Histoplasmosis Induction and Consolidation Therapy Factorial Randomized Clinical Trial (HISTO-FACT)

Abstract Histoplasma capsulatum causes histoplasmosis, which is estimated to occur in ~500,000 persons per year in the U.S. alone and is most common cause of HIV-related mortality in Central and South America. While many cases are asymptomatic or mildly symptomatic, disseminated histoplasmosis (particularly in those with immune compromise) leads to significant morbidity and mortality. Current therapy for moderate-severe histoplasmosis consists of induction with daily liposomal amphotericin B (3mg/kg) for 2 weeks followed by at least 12 months of itraconazole consolidation therapy. Despite these treatments, 6-month mortality remains ~25%. Further, these toxic therapies commonly cause drug-drug interactions, kidney injury, electrolyte disturbances which can lead to fatal cardiac arrythmias, liver toxicity and GI symptoms, which commonly cause early discontinuation. Thus, there is a clear clinical need for improved therapies in moderate to severe histoplasmosis. Our team led a phase II clinical trial comparing single high-dose (10mg/kg) liposomal amphotericin B to daily standard dose liposomal amphotericin B for induction therapy in histoplasmosis and found similar efficacy but improved safety in the experimental arm. Posaconazole has excellent in vitro activity against Histoplasma capsulatum, case series’ showing good outcomes in a small number of human cases, and favorable tolerability compared to itraconazole. Lastly, 12 months of consolidation therapy for people with HIV is a remnant from a time when anti-retroviral therapy access and potency were poor – these have improved and six months may be adequate with lower costs and toxicity for patients. We need a large phase III trial to answer these questions. Our overall objective is to reduce morbidity and mortality due to moderate to severe histoplasmosis while improving safety and tolerability of therapy through a phase III, factorial design clinical trial. Our aims are: 1. To assess the safety and efficacy of a single high-dose liposomal amphotericin B (10mg/kg) compared to the standard of care (SOC) daily dosing (3mg/kg) for induction therapy in moderate to severe histoplasmosis. 2. To assess the safety and efficacy posaconazole for consolidation therapy compared to SOC itraconazole in moderate to severe histoplasmosis. 3. To assess the safety and efficacy of 6 months of consolidation therapy compared to the SOC 12 months of consolidation therapy in persons with HIV on appropriate antiretroviral therapy. This proposal has the potential to completely change every aspect of therapy for moderate to severe histoplasmosis. If successful, this trial would lead to histoplasmosis therapies that are less toxic, more tolerable and more affordable, translating to better outcomes in histoplasmosis and shorter hospitalizations. These results would change WHO, PAHO and U.S. guidelines for histoplasmosis.