In low and middle-income countries, the prevalence of cryptococcal antigenemia (CrAg+) averages 7.2% (95% confidence interval (CI), 6.8-7.6%) among persons with CD4<100 cells/µL. CrAg+ persons are at elevated risk of mortality compared to persons without cryptococcal antigenemia (CrAg-) who are HIV-infected. Although preemptive fluconazole therapy can halt the progression from asymptomatic antigenemia to symptomatic cryptococcal meningitis and death, risk factors for progression to cryptococcal meningitis are unknown.
We assessed 6-month survival of CrAg+ persons who received preemptive fluconazole monotherapy of 800mg/day for 2 weeks and then 400mg/day for 8 weeks, as part of a stepped-wedge randomized trial evaluating CrAg screening at 18 Ugandan clinics. During the intervention, CrAg screening was reflexively performed at the time of CD4 result, when CD4<100 cells/µL. ART was initiated 2 weeks after fluconazole therapy initiation. We assessed 6-month breakthrough cryptococcal meningitis rates, and survival with respect to baseline CrAg titers and CD4 counts.
From 2,135 persons screened with CD4<100 cells/µL, the CrAg+ prevalence was 7.1% (95%CI: 6.1-8.2). 152 asymptomatic CrAg+ HIV-infected, ART-naïve adults received fluconazole. Among 151 CrAg+ persons with baseline titers, 39% (n=59) had a pre-ART CrAg titer of ≥1:160 and 61% (n=92) of <1:160. 11 of the 151 participants went on to develop cryptococcal meningitis within 6 months; and patients with titers ≥1:160 were at elevated risk versus those with titers <1:160 (Hazard Ratio (HR)=5.4; 95%CI: 1.1-27.3; P=.04). Overall 6-month survival was 78%. Patients with CrAg titer ≥1:160 had 2.5-fold higher 6-month mortality risk versus those with titers <1:160 when receiving preemptive therapy (HR=2.5; 95%CI: 1.2-5.2; P=.01). When stratified by CD4 (>50 vs. 50 cells/µL), only those with low CD4 and titers ≥1:160 were at elevated risk for failure (versus high CD4, <1:160 titer patients) (HR=3.2; 95%CI: 1.1-9.5; P=.04). All patients with titers ≥1:1000 were at elevated risk for failure, irrespective of CD4 (HR=2.3; 95%CI: 1.0-4.9; P=.04).
Among CrAg+ persons with baseline CrAg titer of ≥1:160, 32% failed preemptive fluconazole therapy and died despite receiving recommended preemptive therapy. Developing semi-quantitative rapid CRAG tests may be warranted to stratify those at risk of death in whom more aggressive antifungal preemptive therapy may be necessary, especially among patients with extremely low CD4 values.