Fluconazole plus flucytosine versus fluconazole alone for adults with HIV-associated cryptococcal antigenaemia identified through screening: a multi-centre phase III randomised-controlled trial.
| Title: | Fluconazole plus flucytosine versus fluconazole alone for adults with HIV-associated cryptococcal antigenaemia identified through screening: a multi-centre phase III randomised-controlled trial. |
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| Authors: | Murphy K; Wits Mycology Division, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. kmurphy@witshealth.co.za.; Department of Medicine, Wellcome Centre for Infectious Disease Research in Africa, and Neuroscience Institute, University of Cape Town, Cape Town, South Africa. kmurphy@witshealth.co.za.; Nel JS; Division of Infectious Diseases, Department of Medicine, Helen Joseph Hospital, University of the Witwatersrand, Johannesburg, South Africa.; Moosa MY; Division of Infectious Disease, Department of Internal Medicine, Victoria Mxenge Hospital, Nelson R. Mandela School of Medicine. University of KwaZulu-Natal, Durban, South Africa.; Wilson DP; Department of Internal Medicine, Harry Gwala Regional Hospital, Nelson R. Mandela School of Medicine. University of KwaZulu-Natal, Durban, South Africa.; Tsitsi M; Department of Internal Medicine, Chris Hani Baragwanath Academic Hospital, University of the Witwatersrand, Johannesburg, South Africa.; Mfinanga S; National Institute for Medical Research, Muhimbili Medical Research Centre, Dar es Salaam, Tanzania.; Kivuyo S; National Institute for Medical Research, Muhimbili Medical Research Centre, Dar es Salaam, Tanzania.; Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.; Kyazze D; Infectious Diseases Unit, Department of Internal Medicine, Livingstone Tertiary Hospital, Walter Sisulu University, Gqeberha, South Africa.; Alam N; Department of Internal Medicine, Dora Nginza Hospital, Walter Sisulu University, Gqeberha, South Africa.; Meintjes G; Department of Medicine and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.; Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK.; Eriksson M; Wits Mycology Division, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.; Adams J; Infection and Immunity Research Institute, School of Health and Medical Sciences City St George's, University of London, London, UK.; Menezes C; Department of Internal Medicine, Chris Hani Baragwanath Academic Hospital, University of the Witwatersrand, Johannesburg, South Africa.; Variava E; Department of Internal Medicine, Tshepong Hospital, University of the Witwatersrand, Klerksdorp, South Africa.; Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.; Black J; Department of Medicine, Walter Sisulu University, Gqeberha, South Africa.; Bremer M; Wits Mycology Division, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.; Department of Medical Microbiology, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa.; Dat VQ; Department of Infectious Diseases, Hanoi Medical University, Hanoi, Vietnam.; Le T; Division of Infectious Diseases and International Health, Duke University School of Medicine, Durham, NC, USA.; Tropical Medicine Research Center for Talaromycosis in Vietnam, Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam.; Schutz C; Department of Medicine, Institute of Infectious Disease and Molecular Medicine and Wellcome Centre for Infectious Disease Research in Africa, University of Cape Town, Cape Town, South Africa.; Loyse A; Infection and Immunity Research Institute, School of Health and Medical Sciences City St George's, University of London, London, UK.; Wake RM; Wits Mycology Division, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.; Infection and Immunity Research Institute, School of Health and Medical Sciences City St George's, University of London, London, UK.; Lawrence DS; Wits Mycology Division, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.; Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.; Botswana Harvard Health Partnership, Gaborone, Botswana.; Wang D; Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK.; Jaffar S; Institute for Global Health, University College London, London, UK.; Jarvis JN; Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.; Botswana Harvard Health Partnership, Gaborone, Botswana.; Harrison TS; Infection and Immunity Research Institute, School of Health and Medical Sciences City St George's, University of London, London, UK.; MRC Centre of Medical Mycology, University of Exeter, Exeter, UK.; Molloy SF; Wits Mycology Division, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.; Infection and Immunity Research Institute, School of Health and Medical Sciences City St George's, University of London, London, UK.; Govender NP; Wits Mycology Division, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. nelesh.govender@wits.ac.za.; Infection and Immunity Research Institute, School of Health and Medical Sciences City St George's, University of London, London, UK. nelesh.govender@wits.ac.za.; MRC Centre of Medical Mycology, University of Exeter, Exeter, UK. nelesh.govender@wits.ac.za.; Division of Medical Microbiology, University of Cape Town, Cape Town, South Africa. nelesh.govender@wits.ac.za. |
| Source: | Trials [Trials] 2026 Mar 24; Vol. 27 (1). Date of Electronic Publication: 2026 Mar 24. |
| Publication Type: | Journal Article; Clinical Trial Protocol |
| Language: | English |
| Journal Info: | Publisher: BioMed Central Country of Publication: England NLM ID: 101263253 Publication Model: Electronic Cited Medium: Internet ISSN: 1745-6215 (Electronic) Linking ISSN: 17456215 NLM ISO Abbreviation: Trials Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [London] : BioMed Central, 2006- |
