Early ART After Cryptococcal Meningitis Is Associated With Cerebrospinal Fluid Pleocytosis and Macrophage Activation in a Multisite Randomized Trial

James E Scriven, Joshua Rhein, Katherine Huppler Hullsiek, Maximilian von Hohenberg, Grace Linder, Melissa A Rolfes, Darlisha A Williams, Kabanda Taseera, David B Meya, Graeme Meintjes, David R Boulware, COAT Team, James E Scriven, Joshua Rhein, Katherine Huppler Hullsiek, Maximilian von Hohenberg, Grace Linder, Melissa A Rolfes, Darlisha A Williams, Kabanda Taseera, David B Meya, Graeme Meintjes, David R Boulware, COAT Team

Abstract

Introduction: Earlier antiretroviral therapy (ART) initiation in cryptococcal meningitis resulted in higher mortality compared with deferred ART initiation (1-2 weeks vs 5 weeks postmeningitis diagnosis). We hypothesized this was due to ART-associated immune pathology, without clinically recognized immune reconstitution inflammatory syndrome.

Methods: Three macrophage activation markers and 19 cytokines/chemokines were measured from cryopreserved cerebrospinal fluid (CSF) and serum during the Cryptococcal Optimal ART Timing (COAT) trial. Comparisons were made between trial arms (early vs deferred) at 1, 8, 14, and 21 days following meningitis diagnosis.

Results: More participants with early ART initiation had CSF white cell count (WCC) ≥5/µL at day 14 (58% vs 40%; P = .047), after a median of 6-days ART. Differences were mainly driven by participants with CSF WCC <5/µL at meningitis diagnosis: 28% (10/36) of such persons in the early ART group had CSF WCC ≥5/µL by day 14, compared with 0% (0/27) in the deferred arm (P = .002). Furthermore, Kampala participants (the largest site) receiving early ART had higher day-14 CSF levels of interleukin-13 (P = .04), sCD14 (P = .04), sCD163 (P = .02), and CCL3/MIP-1α (P = .02), suggesting increased macrophage/microglial activation.

Conclusions: Early ART initiation in cryptococcal meningitis increased CSF cellular infiltrate, macrophage/microglial activation, and T helper 2 responses within the central nervous system. This suggests that increased mortality from early ART in the COAT trial was immunologically mediated.

Keywords: AIDS; HIV; IRIS; cryptococcal meningitis; immunology; macrophage; randomized controlled trial; sCD14; sCD163.

© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Summary of participants and cerebrospinal fluid (CSF) sampling in the Cryptococcal Optimal ART Timing (COAT) trial. Abbreviations: ART, antiretroviral therapy; HIV, human immunodeficiency virus.
Figure 2.
Figure 2.
A, Differences in cerebrospinal fluid (CSF) white cell count (WCC) between trial arms during the 14 days of amphotericin therapy. WCCs are shown as dots, diamonds indicate the geometric mean and 95% confidence interval (CI), the percentage of participants with WCC <5 are shown below along with total numbers. There were no significant differences in geometric mean CSF WCC between early antiretroviral therapy (ART) and deferred ART. However, at the end of antifungal induction therapy (amphotericin day 14), the percentage of participants with CSF WCC <5 cells/µL was significantly lower in the early ART (42%) compared with the deferred ART group (60%; χ2 test, P = .047). B, Effect of early ART initiation on CSF WCC after antifungal induction therapy in participants with CSF WCC <5/µL at cryptococcal meningitis (CM) diagnosis. A similar number of participants in each trial arm had CSF WCC <5/µL at presentation (left). However, a significantly increased proportion of participants in the early ART group had WCC ≥5/µL at day 14 (top right) compared to deferred ART (bottom right) (Fisher's exact P = .0008).
Figure 3.
Figure 3.
Differences in day 14 cerebrospinal fluid (CSF) biomarkers between Cryptococcal Optimal ART Timing (COAT) trial groups enrolled in Kampala, Uganda. Significantly increased concentration of interleukin 13 (IL-13), macrophage inflammatory protein (MIP)-1α/CCL3, and the macrophage activation markers sCD14 and sCD163, were noted at day 14 in participants in the early antiretroviral therapy (ART) group compared to deferred ART group in Kampala. P values from linear regression models. CSF IL-13 was undetectable in 8% (3/36) in the early ART and 29% (12/41) in the deferred ART (Fisher's exact P = .02.).
Figure 4.
Figure 4.
Differences in serum and cerebrospinal fluid (CSF) biomarkers between subjects with normal or raised CSF white cell count (WCC) at Cryptococcal Optimal ART Timing randomization (median amphotericin day 8). Participants who had a normal CSF WCC (Supplementary Table 4A and 4B present detailed data for CSF and blood, respectively.

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