CNS Penetration Effectiveness Research Articles

Switching to Low Neurotoxic Antiretrovirals to Improve Neurocognition Among People Living With HIV-1-Associated Neurocognitive Disorder: The MARAND-X Randomized Clinical Trial

Background: The pathogenesis of HIV-associated neurocognitive (NC) impairment is multifactorial, and antiretroviral (ARV) neurotoxicity may contribute. However, interventional pharmacological studies are limited. Methods: Single-blind, randomized (1:1), controlled trial to assess the change of NC performance (Global Deficit Score, GDS, and domain scores) in PLWH with NC impairment randomized to continue their standard of care treatment or to switch to a less neurotoxic ARV regimen: darunavir/cobicistat, maraviroc, emtricitabine (MARAND-X). Participants had plasma and cerebrospinal fluid HIV RNA< 50 copies/mL, R5-tropic HIV, and were on ARV regimens that did not include efavirenz and darunavir. The change of resting-state electroencephalography was also evaluated. The outcomes were assessed at week 24 of the intervention through tests for longitudinal paired data and mixed-effect models. Results: Thirty-eight participants were enrolled and 28 completed the follow-up. Global Deficit Score improved over time but with no difference between arms in longitudinal adjusted models. Perceptual functions improved in the MARAND-X, while long-term memory improved only in participants within the MARAND-X for whom the central nervous system penetration-effectiveness (CNS penetration effectiveness) score increased by ≥3. No significant changes in resting-state electroencephalography were observed. Conclusions: In this small but well-controlled study, the use of less neurotoxic ARV showed no major beneficial effect over an unchanged regimen. The beneficial effects on the memory domain of increasing CNS penetration effectiveness score suggest that ARV neuropenetration may have a role in cognitive function.

Modeling Antiretrovial Treatment to Mitigate HIV in the Brain: Impact of the Blood-Brain Barrier.

Current research in Human Immunodeficiency Virus (HIV) focuses on eradicating virus reservoirs that prevent or dampen the effectiveness of antiretroviral treatment (ART). One such reservoir, the brain, reduces treatment efficacy via the blood-brain barrier (BBB), causing an obstacle to drug penetration into the brain. In this study, we develop a mathematical model to examine the impact of the BBB on ART effectiveness for mitigating brain HIV. A thorough analysis of the model allowed us to fully characterize the global threshold dynamics with the viral clearance and persistence in the brain for the basic reproduction number less than unity and greater than unity, respectively. Our model showed that the BBB has a significant role in inhibiting the effect of ART within the brain despite the effective viral load suppression in the plasma. The level of impact, however, depends on factors such as the CNS Penetration Effectiveness (CPE) score, the slope of the drug dose-response curves, the ART initiation timing, and the number of drugs in the ART protocol. These results suggest that reducing the plasma viral load to undetectable levels due to some drug regimen may not necessarily indicate undetectable levels of HIV in the brain. Thus, the effect of the BBB on viral suppression in the brain must be considered for developing proper treatment protocols against HIV infection.

Association of combination antiretroviral therapy with risk of neurological diseases in patients with HIV/AIDS in Taiwan: a nested case-control study.

