Reflexive laboratory-based cryptococcal antigen screening and preemptive fluconazole therapy for cryptococcal antigenemia in HIV-Infected Individuals with CD4 <100 Cells/μL: A Stepped-Wedge, Cluster-Randomized Trial

David B. Meya, Agnes N. Kiragga, Elizabeth Nalintya, Bozena M. Morawski, Radha Rajasingham, Benjamin J. Park, Anthony Mubiru, Jonathan E. Kaplan, Yukari C. Manabe, David R. Boulware

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


BACKGROUND: HIV-infected persons with cryptococcal antigenemia (CrAg) are at high risk for meningitis or death. We evaluated the effect of CrAg screening and preemptive fluconazole therapy, adjunctive to antiretroviral therapy (ART), on 6-month survival among persons with advanced HIV/AIDS.

METHODS: We enrolled HIV-infected, ART-naive participants with <100 CD4 cells/µL, in a stepped-wedge, cluster-randomized trial from July 2012 to December 2014 at 17 Ugandan clinics. Clinics participated in a prospective observational phase, followed by an interventional phase with laboratory-based, reflexive CrAg screening of residual CD4 count plasma. Asymptomatic CrAg+ participants received preemptive fluconazole therapy. We assessed 6-month survival using Cox-regression, adjusting for nadir CD4, calendar time, and stepped-wedge steps.

RESULTS: We included 1280 observational and 2108 interventional participants, of whom 9.3% (195/2108) were CrAg+. CD4-, time-, and stepped-wedge-adjusted analyses demonstrated no difference in survival in the observational vs the interventional arms (hazard ratio = 1.34; 95% confidence interval: 0.86 to 2.10; P = 0.20). Fewer participants initiated ART in the interventional (73%) versus the observational phase (82%, P < 0.001). When ART initiation was modeled as a time-dependent covariate or confounder, survival did not differ. However, 6-month mortality of participants with CrAg titers <1:160 and CrAg-negative patients did not differ. Patients with CrAg titers ≥1:160 had 2.6-fold higher 6-month mortality than patients with titers <1:160.

CONCLUSIONS: We observed no overall survival benefit of the CrAg screen-and-treat intervention. However, preemptive antifungal therapy for asymptomatic cryptococcosis seemed to be effective in patients with CrAg titer <1:160. A more aggressive approach is required for persons with CrAg titer ≥1:160.

Original languageEnglish (US)
Pages (from-to)182-189
Number of pages8
JournalJournal of Acquired Immune Deficiency Syndromes
Issue number2
StatePublished - Feb 1 2019

Bibliographical note

Funding Information:
Supported by the President’s Emergency Plan for AIDS Relief (PEPFAR) through the Centers for Disease Control and Prevention (CDC) under the terms of U01GH000517. D.R.B., B.M.M., R.R., and M.A.R. received support from Fogarty International Center (FIC) and National Institute of Neurologic Diseases and Stroke (R01NS086312 and R25TW009345), Y.C.M. receives support from FIC (D43 TW009771), and D.B.M. was also supported by DELTAS Africa Initiative grant # DEL-15-011 to THRiVE-2. The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences (AAS)’s Alliance for Accelerating Excellence in Science in Africa (AESA) and supported by the New Partnership for Africa’s Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust grant #107742/Z/15/Z and the UK government. The views expressed in this publication are those of the author(s) and not necessarily those of AAS, NEPAD Agency, Wellcome Trust, or the UK government.

Publisher Copyright:
© 2018 Wolters Kluwer Health, Inc. All rights reserved.


  • HIV
  • clinical trial
  • cryptococcal meningitis
  • cryptococcus
  • fluconazole
  • preventative therapy
  • Cryptococcosis/diagnosis
  • Guidelines as Topic
  • Humans
  • Chemoprevention/methods
  • Male
  • CD4 Lymphocyte Count
  • AIDS-Related Opportunistic Infections/diagnosis
  • HIV Infections/drug therapy
  • Antigens, Fungal/blood
  • Mass Screening
  • Fluconazole/therapeutic use
  • Adult
  • Female
  • Antifungal Agents/therapeutic use
  • Cluster Analysis

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Observational Study
  • Randomized Controlled Trial
  • Journal Article
  • Research Support, N.I.H., Extramural


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