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      HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors

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          Abstract

          Combination antiretroviral therapy (CART) has greatly reduced medical morbidity and mortality with HIV infection, but high rates of HIV-associated neurocognitive disorders (HAND) continue to be reported. Because large HIV-infected (HIV+) and uninfected (HIV−) groups have not been studied with similar methods in the pre-CART and CART eras, it is unclear whether CART has changed the prevalence, nature, and clinical correlates of HAND. We used comparable methods of subject screening and assessments to classify neurocognitive impairment (NCI) in large groups of HIV + and HIV − participants from the pre-CART era (1988–1995; N = 857) and CART era (2000–2007; N = 937). Impairment rate increased with successive disease stages (CDC stages A, B, and C) in both eras: 25%, 42%, and 52% in pre-CART era and 36%, 40%, and 45% in CART era. In the medically asymptomatic stage (CDC-A), NCI was significantly more common in the CART era. Low nadir CD4 predicted NCI in both eras, whereas degree of current immunosuppression, estimated duration of infection, and viral suppression in CSF (on treatment) were related to impairment only pre-CART. Pattern of NCI also differed: pre-CART had more impairment in motor skills, cognitive speed, and verbal fluency, whereas CART era involved more memory (learning) and executive function impairment. High rates of mild NCI persist at all stages of HIV infection, despite improved viral suppression and immune reconstitution with CART. The consistent association of NCI with nadir CD4 across eras suggests that earlier treatment to prevent severe immunosuppression may also help prevent HAND. Clinical trials targeting HAND prevention should specifically examine timing of ART initiation.

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          Most cited references 36

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          HIV-associated cognitive impairment before and after the advent of combination therapy.

          The objective of this study was to describe the occurrence of HIV dementia and neuropsychological testing abnormalities in a new cohort of HIV-seropositive individuals at high risk for HIV dementia and to compare these results to a cohort before the advent of highly active antiretroviral therapy (HAART). HAART has been associated with improvements in cognitive performance in some HIV-infected patients. However, it is uncertain whether HAART has changed the frequency of specific neurocognitive abnormalities. Baseline data from 272 HIV-seropositive subjects in the Dana cohort recruited from January, 1994, to December, 1995, and 251 HIV-seropositive subjects in the Northeastern AIDS Dementia Consortium (NEAD) cohort recruited from April, 1998, to August, 1999, were compared. Participants in both cohorts received nearly identical assessments. After adjusting for differences in age, education, gender, race, and CD4 count between the two cohorts, there were no differences in the occurrence of HIV dementia or abnormalities either 1 SD or 2 SDs below established norms for any of the neuropsychological tests. Even though HAART has reduced the incidence of HIV dementia, HIV-associated cognitive impairment continues to be a major clinical problem among individuals with advanced infection.
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            Medication adherence in HIV-infected adults: effect of patient age, cognitive status, and substance abuse.

            To examine the predictors of antiretroviral adherence among HIV-infected adults, with a particular focus on advancing age, neuropsychological dysfunction, and substance abuse. : Prospective observational design. Participants were 148 HIV-infected adults between the ages of 25 and 69 years, all on a self-administered antiretroviral regimen. Medication adherence was tracked over a one-month period using an electronic monitoring device (medication event monitoring system caps). All participants completed a comprehensive battery of neuropsychological tests as well as a structured psychiatric interview. The mean adherence rate for the entire cohort was 80.7%, with older patients (> or = 50 years) demonstrating significantly better medication adherence than younger patients (87.5 versus 78.3%). Logistic regression analyses found that older patients were three times more likely to be classified as good adherers (defined as > or = 95% adherent). Neurocognitive impairment conferred a 2.5 times greater risk of poor adherence. Among the older patients, those who were classified as poor adherers performed significantly worse on neuropsychological testing, particularly on measures of executive function and psychomotor speed. Current drug abuse/dependence, but not current alcohol abuse/dependence, was also associated with sub-optimal medication adherence. Although older age is associated with higher rates of antiretroviral adherence, older participants who were cognitively impaired showed disproportionate difficulty in adequately adhering to their medication regimen. As such, efforts to detect neuropsychological dysfunction, particularly among older patients, and a thorough assessment of substance abuse, appear to be essential for the effective treatment of HIV-infected adults.
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              Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance.

               R. Ellis,  David Clifford,   (2009)
              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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                Author and article information

                Contributors
                rheaton@ucsd.edu
                dofranklin@ucsd.edu
                Journal
                J Neurovirol
                Journal of Neurovirology
                Springer US (Boston )
                1355-0284
                1538-2443
                21 December 2010
                21 December 2010
                February 2011
                : 17
                : 1
                : 3-16
                Affiliations
                [1 ]University of California, San Diego, CA USA
                [2 ]Washington University, St. Louis, MO USA
                [3 ]Mt. Sinai School of Medicine, New York, NY USA
                [4 ]University of Washington, Seattle, Seattle, WA USA
                [5 ]University of Texas Medical Branch, Galveston, TX USA
                [6 ]Johns Hopkins University, Baltimore, MD USA
                Article
                6
                10.1007/s13365-010-0006-1
                3032197
                21174240
                © The Author(s) 2010
                Categories
                Article
                Custom metadata
                © Journal of NeuroVirology, Inc. 2011

                Microbiology & Virology

                hiv dementia, combination antiretroviral therapy, hiv

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