Higher Dose Oral Fluconazole for the Treatment of AIDS-related Cryptococcal Meningitis (HIFLAC)—report of A5225, a multicentre, phase I/II, two-stage, dose-finding, safety, tolerability and efficacy randomised, amphotericin B-controlled trial of the AIDS Clinical Trials Group

PLOS ONE RESEARCH ARTICLE a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 OPEN ACCESS Citation: Lalloo UG, Komarow L, Aberg JA, Clifford DB, Hogg E, McKhann A, et al. (2023) Higher Dose Oral Fluconazole for the Treatment of AIDS-related Cryptococcal Meningitis (HIFLAC)—report of A5225, a multicentre, phase I/II, two-stage, dosefinding, safety, tolerability and efficacy randomised, amphotericin B-controlled trial of the AIDS Clinical Trials Group. PLoS ONE 18(2): e0281580. https:// doi.org/10.1371/journal.pone.0281580 Higher Dose Oral Fluconazole for the Treatment of AIDS-related Cryptococcal Meningitis (HIFLAC)—report of A5225, a multicentre, phase I/II, two-stage, dose-finding, safety, tolerability and efficacy randomised, amphotericin B-controlled trial of the AIDS Clinical Trials Group Umesh G. Lalloo ID1☯*, Lauren Komarow2☯, Judith A. Aberg ID3☯, David B. Clifford4☯, Evelyn Hogg5☯, Ashley McKhann2☯, Aggrey Bukuru6‡, David Lagat7‡, Sandy Pillay1‡, Vidya Mave8‡, Khuanchai Supparatpinyo9‡, Wadzanai Samaneka10‡, Deborah Langat11‡, Eduardo Ticona12‡, Sharlaa Badal-Faesen13‡, Robert A. Larsen14‡, the ACTG A5225 Team¶ 1 Durban University of Technology, Durban, South Africa, 2 Harvard TH Chan School of Public Health, Boston, Massachusetts, and The Biostatistics Center, The George Washington University, Rockville, Maryland, United States of America, 3 Icahn School of Medicine at Mount Sinai, New York, New York, United States of America, 4 Washington University School of Medicine, St Louis, Missouri, United States of America, 5 Social & Scientific Systems, Inc., a DLH Holdings Company, Silver Spring, Maryland, United States of America, 6 Joint Clinical Research Centre, Kampala, Uganda, 7 MOI University Teaching Hospital, Eldoret, Kenya, 8 BJ Medical School, Pune, Maharashtra, India, 9 Research Institute for Health Sciences, Chang Mai, Thailand, 10 University of Zimbabwe, Harare, Zimbabwe, 11 KEMRI Walter Reed Project, Kericho, Kenya, 12 Hospital Nacional Dos de Mayo, Lima, Peru, 13 University of Witwatersrand, Johannesburg, South Africa, 14 University of Southern California, Los Angeles, California, United States of America ☯ These authors contributed equally to this work. ‡ AB, DL, SP, VM, KS, WS, DL, ET, SBF and RAL also contributed equally to this work. ¶ Membership of the ACTG A5225 Team is provided in the Acknowledgments. * Editor: Renee Ridzon, National Institute of Allergy and Infectious Diseases, UNITED STATES Received: September 29, 2021 Abstract Accepted: January 16, 2023 Published: February 13, 2023 Background Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here: https://doi.org/10.1371/journal.pone.0281580 The WHO recommended 1200mg/day of fluconazole (FCZ) in the induction phase of cryptococcal meningitis (CM) in HIV prior to 2018 in regions where amphotericin-B (AMB) was unavailable. A 2-stage AMB-controlled, dose-escalation study to determine the maximum tolerated dose and the safety/efficacy of an induction-consolidation strategy of higher doses FCZ (1200mg-2000mg/day), adjusted for weight and renal function (eGFR)in adults with CM was undertaken. Copyright: © 2023 Lalloo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Methods In Stage-1, three induction doses of FCZ (1200mg/day, 1600mg/day and 2000mg/day) were tested in sequential cohortsand compared with AMB in a 3:1 ratio. A particular dose was not tested in Stage 2 if there were significant predetermined safety or efficacy concerns. PLOS ONE | https://doi.org/10.1371/journal.pone.0281580 February 13, 2023 1 / 21 PLOS ONE High dose fluconazole for AIDS-related cryptococcal meningitis Data Availability Statement: Due to confidentiality issues and ethical restrictions, study data are available upon request from sdac.data@sdac. harvard.edu with the written agreement of the AIDS Clinical Trials Group. In Stage-2, the 1200mg dose was excluded per protocol because of increased mortality, and participants were randomised to 1600mg, 2000mg FCZ or AMB in a 1:1:1 ratio. Funding: Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH) under Award Number UM1 AI068634, UM1 AI068636 and UM1 AI106701; clinical trial aidsinfo.nih.gov/clinical-trials/details/ NCT00885703. One hundred and sixty eight participants were enrolled with 48, 50, and 48 in the AMB, 1600mg and 2000mg cohorts. The Kaplan Meier proportion for mortality (90% CI) at 10 and 24 weeks for AMB was 17% (10, 29) and 24% (15, 37), compared to 20% (12, 32) and 30% (20, 43) for 1600mg, and 33% (23, 46) and 38% (27, 51) for 2000mg/day FCZ. With the exception of a higher incidence of gastrointestinal side effects in the 2000mg cohort, both induction doses of FCZ were safe and well tolerated. There were no life-threatening changes in electrocardiogram QTc which were similar across all doses of FCZ and AMB. The median (IQR) change in log10 cryptoccal colony forming units (CFU) from week 0 to week 2 was -8(-4.1,-1.9) for AMB; -2.5(-4.0, -1.4) for 1600mg FCZ and -8 (-3.2, -1.0) for 2000mg FCZ. The proportion (90% CI) CSF CM negative at 10 weeks was 81%(71,90) for AMB; 56%(45,69) for 1600mg FCZ and 60%(49,73) for 2000mg FCZ. Competing interests: The authors have declared that no competing interests exist. Findings Interpretation Induction phase weight and renal-adjusted doses of 1600mg and 2000mg/day FCZ for CM were safe and well tolerated except for increased GI side effects in the 2000mg/day dose, and had similar times to achieve CSF sterilization, but took significantly longer than AMB. The WHO recommended 1200mg FCZ was associated with a high mortality. While not statistically significant, mortality was numerically lower in the AMB compared to 1600mg and 2000mg FCZ These data make a case for a phase 3 study of higher doses of FZC. Introduction An estimated 220 000 cases and 180 000 deaths occur annually from cryptococcal meningitis (CM), mostly in sub-Saharan Africa [1]. The USA guideline for management of CM in persons with HIV (PWH) is 2 weeks amphotericin-B (AMB) combined with flucytosine followed by fluconazole (FCZ) at 400mg/day for 8 weeks [2]. Prevention of relapse is FCZ continued at 200mg/day in the maintenance phase for one year and the CD4 count exceeds 100 cells/ulL with complete virologic suppression for at least 3 months on antiretroviral therapy (ART) [2]. Flucytosine is expensive and unavailable in most high burden, resource limited setting and is unregistered throughout Africa [3–5]. AMB is frequ (...truncated)