Independent association between rate of clearance of infection and clinical outcome of HIV-associated cryptococcal meningitis: analysis of a combined cohort of 262 patients

Abstract

Background: Progress in therapy for cryptococcal meningitis has been slow because of the lack of a suitable marker of treatment response. Previously, we demonstrated the statistical power of a novel endpoint, the rate of clearance of infection, based on serial quantitative cultures of cerebrospinal fluid, to differentiate the fungicidal activity of alternative antifungal drug regimens. We hypothesized that the rate of clearance of infection should also be a clinically meaningful endpoint.

Methods: We combined data from cohorts of patients with human immunodeficiency virus-associated cryptococcal meningitis from Thailand, South Africa, and Uganda, for whom the rate of clearance of infection was determined, and clinical and laboratory data prospectively collected, and explored the association between the rate of clearance of infection and mortality by Cox survival analyses.

Results: The combined cohort comprised 262 subjects. Altered mental status at presentation, a high baseline organism load, and a slow rate of clearance of infection were independently associated with increased mortality at 2 and 10 weeks. Rate of clearance of infection was associated with antifungal drug regimen and baseline cerebrospinal fluid interferon-gamma levels.

Conclusions: The results support the use of the rate of clearance of infection or early fungicidal activity as a means to explore antifungal drug dosages and combinations in phase II studies. An increased understanding of how the factors determining outcome interrelate may help clarify opportunities for intervention.

Figure 1

Frequency distribution for rate of clearance of infection (logCFU/ml CSF/day) in the combined cohort

Figure 2

Kaplan-Meier survival curves by A. altered mental status at presentation (yes or no), B. baseline CSF organism load (categorized into tertiles: <4.95, 4.95-5.87, and >5.87 log CFU/ml CSF), and C. rate of clearance of infection (categorized into quartiles: >−0.18, −0.18-0.33, −0.33-0.55, <−0.55 log CFU/ml CSF/day)

Figure 3

Association of baseline CSF cytokine levels (median, IQR) and CD4 cell counts. CD4 cell counts were categorized into quartiles: 1st quartile 0-8, 2^nd quartile 9-25, 3^rd quartile 26-56, 4^th quartile ≥57, × 10⁶cells/L

Figure 4

A model illustrating possible relationships between factors associated with rate of clearance of infection and survival. Proposed causal links are shown with solid arrows, non-causal associations with long-dashed arrows, and speculative associations with short-dashed arrows.