both?
How can the specific impact of antigen detection on the incidence and mortality trends of HIV-associated histoplasmosis be evaluated compared with conventional practices for diagnosing histoplasmosis and the future development of more molecular biology assays?
What are the best definitions for severity of disease among people with histoplasmosis?
Among people with a clinical and immune response to therapy, can maintenance antifungal therapy be safely discontinued earlier than 12 months?
Do people with central nervous system involvement have a higher incidence of Histoplasma-related immune reconstitution inflammatory syndrome and associated mortality? In relation to this, what is the optimal time to start antiretroviral therapy?
When will Histoplasma antigen detection and liposomal amphotericin B be affordable to people with histoplasmosis in low- and middle-income countries?
What are the outcomes of treating TB and histoplasmosis coinfection?
What is the impact of genetic varieties of Histoplasma on the epidemiology and treatment response to histoplasmosis?
What are the alternative antifungal drugs or alternative treatment stewardship in the pipeline that might help increase the efficacy and decrease the secondary effects and toxicity of the recommended therapy?
The optimal dose of liposomal amphotericin B has not been determined for people living with HIV who have disseminated histoplasmosis. Based on the experience with leishmaniasis, and more recently with cryptococcosis, high doses of liposomal amphotericin B given for short periods (including as a single dose) may work as well as standard (3 mg/kg) doses given for two weeks. A randomized multicenter Phase 2 clinical trial (NCT04059770) is planned to evaluate the activity of three regimens of liposomal amphotericin B in Brazil, for disseminated histoplasmosis in hospitalized adults living with HIV: (1) 10 mg/kg single dose; (2) 10 mg/kg on day one followed by 5 mg/kg on day three; and (3) 3 mg/kg for two weeks. All induction regimens will be followed by itraconazole at 400 mg/day for one year. The study is estimated to be completed in October 2021. The incidence of immune reconstitution inflammatory syndrome should be quantified prospectively, and its severity should be described.
