Single High-dose of Liposomal Amphotericin B in Combination With B/F/TAF for HIV/AIDS-associated Talaromycosis

Scientific Basis/Rationale Talaromycosis caused by Talaromyces marneffei (TM) is a highly aggressive fungal infection predominantly observed in people living with HIV (PLWH). The mortality rate for untreated talaromycosis ranges from 75% to 97%, and where the infection is uncontrolled in PLWH, the fatality rate can approach 100%. Talaromycosis is endemic in South-East Asia and parts of China and India, contributing to a significant burden in these areas [1]. Notebly, talaromycosis is responsible for one-sixth of AIDS-related hospitalizations and exhibits a high mortality rate. In China, approximately 99% of TM infections are concentrated in the southern region, where it is one of the leading causes of AIDS-associated deaths. The endemic range of talaromycosis has expanded beyond traditional regions in southern China, Southeast Asian countries and Northeast India, now encompassing 34 countries and regions worldwide. The case fatality rate for untreated talaromycosis remains alarmingly high, between 75% and 100% [1, 2].

The antifungal management of talaromycosis in PLWH involves three phases: induction, consolidation and maintenance, with the induction phase being of paramount importance. Based on findings from the Itraconazole versus AmphotericinB for Penicilliosis (IVAP) studies and observational studies, the DHHS guidelines recommend amphotericin B for induction therapy, with liposomal amphotericin B (L-AMB) as the preferred agent due to its superior safety profile and favorable clinical outcome [3]. Historically, Chinese AIDS treatment guidelines have recommended amphotericin B deoxycholate (AMB d, 0.5-0.7mg/kg/d) as the standard therapy for AIDS-associated talaromycosis. However, the nephrotoxicity and adverse effects including anemia and electrolyte disturbances associated with AMB d have resulted in suboptimal therapeutic outcomes [4, 5]. L-AMB has demonstrated reduced toxicity, enhanced safety and prolonged tissue half-life [2, 6]. Following its introduction to China in June 2023, L-AMB (3-5mg/kg/d) is now recommended in updated local guidelines for HIV-associated talaromycosis [7]. Nevertheless, given the relatively recent clinical availability of L-AMB, clinical experience and data on its use in people living with HIV (PLWH) in China remain limited.

The use of single high-dose L-AMB has been explored in clinical trials for various fungal infections [8, 9]. Due to its reduced drug-induced toxicity, higher doses of L-AMB can be administered safely [10]. WHO has endorsed single high-dose L-AMB for the treatment of cryptococcal meningitis based on findings from the Ambition study [10]. Additionally, a Phase II trial investigating HIV/AIDS-associated disseminated histoplasmosis showed that a one-day induction therapy with 10 mg/kg L-AMB was both safe and effective [6]. Despite these promising findings, this therapeutic approach has not yet been rigorously evaluated in the context of HIV-associated talaromycosis.

The optimal timing of initiation of antiretroviral therapy (ART) for HIV-associated talaromycosis remains uncertain. DHHS guidelines recommend starting ART 1 week after initiating amphotericin B therapy [3]. Bictegravir/Emtricitabine/Tenofovir Alafenamide Fumarate (B/F/TAF) is a single-tablet regimen recommended for the rapid initiation of ART (within 7 days after HIV diagnosis) in PLWH, offering potent viral suppression and a favorable safety profile. However, there is a paucity of data regarding the use of regimen in PLWH with advanced opportunistic infection (OIs), including HIV-associated talaromycosis.

Hypothesis The investigators hypothesize that a single high dose regimen of L-AMB (10 mg/kg) as induction therapy for HIV-associated talaromycosis is non-inferior to the conventional administration of AmBD (0.5-0.7mg/kg/d) in terms of efficacy and is associated with an improved safety profile. Specifically, the investigators expected that key clinical outcomes including the proportion of participants who achieve clinical resolution on day 14, the rate of fungal clearance during the induction phase, the time to clinical symptom remission, and the mortality rate of patients will be comparable to those observed with conventional AmBD therapy. Additionally, the investigators anticipant a reduction in the incidence of grade 3 or above adverse events, defined by clinical or laboratory criteria. Furthermore, the investigators propose that rapid initiation of B/F/TAF within 7 days after antifungal therapy is feasible in this population. This can be demonstrated by observing indicators such as HIV suppression rate, occurrence and progression of immune reconstitution inflammatory syndrome (IRIS), the absolute median or percentage change in laboratory values (such as CD4 T cell counts) as well as the patient-reported outcomes(PROs).