Heterogeneous neurocognitive impairment remains an important issue, even in the era of combination antiretroviral therapy (cART), with an incidence ranging from 15% to 65%. Although ART drugs with higher penetration scores to the central nervous system (CNS) show better HIV replication control in the CNS, the association between CNS penetration effectiveness (CPE) scores and neurocognitive impairment remains inconclusive. To explore whether ART exposure is associated with the risk of neurological diseases among patients with HIV/AIDS, this study in Taiwan involved 2,571 patients with neurological diseases and 10,284 matched, randomly selected patients without neurological diseases between 2010 and 2017. A conditional logistic regression model was used in this study. The parameters for ART exposure included ART usage, timing of exposure, cumulative defined daily dose (DDD), adherence, and cumulative CPE score. Incident cases of neurological diseases, including CNS infections, cognitive disorders, vasculopathy, and peripheral neuropathy, were obtained from the National Health Insurance Research Database in Taiwan. Odds ratios (ORs) for the risk of neurological diseases were conducted using a multivariate conditional logistic regression model. Patients with a history of past exposure (OR: 1.68, 95% confidence interval [CI]:1.22-2.32), low cumulative DDDs (< 2,500) (OR: 1.28, 95% CI: 1.15-1.42), low adherence (0 < adherence (ADH) ≤ 0.8) (OR: 1.46, 95% CI: 1.30-1.64), or high cumulative CPE scores (>14) (OR: 1.34, 95% CI: 1.14-1.57) had a high risk of neurological diseases. When stratified by classes of ART drugs, patients with low cumulative DDDs or low adherence had a high risk of neurological diseases, including NRTIs, PIs, NNRTIs, INSTIs, and multi-drug tablets. Subgroup analyses also suggested that patients with low cumulative DDDs or low adherence had a high risk of neurological diseases when they had high cumulative CPE scores. Patients with high cumulative DDDs or medication adherence were protected against neurological diseases only when they had low cumulative CPE scores (≤ 14). Patients may be at risk for neurological diseases when they have low cumulative DDDs, low adherence, or usage with high cumulative CPE scores. Continuous usage and low cumulative CPE scores of ART drugs may benefit neurocognitive health in patients with HIV/AIDS.

CNS efficacy parameters of combination antiretroviral therapy in chronic HIV infection: A multi-voxel magnetic resonance spectroscopy study.

This study aimed to determine the correlations of combination antiretroviral therapy (cART) efficacy parameters in the central nervous system (CNS) with a neurometabolic profile on magnetic resonance spectroscopy (MRS) in virally suppressed, neurologically asymptomatic HIV+ individuals. In total, 32 HIV+ individuals on stable cART with an average age of 41.97 ± 10.12 years and with available clinical data, CNS penetration effectiveness (CPE), and monocyte efficacy (ME) scores underwent multi-voxel MRS. The parameters of neuronal number/function (NAA/Cr), membrane turnover (Cho/Cr), and glial proliferation (mI/Cr) were analyzed in supratentorial white and gray matter. Correlations of CPE and ME with neurometabolic ratios were performed using Pearson's correlation test. Statistical significance was set at p < 0.05. A strong positive correlation was observed between Cho/Cr and CPE in the left parietal subcortical white matter (r = 0.577, p = 0.001). A strong positive correlation between NAA/Cr and ME was obtained in the left (r = 0.521, p = 0.003) and the right (r = 0.494, p = 0.005) posterior cingulate. A strong negative correlation between ME and Cho/Cr ratios was observed in the right frontal deep white matter (r = -0.569, p = 0.001). Indices designed to assess cART efficacy in CNS failed to present significant correlations with the neurometabolic profile obtained using MRS. There is a need to define more potent non-invasive tools for neuroinflammation assessment given the prolonged life expectancy in the HIV+ population.

Assessment of neurocognitive disorders in HIV infected patients receiving combination of anti-retroviral therapy at a tertiary care hospital - An observational study

cARTTherapy (combination antiretroviral therapy) has improved the live expectancy of people living with HIV (PLHIV). But HIV associated neurocognitive disorders (HAND) are still prevalent. One of the factors associated could be the cARTtherapy itself. The study aims to calculate the prevalence of HAND and associated risk factors in PLHIV who are on Cart therapy and to compare the efficiency of MMSE and IHDS scales in the assessment of HAND. A case-control study involving 54 PLHIV on cART therapy and 27 HIV negative controls were screened for their neurocognition by two neuropsychological tests such as MMSE and IHDS, followed by staging into Asymptomatic Neurological Impairment (ANI), Mild Neurocognitive Impairment (MND), HIV Associated Dementia (HAD) in PLHIV. Statistical analysis was done using suitable software. The overall prevalence of HAND in our study was found to be 70.37%. Prevalence estimates for specific HAND diagnoses were 57.89% ANI, 28.9% MND, and 13.1 % HAD. IHDS demonstrated good screening ability for HAND with an optimal cut-off score of 10, high sensitivity of 70% and minimal specificity. Age, male gender, low literacy, presence of comorbidities, severity of the disease, cART regimen with low CPE (CNS penetration effectiveness) score were strongly correlated. Study findings suggest that IHDS serves as a better screening tool for HAND with greater sensitivity and can facilitate further cognitive evaluation. The overall prevalence was found to be equivalent to that of the recently reported studies.

