Baseline C-reactive Protein as a Risk Factor for Cryptococcal Meningitis and Death in HIV-associated Cryptococcal Antigenemia With CrAg Titer as an Effect Modifier

Background. Persons with HIV and cryptococcal antigenemia are at high risk of progression to cryptococcal meningitis or death. Baseline cryptococcal antigen (CrAg) plasma titer ≥1:160 is a known risk factor for poor outcomes, but other risk factors are unknown. In HIV-associated cryptococcal meningitis, baseline serum C-reactive protein (CRP) concentrations are positively associated with increased mortality. We hypothesized that CRP might also be associated with meningitis or death in persons with cryptococcal antigenemia. Methods. We measured plasma CrAg titers and CRP concentrations on cryopreserved serum from prospectively enrolled persons with HIV and cryptococcal antigenemia. Using time-to-event analyses, we compared 24-week meningitis-free survival in persons with normal CRP (<8 mg/L) and elevated CRP (≥8 mg/L). Logistic regression was used to assess how CRP concentration and CrAg titer might interact as covariates. Results. Of the 94 persons with elevated CRP, 19 (20.2%) developed meningitis or death, whereas of the 88 persons with normal CRP, 8 (9.1%) developed meningitis or death (P = .035). Persons with CrAg titer <1:160 and normal CRP had an ∼5% (3/61) event rate, whereas those with CrAg titer <1:160 but elevated CRP had an ∼20% (12/59) event rate. Importantly, we identified a statistically significant interaction effect between CrAg titer and CRP groups, in which elevated CRP increased risk in the low CrAg titer group (odds ratio, 1.54; 95% confidence interval, 1.16–2.04), but this effect was not present in high CrAg titer group (odds ratio, 0.78; 95% confidence interval, .53–1.15). Conclusions. Our findings demonstrate that CrAg titer may modify the direction of effect of CRP with meningitis-free survival; future studies should account for this interaction.