Liposomal Amphotericin B and Flucytosine Antifungal Strategy for Talaromycosis (LAmB-FAST)

Talaromycosis (formerly known as penicilliosis) is caused by the dimorphic fungus Talaromyces marneffei (Tm) endemic in Southeast Asia where it is a leading the cause of death among people with advanced HIV disease (AHD, CD4 count \<200 cells/mm3 and/or WHO disease stage III or IV). Despite the mortality on treatment as high as 30%, current treatment options are limited to just two drugs: amphotericin B deoxycholate (DAmB) - which has substantial toxicity, and itraconazole - which has poor bioavailability.

As a roadmap to identify safer and more effective antifungal strategies, LAmB-FAST applies major advances made in HIV-associated mycoses to accelerate treatment for HIV-associated talaromycosis. First, clinical trials in cryptococcosis showed that shorter courses (5 to 7 days) of DAmB was as effective and less toxic than the standard 14-day course of DAmB. The recent AMBITION cryptococcal meningitis showed that a single 10 mg/kg dose of liposomal amphotericin B (LAmB) was as effective as 7 to 14 days of DAmB but had 30% less toxicity, leading to rapid endorsement by the WHO as the first-line therapy for cryptococcal meningitis in 2022. A single LAmB induction therapy strategy has also been demonstrated in a phase II HIV-associated histoplasmosis trial which showed that a single 10 mg/kg dose of LAmB had similar mortality compared to 2 doses or 14 daily doses of LAmB. Second, the addition of flucytosine (5FC) to DAmB has been shown to improves fungal clearance in the cerebrospinnal fluid and survival of patients with cryptococcal meningitis. These advances in other HIV-associated mycoses lead us to hypothesize that 1) a single 10mg/kg dose of LAmB will be superior to 14 days of DAmB and 2) the addition of 5FC will be superior to DAmB or LAmB alone in the induction therapy of talaromyosis.

LAmB-FAST will test three related but independent specific aims: AIM 1: To determine if a single 10mg/kg dose of LAmB is superior to 14 days of DAmB in Tm complication-free survival. AIM 2:

To determine if combination therapy with 5FC is superior to DAmB or LAmB alone in Tm complication-free survival.

The primary outcome (for both AIM 1 and AIM 2) is hazard of a composite of death, Tm complications, and adverse events (AEs) grade 3 or higher.

The secondary outcomes include:

1. All-cause mortality; 2. Fungal clearance rate over first 14 days; 3. A novel 4-scale hierarchical outcome of i. Mortality, ii. Tm complications, iii. AEs grade 3, iv. Quality of life scores; 4. Rates of Tm DNA and Tm antigen decline over first 12 weeks.

AIM 3 will leverage access to a well-characterized and treated talaromycosis cohort in AIM 1 and AIM 2 to conduct a follow-on nested randomized controlled sub-study testing whether a HIV viral load guided strategy of stopping itraconazole chemoprophylaxis (STOP SHORT) is non-inferior to the current CD4 guided strategy in the prevention of talaromycosis relapse and death.

• All cause mortality [Time frame: up to 24 weeks]
• Fungal clearance rate as measured by early fungicidal activity (EFA) in log10 CFUs/mL/day [Time frame: 14 days]
• Composite ordinal desirability of outcome ranking (DOOR) scale [Time frame: over 24 weeks]
• Change in Talaromyces marneffei DNA in copies/mL/week [Time frame: baseline to 24 weeks]
• Change in Talaromyces marneffei antigen in µg/mL/week [Time frame: baseline to 24 weeks]