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HIV-Associated Neurocognitive Disorder (HAND) and the Prospect of Brain-Penetrating Protease Inhibitors for Antiretroviral Treatment.

ABSTRACT: The advent of combined active antiretroviral therapy (cART) dramatically improved HIV management and patient care of HIV-infected individuals. This treatment regimen resulted in a significant reduction of HIV/AIDS-related mortality and greatly improved life expectancies of those patients with access to cART. However, among many HIV-related complications, neurocognitive dysfunction, known as HIV-associated neurocognitive disorder (HAND) has been a major issue. While the cART regimen has been effective in reduction of HAND in many patients, the prevalence of HAND is increasing as HIV/AIDS patients live longer. HIV infection and its subsequent manifestation of HAND is complex. It is evident that the brain can serve as a sanctuary for HIV replication and HAND can remain in patients even with cART treatment due to poor blood-brain barrier permeability of the majority of current antiretroviral agents. Conceivably, cART needs to have improved CNS penetration properties for effective treatment and possible prevention of HAND. Therefore, design and development of new antiretroviral agents that can penetrate into the CNS effectively, could block HIV replication and significantly reduce the viral load in cerebrospinal fluid. This may prevent HAND and related symptoms. HIV protease inhibitors (PIs) are a critical component of cART. Over the years, we have designed and synthesized a range of highly potent and novel PIs including the FDA approved drug, darunavir, which is used as a first-line treatment. In an effort to improve CNS penetration, we have been involved in the design and development of potent PIs with improved in vitro brain penetration properties. Herein we provide a brief review that cover insights and discussion of HAND and our work on PI development to ameliorate HIV-associated neurocognitive disorders.

SUBMITTER: Ghosh AK

PROVIDER: S-EPMC6034681 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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HIV-Associated Neurocognitive Disorder (HAND) and the Prospect of Brain-Penetrating Protease Inhibitors for Antiretroviral Treatment.

Ghosh Arun K AK Sarkar Anindya A Mitsuya Hiroaki H

Medical research archives 20170415 4

The advent of combined active antiretroviral therapy (cART) dramatically improved HIV management and patient care of HIV-infected individuals. This treatment regimen resulted in a significant reduction of HIV/AIDS-related mortality and greatly improved life expectancies of those patients with access to cART. However, among many HIV-related complications, neurocognitive dysfunction, known as HIV-associated neurocognitive disorder (HAND) has been a major issue. While the cART regimen has been effe ...[more]

PMID: 29984302

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Project description:BackgroundHIV infection is associated with significant neurocognitive deficits making maximization of cognitive function among children receiving antiretroviral therapy (ART) a public health imperative. Non-protease inhibitors (non-PIs) achieve higher drug levels in the cerebral spinal fluid (CSF) compared to PIs, potentially leading to better neurocognitive function by reducing CSF viral load and inflammation. ART that maximises children's neurodevelopment and school achievement could result in improved quality of life and productivity as adults, but little research to date has examined whether non-PI ART is associated with better neurocognitive outcomes. We compared the neurocognitive function between children living with HIV receiving PI-based and non PI-based ART.MethodsWe recruited a consecutive sample of clinically stable Ugandan children living with HIV aged 5-12 years who received PI-based or non PI-based ART for ≥ 1 year (viral load < 1000 copies). Neurocognitive function was assessed using the Kaufman Assessment Battery for Children, the Test of Variables of Attention, and Bruininks-Oseretsky Test of Motor Proficiency. Age-adjusted neurocognitive z-scores for the two groups were compared using linear regression models in STATA version 13. The Hommel's method was used to adjust for multiple testing.ResultsWe enrolled 76 children living with HIV; 34 on PI ART and 42 on non-PI ART. Mean (±SD) age was greater in the non-PI vs. PI group (9.5 ± 1.9 vs. 8.5 ± 2.0) years (p = 0.03). Children in the non-PI group had lower socioeconomic scores (5.7 ± 3.3 vs. 7.4 ± 2.8, p = 0.02). There was no difference in neurocognitive function between the groups (adjusted p > 0.05) for KABC and TOVA. Children in the PI group had better total BOT scores than their counterparts (46.07 ± 1.40) vs. 40.51 (1.24), p = 0.03).ConclusionsWe detected no difference in neurocognitive function among children on PI and non PI-based ART therapy based on KABC and TOVA tests. Children on PI based ART had better motor function than their counterparts. We recommend a prospective study with a larger sample size.

Project description:PurposeThis study aimed to determine if people living with HIV (PLWH) in preclinical human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND), with no clinical symptoms and without decreased daily functioning, suffer from brain volumetric alterations and its patterns.MethodFifty-nine male PLWH at the HAND preclinical stage were evaluated, including 19 subjects with asymptomatic neurocognitive impairment (ANI), 17 subjects with cognitive abnormality that does not reach ANI (Not reach ANI), and 23 subjects with cognitive integrity. Moreover, 23 healthy volunteers were set as the seronegative normal controls (NCs). These individuals underwent sagittal three-dimensional T1-weighted imaging (3D T1WI). Quantified data and volumetric measures of brain structures were automatically segmented and extracted using AccuBrain®. In addition, the multiple linear regression analysis was performed to analyze the relationship of volumes of brain structures and clinical variables in preclinical HAND, and the correlations of the brain volume parameters with different cognitive function states were assessed by Pearson's correlation analysis.ResultsThe significant difference was shown in the relative volumes of the ventricular system, bilateral lateral ventricle, thalamus, caudate, and left parietal lobe gray matter between the preclinical HAND and NCs. Furthermore, the relative volumes of the bilateral thalamus in preclinical HAND were negatively correlated with attention/working memory (left: r = -0.271, p = 0.042; right: r = -0.273, p = 0.040). Higher age was associated with increased relative volumes of the bilateral lateral ventricle and ventricular system and reduced relative volumes of the left thalamus and parietal lobe gray matter. The lower CD4+/CD8+ ratio was associated with increased relative volumes of the left lateral ventricle and ventricular system. Longer disease course was associated with increased relative volumes of the bilateral thalamus. No significant difference was found among preclinical HAND subgroups in all indices, and the difference between the individual groups (Not reach ANI and Cognitive integrity groups) and NCs was also insignificant. However, there was a significant difference between ANI and NCs in the relative volumes of the bilateral caudate and lateral ventricle.ConclusionMale PLWH at the HAND preclinical stage suffer from brain volumetric alterations. AccuBrain® provides potential value in evaluating HIV-related neurocognitive dysfunction.

Dataset Information

HIV-Associated Neurocognitive Disorder (HAND) and the Prospect of Brain-Penetrating Protease Inhibitors for Antiretroviral Treatment.

Publications

HIV-Associated Neurocognitive Disorder (HAND) and the Prospect of Brain-Penetrating Protease Inhibitors for Antiretroviral Treatment.

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