Abnormal Magnetic Resonance Image Signature in Virologically Stable HIV Individuals.

With implementation of combination antiretroviral therapy (cART), changes to brain integrity in people with HIV (PWH) are subtle compared to those observed in the pre-cART era. T1-weighted/T2-weighted (T1w/T2w) ratio has been proposed as a measure of cortical myelin. This study examines T1w/T2w values between virologically controlled PWH and persons without HIV (PWoH). Virologically well-controlled PWH (n = 164) and PWoH (n = 120) were compared on global and regional T1w/T2w values. T1w/T2w values were associated with HIV disease variables (nadir and current CD4 T-cell count, and CNS penetration effectiveness of cART regimen) in PWH, and as a function of age for both PWoH and PWH. PWH had reduced global and regional T1w/T2w values compared to PWoH in the posterior cingulate cortex, caudal anterior cingulate cortex, and insula. T1w/T2w values did not correlate with HIV variables except for a negative relationship with CNS penetration effectiveness. Greater cardiovascular disease risk and older age were associated with lower T1w/T2w values only for PWH. T1w/T2w values obtained from commonly acquired MRI protocols differentiates virologically well-controlled PWH from PWoH. Changes in T1w/T2w ratio do not correlate with typical HIV measures. Future studies are needed to determine the biological mechanisms underlying this measure.

Elevation of brain ADC (apparent diffusion coefficient) in HIV-associated neurocognitive disorders and evolution after treatment: A pilot study

BackgroundThirty to 50% of HIV-infected patients develop HIV-Associated Neurocognitive Disorders (HAND) despite virological control. The previously published Neuro+3 study showed their neurocognitive status can be improved by intensifying antiviral therapy. Our study is a part of the Neuro3+ study and aims to study apparent diffusion coefficient (ADC) as a biomarker for neurological improvement. Patients and methodsWe prospectively included 31 patients with HAND. They received therapy with better CNS Penetration Effectiveness (CPE) score with two-year follow-up. Cognitive status was assessed at day 0 (D0) and week 96 (W96) using Frascati 3-stage classification and Global Deficit Score (GDS). Brain MRI at D0 and W96 assessed morphological data (white matter hyperintensities, opportunistic infections, ischemic lesions, atrophy) and measured whole brain apparent diffusion coefficient (ADC). We compared their data with a control group of 20 healthy patients with similar ages and sex ratio. ResultsAfter ARV intensification, cognitive status was significantly improved: GDS (n = 1,4 vs 1,0 p = 0.01) and Frascati scale (2HAD/22MND/7ANI vs 1HAD/8MND/17ANI p = 0.001). Mean ADC was significantly higher in patients at inclusion than in controls (0.88 × 10−3 mm2/s ± 0.06 vs 0.81 × 10−3 mm2/s ± 0.04, p = 0.0001). ADC decreased after treatment (0.88 × 10−3 mm2/s ± 0.06 vs 0.85 × 10−3 mm2/s ± 0.06 (p = 0,04). In subgroup analysis, ADC significantly decreased in clinically improved patients (0.89 × 10−3 mm2/s ± 0.07 vs 0.85 × 10−3 mm2/s ± 0.07 (p = 0,03)) and did not significantly change in non-clinically improved patients (0.86 × 10−3 mm2/s ± 0.07 vs 0.84 × 10−3 mm2/s ± 0.07 (p = 0,31)). After treatment, there was no significant difference between patients and controls (0.85 × 10−3 mm2/s ± 0.06 vs 0.81 × 10−3 mm2/s ± 0.04, p = 0.17). ConclusionWhole-brain ADC is a good biomarker of HIV-associated neurocognitive disorders. It is significantly increased in patients with HAND compared with controls and significantly decreases after treatment. It is all the more important to have a quantitative biomarker as conventional imaging does not contribute to the diagnosis.

