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Randomized Controlled Trial
. 2025 Feb 5;80(1):129-136.
doi: 10.1093/cid/ciae266.

Adjunctive Single-Dose Liposomal Amphotericin to Prevent Cryptococcal Meningitis in People With HIV-Associated Cryptococcal Antigenemia and Low Plasma Cryptococcal Antigen Titers

David B Meya  1   2 , Elizabeth Nalintya  1 , Caleb P Skipper  3 , Paul Kirumira  1 , Peruth Ayebare  1 , Rose Naluyima  1 , Teopista Namuli  1 , Fred Turya  1 , Stewart Walukaga  1 , Nicole Engen  4 , Kathy H Hullsiek  4 , Abduljewad Wele  4 , Biyue Dai  4 , David R Boulware  3 , Radha Rajasingham  3
Affiliations
Randomized Controlled Trial

Adjunctive Single-Dose Liposomal Amphotericin to Prevent Cryptococcal Meningitis in People With HIV-Associated Cryptococcal Antigenemia and Low Plasma Cryptococcal Antigen Titers

David B Meya et al. Clin Infect Dis. .

Abstract

Background: Cryptococcal meningitis is a leading cause of AIDS-related mortality. Cryptococcal antigen (CrAg) predicts the development of meningitis. Historically, despite standard- of-care fluconazole, 25%-30% of asymptomatic CrAg-positive persons develop breakthrough meningitis or death. We evaluated whether adding single high-dose liposomal amphotericin B to standard pre-emptive fluconazole therapy could improve meningitis-free survival.

Methods: Participants with human immunodeficiency virus (HIV) and asymptomatic cryptococcal antigenemia in Uganda were randomized to liposomal amphotericin B (10 mg/kg once) with fluconazole or fluconazole alone through 24 weeks. We compared 24-week, meningitis-free survival time between treatment groups. After the second interim review, the Data Safety and Monitoring Board recommended no further enrollment of participants with low plasma CrAg lateral flow assay titers (≤1:80) due to futility. Herein, we present the results of participants with low plasma CrAg titers.

Results: 168 participants enrolled into the ACACIA trial had low plasma CrAg titers (≤1:80). During 24 weeks of follow-up, meningitis or death occurred in 14.5% (12/83) of participants randomized to liposomal amphotericin B with fluconazole versus 10.6% (9/85) assigned to fluconazole alone (hazard ratio, 1.42; 95% CI, .60-3.36; P = .431). Adverse events were more frequent in participants assigned to the intervention versus standard-of-care (28% vs 12%; P = .011).

Conclusions: Among CrAg-positive persons with low titers (≤1:80), the addition of single-dose liposomal amphotericin B to fluconazole as pre-emptive therapy provided no additional clinical benefit. This trial provides supportive evidence that, in asymptomatic populations with low plasma CrAg titers, lumbar punctures are likely unnecessary as administration of meningitis treatment did not improve outcomes.

Clinical trials registration: Clinicaltrials.gov (NCT03945448).

Keywords: HIV; cryptococcal antigen; cryptococcosis; meningitis.

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Conflict of interest statement

Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Consolidated Standards of Reporting Trials (CONSORT) diagram describing screening, reasons for exclusion, and enrollment. Abbreviation: CrAg, cryptococcal antigen.
Figure 2.
Figure 2.
Kaplan-Meier curve comparing 24-week meningitis-free survival among participants assigned to liposomal amphotericin versus standard-of-care treatment. Among persons with a CrAg titer ≤1:80, there was no statistical difference in meningitis-free survival, with a hazard ratio of 1.42 (95% CI, .60–3.36; P = .43). Abbreviation: CrAg, cryptococcal antigen.
See this image and copyright information in PMC

References

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