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

Jarvis, JN; Leeme, TB; Molefi, M; Chofle, AA; Bidwell, G; Tsholo, K; Tlhako, N; Mawoko, N; Patel, RKK; Tenforde, MW; et al. Jarvis, JN; Leeme, TB; Molefi, M; Chofle, AA; Bidwell, G; Tsholo, K; Tlhako, N; Mawoko, N; Patel, RKK; Tenforde, MW; Muthoga, C; Bisson, GP; Kidola, J; Changalucha, J; Lawrence, D; Jaffar, S; Hope, W; Molloy, SLF; Harrison, TS (2019) Short-course High-dose Liposomal Amphotericin B for Human Immunodeficiency Virus–associated Cryptococcal Meningitis: A Phase 2 Randomized Controlled Trial. Clin Infect Dis, 68 (3). pp. 393-401. ISSN 1537-6591 https://doi.org/10.1093/cid/ciy515
SGUL Authors: Harrison, Thomas Stephen

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Abstract

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.

Item Type: Article
Additional Information: This is a pre-copyedited, author-produced version of an article accepted for publication in Clinical Infectious Diseases following peer review. The version of record Joseph N Jarvis, Tshepo B Leeme, Mooketsi Molefi, Awilly A Chofle, Gabriella Bidwell, Katlego Tsholo, Nametso Tlhako, Norah Mawoko, Raju K K Patel, Mark W Tenforde, Charles Muthoga, Gregory P Bisson, Jeremiah Kidola, John Changalucha, David Lawrence, Shabbar Jaffar, William Hope, Síle F Molloy, Thomas S Harrison; Short-course High-dose Liposomal Amphotericin B for Human Immunodeficiency Virus–associated Cryptococcal Meningitis: A Phase 2 Randomized Controlled Trial, Clinical Infectious Diseases, Volume 68, Issue 3, 18 January 2019, Pages 393–401 is available online at: https://doi.org/10.1093/cid/ciy515
Keywords: Microbiology, 06 Biological Sciences, 11 Medical And Health Sciences
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: Clin Infect Dis
ISSN: 1537-6591
Language: eng
Dates:
DateEvent
18 January 2019Published
26 June 2018Published Online
18 June 2018Accepted
Publisher License: Publisher's own licence
Projects:
Project IDFunderFunder ID
P30 AI 045008National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
PubMed ID: 29945252
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/109961
Publisher's version: https://doi.org/10.1093/cid/ciy515

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