Attenuated Central Nervous System Infection in Advanced HIV/AIDS With Combination Antiretroviral Therapy

Gertrude H. Sergievsky Center, Columbia University, New York, New York, United States
JAMA Neurology (Impact Factor: 7.42). 12/2004; 61(11):1687-96. DOI: 10.1001/archneur.61.11.1687
Source: PubMed


Before the introduction of combination antiretroviral therapy (CART), neurological disease correlated with cerebrospinal fluid (CSF) levels of human immunodeficiency virus (HIV) RNA.
To investigate the relationships among HIV RNA levels, immune activation markers, and neurological status in patients receiving CART.
Multicenter cohort study.
Academic neurology departments.
A total of 371 patients unselected for neurological complaints and with CD4 cell counts less than 200/microL or with cognitive symptoms and CD4 cell counts less than 300/microL were enrolled into the Northeastern AIDS Dementia cohort in 1998-2002. Diagnoses of HIV-associated dementia (HIV-D) and minor cognitive-motor disorder (MCMD) were obtained with a computerized algorithm. Plasma and CSF levels of HIV RNA, monocyte chemotactic protein 1, macrophage colony-stimulating factor, and tumor necrosis factor alpha were quantified.
The mean +/- SD age was 41.5 +/- 7.2 years, and the mean +/- SD educational level was 12.3 +/- 2.2 years. Seventy percent of the cohort was black, and 30% were women. The mean +/- SD CD4 cell count was 136.8 +/- 87.9/microL, and CART was used in 71%. Twenty-nine percent of the patients were unimpaired (n = 106), 36% had MCMD (n = 133), and 35% had HIV-D (n = 128). Mean log(10) CSF HIV RNA copies per milliliter was 2.6 +/- 0.8, with no differences among the neurological groups, even after adjustments for baseline CD4 cell counts and antiretroviral therapy. Cerebrospinal fluid HIV RNA was undetectable in 47% of unimpaired, 46% of MCMD, and 43% of HIV-D patients (P = .91). Plasma levels of monocyte chemotactic protein type 1 and tumor necrosis factor alpha correlated weakly with HIV RNA levels but did not distinguish those with neurological deficits.
In contrast to observations in individuals not treated with CART, we found no relationship between CSF markers and neurological status in this CART-using cohort with advanced HIV/AIDS. This was not explicable by demographic differences or plasma virological control. CART may substantially attenuate the degree of central nervous system HIV infection and immune activation, and in CART users, CSF HIV RNA and immune activation markers may fail to discriminate milder degrees of HIV-D and MCMD.

