Marra CM, Zhao Y, Clifford DB, Letendre S, Evans S, Henry K, et al. Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance

Department of Neurology, University of Washington School of Medicine, Seattle, USA.
AIDS (London, England) (Impact Factor: 5.55). 06/2009; 23(11):1359-66. DOI: 10.1097/QAD.0b013e32832c4152
Source: PubMed


To determine whether antiretroviral regimens with good central nervous system (CNS) penetration control HIV in cerebrospinal fluid (CSF) and improve cognition.
Multisite longitudinal observational study.
Research clinics.
One hundred and one individuals with advanced HIV beginning or changing a new potent antiretroviral regimen were enrolled in the study. Data for 79 participants were analyzed. Participants underwent structured history and neurological examination, venipuncture, lumbar puncture, and neuropsychological tests at entry, 24, and 52 weeks.
Antiretroviral regimens were categorized as CNS penetration effectiveness (CPE) rank of at least 2 or less than 2. Generalized estimating equations were used to examine associations over the course of the study.
Concentration of HIV RNA in CSF and blood and neuropsychological test scores (NPZ4 and NPZ8).
Odds of suppression of CSF HIV RNA were higher when CPE rank was at least 2 than when it was less than 2. Odds of suppression of plasma HIV RNA were not associated with CPE rank. Among participants with impaired neuropsychological performance at entry, those prescribed regimens with a CPE rank of at least 2 or more antiretrovirals had lower composite NPZ4 scores over the course of the study.
Antiretroviral regimens with good CNS penetration, as assessed by CPE rank, are more effective in controlling CSF (and presumably CNS) viral replication than regimens with poorer penetration. In this study, antiretrovirals with good CNS penetration were associated with poorer neurocognitive performance. A larger controlled trial is required before any conclusions regarding the influence of specific antiretrovirals on neurocognitive performance should be made.

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Available from: David B Clifford, Feb 10, 2014
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    • "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•]. "
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    ABSTRACT: The success of combination antiretroviral therapy (cART) in transforming the lives of HIV-infected individuals with access to these drugs is tempered by the increasing threat of HIV-associated neurocognitive disorders (HAND) to their overall health and quality of life. Intensive investigations over the past two decades have underscored the role of host immune responses, inflammation, and monocyte-derived macrophages in HAND, but the precise pathogenic mechanisms underlying HAND remain only partially delineated. Complicating research efforts and therapeutic drug development are the sheer complexity of HAND phenotypes, diagnostic imprecision, and the growing intersection of chronic immune activation with aging-related comorbidities. Yet, genetic studies still offer a powerful means of advancing individualized care for HIV-infected individuals at risk. There is an urgent need for 1) longitudinal studies using consistent phenotypic definitions of HAND in HIV-infected subpopulations at very high risk of being adversely impacted, such as children, 2) tissue studies that correlate neuropathological changes in multiple brain regions with genomic markers in affected individuals and with changes at the RNA, epigenomic, and/or protein levels, and 3) genetic association studies using more sensitive subphenotypes of HAND. The NIH Brain Initiative and Human Connectome Project, coupled with rapidly evolving systems biology and machine learning approaches for analyzing high-throughput genetic, transcriptomic and epigenetic data, hold promise for identifying actionable biological processes and gene networks that underlie HAND. This review summarizes the current state of understanding of host genetic factors predisposing to HAND in light of past challenges and suggests some priorities for future research to advance the understanding and clinical management of HAND in the cART era.
    Preview · Article · Jul 2014 · Current HIV/AIDS Reports
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    • "Virus-related factors, such as resistant virus species and persistent viral DNA in the CNS, may contribute to the persistence of HAND in the post-cART era. One recent focus in HIV neurovirology is the development of ARVs with greater CNS penetrance (Letendre et al. 2008; Marra et al. 2009; Tozzi et al. 2009; Edén et al. 2010; Heaton et al. 2010; Garvey et al. 2011; Smurzynski et al. 2011). However, potential ARV toxicity in the CNS remains largely unexplored. "
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    ABSTRACT: HIV-associated neurocognitive disorder (HAND), characterized by a wide spectrum of behavioral, cognitive, and motor dysfunctions, continues to affect approximately 50 % of HIV(+) patients despite the success of combination antiretroviral drug therapy (cART) in the periphery. Of note, potential toxicity of antiretroviral drugs in the central nervous system (CNS) remains remarkably underexplored and may contribute to the persistence of HAND in the cART era. Previous studies have shown antiretrovirals (ARVs) to be neurotoxic in the peripheral nervous system in vivo and in peripheral neurons in vitro. Alterations in lipid and protein metabolism, mitochondrial damage, and oxidative stress all play a role in peripheral ARV neurotoxicity. We hypothesized that ARVs also induce cellular stresses in the CNS, ultimately leading to neuronal damage and contributing to the changing clinical and pathological picture seen in HIV-positive patients in the cART era. In this report, we show that ARVs are neurotoxic in the CNS in both pigtail macaques and rats in vivo. Furthermore, in vitro, ARVs lead to accumulation of reactive oxygen species (ROS), and ultimately induction of neuronal damage and death. Whereas ARVs alone caused some activation of the endogenous antioxidant response in vitro, augmentation of this response by a fumaric acid ester, monomethyl fumarate (MMF), blocked ARV-induced ROS generation, and neuronal damage/death. These findings implicate oxidative stress as a contributor to the underlying mechanisms of ARV-induced neurotoxicity and will provide an access point for adjunctive therapies to complement ARV therapy and reduce neurotoxicity in this patient population.
    Full-text · Article · Jan 2014 · Journal of NeuroVirology
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    • "The CNS Penetration Effectiveness (CPE) Scale introduced by Letendre and colleagues [58] provides a quantitative index of the relative capacity for an antiretroviral drug to cross the blood brain barrier. However, the relationship between CNS penetration effectiveness of antiretroviral (cART) cocktails and neurocognitive performance is not straightforward, with some studies reporting positive relationships between CPE scores and neurocognitive performance [59]–[61], whereas others report inverse [62], [63] or no relationships [64]. In terms of computational modeling, it should be noted that the validity of the conclusions must be understood within the limits of the fit of the computational models. "
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    ABSTRACT: Drug users and HIV-seropositive individuals often show deficits in decision-making; however the nature of these deficits is not well understood. Recent studies have employed computational modeling approaches to disentangle the psychological processes involved in decision-making. Although such approaches have been used successfully with a number of clinical groups including drug users, no study to date has used computational modeling to examine the effects of HIV on decision-making. In this study, we use this approach to investigate the effects of HIV and drug use on decision-making processes in women, who remain a relatively understudied population. Fifty-seven women enrolled in the Women's Interagency HIV Study (WIHS) were classified into one of four groups based on their HIV status and history of crack cocaine and/or heroin drug use (DU): HIV+/DU+ (n = 14); HIV+/DU- (n = 17); HIV-/DU+ (n = 14); and HIV-/DU- (n = 12). We measured decision-making with the Iowa Gambling Task (IGT) and examined behavioral performance and model parameters derived from the best-fitting computational model of the IGT. Although groups showed similar behavioral performance, HIV and DU exhibited differential relationship to model parameters. Specifically, DU was associated with compromised learning/memory and reduced loss aversion, whereas HIV was associated with reduced loss aversion, but was not related to other model parameters. Results reveal that HIV and DU have differential associations with distinct decision-making processes in women. This study contributes to a growing line of literature which shows that different psychological processes may underlie similar behavioral performance in various clinical groups and may be associated with distinct functional outcomes.
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