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A phase II randomized controlled trial adding oral flucytosine to high-dose fluconazole, with short-course amphotericin B, for cryptococcal meningitis

Jackson, AT; Nussbaum, JC; Phulusa, J; Namarika, D; Chikasema, M; Kanyemba, C; Jarvis, JN; Jaffar, S; Hosseinipour, MC; van der Horst, C; et al. Jackson, AT; Nussbaum, JC; Phulusa, J; Namarika, D; Chikasema, M; Kanyemba, C; Jarvis, JN; Jaffar, S; Hosseinipour, MC; van der Horst, C; Harrison, TS (2012) A phase II randomized controlled trial adding oral flucytosine to high-dose fluconazole, with short-course amphotericin B, for cryptococcal meningitis. AIDS, 26 (11). 1363 - 1370 (8). ISSN 0269-9370 https://doi.org/10.1097/QAD.0b013e328354b419
SGUL Authors: Harrison, Thomas Stephen Jarvis, Joseph Nicholas

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Abstract

Background: Cryptococcal meningitis in Africa is associated with up to 70% mortality at 3 months and 500 000 deaths annually. We examined strategies to improve on fluconazole (FLU) monotherapy: addition of flucytosine (5-FC) and/or addition of short-course amphotericin B (AmB). Methods: In step 1, previously reported, patients were randomized to receive FLU 1200 mg per day with or without 5-FC 100 mg/kg per day for 14 days. In step 2, 43 patients were similarly randomized, with addition of AmB 1 mg/kg per day for 7 days to both arms. After 2 weeks, patients received FLU monotherapy and were followed to 10 weeks. The primary endpoint was rate of clearance of infection (early fungicidal activity, EFA). Secondary endpoints related to safety and mortality. Results: Forty patients (25% with Glasgow Coma Scale <15) were analyzed. EFA for the triple combination arm was greater than that for AmB–FLU: -0.50 ± 0.15 log CFU/day vs. -0.38 ± 0.19 log colony forming units per day (P = 0.03); and greater than that for step 1 with FLU–5-FC (-0.28 ± 0.17) or FLU alone (-0.11 ± 0.09). Combined analysis across steps revealed that addition of 5-FC and AmB had significant, independent additive effects on EFA, with trends toward fewer early deaths with addition of 5-FC (4/41 vs. 11/39, P = 0.05) and fewer deaths overall with addition of AmB (13/39 vs. 20/40, P = 0.1). Conclusion: Addition of 5-FC and short-course AmB to high-dose FLU significantly enhanced EFA and may be associated with favorable trends in survival. Both these strategies should be tested in a larger phase III study.

Item Type: Article
Additional Information: PubMed ID: 22526517
Keywords: AIDS-Related Opportunistic Infections, Acquired Immunodeficiency Syndrome, Administration, Oral, Adult, Aged, Amphotericin B, Antifungal Agents, Drug Therapy, Combination, Female, Fluconazole, Flucytosine, Humans, Malawi, Male, Meningitis, Cryptococcal, Middle Aged, Treatment Outcome, Young Adult, Science & Technology, Life Sciences & Biomedicine, Immunology, Infectious Diseases, Virology, AIDS, amphotericin B, cryptococcal, fluconazole, flucytosine, meningitis, HIV, INFECTION, BURDEN, COHORT, AFRICA, UGANDA, ADULTS, AIDS, amphotericin B, cryptococcal, fluconazole, flucytosine, meningitis
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: AIDS
ISSN: 0269-9370
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Dates:
DateEvent
17 July 2012Published
Web of Science ID: WOS:000306130700006
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URI: https://openaccess.sgul.ac.uk/id/eprint/102766
Publisher's version: https://doi.org/10.1097/QAD.0b013e328354b419

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