The effect of antiretroviral therapy with high central nervous system penetration on HIV-related cognitive impairment: a systematic review and meta-analysis

ABSTRACT Chronic complications are a significant concern for people living with HIV/AIDS (PLWHA) infection. HIV-associated neurocognitive disorders (HAND) are prevalent in PLWHA. Yet, the efficacy of medications that penetrate the central nervous system (CNS) at preventing or slowing the progression of HAND remains largely unknown. The objective of this study was to determine whether high CNS penetration effectiveness (CPE) regimens improve neurocognitive test scores in PLWHA on combined antiretroviral therapy (cART). Primary literature evaluating cognitive outcomes based on CPE score of cART regimens in PLWHA was assembled from PubMed/Medline and EMBASE. Both randomized controlled trials and observational studies with at least 12 weeks of follow-up were included. A meta-analysis was conducted to calculate the standardized mean difference. Eight trials including a total of 3,303 patients with 13,103 person-years of follow-up were included in the systematic review. Four trials (n = 366 patients) met our inclusion criteria and were included in the meta-analysis. In the meta-analysis, HIV regimens with a high CPE score did not affect NPZ-4 or GDS scores (standardized mean difference (SMD) 0.10, 95% CI −0.19, 0.38; I2 = 26%). Future studies with larger sample sizes are warranted to prospectively evaluate the relationship between CPE and progression of HAND.

HIV Antiretroviral Medication Neuropenetrance and Neurocognitive Outcomes in HIV+ Adults: A Review of the Literature Examining the Central Nervous System Penetration Effectiveness Score.

This literature review summarizes the existing research examining the CNS penetration effectiveness (CPE) score and neurocognitive outcomes (i.e., neuropsychological assessment and neurocognitive screening) in HIV+ individuals. Despite the effectiveness of Combined Antiretroviral Therapy (CART) in reducing mortality and morbidity in HIV and controlling viral replication, HIV often persists in the Central Nervous System (CNS), and rates of neurocognitive impairment remain higher than predicted in the post-CART era. The CPE score was developed to rank antiretroviral regimens on their ability to penetrate the CNS and potency in inhibiting the virus, and it has been examined in relation to neurocognitive functioning for over a decade. Based on the results of 23 studies, we conclude that CPE is not as strongly associated with neurocognitive outcomes as initially hypothesized, although higher CPE ARV regimens may be associated with modest, improved outcomes in global neurocognitive functioning, and to a lesser extent attention/working memory and learning/memory. Conclusions, however, are limited by the heterogeneity in study design and methods, and the lack of a more recent CPE metric update. It is recommended that future research in this area employ comprehensive, standardized neuropsychological test batteries and examine domain-level performance, and use the newer 2010 CPE metric, although an updated CPE ranking is urgently needed.

Natural Bioactives as Potential Therapeutic Modalities Against NeuroAIDS.

