Cognitive function after several years of antiretroviral therapy with stable central nervous system penetration score

Abstract

ObjectivesPrevious studies in HIV-infected populations have yielded conflicting results on the effect of antiretroviral therapy (ART) on cognition. Our objective was to investigate the effect of several years of ART with stable central nervous system penetration effectiveness (CPE) score on neuropsychological performance in HIV-infected individuals. MethodsWe analysed a clinical cohort of HIV-infected patients who initiated ART between June 2003 and December 2006 and maintained stable CPE scores. Patients were evaluated with a short neuropsychological battery. Using linear regression, we examined the relationship between results of cognitive tests and CPE scores in all patients. ResultsPatients were divided into three similarly sized groups (CPE Յ 1, CPE between 1.5 and 2.5, and CPE Ն 2.5). We found that ART with high CPE scores was associated with poorer executive performances in HIV-1-infected patients. ConclusionThese results suggest that cognitive performance in treated HIV-infected patients could be influenced by ART.Keywords: antiretroviral therapy, central nervous system penetration effectiveness (CPE) score, cognition, HIV Accepted 8 August 2012 IntroductionNeurocognitive impairment was described in HIV-infected patients prior to the introduction of antiretroviral therapy (ART). At that time, several studies showed that HIV RNA levels in cerebrospinal fluid (CSF) correlated with the severity of HIV-associated dementia [1,2]. The advent of ART led to undetectability of plasma virus load in about 80% of treated patients, together with a dramatic decrease in the incidence of HIV-associated dementia [3]. However, neurocognitive impairment still occurs, even in patients with blood CD4 counts within the normal range and undetectable plasma and CSF viral load [4]. Cognitive function is a real concern in long-term treated HIV-positive patients because cognitive decline has been linked to all-cause mortality.Several studies have demonstrated that ART regimens with high central nervous system penetration effectiveness (CPE) ranks improved neurocognitive functioning, but others have reported the opposite finding [5][6][7], while two recent studies detected neither positive nor negative effects of ART on cognition [8,9] To explore the link between cognitive performance and CPE score after 4 to 7 years of ART with a stable CPE score, we carried out a cross-sectional study exploring neurocognition in HIV-infected patients [10]. The secondary objective was to correlate cognition changes with various classes of treatment. MethodsPatients were selected from a database of patients followed in the Department of Internal Medicine at Lariboisière Hospital (Paris, France). For this study, a homogenous group of patients with stable CPE scores were selected from this clinical cohort, who initiated ART between June 2003 and December 2006. After the screening, we selected patients according to our inclusion criteria, which were [1]: patients who continued to receive their first treatment unchanged during this period or who switch...

Genetic, Transcriptomic, and Epigenetic Studies of HIV-Associated Neurocognitive Disorder

“…Interestingly, gene expression in the HIV+ brains did not correlate with brain viral burden, suggesting that even high CNS penetration effectiveness (CPE) 150 , which has been shown to reduce CSF viral load 151 , may not reduce transcriptomic dysregulation. Indeed, the absence of an association between CPE and brain transcriptome by our group when utilizing both standard differential expression analysis and WGCNA 145 would help to explain the equivocal results of studies examining the relationship between CPE and HIV-related neurocognitive dysfunction to date 152-156 .…”

Host Genetic Factors Predisposing to HIV-Associated Neurocognitive Disorder

“…The contribution of complex drug interactions, side effects when taking an increased number of drugs for advanced disease, and known mitochondrial effects of older dideoxynucleoside reverse-transcriptase-inhibitors such as stavudine and didanosine, to NCI is unknown [8, 95]. Transcriptomic studies evaluating the impact of cART on gene expression patterns in HAND in brain tissue reveal alterations in expression of about 100 immune-regulatory, cell-cycle, and myelin-pathway genes that are not correlated either with brain viral burden or to antiretroviral drug CNS penetration effectiveness (CPE) score, suggesting a possible explanation for the difficulty to date in correlating CPE scores to neurocognitive outcomes despite their association with reduced CSF viral load [8, 96•].…”

Altered Oligodendrocyte Maturation and Myelin Maintenance: The Role of Antiretrovirals in HIV-Associated Neurocognitive Disorders

“…Conversely, impaired myelination can disrupt proper signaling and hasten axonal degeneration resulting in neurological dysfunction (27, 28). Although sustained effects of continuing viral replication and treatment noncompliance are suggested to underlie continuing neurocognitive impairment, antiretrovirals themselves may contribute to the pathogenesis of HAND (29–31). Crucially, while antiretroviral-mediated toxicity has been reported in primary rat cortical neurons (32, 33), to date there are no published studies addressing the effects of antiretrovirals on oligodendrocytes, the myelin forming cells of the CNS.…”