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Increased Intrathecal Immune Activation in Virally Suppressed HIV-1 Infected Patients with Neurocognitive Impairment
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Increased Intrathecal Immune Activation in Virally Suppressed HIV-1 Infected Patients with Neurocognitive Impairment
Arvid Eden1*, Thomas D. Marcotte2, Robert K. Heaton2, Staffan Nilsson3,
Henrik Zetterberg4,5, Dietmar Fuchs6, Donald Franklin2, Richard W. Price7, Igor Grant2, Scott L. Letendre2, Magnus Gisslen1
Conclusions
The findings in this study indicate that milder HAND forms may be a clinically significant reflection of an ongoing pathologic process within the CNS in some patients, where viral suppression alone is not sufficient to eliminate neuronal inflammation. The correlation found between CSF neopterin and NFL in subjects with neurocognitive impairment also indicates a mechanistic association between immune activation, neuronal damage and neurocognitive impairment during effective ART. Although standard ART is likely sufficient to prevent neurologic complications in most patients, effective control of viral replication through ART alone may not be sufficient in all cases. Methods of identifying individual patients at risk of developing, as well as progressing in HAND are needed, where the use of CSF biomarkers and neuropsychological testing will likely continue to be important tools.
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]. However, 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% [2-5].
Although the clinical relevance of the milder forms of HAND, particularly ANI, has been questioned [15, 16], recent data have suggested an increased risk of progression to symptomatic impairment in subjects diagnosed with ANI compared to neurocognitively unimpaired subjects, supporting the value of an ANI diagnosis in the clinical setting [17]. However, it is not fully established whether or not progression in neurocognitive impairment represents an ongoing pathologic process within the CNS that continues even in the face of functioning ART.Although residual inflammatory activity in the CNS is present in many virally suppressed patients, the clinical significance of continuous low level intrathecal immune activation during effective ART remains unclear. The aims of the current study were to investigate if milder forms of HAND (ANI and MND) were associated with CSF markers of neuronal damage (NFL) and immune activation (neopterin) despite effective viral suppression, and if CSF biomarkers were associated with disease progression in patients with neurocognitive impairment.
The clinical and pathological importance of the milder HAND forms (particularly ANI) has been questioned in patients responding well to ART. In the present study of effectively treated, virally suppressed HIV-1 infected patients, we demonstrate that patients with milder forms of HAND (ANI and MND) had a higher degree of intrathecal immune activation than patients without neurocognitive impairment, suggesting that even the milder forms of HAND may represent a clinically significant pathologic process within the CNS. Moreover, the correlation between CSF NFL and neopterin found in the NCI patient group, but not in the NCN group, indicates a mechanistic association between CNS inflammation, neuronal damage and neurocognitive impairment during effective ART.
Abstract
Objective
Although 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 Methods
We 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.
Results
Geometric 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).
CSF biomarkers and neurocognitive impairment
An overview of the distribution of CSF biomarkers at baseline and follow up in the study groups is shown in Fig 1. Baseline median (IQR) CSF NFL levels were 577 (371-769) ng/l in the NCI group and 462 (364-552) ng/l in the NCN group. At follow up, corresponding levels were 561 (385-746) and 435 (375-535) ng/l, respectively.
Fig 2 shows the relationship between NFL and neurocognitive status in the study subjects. Although the difference corresponded to 18% higher geometric mean CSF NFL levels in the NCI group, this was not statistically significant in linear mixed effects model analysis (p = 0.12). Moreover, CSF NFL increases with normal ageing, and after adding age as a covariate in the model, the corresponding difference in CSF NFL levels between study groups was 12% (p = 0.27).
CSF neopterin levels were higher in the NCI group. Baseline median (IQR) neopterin was 7.2 (4.9-10.9) nmol/l in the NCI-group, and 4.8 (4.7-7.4) nmol/l in the NCN group. At follow up, neopterin in the NCI and NCN groups was 6.3 (4.8-10.2) and 4.9 (4.6-7.2) nmol/l, respectively. In linear mixed model analysis of log10 CSF neopterin, this difference corresponded to 25% higher geometric mean CSF neopterin levels in the NCI group (p = 0.04) (Fig 3).
CSF biomarkers and progression of impairment
Overall, 32 subjects within the NCI group experienced a NP-decline from baseline to follow up, while 38 subjects remained stable. No significant difference in CSF NFL was seen between NCI-stable or NCI-decline subjects (p = 0.5) (Fig 2). Median (IQR) CSF NFL at baseline was 580 (374-798) ng/l in NCI-stable and 555 (347-744) ng/l in NCI-decline subjects. At follow up, corresponding CSF NFL was 586 (409-786) and 536 (320-735) ng/l, respectively. Additionally, no significant difference was found in the proportion of patients with abnormal age-adjusted CSF NFL in the subjects with NCI decline (4/32) compared to NCI-stable patients (9/38) (p = 0.4)
Median (IQR) baseline CSF neopterin was 7.0 (4.9-9.4) nmol/l in NCI-stable and 7.7 (4.9-13.0) in NCI-decline subjects. Corresponding CSF neopterin at follow up was 6.1 (4.8-9.3) and 6.3 (4.9-13.6) nmol/l, respectively. Although geometric mean CSF neopterin was 21% higher in NCI-decline patients, this difference did not reach statistical significance (p = 0.1) (Fig 3). Furthermore, we found no significant difference in the proportion of abnormal CSF neopterin in patients with NCI-decline (12/32) compared to NCI-stable patients (12/38) (p = 0.6).
Conclusions
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. Together these findings suggest that NCI despite ART may represent an active pathological process within the CNS that needs further characterization in prospective studies.
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