Neglected Diseases
Histoplasmosis is a fungal infection caused by the dimorphic fungi Histoplasma capsulatum, transmitted via inhalation of spores from contaminated soil. In most cases, histoplasmosis presents as an asymptomatic infection or self-limited flu-like illness. Individuals with a compromised T-cell immune response, such as those with HIV, can develop more serious diseases, including chronic pulmonary histoplasmosis or disseminated histoplasmosis – conditions that have a striking similarity with the pulmonary and miliary forms of tuberculosis, respectively, making clinical differentiation difficult.
Histoplasma is mostly found in the Americas but has been reported in most countries, including in Africa and Asia. The HIV/AIDS pandemic resulted in an increased incidence of the more severe disseminated form of histoplasmosis in endemic regions of the Americas, particularly in Latin America, where over 15,000 new cases and 4,500 deaths from disseminated histoplasmosis are reported each year among people living with HIV/AIDS (PLWHA). Recent estimates suggest that there is a higher incidence of histoplasmosis than of TB among PLWHA in Latin America and that histoplasmosis causes more deaths.
Timely diagnosis and early start of treatment are critical for histoplasmosis management, as disseminated histoplasmosis is often fatal if left untreated. Clinical guidelines for managing histoplasmosis recommend a year-long treatment with liposomal amphotericin B and itraconazole. Though highly efficacious, the parenteral liposomal amphotericin B is heat unstable, and itraconazole presents significant drug-drug interaction with anti-tubercular and anti-retroviral medications, thus requiring monitoring of its blood concentrations, limiting LMIC use. There is a need for new treatments, preferably oral, with shorter duration, that are safe in combination with other therapies. Most new investigational agents are in early-stage development, with only the triterpenoid antifungal by Scynexis Inc., Ibrexafungerp, undergoing a Phase III trial for histoplasmosis. Current techniques for diagnosing Histoplasma are mainly laboratory-based with inconsistent sensitivity, making them unsuitable in poor-resource settings. Highly sensitive and specific point-of-care tests, which are appropriate for LMIC settings are urgently needed – such as antigen-based RDT from MiraVista diagnostics.
An in-vitro study showed that mebendazole could potentially be repurposed for the treatment of histoplasmosis. Ibrexafungerp, developed by Scynexis Inc, reported interim analysis from its ongoing Phase III trial showing positive responses for invasive candidiasis, vulvovaginal candidiasis, and invasive aspergillosis. Although histoplasmosis was one of the fungal conditions included in the trial, investigators have not yet reported any data showing effectiveness against histoplasmosis, potentially suggesting there are no significant effects. An enzyme-linked immunospot (ELISpot) assay was developed using yeast cell lysate antigen prepared from a representative North American Histoplasma capsulatum strain. The histoSPOT assay was found to be 78% sensitive and 100% specific as an aid to diagnosing histoplasmosis in people with suspected active disease.