With the introduction of antiretroviral therapy, the worldwide AIDS-related deaths have decreased, and life expectancy has increased, including the prevalence of AIDS-related neurological disorders or neuroAIDS. HIV-associated neurocognitive disorders such as mild neurocognitive disorder and asymptomatic neurocognitive impairment have largely remained stable or increased among the HIV-infected individuals in the combination antiretroviral therapy era. The emerging evidence that antiretrovirals with high CNS penetration effectiveness score contribute to the neurotoxicity and HIV-associated neurocognitive disorders has ushered the search for natural, nontoxic bioactive constituents having pre-established neuroprotective, anti-inflammatory, and restorative neurocognitive activity. In this review, we have highlighted the probable mechanism of neuroAIDS infection, the problem with the existing antiretroviral therapy, along with various bioactive constituents with in vivo, in vitro, or ex vivo evidence of their neuroprotective activity that can be used as an adjuvant with the current combination antiretroviral therapy regimen or can even serve as an alternate to the antiretrovirals for treatment of HIV associated neurocognitive disorder.

Interrogating the impact of combination antiretroviral therapies on HIV‐associated neurocognitive disorders

Although the advent of Combination Antiretroviral Therapy (cART) has greatly reduced the prevalence of HIV-Associated Dementia, the most severe form of HIV-Associated Neurocognitive Disorder (HAND), the incidence of the milder forms of HAND have risen. The explanations proposed include persistent central nervous system (CNS) viraemia and the neurotoxicity of chronic cART regimens. Nonetheless, controversies in HAND prevalence estimates, alongside a lack of consensus on the significance of CNS Penetration Effectiveness (CPE) have added to the complexity of elucidating the role of cART in HAND. The present review will evaluate the evidence underlying these explanations, as well as highlighting the need for improved trial designs and the incorporation of emerging biomarkers and neuroimaging tools. A review of the current literature investigating cART neurotoxicity, controversies in HAND prevalence estimates, CNS Penetration Effectiveness, and neuroprotective adjuvant therapies. Ultimately, the inadequacy of cART in achieving complete preservation of the CNS underscores the imminent need for neuroprotective adjuvant therapies, where the efficacy of combining multiple adjuvant classes presents a potential therapeutic frontier which must be interrogated.

Accelerated epigenetic aging in adolescents living with HIV is associated with altered development of brain structures.

We recently demonstrated that adolescents perinatally infected with HIV-1 (PHIV+) have accelerated aging as measured by a highly accurate epigenetic biomarker of aging known as the epigenetic clock. However, whether epigenetic age acceleration in PHIV+ impacts brain development at the macro- and microstructural levels of brain anatomy has not been studied. We report on a cross-sectional study of PHIV+ enrolled in the Cape Town Adolescent Antiretroviral Cohort (CTAAC). The Illumina Infinium Methylation EPIC array was used to generate DNA methylation data from the blood samples of 180 PHIV+ aged 9 to 12years. The epigenetic clock software and method was used to estimate two measures, epigenetic age acceleration (AgeAccelerationResidual) and extrinsic epigenetic age acceleration (EEAA). Each participant underwent T1 structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). In order to investigate the associations of chronological age, sex, epigenetic age acceleration and treatment variables (CNS penetration effectiveness score (CPE)) of antiretroviral regimen on brain structure in PHIV+, we developed stepwise multiple regression models in R (version 3.4.3, 2017) including grey and white matter volumes, cortical thickness, cortical surface area and DTI measures of white matter microstructural integrity. The mean DNAm age (16.01years) of the participants was higher than their mean chronological age (10.77years). Epigenetic age acceleration contributed more to regional alterations of brain volumes, cortical thickness, cortical surface areas and neuronal microstructure than chronological age, in a range of regions. CPE positively contributed to volume of the brain stem. Understanding the drivers of epigenetic age acceleration could lead to valuable insights into structural brain alterations, and the persistence of neurocognitive disorders in seen in PHIV+ .

