Abstract
BackgroundNeopterin, a biomarker of macrophage activation, is elevated in the cerebrospinal fluid (CSF) of most HIV-infected individuals and decreases after initiation of antiretroviral therapy (ART). We studied decay characteristics of neopterin in CSF and blood after commencement of ART in HIV-infected subjects and estimated the set-point levels of CSF neopterin after ART-mediated viral suppression.MethodsCSF and blood neopterin were longitudinally measured in 102 neurologically asymptomatic HIV-infected subjects who were treatment-naïve or had been off ART for ≥ 6 months. We used a non-linear model to estimate neopterin decay in response to ART and a stable neopterin set-point attained after prolonged ART. Seven subjects with HIV-associated dementia (HAD) who initiated ART were studied for comparison.ResultsNon-HAD patients were followed for a median 84.7 months. Though CSF neopterin concentrations decreased rapidly after ART initiation, it was estimated that set-point levels would be below normal CSF neopterin levels (<5.8 nmol/L) in only 60/102 (59%) of these patients. Pre-ART CSF neopterin was the primary predictor of set-point (P <0.001). HAD subjects had higher baseline median CSF neopterin levels than non-HAD subjects (P <0.0001). Based on the non-HAD model, only 14% of HAD patients were predicted to reach normal levels.ConclusionsAfter virologically suppressive ART, abnormal CSF neopterin levels persisted in 41% of non-HAD and the majority of HAD patients. ART is not fully effective in ameliorating macrophage activation in CNS as well as blood, especially in subjects with higher pre-ART levels of immune activation.
Highlights
Neopterin is a low-molecular weight pteridine (253 Dalton), predominantly produced by macrophages and related cells after stimulation with IFN-γ [1], which serves as a sensitive marker of activation of these cells
cerebrospinal fluid (CSF) levels of neopterin are elevated throughout the course of HIV infection with highest values occurring in patients with HIV-associated dementia (HAD) and
Because this study focused on neopterin concentrations among virologically suppressed patients, only subjects with viral suppression after initiation of antiretroviral therapy (ART) were included
Summary
Neopterin was measured by a commercially available radio-immunoassay or enzyme-linked immunosorbent assay (Neopterin RIA and EIA, BRAHMS, Hennigsdorf, Germany) [13]. Other models involving factors potentially associated with longterm neopterin levels were considered They included longitudinally measured HIV RNA levels in the CSF and plasma and CD4+ T-cell counts at the start of therapy. In addition to producing point estimates of the neopterin set-point for each subject, we tested whether the estimated set-point corresponding to the median and third quartile levels of baseline CSF and blood neopterin in the neurologically asymptomatic population was significantly higher than the upper limit of normal using the Wald chi-square test. Using the model developed for the neurologically asymptomatic patients, we tested whether the estimated CSF and blood neopterin set-point corresponding to the median and third quartile levels of baseline CSF and blood neopterin among subjects with HAD was significantly higher than the upper limit of normal of CSF and blood neopterin levels in the same manner. All analyses were performed with R version 2.11.1 (The R Foundation for Statistical Computing)
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