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

ABSTRACT Talaromycosis is caused by the dimorphic fungus Talaromyces marneffei (Tm) endemic in Southeast Asia where it is a leading the cause of death among patients with advanced HIV disease with a mortality on treatment of 30%. Treatment options are limited to just two drugs: amphotericin B deoxycholate (DAmB) which has substantial

toxicity and itraconazole which has poor bioavailability. Our research team has recently delivered the landmark IVAP trial demonstrating the superiority of DAmB over itraconazole in survival and rate of fungal clearance, propelling DAmB as the first-line therapy in 2019. Although highly potent, DAmB infusion over 14 days is

associated with serious toxicity; hence the drug has largely been abandoned in high-income countries. As a roadmap to identify safer and more effective antifungal strategies, our proposal applies three major advances made in AIDS-associated mycoses to accelerate treatment for talaromycosis. First, clinical trials in

cryptococcosis show that shorter (5-7 days) courses of DAmB is as effective but less toxic than the standard 14- day course. Second, the AMBITION trial has shown that a single 10 mg/kg dose of liposomal amphotericin B (LAmB) is as effective as 7-14 days of DAmB but has 30% less toxicity, leading to rapid endorsement by the

WHO as the first-line therapy for cryptococcal meningitis in 2022. Third, addition of flucytosine (5FC) to DAmB has been shown to be safe, improves fungal clearance and survival. These advances in cryptococcosis 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 Tm complication free survival. We will build on our experience in leading the five-center IVAP trial in Vietnam to conduct a factorial, partially placebo-controlled trial to test two hypotheses within one LAmB-FAST trial, thus cutting time to knowledge and cost by half. We propose three

related but independent specific aims: AIM 1. Determine if a single 10mg/kg dose of LAmB is superior to 14 days of DAmB in Tm complication-free survival. AIM 2. Determine if combination therapy with 5FC is superior to DAmB or LAmB alone in Tm complication-free survival. The primary outcome for both aims 1 and 2 is hazard of a composite of death, Tm

complications, and AEs grade 3 or higher. 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. AE grade 3, iv. Quality of life scores; 3) Rates of Tm DNA and Tm antigen decline over first 12 weeks. In AIM 3,

we will leverage rare access to a well-characterized and treated talaromycosis cohort 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 the current CD4 guided strategy in the prevention of

talaromycosis relapse and death. Impact statement. The results of this trial are likely to change treatment guidelines for talaromycosis.