The purpose of the study is threefold:

1. Assess the safety and efficacy of a single high-dose intravenous (LAmB 10mg/kg) compared to the SOC daily dosing (3mg/kg) of the same medication for induction therapy in moderate to severe histoplasmosis.
2. Assess the safety and efficacy of oral posaconazole 300mg delayed-release tablets three times daily for two days then once daily for consolidation therapy compared to SOC oral itraconazole 200 mg capsules three times daily for three days then twice daily in moderate to severe histoplasmosis
3. 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.

Inclusion Criteria:

• Age ≥18 years
• Hospitalized with suspected histoplasmosis b
• Diagnosis of confirmed or probable histoplasmosis (via positive Histoplasma antigen test, culture, histopathology or microscopy)
• Provision of Informed Consent by participant or surrogate c

Exclusion Criteria:

• Previous diagnosis of histoplasmosis
• Pregnant persons (all persons who could potentially be pregnant will have a pregnancy test prior to enrollment, and if negative, must agree to contraception for the duration of the study)
• Breastfeeding and unable to stop for the duration of the study
• Renal impairment (serum creatinine or blood urea nitrogen (BUN) >2.0x upper limit of normal)
• Allergy or contraindication to a study medicine
• More than one dose of an amphotericin product in the prior 7 days
• Suspected central nervous system involvement of histoplasmosis
• Likely to die in the next 48 hours in the judgment of the investigator
• Unlikely to follow up for the duration of the study in the judgement of the investigator
• Significant drug-drug interaction with itraconazole or posaconazole (such as rifampin in persons with TB)
• Current diagnosis of cryptococcosis or leishmaniasis
• QTc interval consistently >450 milliseconds
• Prisoners
• Unable to take oral medications