Change in Plasma Cryptococcal Antigen Titer Is Not Associated With Survival Among Human Immunodeficiency Virus–infected Persons Receiving Preemptive Therapy for Asymptomatic Cryptococcal Antigenemia

To the Editor—Current World Health Organization (WHO) guidelines recommend cryptococcal antigen (CrAg) screening in blood among those human immunodeficiency virus (HIV)-infected persons not receiving effective antiretroviral therapy (ART), with CD4 values <100 cells/µL, and to consider testing those not on ART with CD4 values between 100–200 cells/µL [1]. This recommendation is based on prior studies demonstrating that a “screen-and-treat” program identifying CrAg-positive persons and giving preemptive fluconazole therapy, in combination with an ART adherence intervention, prevents invasive cryptococcal disease and death [2].

There has been growing interest in the utility of serum/plasma CrAg as a prognostic tool in cryptococcal infection [3]. In 4 cohorts, patients with asymptomatic cryptococcal antigenemia and baseline serum/plasma titers of ≥1:160 experienced worse outcomes [3]. Those with baseline serum/plasma titers of ≤1:80 have an 80% chance of survival to 6 months, those with titers of 1:160–1:2560 have a 66% survival rate, and those with titers of ≥1:2560 have a 45% survival rate [3]. While higher titers portend worse outcomes, the value of monitoring sequential serum/plasma CrAg titers in asymptomatic CrAg-positive patients is unclear. In 2 cryptococcal meningitis cohorts, changes in cerebrospinal fluid CrAg titers were unrelated to outcomes [4, 5]. This relationship between titers and prognoses have not been explored in asymptomatic cryptococcal antigenemia.

The data presented here, part of the work performed by the Operational Research for Cryptococcal Antigen Screening (ORCAS) study team from July 2012–December 2014, represent a cohort of HIV-infected, ART-naive Ugandans with CD4 values <100 cells/µL [6]. Exclusion criteria were overt signs of meningitis or cerebrospinal fluid being CrAg positive. Newly enrolled patients received a lab-based reflexive plasma CrAg lateral flow assay (LFA; Immy Inc., Norman, OK) if their CD4 value was <100 cells/µL. Eligible CrAg-positive patients received fluconazole therapy (800 mg/d for 2 weeks, followed by 400 mg/d for 8 weeks), per the WHO rapid advice at the time. ART was initiated after 2 weeks of fluconazole therapy. Patients were included in these analyses if they survived at least 6 weeks.

We measured plasma CrAg LFA at 0, 6, and 26 weeks of fluconazole therapy. Figure 1 displays the baseline and 6-week titers among those surviving to 6 months (n = 107; Figure 1A–C) and among those who survived at least 6 weeks but died prior to 26 weeks (n = 7; Figure 1D). There was no association between changes in baseline to 6-week titers and the chance of survival to 26 weeks, based on Mann-Whitney U-test analysis (P = .60). Among participants who died between 6 and 26 weeks, there was a median 2-fold increase in titers (interquartile range [IQR], 2-fold decrease to 4-fold increase). Visually, one can appreciate the variability on an individual patient level. Among 26-week survivors, there was a median of no change in titers (IQR, 4-fold decrease to 2-fold increase). Even among those whose titers increased between baseline and 6 weeks, the positive predictive value for death was low for a 2-fold (16%, 4/25) or 4-fold (18%, 3/17) increase. There was no statistically significant relationship between the chance of survival to 26 weeks and a change in CrAg LFA titers from baseline to 6 weeks among HIV-infected persons with asymptomatic cryptococcal antigenemia receiving fluconazole preemptive therapy. Among asymptomatic CrAg-positive patients enrolled in the ORCAS study, longitudinal plasma CrAg titers are not beneficial during fluconazole therapy.

Figure 1.

Change in plasma cryptococcal antigen over weeks of fluconazole therapy among those with asymptomatic antigenemia. Each plot displays the CrAg titer values for individual patients at enrollment (0 weeks) and at a 6-week follow-up. A–C, Those who survived to a 6-month follow-up, randomly distributed into 3 plots to allow better visualizations of individual responses. D, Those who did not survive to a 6-month follow-up. The median CrAg titer at 26 weeks was 40 (interquartile range 10–180) among all those who survived to 26 weeks. Abbreviation: CrAg, cryptococcal antigen.

Notes

Disclaimer. The findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of the funding agencies.

Financial support. This work was supported by the President’s Emergency Plan for AIDS Relief (PEPFAR) though the Centers for Disease Control and Prevention (grant number U01GH000517).

Potential conflicts of interest. M. F. P., D. R. B., D. B. M., E. N., and R. R. have received grant support from the National Institute of Allergy and Infectious Diseases. All other authors report no potential conflicts. 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.