Cellular Phenotype and Activation in Cerebrospinal Fluid following Antiretroviral Therapy-Associated Cryptococcal Meningitis – a case for withholding ART?

Meya DB^1,2 Okurut S², Bangdiwala A¹, Rhein J¹, Cose S³, Boulware DR¹, Janoff E⁴

¹University of Minnesota, Minneapolis, MN, USA; ²Infectious Diseases Institute, Kampala, Uganda; ³MRC/UVRI Uganda Research Unit on AIDS, Entebbe Uganda; ⁴Mucosal and Vaccine Research Program Colorado (MAVRC), University of Colorado Denver, CO, USA

Background:

Cryptococcal meningitis accounts for 15% of AIDS-related deaths. Increased antiretroviral therapy (ART) availability in Africa has led to more patients developing ART-associated cryptococcosis. ART-associated CM within 14 days of ART initiation (recent ART) has detrimental outcomes compared to CM in ART-naïve patients. It is unclear whether these outcomes are attributable to altered cellular immune activation.

Methods:

In a 1:2 case control study nested in a cryptococcal meningitis trial in Kampala, Uganda, we characterized T cell, monocyte lineage and activation status in cerebrospinal fluid (CSF) of HIV-infected patients with CM by ART status – initiated ART in the prior 14 days (recent ART, n=8) and ART naïve (n=16).

Results:

At baseline, ART naïve patients had higher fungal burden compared to the recent ART group, 5.0 log₁₀ colony forming units (CFU)/ml of CSF (interquartile range [IQR], 4.1-5.6) vs 3.1 log₁₀ CFUs/ml (2.2-4.1; P=0.015). CD8 T cell activation (HLA-DR⁺CD38⁺ expression) in CSF was higher among ART-naïve compared to the recent ART patients, 46% (28-58) vs 18% (8.3- 27.0. P=0.02). There was a trend to lower classical monocyte activation (CD163⁺HLA-DR⁺ expression) in the recent ART group compared to the ART naïve participants; 1.0% (0.0-4.3) vs 14% (2.0-30.0, P=0.07).

Conclusions:

We found decreased CD8 T cell and classical monocyte subset activation in cerebrospinal fluid among CM patients recently initiated on ART compared to ART-naïve patients. Lower non-classical monocyte activation was associated with death by 2 weeks. Whether these differences in innate and adaptive immune responses account for the observed outcomes requires further study.