Short-course High-dose Liposomal Amphotericin B for Human Immunodeficiency Virus–associated Cryptococcal Meningitis: A Phase 2 Randomized Controlled Trial

Jarvis, Joseph N; Leeme, Tshepo B; Molefi, Mooketsi; Chofle, Awilly A; Bidwell, Gabriella; Tsholo, Katlego; Tlhako, Nametso; Mawoko, Norah; Patel, Raju K K; Tenforde, Mark W; Muthoga, Charles; Bisson, Gregory P; Kidola, Jeremiah; Changalucha, John; Lawrence, David; Jaffar, Shabbar; Hope, William; Molloy, Síle F; Harrison, Thomas S

doi:10.1093/cid/ciy515

Cited by 86Fungal Infections and StudiesAntifungal resistance and susceptibilityBacterial Infections and Vaccines

Short-course High-dose Liposomal Amphotericin B for Human Immunodeficiency Virus–associated Cryptococcal Meningitis: A Phase 2 Randomized Controlled Trial

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Jarvis, Joseph N, Leeme, Tshepo B, Molefi, Mooketsi, Chofle, Awilly A, Bidwell, Gabriella, Tsholo, Katlego, Tlhako, Nametso, Mawoko, Norah +11 more·2019·Clinical Infectious Diseases

DOI 10.1093/cid/ciy515PMC PMC6336908

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Background: We performed a phase 2 noninferiority trial examining the early fungicidal activity (EFA) of 3 short-course, high-dose liposomal amphotericin B (L-AmB) regimens for cryptococcal meningitis (CM) in Tanzania and Botswana. Methods: Human immunodeficiency virus (HIV)-infected adults with CM were randomized to (i) L-AmB 10 mg/kg on day 1 (single dose); (ii) L-AmB 10 mg/kg on day 1 and 5 mg/kg on day 3 (2 doses); (iii) L-AmB 10 mg/kg on day 1 and 5 mg/kg on days 3 and 7 (3 doses); or (iv) L-AmB 3 mg/kg/day for 14 days (control). All patients also received oral fluconazole 1200 mg/day for 14 days. Primary endpoint was mean rate of clearance of cerebrospinal fluid cryptococcal infection (EFA). Noninferiority was defined as an upper limit of the 2-sided 95% confidence interval (CI) of difference in EFA between intervention and control <0.2 log10 colony-forming units (CFU)/mL/day. Results: Eighty participants were enrolled. EFA for daily L-AmB was -0.41 log10 CFU/mL/day (standard deviation, 0.11; n = 17). Difference in mean EFA from control was -0.11 (95% CI, -.29 to .07) log10 CFU/mL/day faster with single dose (n = 16); -0.05 (95% CI, -.20 to .10) log10 CFU/mL/day faster with 2 doses (n = 18); and -0.13 (95% CI, -.35 to .09) log10 CFU/mL/day faster with 3 doses (n = 18). EFA in all short-course arms was noninferior to control. Ten-week mortality was 29% (n = 23) with no statistical difference between arms. All arms were well tolerated. Conclusions: Single-dose 10 mg/kg L-AmB was well tolerated and led to noninferior EFA compared to 14 days of 3 mg/kg/day L-AmB in HIV-associated CM. Induction based on a single 10 mg/kg L-AmB dose is being taken forward to a phase 3 clinical endpoint trial. Clinical Trials Registration: ISRCTN 10248064.

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A phase II trial demonstrated that a single high dose of LAmB is of equivalent efficacy to a 7-day course of DAmB.
“a phase II trial demonstrated that a single high dose of LAmB is of equivalent efficacy to a 7-day course of DAmB10”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [10]

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slope and were excluded from EFA calculation as sterility would have been achieved before that day's LP are shown in the dotted grey line. (C) Adjusted difference in mean EFA between intervention arms and control. All 3 short-course treatment arms remained non-inferior to control when adjusted for i) baseline fungal burden (QCC); ii) baseline CD4 count; iii) baseline mental status; iv) QCC and CD4 count; v) QCC, CD4 count and mental status and vi) QCC, CD4 count, mental status, sex, age, and ART status. · DOI

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Authors: Jarvis, J. N., Leeme, T. B., Molefi, M., Chofle, A. A., Bidwell, G., Tsholo, K., Tlhako, N., Mawoko, N., Patel, R. K. K., Tenforde, M. W., Muthoga, C., Bisson, G. P., Kidola, J., Changalucha, J., Lawrence, D., Jaffar, S., Hope, W., Molloy, S. F., & Harrison, T. S.
Affiliations: University of Botswana (BW)
University of Pennsylvania (US)
National Institute for Medical Research (TZ)
National Institute of Medical Research, Mwanza, Tanzania
London School of Hygiene & Tropical Medicine (GB)
Liverpool School of Tropical Medicine (GB)
University of Liverpool (GB)
Centre for Global Health, Institute for Infection and Immunity, St George’s University of London, United Kingdom
St George's, University of London (GB)
Corresponding author: Jarvis, Joseph N
ORCID: Jarvis, Joseph N
Leeme, Tshepo B
Molefi, Mooketsi
Bidwell, Gabriella
Tenforde, Mark W
Muthoga, Charles
Changalucha, John
Lawrence, David
Jaffar, Shabbar
Hope, William
Harrison, Thomas S
Venue: Clinical Infectious Diseases
Publisher: Oxford University Press (OUP)
Published: 2018-06-26
Volume: 68
Issue: 3
Pages: 393-401
ISSN: 1058-4838 (ISSN-L)
1537-6591
DOI: 10.1093/cid/ciy515
PMC: PMC6336908
OpenAlex: W2809879222
Cited by: 86
References: 29
Citations by year: 2026: 9 · 2025: 3 · 2024: 8 · 2023: 5 · 2022: 14 · 2021: 17 · 2020: 15 · 2019: 10 · 2018: 5
FWCI: 9.17
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations: Clinical Infectious Diseases (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
LSTM Online Archive (Liverpool School of Tropical Medicine) (acceptedVersion)
LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
St George's Online Research Archive (St George's University of London) (acceptedVersion)
Funders: Penn Center for AIDS Research
National Institutes of Health (P30 AI 045008)
Topics: Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Life Sciences › Immunology and Microbiology › Microbiology › Bacterial Infections and Vaccines
Keywords: cryptococcal meningitis, HIV coinfection, liposomal amphotericin B, fluconazole, non-inferiority, mortality, tolerability, sub-Saharan Africa, cryptococcal antigen serology, CD4 count, antiretroviral therapy
MeSH terms: Adult, Amphotericin B, Antifungal Agents, Botswana, Cerebrospinal Fluid, Cryptococcus neoformans, Female, Humans, Male, Tanzania, HIV Infections, Treatment Outcome, Meningitis, Cryptococcal

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Short-course High-dose Liposomal Amphotericin B for Human Immunodeficiency Virus–associated Cryptococcal Meningitis: A Phase 2 Randomized Controlled Trial

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