Increased Intrathecal Immune Activation in Virally Suppressed HIV-1 Infected Patients with Neurocognitive Impairment.

Arvid Edén,Richard W Price,Henrik Zetterberg,Igor Grant,Staffan Nilsson,Donald Franklin,Thomas D Marcotte,Scott L Letendre,Dietmar Fuchs,Magnus Gisslén,Robert K Heaton,Kersten Kurt Koelsch

doi:10.1371/journal.pone.0157160

Abstract

ObjectiveAlthough milder forms of HIV-associated neurocognitive disorder (HAND) remain prevalent, a correlation to neuronal injury has not been established in patients on antiretroviral therapy (ART). We examined the relationship between mild HAND and CSF neurofilament light protein (NFL), a biomarker of neuronal injury; and CSF neopterin, a biomarker of CNS immunoactivation, in virally suppressed patients on antiretroviral therapy (ART).Design and MethodsWe selected 99 subjects on suppressive ART followed longitudinally from the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study. Based on standardized comprehensive neurocognitive performance (NP) testing, subjects were classified as neurocognitively normal (NCN; n = 29) or impaired (NCI; n = 70). The NCI group included subjects with asymptomatic (ANI; n = 37) or mild (MND; n = 33) HAND. CSF biomarkers were analyzed on two occasions.ResultsGeometric mean CSF neopterin was 25% higher in the NCI group (p = 0.04) and NFL and neopterin were significantly correlated within the NCI group (r = 0.30; p<0.001) but not in the NCN group (r = -0.13; p = 0.3). Additionally, a trend towards higher NFL was seen in the NCI group (p = 0.06).ConclusionsMild HAND was associated with increased intrathecal immune activation, and the correlation between neopterin and NFL found in NCI subjects indicates an association between neurocognitive impairment, CNS inflammation and neuronal damage. Together these findings suggest that NCI despite ART may represent an active pathological process within the CNS that needs further characterization in prospective studies.

Highlights

With antiretroviral therapy (ART) the incidence of HIV-associated dementia (HAD), the most severe form of HIV-associated neurocognitive disorders (HAND), has been dramatically reduced [1, 2]
Geometric mean CSF neopterin was 25% higher in the neurocognitively impaired (NCI) group (p = 0.04) and neurofilament protein (NFL) and neopterin were significantly correlated within the NCI group (r = 0.30; p
Mild HAND was associated with increased intrathecal immune activation, and the correlation between neopterin and NFL found in NCI subjects indicates an association between neurocognitive impairment, CNS inflammation and neuronal damage

Summary

Introduction

With antiretroviral therapy (ART) the incidence of HIV-associated dementia (HAD), the most severe form of HIV-associated neurocognitive disorders (HAND), has been dramatically reduced [1, 2] Despite this clear effect on more severe CNS disease, a number of studies have reported a substantial prevalence of mainly the milder HAND forms asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorder (MND) ranging from 18% to as high as 35–69% [2,3,4,5]. While ART generally reduces immune activation, many patients still have residual immune activation in the CNS despite viral suppression, and CSF neopterin frequently remains elevated even in patients on long-term effective therapy [13, 14]

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Conclusion