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

Jane Gakuru; Enock Kagimu; Biyue Dai; Samuel Okurut; Laura Nsangi; Nathan C Bahr; Michael Okirwoth; Olivie C Namuju; Joseph N Jarvis; David S Lawrence; Cynthia Ahimbisibwe; Jayne Ellis; Kizza Kandole Tadeo; David R Boulware; David B Meya; Lillian Tugume

doi:10.1093/cid/ciae413

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

Clin Infect Dis. 2024 Aug 24:ciae413. doi: 10.1093/cid/ciae413. Online ahead of print.

Authors

Jane Gakuru¹, Enock Kagimu¹, Biyue Dai², Samuel Okurut¹, Laura Nsangi¹, Nathan C Bahr³, Michael Okirwoth¹, Olivie C Namuju¹, Joseph N Jarvis^{4

5}, David S Lawrence^{4

5

6}, Cynthia Ahimbisibwe¹, Jayne Ellis^{1

4}, Kizza Kandole Tadeo¹, David R Boulware³, David B Meya^{1

3

7}, Lillian Tugume¹

Affiliations

¹ Infectious Diseases Institute, Makerere University, Kampala, Uganda.
² Division of Biostatistics and Health Data Science, University of Minnesota, Minneapolis, MN, USA.
³ Division of Infectious Diseases & International Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
⁴ Clinical Research Department, London School of Hygiene and Tropical Medicine, Keppel Street, London, UK.
⁵ Botswana Harvard Health Partnership, Gaborone, Botswana.
⁶ School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
⁷ College of Health Sciences, Makerere University, Kampala, Uganda.

PMID: 39180324
DOI: 10.1093/cid/ciae413

Abstract

Background: In 2022, the World Health Organization (WHO) recommended a single 10mg/kg dose of liposomal amphotericin B in combination with 14 days of flucytosine and fluconazole (AMBITION-cm regimen) for induction therapy of 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 2018-2021. No significant difference in 10-week survival occurred between the observational cohort (68.6%; 95%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).

Conclusion: 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.