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Single high-dose liposomal amphotericin based regimen for treatment of HIV-associated Cryptococcal Meningitis: results of the phase-3 Ambition-cm Randomised Trial

Title
Single high-dose liposomal amphotericin based regimen for treatment of HIV-associated Cryptococcal Meningitis: results of the phase-3 Ambition-cm Randomised Trial
Presenter
David S Lawrence
Authors
D.S Lawrence * (1,2), D.B Meya (3), E. Kagimu (3), J. Kasibante (3), E. Mpoza (3), M. Rutakingirwa (3), K. Ssebambulidde (3), L. Tugume (3), J. Rhein (4,3), D.R Boulware (4,3), H. Mwandumba (5,6), M. Alufandika (5), H. Mzinganjira (5), C. Kanyama (7), M.C Hosseinipour (7), C. Chawinga (7), G. Meintjes (8), C. Schutz (8), K. Comins (8), A. Singh (8), C. Muzoora (3), S. Jjunju (3), E. Nuwagira (3), M. Mosepele (2,9), T. Leeme (2), K. Siamisang (2), C.E Ndhlovu (10), A. Hlupeni (10), C. Mutata (10), E. van Widenfelt (6), W. Hope (11), O. Lortholary (12), D.G Lalloo (6), A. Loyse (13), T. Chen (6), S.F Molloy (13), T. Boyer-Chammard (12), D. Wang (6), N. Youssouf (1,2), S. Jaffar (6), T.S Harrison (14,15,16), J.N Jarvis (1,2), & The Ambition Study Group (1)
Institutions
(1) London School of Hygiene and Tropical Medicine, Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London, United Kingdom, (2) Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana, (3) Makerere University, Infectious Diseases Institute, Kampala, Uganda, (4) University of Minnesota, Department of Medicine, Minneapolis, United States, (5) Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi, (6) Liverpool School of Tropical Medicine, Department of Clinical Sciences and International Public Health, Liverpool, United Kingdom, (7) Lilongwe Medical Relief Trust (UNC Project), Lilongwe, Malawi, (8) University of Cape Town, Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Institute of Infectious Disease and Molecular Medicine, Cape Town, South Africa, (9) University of Botswana, Department of Internal Medicine, Gaborone, Botswana, (10) University of Zimbabwe College of Health Sciences, Department of Medicine, Harare, Zimbabwe, (11) University of Liverpool, Liverpool, United Kingdom, (12) Institut Pasteur, Molecular Mycology Unit and National Reference Centre for Invasive Mycoses, Paris, France, (13) St George''s University of London, Institute for Infection and Immunity, London, United Kingdom, (14) St George''s University of London, Centre for Global Health, Institute of Infection and Immunity, London, United Kingdom, (15) St George''s University Hospitals NHS Foundation Trust, Clinical Academic Group in Infection and Immunity, London, United Kingdom, (16) University of Exeter, MRC Centre for Medical Mycology, Exeter, United Kingdom

BACKGROUND: Cryptococcal meningitis (CM) is a leading cause of HIV-related mortality. Based on phase-II study data showing that a single high-dose of 10mg/kg liposomal amphotericin-B (AmBisome, Gilead Sciences Inc) was non-inferior to 14 days of standard dosing in clearing Cryptococcus from the cerebrospinal fluid we performed a phase-III randomised controlled non-inferiority trial to examine the impact of a single high-dose of AmBisome in averting all-cause mortality from CM.
METHODS: HIV-positive adults with a first episode of CM in Botswana, Malawi, South Africa, Uganda and Zimbabwe were randomised to induction therapy of either (i) single, high-dose AmBisome (10mg/kg) given with 14 days of flucytosine 100mg/kg/day and fluconazole 1200mg/day (AmBisome) or (ii) 7 daily doses of amphotericin B deoxycholate (1mg/kg) plus 7 days of flucytosine 100mg/kg/day, followed by 7 days of fluconazole 1200mg/day (control). All participants received consolidation therapy of fluconazole 800mg/day for eight weeks. The primary endpoint was all-cause mortality at 10 weeks with the trial powered to show non-inferiority with a 10% margin.
RESULTS: We randomised 844 participants from January 2018 to February 2021. 60.2% were men, with median age of 37 years, median CD4 of 27 cells/mm2, and 28.5% had abnormal mental status; 30 participants met early withdrawal exclusion criteria, leaving 814 in the intention-to-treat (ITT) population. None were lost to follow-up. In the primary ITT analysis 10-week mortality was 24.82% (101/407) in the AmBisome arm and 28.75% (117/407) in the control arm. The difference in mortality between the AmBisome arm and control arm was -3.93%, with the upper limit of the 1-sided 95%CI for the difference being 1.17%, well below the pre-specified 10% non-inferiority margin. The single high-dose AmBisome treatment was well tolerated.

CONCLUSIONS: Single high-dose AmBisome on a backbone of flucytosine and fluconazole was non-inferior to the current WHO recommended standard of care for HIV-associated cryptococcal meningitis.