Improvement of HIV-associated neurocognitive disorders after antiretroviral therapy intensification: the Neuro+3 study

Despite the effectiveness of antiretroviral (ARV) therapy to control HIV infection, HIV-associated neurocognitive disorders (HAND) remain frequent. The Neuro+3 study assessed the cognitive improvement associated with ARV intensification based on increased CNS penetration effectiveness (CPE) scoring ≥+3 and total CPE score ≥9. Thirty-one patients, aged 18-65 years, with confirmed diagnosis of HAND and effective ARV therapy were included. The cognitive improvement was measured using Frascati three-stage classification and global deficit score (GDS) after 48 and 96 weeks of ARV intensification. Ultrasensitive HIV-RNA, neopterin, soluble CD14, CCL2, CXCL10, IL6, IL8 and NF-L were measured in plasma and cerebrospinal fluid at Day 0 (baseline), Week 48 (W48) and W96. The intensified ARV was associated with a median (IQR) CPE score increase from 6 (4-7) at baseline to 10 (9-11). From baseline to W96, the median (IQR) GDS decreased from 1.4 (0.8-2.2) to 1.0 (0.6-2.0) (P = 0.009); HAND classification improved from 2 to 1 HIV-associated dementia, 22 to 8 mild neurocognitive disorders, 7 to 17 asymptomatic neurocognitive impairment and 0 to 5 patients without any neurocognitive alterations (P = 0.001). In multivariable linear regression analysis, GDS improvement at W96 was significantly associated with CPE score ≥9 after intensification (P = 0.014), CD4 lymphocyte increase at W48 (P < 0.001) and plasma CXCL10 decrease at W96 (P = 0.001). In patients with HAND, a significant cognitive improvement was observed after the ARV intensification strategy, with a higher CPE score. Cognitive improvement was more often observed in the case of a switch of two drug classes, arguing for better control of CNS HIV immune activation.

The Efficiency of the Fight Against HIV, in Constanta, from the Perspective of Neurological Complications

Abstract In order to control and end the AIDS epidemic, we all need to hit the 0-0-0 target. That means 0 HIV infections, 0 mortality caused by AIDS and 0 discrimination. We performed a retrospective observational analytical study on 166 HIV positive patients with a neurological complication, diagnosed between June 2012 and June 2020, in Clinical Infectious Diseases Hospital of Constanta. We collected data from the observational charts that revealed if the patient was known with HIV infection at the time of the neurological complication diagnosis, information about the treatment (how many treatment regimens, classes of antiretroviral drugs, CNS Penetration-Effectiveness Rank), treatment compliance. The patients were divided into two groups: first group “opportunistic infections (OI)” and second group “other neurological conditions (ONC)”. 16 patients (9,6%) have the neurological condition as first manifestation of HIV infection. Opportunistic infections, correlated with a poor immunological status continue to have a high percentage (46,98%) of neurological complications, being associated with a poor treatment compliance (p&lt;0,001). Integrase inhibitors were associated, in this study, more with opportunistic infections and less with other neurological conditions (OR=2,885; 95% IC), this finding needs further research. Long term survivors have problems with treatment compliance manifesting treatment fatigue, even if they have treatment regimens with good CNS penetrability. Poor compliance is associated with high risk of opportunistic infections and opportunistic infections have a higher mortality than other neurological complications. Our task for the future is to find ways to improve treatment adherence in order for HIV patients to have a better and longer life.

Risk Factors of Asymptomatic Neurocognitive Impairment in People Living with HIV in an Indian Cohort.

