(O1) Antiretroviral treatment initiated at high CD4 cell counts does not normalize cerebrospinal fluid markers of immune activation

Författare/Medförfattare

Frida Rydberg(1,2), Aylin Yilmaz(1,2), Lars Hagberg(1,2), Dietmar Fuchs(3), Magnus Gisslén(1,2)

Affiliates

1Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 2Region Västra Götaland, Sahlgrenska University Hospital, Department of Infectious Diseases, Gothenburg, Sweden; 3Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Innsbruck, Austria

Abstrakt

Background
HIV infects cells in the central nervous system (CNS), mainly microglia and perivascular macrophages, and induces a chronic intrathecal immune activation. Similar to its effect outside the CNS, antiretroviral treatment (ART) substantially decreases CNS inflammation and CD4+ T-cell trafficking through the cerebrospinal fluid (CSF) is often reduced to near normal levels. Yet, CSF levels of neopterin, a pteridine marker of primarily macrophage/microglia activation, have been found to be stably increased in the majority of persons living with HIV (PLWH) who begin treatment during the chronic phase of HIV infection when the immune function is impaired. By contrast, CSF neopterin is essentially normalized when ART is initiated early, during acute HIV infection (AHI). The aim of this study was to evaluate if CSF immune activation biomarkers normalize to a larger extent in PLHIV with chronic HIV who start ART at high, as compared to starting treatment at low CD4-cell counts.

Methods
176 neuroasymptomatic patients who started ART during chronic HIV were retrospectively included from the longitudinal prospective Gothenburg CSF cohort study and followed for in median 5.0 (mean 6.1) years. Lumbar punctures were performed at baseline before ART, after 1, and >3 years. Twenty-two participants had a CD4 nadir <50; 31 between 50 and 199; 32 between 200 and 349; 13 between 350 and 499; and 13 ≥500 cells/µL. Neopterin concentrations were measured using a commercially available immunoassay (NEOPT-SCR.EIA 384 Det., Thermo Fisher Scientific – BRAHMS GmbH, Henningsdorf, Germany) with an upper normal reference value of 5.8 nmol/L in CSF.

Results
A significant inverse correlation between CD4 cell count and CSF neopterin was found at baseline (r = -0.25, p 3 years ART. 15% of participants with the highest CD4 nadir (>500) had normal CSF neopterin (<5.8 nmol/L) compared to 0% of those with the lowest CD4 nadir (3 years of ART, 57% and 50% respectively had normal CSF neopterin.

Discussion
In contrast to ART initiation during acute HIV-infection, chronically HIV-infected patients starting ART at high CD4 cell counts do not normalize the macrophage/microglial activation marker CSF neopterin to any greater extent than if treatment is started later with low CD4 cell counts. This may reflect the inability of ART to affect the CNS reservoir that has been established already before the early phases of the chronic infection.