Implementation of Single High-dose Liposomal Amphotericin B Based Induction Therapy for Treatment of HIV-associated Cryptococcal Meningitis in Uganda: A Comparative Prospective Cohort Study

Abstract

Background: In 2022, the World Health Organization (WHO) recommended a single 10 mg/kg dose of liposomal amphotericin B in combination with 14 days of flucytosine and fluconazole (AMBITION-cm regimen) for induction therapy of human immunodeficiency virus (HIV)-associated cryptococcal meningitis, based on the results of the multisite AMBITION-cm trial. We evaluated outcomes after real-world implementation of this novel regimen in Uganda.

Methods: We enrolled Ugandan adults with cryptococcal meningitis into an observational cohort receiving the AMBITION-cm regimen with therapeutic lumbar punctures in routine care during 2022-2023. We compared 10-week survival and CSF early fungicidal activity with the outcomes observed in the AMBITION-cm clinical trial conducted at the same sites.

Results: During 2022-2023, 179 adults were treated with the AMBITION-cm regimen via routine care and compared to the 171 adults randomized to the AMBITION-cm trial interventional arm in Uganda from 2018 to 2021. No significant difference in 10-week survival occurred between the observational cohort (68.6%; 95% confidence interval [CI]: 61.6%-76.3%) and AMBITION-cm trial participants in the intervention arm (71.7%; 95% CI: 65.2%-78.8%; absolute risk difference = -3.1%; 95% CI: -13.1% to 6.9%; P = .61). Early fungicidal activity did not differ (0.42 vs 0.39 log10CFU/mL/day; P = .80) between groups. Among observational cohort participants discharged alive initially and for whom follow-up data were available, the incidence of re-hospitalizations due to persistently elevated intracranial pressure was 2.8% (4/144).

Conclusions: The AMBITION-cm regimen for cryptococcal meningitis resulted in similar outcomes as observed in the AMBITION-cm clinical trial when implemented in routine care. Intracranial pressure management during hospitalization and awareness after discharge are key components of optimizing outcomes.

Keywords: HIV; advanced HIV disease; cryptococcal meningitis; implementation; liposomal amphotericin B.

Graphical Abstract

This graphical abstract is also available at Tidbit: https://tidbitapp.io/tidbits/implementation-of-single-high-dose-liposomal-amphotericin-b-based-induction-therapy-in-routine-care-for-treatment-of-hiv-associated-cryptococcal-meningitis-in-uganda-a-comparative-prospective-cohort-stud-b692ee8c-4574-4651-9bcf-7bf8c8d3afde?utm_campaign=tidbitlinkshare&utm_source=IO

Figure 1.

Cumulative 10-week all-cause mortality after cryptococcal meningitis. Comparison between the observational cohort in routine care and clinical trial group (AMBITION-cm trial intervention arm). Survival through 10 weeks did not statistically differ across study groups. Outcome data to 10 wks were available for 81% (145/179) of observational cohort participants with 32 in total lost to follow-up by 4 wks, and 34 (17%) in total lost to follow-up by 10 wks after diagnosis with right-hand censoring. One participant died on day 70. Abbreviation: AMBITION-cm, single 10 mg/kg dose of liposomal amphotericin B combined with 14-days of flucytosine and fluconazole.

Figure 2.

Frequency of lumbar punctures over time among participants in the observational cohort. The number of days from diagnosis of cryptococcal meningitis were categorized as follows: Day 1 window (within 3 d), day 7 window (4–9 d), and day 14 window (10–18 d); ≥2 d, over time. Number of days from diagnosis of cryptococcal meningitis. Abbreviation: LP, lumbar puncture.