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      HIV Cerebrospinal Fluid Escape and Neurocognitive Pathology in the Era of Combined Antiretroviral Therapy: What Lies Beneath the Tip of the Iceberg in Sub-Saharan Africa?

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          Abstract

          Neurocognitive impairment remains an important HIV-associated comorbidity despite combination antiretroviral therapy (ART). Since the advent of ART, the spectrum of HIV-associated neurocognitive disorder (HAND) has shifted from the most severe form to milder forms. Independent replication of HIV in the central nervous system despite ART, so-called cerebrospinal fluid (CSF) escape is now recognised in the context of individuals with a reconstituted immune system. This review describes the global prevalence and clinical spectrum of CSF escape, it role in the pathogenesis of HAND and current advances in the diagnosis and management. It highlights gaps in knowledge in sub-Saharan Africa where the HIV burden is greatest and discusses the implications for this region in the context of the global HIV treatment scale up.

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          HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study.

          This is a cross-sectional, observational study to determine the frequency and associated features of HIV-associated neurocognitive disorders (HAND) in a large, diverse sample of infected individuals in the era of combination antiretroviral therapy (CART). A total of 1,555 HIV-infected adults were recruited from 6 university clinics across the United States, with minimal exclusions. We used standardized neuromedical, psychiatric, and neuropsychological (NP) examinations, and recently published criteria for diagnosing HAND and classifying 3 levels of comorbidity (minimal to severe non-HIV risks for NP impairment). Fifty-two percent of the total sample had NP impairment, with higher rates in groups with greater comorbidity burden (40%, 59%, and 83%). Prevalence estimates for specific HAND diagnoses (excluding severely confounded cases) were 33% for asymptomatic neurocognitive impairment, 12% for mild neurocognitive disorder, and only 2% for HIV-associated dementia (HAD). Among participants with minimal comorbidities (n = 843), history of low nadir CD4 was a strong predictor of impairment, and the lowest impairment rate on CART occurred in the subset with suppressed plasma viral loads and nadir CD4 ≥200 cells/mm(3) (30% vs 47% in remaining subgroups). The most severe HAND diagnosis (HAD) was rare, but milder forms of impairment remained common, even among those receiving CART who had minimal comorbidities. Future studies should clarify whether early disease events (e.g., profound CD4 decline) may trigger chronic CNS changes, and whether early CART prevents or reverses these changes.
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            Updated research nosology for HIV-associated neurocognitive disorders.

            In 1991, the AIDS Task Force of the American Academy of Neurology published nomenclature and research case definitions to guide the diagnosis of neurologic manifestations of HIV-1 infection. Now, 16 years later, the National Institute of Mental Health and the National Institute of Neurological Diseases and Stroke have charged a working group to critically review the adequacy and utility of these definitional criteria and to identify aspects that require updating. This report represents a majority view, and unanimity was not reached on all points. It reviews our collective experience with HIV-associated neurocognitive disorders (HAND), particularly since the advent of highly active antiretroviral treatment, and their definitional criteria; discusses the impact of comorbidities; and suggests inclusion of the term asymptomatic neurocognitive impairment to categorize individuals with subclinical impairment. An algorithm is proposed to assist in standardized diagnostic classification of HAND.
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              HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors

              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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                Author and article information

                Journal
                Brain Sci
                Brain Sci
                brainsci
                Brain Sciences
                MDPI
                2076-3425
                20 October 2018
                October 2018
                : 8
                : 10
                : 190
                Affiliations
                [1 ]Division of Infection and Immunity, University College London, London WC1E 6BT, UK; ravindra.gupta@ 123456ucl.ac.uk
                [2 ]Africa Health Research Institute, KwaZulu-Natal Durban 4001, South Africa
                [3 ]Institute for Global Health, University College London, London WC1E 6BT, UK; lewis.haddow@ 123456ucl.ac.uk
                [4 ]RK Khan Hospital, KwaZulu-Natal Durban 4092, South Africa; jbrijkumar@ 123456gmail.com
                [5 ]Department of Infectious Diseases, University of KwaZulu-Natal, Durban 4041, South Africa; Moosay@ 123456ukzn.ac.za
                [6 ]Institute of Infection and Global Health, University of Liverpool, Liverpool L69 3BX, UK; L.Benjamin@ 123456liverpool.ac.uk
                Author notes
                [* ]Correspondence: d.collier@ 123456ucl.ac.uk ; Tel.: +44-(0)20-3108-2119
                Author information
                https://orcid.org/0000-0001-5446-4423
                https://orcid.org/0000-0001-6191-4023
                https://orcid.org/0000-0002-9685-1664
                https://orcid.org/0000-0001-9751-1808
                Article
                brainsci-08-00190
                10.3390/brainsci8100190
                6211092
                30347806
                e1899780-19e0-48d1-bcfa-2916ee0dec44
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 28 September 2018
                : 17 October 2018
                Categories
                Review

                hiv,central nervous system,escape,discordance,independent replication,resistance

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