| MeSH Terms: | Fluconazole*/adverse effects ; Fluconazole*/therapeutic use ; Fluconazole*/economics ; Fluconazole*/administration & dosage ; Flucytosine*/adverse effects ; Flucytosine*/therapeutic use ; Flucytosine*/economics ; Flucytosine*/administration & dosage ; Antifungal Agents*/adverse effects ; Antifungal Agents*/therapeutic use ; Antifungal Agents*/administration & dosage ; Antifungal Agents*/economics ; Meningitis, Cryptococcal*/drug therapy ; Meningitis, Cryptococcal*/diagnosis ; Meningitis, Cryptococcal*/mortality ; Meningitis, Cryptococcal*/microbiology ; Meningitis, Cryptococcal*/immunology ; Meningitis, Cryptococcal*/blood ; HIV Infections*/mortality ; HIV Infections*/diagnosis ; HIV Infections*/drug therapy ; HIV Infections*/complications ; AIDS-Related Opportunistic Infections*/drug therapy ; AIDS-Related Opportunistic Infections*/diagnosis ; AIDS-Related Opportunistic Infections*/microbiology ; AIDS-Related Opportunistic Infections*/mortality ; AIDS-Related Opportunistic Infections*/immunology ; Antigens, Fungal*/blood; Humans ; South Africa ; Adult ; Drug Therapy, Combination ; Treatment Outcome ; Tanzania ; Time Factors ; Clinical Trials, Phase III as Topic ; Randomized Controlled Trials as Topic ; Multicenter Studies as Topic |
| Abstract: | Background: Despite the expansion of antiretroviral treatment programmes, the incidence and mortality of HIV-associated cryptococcal meningitis remain high in Africa. Cryptococcal antigen (CrAg) in the blood precedes meningitis. CrAg screening of individuals with advanced HIV disease, combined with pre-emptive fluconazole treatment, reduces the risk of cryptococcal meningitis and associated mortality. However, mortality among individuals with antigenaemia treated with fluconazole is higher than that of CD4-matched individuals with a CrAg-negative test. Autopsy studies have found that cryptococcal disease remains an important cause of death in people with antigenaemia despite pre-emptive antifungal treatment. This suggests a need for more potent treatment for antigenaemia. Flucytosine, combined with fluconazole, is an effective and safe oral treatment for cryptococcal meningitis, and flucytosine has become more widely available as a generic formulation. This trial aims to determine whether combination treatment of fluconazole plus flucytosine is superior to fluconazole monotherapy in reducing all-cause mortality among adults with antigenaemia without evidence of meningitis.; Methods: This multi-centre, open-label phase III randomised-controlled trial embedded in routine CrAg screening programmes in South Africa and Tanzania will compare 14 days of fluconazole (1200 mg/day) plus flucytosine (100 mg/kg/day) to fluconazole (1200 mg/day) alone for the treatment of adults with advanced HIV disease, a blood CrAg-positive test and without evidence of meningitis. Following this 2-week induction therapy, all participants are given fluconazole consolidation and maintenance therapy per local guidelines. The primary endpoint is all-cause mortality at 6 months (superiority analysis). Secondary endpoints include time to all-cause mortality, cryptococcal meningitis-free survival and incidence of symptomatic cryptococcal meningitis, proportion of participants with grade 3 or 4 adverse events, efficacy outcomes by baseline CrAg titre/CrAg semi-quantitative assay score, and health service and household costs per life year saved. A total of 600 participants will be enrolled, 300 per arm, sufficient to detect a 40% relative reduction in mortality with 91% power.; Discussion: An all-oral combination regimen of flucytosine with fluconazole, tested in adults with early cryptococcal disease across a range of baseline CrAg titres, could be an easy-to-administer, safe, and implementable alternative if found to be superior to the current World Health Organization recommended standard of fluconazole monotherapy.; Trial Registration: ISRCTN30579828, registered 04 March 2021, and SANCTR DOH-27-122021-6511, registered 06 December 2021.; (© 2026. The Author(s).) |
| Competing Interests: | Declarations. Ethics approval and consent to participate {24}: Approval for the trial has been obtained from the following research ethics committees: St George’s Research Ethics Committee, reference 2020.0308. University of the Witwatersrand Human Research Ethics Committee, reference 210305. University of Kwazulu-Natal Biomedical Research Ethics Committee, reference 00002777–2021. Walter Sisulu University Health Research Ethics Committee, reference 067.2021. University of Cape Town Human Research Ethics Committee, reference 274/2021. National Institute for Medical Research, Tanzania, reference NIMR/HQ/R.8c/Vol.I/3725. Written informed consent to participate is obtained from all participants. Consent for publication {32}: A model consent form is available on request. Competing interests {28}: The authors declare that they have no competing interests. |
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| Grant Information: | MR/V005731/1 United Kingdom MRC_ Medical Research Council |
| Contributed Indexing: | Keywords: Advanced HIV disease (AHD); Cryptococcal antigen (CrAg); Cryptococcal meningitis (CM); Cryptococcosis; Fluconazole; Flucytosine; Human immunodeficiency virus (HIV); Randomised controlled trial |
| Substance Nomenclature: | 8VZV102JFY (Fluconazole); D83282DT06 (Flucytosine); 0 (Antifungal Agents); 0 (Antigens, Fungal) |
| Entry Date(s): | Date Created: 20260325 Date Completed: 20260501 Latest Revision: 20260503 |
| Update Code: | 20260503 |
| PubMed Central ID: | PMC13134226 |
| DOI: | 10.1186/s13063-026-09520-x |
| PMID: | 41877274 |
| Database: | MEDLINE |
Journal Article; Clinical Trial Protocol