AMBITION Protocol Reduces Toxicity Without Compromising Outcomes in HIV-Associated Cryptococcal Meningitis: JAMA

A new study published in the Journal of American Medical Association showed no differences in mortality or recurrence between the AMBITION treatment and a daily amphotericin-based regimen in HIV-associated cryptococcal meningitis, however there were fewer severe side effects.

One major cause of death and morbidity among HIV-positive individuals is cryptococcal meningitis (CM). Amphotericin plus flucytosine, the standard induction treatment for CM, is linked to serious side effects. Thus, this study evaluated the mortality and CM recurrence outcomes of treating CM in a high-resource situation using the AMBITION regimen (single-dose liposomal amphotericin with two weeks of fluconazole and flucytosine).

People with HIV treated for CM using the AMBITION protocol from August 1, 2022, to July 31, 2024, and a control population acquiring a guideline-compliant, daily amphotericin-based regimen from August 1, 2020, to July 31, 2022, were included in this pre-post cohort study at Los Angeles General Medical Center, a sizable safety net hospital (80% Medicaid-covered, 5% uninsured). Ages under 18, alternative diagnoses, transfers during induction, and deaths within 48 hours of admission were among the exclusion criteria.

The exposure group underwent the AMBITION protocol, which included a single infusion of liposomal amphotericin (10 mg/kg) and 14 days of high-dose fluconazole (1200 mg/d) and flucytosine (100 mg/kg/d). For 14 days, the control group received lipid-based amphotericin (3–5 mg/kg/d) and flucytosine (100 mg/kg/d).

During the course of the study, 60 eligible patient episodes were found. Overall, 26 patients (43.3%) received the control regimen, while 34 patients (56.7%) received the AMBITION program. 6 patients in the control group (23.1%) and nine patients in the intervention group (26.5%) lost to follow-up by 90 days.

19 out of 25 patients who received the AMBITION regimen experienced the composite outcome (76.0%) compared to 7 out of 20 patients in the control group (35.0%) (P =.006). The AMBITION arm experienced fewer serious adverse events (7 [20.6%] vs. 16 [61.5%]; P =.001), which contributed to the difference in composite outcome rates.

Furthermore, fewer patient-directed discharges occurred in patients undergoing the AMBITION treatment (4 [11.8%] vs. 9 [34.6%]; P =.03). Overall, a clinical experience at a big safety net hospital in the US summarized the results of the massive AMBITION RCT, which was carried out in an LMIC context.

Source:

Clark, D., Barranco-Trabi, J., Goo, I., Chyz, M., Manchala, G., Davar, K., Freling, S., Wald-Dickler, N., Baden, R., & Spellberg, B. (2026). Single-dose liposomal amphotericin plus fluconazole and flucytosine for cryptococcal meningitis at a US public hospital. JAMA Network Open, 9(1), e2553552. https://doi.org/10.1001/jamanetworkopen.2025.53552