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

Abstract

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.

FIGURE 1.

Consort diagram: Patients on ART with a CD4 <100 cells/µL were excluded during screening. Similarly, we excluded CrAg-positive persons who were seen in the clinic by the nurse counselor after having already initiated ART (n = 18). 4.8% (124 of 2572) did not have a CrAg test performed due to insufficient amount of plasma, or the leftover plasma was inadvertently discarded before CrAg testing. CrAg (−), cryptococcal antigen negative; CrAg (+), cryptococcal antigen positive.

FIGURE 2.

Survival in the observational vs interventional CrAg screening phase among ART-naive patients with CD4 <100 cells/µL and were otherwise eligible for the intervention. HR adjusted for CD4 count, stepped-wedge step, and year of screening, and accounts for within-cluster correlation. Twenty-nine CrAg+ persons were excluded due to fluconazole intervention ineligibility or declined consent. CrAg, cryptococcal antigen.

FIGURE 3.

Survival with CrAg screening intervention among HIV-infected adults with CD4 <100 cells/µL by CrAg status. CrAg (−), cryptococcal antigen negative; CrAg (+), cryptococcal antigen positive.

FIGURE 4.

Incident meningitis or death among patients receiving preemptive fluconazole therapy stratified by baseline plasma CrAg titer and CD4. One participant did not have a baseline CrAg titer measured due to insufficient volume of plasma. Gray line indicates end of fluconazole therapy.