Background Asymptomatic neurocognitive impairment (ANI) in people living with HIV (PLWH) can lower quality of life, reduce drug compliance, increase unemployment, and reduce life expectancy. Objective This study was aimed to identify risk factors of ANI in PLWH in an Indian cohort and explore the usefulness of Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment Score (MoCA) as screening tools. Methods PLWH under follow-up at an antiretroviral treatment center who were 18 to 60 years were included in this study. Patients were excluded if they had any cognitive symptoms, previous history of any central nervous system (CNS) pathology, or any systemic illness. Included patients were subjected to domain wise standardized neuropsychological battery. Six domains were screened including language, attention, speed, memory, sensory motor skills, and executive. Abnormal dysfunctional scores in at least two domains were taken as suggestive of ANI. The two groups thus created, ANI and normal cognition, were evaluated for differences. Variables evaluated as risk factors included age, sex, handedness, education, presence of at least one vascular risk factor, duration of disease, biochemical profile, cluster of differentiation 4 (CD4) count (both current and nadir) HIV viral load, and use of antiretroviral therapy (ART) and its CNS penetration effectiveness (CPE). MMSE and MoCA were also done in all patients. Statistical Analysis Regression analysis was used to find out significant variables. MMSE and MoCA scores were correlated using Spearman’s correlation coefficient. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were also determined Results Three hundred and eighty-four patients were included out of which 185 (48%) had ANI. In the multivariate regression analysis, female sex with odds Ratio (OR) of 1.89 (95% confidence interval [CI]: 1.21–2.79, p < 0.01), education below 10 years with OR = 2.43 (95% CI: 1.56–3.80, p < 0.01) and presence of at least one vascular risk factor with OR = 2.52 (95% CI: 1.67–3.80, p < 0.01) were found to be significant. Both MMSE and MoCA had a high PPV (0.99 and 0.97, respectively) but poor NPV (0.64 and 0.75) below a score of 25 with MoCA scoring slightly better. Both, MMSE and MoCA correlated well with each other. Conclusion Nearly half of our patients had ANI, despite being on ART. Majority of patients were on ART with CPE > 7 and had relatively preserved immune status. Female HIV patients with at least one vascular risk factor and less than 10 years of formal education were found to be at risk for ANI. MMSE and MoCA are not good screening tools to identify this condition.

Clinical Treatment Options and Randomized Clinical Trials for Neurocognitive Complications of HIV Infection: Combination Antiretroviral Therapy, Central Nervous System Penetration Effectiveness, and Adjuvants.

The etiology and pathogenesis of human immunodeficiency virus type-I (HIV)-associated neurocognitive disorders (HAND) remain undetermined and are likely the produce of multiple mechanisms. This can mainly include neuronal injury from HIV, inflammatory processes, and mental health issues. As a result, a variety of treatment options have been tested including NeuroHIV-targeted regimens based on the central nervous system (CNS) penetration effectiveness (CPE) of antiretroviral therapy (ART) and adjuvant therapies for HAND. NeuroHIV-targeted ART regimens have produced consistent and statistically significant HIV suppression in the CNS, but this is not the case for cognitive and functional domains. Most adjuvant therapies such as minocycline, memantine, and selegiline have negligible benefit in the improvement of cognitive function of people living with HIV (PLWH) with mild to moderate neurocognitive impairment. Newer experimental treatments have been proposed to target cognitive and functional symptoms of HAND as well as potential underlying pathogenesis. This review aims to provide an analytical overview of the clinical treatment options and clinical trials for HAND by focusing on NeuroHIV-targeted ART regimen development, CPE, and adjuvant therapies.

Cross-Sectional and Cumulative Longitudinal Central Nervous System Penetration Effectiveness Scores Are Not Associated With Neurocognitive Impairment in a Well Treated Aging Human Immunodeficiency Virus-Positive Population in Switzerland.

