Outcomes of HIV-positive patients with cryptococcal meningitis in the Americas

Abstract

Background: Cryptococcal meningitis (CM) is associated with substantial mortality in HIV-infected patients. Optimal timing of antiretroviral therapy (ART) in persons with CM represents a clinical challenge, and the burden of CM in Latin America has not been well described. Studies suggest that early ART initiation is associated with higher mortality, but data from the Americas are scarce.

Methods: HIV-infected adults in care between 1985-2014 at participating sites in the Latin America (the Caribbean, Central and South America network (CCASAnet)) and the Vanderbilt Comprehensive Care Clinic (VCCC) and who had CM were included. Survival probabilities were estimated. Risk of death when initiating ART within the first 2 weeks after CM diagnosis versus initiating between 2-8 weeks was assessed using dynamic marginal structural models adjusting for site, age, sex, year of CM, CD4 count, and route of HIV transmission.

Findings: 340 patients were included (Argentina 58, Brazil 138, Chile 28, Honduras 27, Mexico 34, VCCC 55) and 142 (42%) died during the observation period. Among 151 patients with CM prior to ART 56 (37%) patients died compared to 86 (45%) of 189 with CM after ART initiation (p=0.14). Patients diagnosed with CM after ART had a higher risk of death (p=0.03, log-rank test). The probability of survival was not statistically different between patients who started ART within 2 weeks of CM (7/24, 29%) vs. those initiating between 2-8 weeks (14/53, 26%) (p=0.96), potentially due to lack of power.

Interpretation: In this large Latin-American cohort, patients with CM had very high mortality rates, especially those diagnosed after ART initiation. This study reflects the overwhelming burden of CM in HIV-infected patients in Latin America.

Keywords: AIDS; AIDS defining events; Cryptococcal meningitis; HIV; Latin America; Opportunistic Infections in HIV.

Figure 1

A) Estimated survival probability by time of CM and start of ART. B) Estimated survival probability for patients who started ART within 2 weeks of CM vs. those starting between 2–8 weeks. Figure A) Survival is statistically lower in ART naïve patients with Cryptococcal Meningitis (CM) compared to those with CM after initiating ART. Figure B) In ART naïve patients, no statistical difference was found comparing those who started ART <2 weeks after CM diagnosis with those who started ART 2–8 weeks after CM diagnosis. Both figures show unadjusted Kaplan-Meier estimates; p-values are from log-rank tests.

Figure 2

Adjusted model for mortality risk over time since the beginning of the cART era. Note: plot adjusted for these values: site=Brazil, Age=20 years, gender=male, Transmission route=Homosexual, CD4 count=50cells/mm3, and CM after ART initiation. Year 0 in x-axis marks the beginning of the cART era. This figure represents the association between mortality and time from a patient’s CM diagnosis to the year that cART was introduced at the patient’s study site. The highest mortality was observed among patients diagnosed with CM before the introduction of cART; mortality declines in the cART era, although there is a plateau in mortality in later years of the cART era.

Figure 3

Predicted survival probability over time according to ART initiation strategy. Dynamic marginal structural models considered the impact of starting ART <2 weeks after CM diagnosis versus starting between 2–8 weeks after diagnosis. In this model, no statistical differences in mortality were seen, with an odds of death for starting ART <2 weeks after CM of 1.09 (95% CI, 0.44–2.67; p=0.84) times higher than for starting between 2–8 weeks.