The prevalence and incidence of neurocognitive impairment in the HAART era

Harvard University, Cambridge, Massachusetts, United States
AIDS (Impact Factor: 5.55). 09/2007; 21(14):1915-21. DOI: 10.1097/QAD.0b013e32828e4e27
Source: PubMed

ABSTRACT HAART suppresses HIV viral replication and restores immune function. The effects of HAART on neurological disease are less well understood. The aim of this study was to assess the prevalence and incidence of neurocognitive impairment in individuals who initiated HAART as part of an AIDS clinical trial.
A prospective cohort study of HIV-positive patients enrolled in randomized antiretroviral trials, the AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trials (ALLRT) study.
We examined the association between baseline and demographic characteristics and neurocognitive impairment among 1160 subjects enrolled in the ALLRT study.
A history of immunosuppression (nadir CD4 cell count < 200 cells/microl) was associated with an increase in prevalent neurocognitive impairment. There were no significant virological and immunological predictors of incident neurocognitive impairment. Current immune status (low CD4 cell count) was associated with sustained prevalent impairment.
The association of previous advanced immunosuppression with prevalent and sustained impairment suggests that there is a non-reversible component of neural injury that tracks with a history of disease progression. The association of sustained impairment with worse current immune status (low CD4 cell count) suggests that restoring immunocompetence increases the likelihood of neurocognitive recovery. Finally, the lack of association between incident neurocognitive impairment and virological and immunological indicators implies that neural injury continues in some patients regardless of the success of antiretroviral therapy on these laboratory measures.

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Available from: Thomas D Parsons, Sep 26, 2015
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    • "Combination antiretroviral therapy (cART) has shifted the nature of human immunodefiency virus (HIV)-infection from a terminal illness to a chronic manageable condition with a life expectancy that has gradually approached that of seronegative persons [Antiretroviral Therapy Cohort Collaboration, 2008; Nakagawa et al., 2013]. However , HIV-infected patients remain at a significantly increased risk of developing HIV-associated neurocognitive disorders (HAND), with 35–70% of all patients (treated and untreated) exhibiting at least subtle impairments on tests of neuropsychological function [Antinori et al., 2007; Cysique and Brew, 2009; Gannon et al., 2011; Heaton et al., 2010, 2011; Robertson et al., 2007; Sacktor et al., 2002; Simioni et al., 2010; Tozzi et al., 2007]. Patients with HAND are more likely to be unemployed, have greater problems with medication adherence, and have lower quality of life [Albert et al., 1995; Heaton et al., 1994, 2004; Kaplan et al., 1995; Marcotte et al., 2004; van Gorp et al., 1999]. "
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    ABSTRACT: Combination antiretroviral therapy transformed human immunodeficiency virus (HIV)-infection from a terminal illness to a manageable condition, but these patients remain at a significantly elevated risk of developing cognitive impairments and the mechanisms are not understood. Some previous neuroimaging studies have found hyperactivation in frontoparietal networks of HIV-infected patients, whereas others reported aberrations restricted to sensory cortices. In this study, we utilize high-resolution structural and neurophysiological imaging to determine whether alterations in brain structure, function, or both contribute to HIV-related cognitive impairments. HIV-infected adults and individually matched controls completed 3-Tesla structural magnetic resonance imaging (sMRI) and a mechanoreception task during magnetoencephalography (MEG). MEG data were examined using advanced beamforming methods, and sMRI data were analyzed using the latest voxel-based morphometry methods with DARTEL. We found significantly reduced theta responses in the postcentral gyrus and increased alpha activity in the prefrontal cortices of HIV-infected patients compared with controls. Patients also had reduced gray matter volume in the postcentral gyrus, parahippocampal gyrus, and other regions. Importantly, reduced gray matter volume in the left postcentral gyrus was spatially coincident with abnormal MEG responses in HIV-infected patients. Finally, left prefrontal and postcentral gyrus activity was correlated with neuropsychological performance and, when used in conjunction, these two MEG findings had a sensitivity and specificity of over 87.5% for HIV-associated cognitive impairment. This study is the first to demonstrate abnormally increased activity in association cortices with simultaneously decreased activity in sensory areas. These MEG findings had excellent sensitivity and specificity for HIV-associated cognitive impairment, and may hold promise as a potential disease marker.
    Human Brain Mapping 11/2014; 36(3). DOI:10.1002/hbm.22674 · 5.97 Impact Factor
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    • "The widespread use of highly effective combination antiretroviral therapy (cART) has led to a clear reduction in the incidence of HIV-associated dementia (HAD), one of the most severe manifestations of HIV-1 CNS infection [4]. Despite this decrease, HIV-1 associated neurocognitive disorders (HANDs) persist in the cART era [5], with an estimated prevalence of approximately 40-50% [6,7]. Proposed in 2007, current research nosology recognizes three major categories of disease: asymptomatic neurocognitive impairment (ANI), HIV-associated mild neurocognitive disorder (MND), and HAD [8]. "
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    Retrovirology 08/2014; 11(1):65. DOI:10.1186/PREACCEPT-1509273248119831 · 4.19 Impact Factor
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    • "Combination antiretroviral therapy (cART), which controls systemic HIV-infection, has improved the health status of a large segment of patients [8]–[10]. Although cART has reduced the overall severity of neurocognitive disorders in HIV-1 patients, the prevalence of HAND remains at approximately 50% [4], [8], [10]–[12]. The persistence of relatively high rates of CNS disease is likely due to a combination of longer patient survival, the relatively poor CNS penetrance of most antiretroviral drugs [4], [13], and their neurotoxic effects [14]. "
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    ABSTRACT: HIV-1 enters the CNS soon after initial systemic infection; within the CNS parenchyma infected and/or activated perivascular macrophages, microglia and astrocytes release viral and cellular toxins that drive secondary toxicity in neurons and other cell types. Our previous work has largely modeled HIV-neuropathology using the individual viral proteins Tat or gp120, with murine striatal neurons as targets. To model disease processes more closely, the current study uses supernatant from HIV-1-infected cells. Supernatant from HIV-1SF162-infected differentiated-U937 cells (HIV+sup) was collected and p24 level was measured by ELISA to assess the infection. Injection drug abuse is a significant risk factor for HIV-infection, and opiate drug abusers show increased HIV-neuropathology, even with anti-retroviral treatments. We therefore assessed HIV+sup effects on neuronal survival and neurite growth/pruning with or without concurrent exposure to morphine, an opiate that preferentially acts through µ-opioid receptors. Effects of HIV+sup ± morphine were assessed on neuronal populations, and also by time-lapse imaging of individual cells. HIV+sup caused dose-dependent toxicity over a range of p24 levels (10-500 pg/ml). Significant interactions occurred with morphine at lower p24 levels (10 and 25 pg/ml), and GSK3β was implicated as a point of convergence. In the presence of glia, selective neurotoxic measures were significantly enhanced and interactions with morphine were also augmented, perhaps related to a decreased level of BDNF. Importantly, the arrest of neurite growth that occurred with exposure to HIV+sup was reversible unless neurons were continuously exposed to morphine. Thus, while reducing HIV-infection levels may be protective, ongoing exposure to opiates may limit recovery. Opiate interactions observed in this HIV-infective environment were similar, though not entirely concordant, with Tat/gp120 interactions reported previously, suggesting unique interactions with virions or other viral or cellular proteins released by infected and/or activated cells.
    PLoS ONE 06/2014; 9(6):e100196. DOI:10.1371/journal.pone.0100196 · 3.23 Impact Factor
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