BackgroundNeurocognitive impairment (NCI) in people with human immunodeficiency virus (PWH) remains a concern despite potent antiretroviral therapy (ART). Higher central nervous system (CNS) penetration effectiveness (CPE) scores have been associated with better CNS human immunodeficiency virus (HIV) replication control, but the association between CPE and NCI remains controversial.MethodsThe Neurocognitive Assessment in the Metabolic and Aging Cohort (NAMACO) study is a subgroup of the Swiss HIV Cohort Study (SHCS) that invited patients aged ≥45 years enrolled in the SHCS and followed-up at NAMACO-affiliated centers in Switzerland to participate between May 2013 and November 2016. In total, 981 patients were enrolled, all of whom underwent standardized neurocognitive assessment. Neurocognitive impairment, if present, was characterized using Frascati criteria. The CPE scores of NAMACO study participants with undetectable plasma HIV-ribonucleic acid at enrollment (909 patients) were analyzed. Cross-sectional CPE scores (at neurocognitive assessment) were examined as potential predictors of NCI in multivariate logistic regression models. The analysis was then repeated taking CPE as a cumulative score (summarizing CPE scores from ART initiation to the time of neurocognitive assessment).ResultsMost patients were male (80%) and Caucasian (92%). Neurocognitive impairment was present in 40%: 27% with HIV-associated NCI (mostly asymptomatic neurocognitive impairment), and 13% with NCI related to other factors. None of the CPE scores, neither cross-sectional nor cumulative, was statistically significantly associated with NCI.ConclusionsIn this large cohort of aviremic PWH, we observed no association between NCI, whether HIV-associated or related to other factors, and CPE score, whether cross-sectional or cumulative.

Targeting the HIV-infected brain to improve ischemic stroke outcome

HIV-associated cerebrovascular events remain highly prevalent even in the current era of antiretroviral therapy (ART). We hypothesize that low-level HIV replication and associated inflammation endure despite antiretroviral treatment and affect ischemic stroke severity and outcomes. Using the EcoHIV infection model and the middle cerebral artery occlusion as the ischemic stroke model in mice, we present in vivo analysis of the relationship between HIV and stroke outcome. EcoHIV infection increases infarct size and negatively impacts tissue and functional recovery. Ischemic stroke also results in an increase in EcoHIV presence in the affected regions, suggesting post-stroke reactivation that magnifies pro-inflammatory status. Importantly, ART with a high CNS penetration effectiveness (CPE) is more beneficial than low CPE treatment in limiting tissue injury and accelerating post-stroke recovery. These results provide potential insight for treatment of HIV-infected patients that are at risk of developing cerebrovascular disease, such as ischemic stroke.

Progressive brain atrophy in chronically infected and treated HIV+ individuals.

Growing evidence points to persistent neurological injury in chronic HIV infection. It remains unclear whether chronically HIV-infected individuals on combined antiretroviral therapy (cART) develop progressive brain injury and impaired neurocognitive function despite successful viral suppression and immunological restoration. In a longitudinal neuroimaging study for the HIV Neuroimaging Consortium (HIVNC), we used tensor-based morphometry tomap the annual rate of change of regional brain volumes (mean time interval 1.0± 0.5 yrs), in 155 chronically infected and treated HIV+ participants (mean age 48.0 ± 8.9years; 83.9% male) . We tested for associations between rates of brain tissue loss and clinical measures of infection severity (nadir or baseline CD4+ cell count and baseline HIV plasma RNA concentration), HIV duration, cART CNS penetration-effectiveness scores, age, as well as change in AIDS Dementia Complex stage. We found significant brain tissue loss across HIV+ participants, including those neuro-asymptomatic with undetectable viral loads, largely localized to subcortical regions. Measures of disease severity, age, and neurocognitive decline were associated with greater atrophy. Chronically HIV-infected and treated individuals may undergo progressive brain tissue lossdespite stable and effective cART, which may contribute to neurocognitive decline. Understanding neurological complications of chronic infection and identifying factors associated with atrophy may help inform strategies to maintain brain health in people living with HIV.

Management of Progressive Multifocal Leukoencephalopathy - Immune Reconstitution Inflammatory Syndrome (PML-IRIS) In a HIV Positive Male with Steroidal Support and Antiretroviral Therapy with Greater CNS Penetration-Effectiveness Score (CPE): A Case

Management of Progressive Multifocal Leukoencephalopathy - Immune Reconstitution Inflammatory Syndrome (PML-IRIS) In a HIV Positive Male with Steroidal Support and Antiretroviral Therapy with Greater CNS Penetration-Effectiveness Score (CPE): A Case