Download full-text


Available from: Daniel Mcclernon, Sep 02, 2014
  • Source
    • "This suggests that the hypothesized linear relationship between cognitive impairment and structural brain loss might be quite weak, as cognitive decline typically lags behind structural brain impairment. Additionally, the current study had a smaller percentage of patients with advanced ADC stage (ADC stage ≥ 1, 14% of the cohort), in part due to the lower incidence of cognitive impairment since the advent of cART (Ances and Ellis, 2007; McArthur et al., 2004). Even so, the unbalanced sample might have limited the statistical power to detect the effect. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cognitive impairment and brain injury are common in people with HIV/AIDS, even when viral replication is effectively suppressed with combined antiretroviral therapies (cART). Metabolic and structural abnormalities may promote cognitive decline, but we know little about how these measures relate in people on stable cART. Here we used tensor-based morphometry (TBM) to reveal the 3D profile of regional brain volume variations in 210 HIV + patients scanned with whole-brain MRI at 1.5 T (mean age: 48.6 ± 8.4 years; all receiving cART). We identified brain regions where the degree of atrophy was related to HIV clinical measures and cerebral metabolite levels assessed with magnetic resonance spectroscopy (MRS). Regional brain volume reduction was linked to lower nadir CD4 + count, with a 1–2% white matter volume reduction for each 25-point reduction in nadir CD4 +. Even so, brain volume measured by TBM showed no detectable association with current CD4 + count, AIDS Dementia Complex (ADC) stage, HIV RNA load in plasma or cerebrospinal fluid (CSF), duration of HIV infection, antiretroviral CNS penetration-effectiveness (CPE) scores, or years on cART, after controlling for demographic factors, and for multiple comparisons. Elevated glutamate and glutamine (Glx) and lower N-acetylaspartate (NAA) in the frontal white matter, basal ganglia, and mid frontal cortex — were associated with lower white matter, putamen and thalamus volumes, and ventricular and CSF space expansion. Reductions in brain volumes in the setting of chronic and stable disease are strongly linked to a history of immunosuppression, suggesting that delays in initiating cART may result in imminent and irreversible brain damage.
    Full-text · Article · Dec 2013 · Clinical neuroimaging
  • Source
    • "Many studies, especially those prior to the development of combination antiretroviral therapies (cART) regimens, have demonstrated an association between measures of disease severity, cognitive function (Brew, Pemberton, Cunningham, & Law, 1997; Childs et al., 1999; McArthur et al., 1997), and the development of dementia (Levy & Bredesen, 1998; Navia, Cho, Petito, & Archives of Clinical Neuropsychology 26 (2011) 614–623 Price, 1986; Navia & Price, 1987) with the onset of cognitive symptoms often heralding death (Ickovics et al., 2001). In the era of cART, the direct relationship between these variables appears to be diminished (McArthur et al., 2004), though it appears that improvement in immunological function and suppressed viral replication will result in observable improvements in cognitive function (Robertson et al., 2004) as well as lessen the risk of developing frank dementia (Sacktor et al., 2001). One common explanation for these diminished associations is that the natural course or trajectory of disease progression has been altered in the era of combination therapies (Egger et al., 1997). "
    [Show abstract] [Hide abstract]
    ABSTRACT: This study examined the association between recent trends in CD4 and viral loads and cognitive test performance with the expectation that recent history could predict cognitive performance. Eighty-three human immunodeficiency virus (HIV)-infected patients with a mean CD4 count of 428 copies/ml were examined in this study (62% with undetectable plasma viral load [PVL]). We investigated the relationships between nadir CD4 cell count, 1-year trends in immunologic function/PVLs, and cognitive performance across several domains using linear regression models. Nadir CD4 cell count was predictive of current executive function (p = .004). One year clinical history for CD4 cell counts and/or PVLs were predictive of executive function, attention/working memory, and learning/memory measures (p < .05). Models that combined recent clinical history trends and nadir CD4 cell counts suggested that recent clinical trends were more important in predicting current cognitive performance for all domains except executive function. This research suggests that recent CD4 and viral load history is an important predictor of current cognitive function across several cognitive domains. If validated, clinical variables and cognitive dysfunction models may improve our understanding of the dynamic relationships between disease evolution and progression and CNS involvement.
    Full-text · Article · Aug 2011 · Archives of Clinical Neuropsychology
  • Source
    • "The widespread use of highly active anti-retroviral therapy (HAART) has altered the spectrum of neurocognitive impairments categorized in HAND. Although the incidence of HAD, the most severe manifestation of HAND, has decreased significantly, the overall prevalence of HAND is still reported in 40-50% of HIV/AIDS patients [6], [19], [20]. The persistence of milder forms of HAND in HIV/AIDS patients undergoing HAART has been partly attributed to the longer life expectancy of the patients [21]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The neuropathological abnormalities of human immunodeficiency virus (HIV)-1 patients abusing illicit drugs suggest extensive interactions between the two agents, thereby leading to increased rate of progression to neurodegeneration. The role of HIV-1 transactivating protein, Tat has been elucidated in mediating neuronal damage via apoptosis, a hallmark of HIV-associated dementia (HAD), however the underlying mechanisms involved in enhanced neurodegeneration by illicit drugs remain elusive. In this study, we demonstrated that morphine enhances HIV-Tat induced toxicity in human neurons and neuroblastoma cells. Enhanced toxicity by Tat and morphine was accompanied by increased numbers of TUNEL positive apoptotic neurons, elevated caspase-3 levels and decreased ratio of anti- and pro-apoptotic proteins, Bcl2/Bax. Tat and morphine together elicited high levels of reactive oxygen species that were NADPH dependent. Significant alterations in mitochondrial membrane homeostasis were also observed with co-exposure of these agents. Extensive studies of mitogen activated protein kinase (MAPK) signaling pathways revealed the involvement of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase-1/2 (ERK1/2) pathways in enhanced toxicity of Tat and morphine. In addition to this, we found that pre-treatment of cells with platelet derived growth factor (PDGF-BB) protected neurons from HIV-Tat and morphine induced damage. PDGF-BB alleviated ROS production, maintained mitochondrial membrane potential, decreased caspase-3 activation and hence protected the cells from undergoing apoptosis. PDGF-BB mediated protection against Tat and morphine involved the phosphatidylinositol-3 kinase (PI3K) pathway, as specific inhibitor of PI3K abrogated the protection conferred by PDGF-BB. This study demonstrates the mechanism of enhanced toxicity in human neurons subjected to co-exposure of HIV protein Tat and morphine, thus implying its importance in HIV positive drug abusers, where damage to the brain is reported to be more severe than non-drug abusers. We have also showed for the first time that PDGF-BB can protect against simultaneous exposure of Tat and morphine, strengthening its role as a neuroprotective agent that could be considered for therapeutic intervention.
    Preview · Article · Mar 2011 · PLoS ONE
Show more