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 | ||||||
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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 | ||||||
Publisher License: | Publisher's own licence | ||||||
Projects: |
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PubMed ID: | 29945252 | ||||||
Go to PubMed abstract | |||||||
URI: | https://openaccess.sgul.ac.uk/id/eprint/109961 | ||||||
Publisher's version: | https://doi.org/10.1093/cid/ciy515 |
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