CNS Penetration Effectiveness Score Research Articles

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.

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.

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.

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.

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.

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

Prevalence and Correlates of Persistent HIV-1 RNA in Cerebrospinal Fluid During Antiretroviral Therapy.

Neurocognitive disorders remain common among human immunodeficiency virus (HIV)-positive adults, perhaps owing to persistent HIV-1 RNA in cerebrospinal fluid (CSF) during antiretroviral therapy (ART). Using a single-copy assay, we measured HIV-1 RNA levels in CSF and plasma specimens from 220 HIV-positive adults who were taking suppressive ART. Fifty-five participants were tested twice. HIV-1 RNA was detected in 42.3% of CSF and 65.2% of plasma samples. Correlates of higher CSF HIV-1 RNA levels included higher nadir and current CD4+ T-cell counts, a plasma HIV-1 RNA level of ≥ 1 copy/mL, and a lower central nervous system penetration-effectiveness score (model P < .001). Worse neurocognitive performance was associated with discordance in HIV-1 RNA detection between plasma and CSF, lower overall CSF HIV-1 RNA level, and longer ART duration, among others (model P < .001). In the longitudinal subgroup, CSF HIV-1 RNA persisted in most participants (69%) over 7 months. Low-level HIV-1 RNA in CSF is common during suppressive ART and is associated with low-level HIV-1 RNA in blood, better immune status, and lower ART drug distribution into CSF. The association between HIV-1 RNA discordance and HIV-associated neurocognitive disorder (HAND) may reflect compartmentalization. The relationship between HAND, lower HIV-1 RNA levels in CSF, and lower CD4+ T-cell counts may reflect disturbances in the immune response to HIV-1 in the CNS.

Better Antiretroviral Central Nervous System Penetration is Not Associated with Reduced Chronic Pain in People Living with Human Immunodeficiency Virus.

To determine if better antiretroviral (ARV) central nervous system (CNS) penetration is associated with reduced rates of chronic pain in people living with HIV (PLWH). Chronic pain remains prevalent in PLWH despite widespread ARV use. Mechanisms underlying this prevalence remain unknown, though neuroinflammation from persistent CNS HIV infection and maladaptive plastic changes in the CNS have been implicated. Here we hypothesize that better CNS ARV penetration, measured using the CNS Penetration-Effectiveness (CPE) score, would decrease rates of chronic pain. We interviewed 254 consecutive adults from an HIV clinic in Chiang Mai, Thailand. We collected data on demographics, HIV history, ARV use, and pain characteristics. Patients were evaluated for depression using a Thai two question Patient Health Questionnaire (PHQ-2). Modified CPE score was calculated using established methods and grouped a priori into "low CPE" (≤7, poor penetration) and "high CPE" (≥8, good penetration). CPE score was compared with chronic pain scores in SPSS using appropriate statistical tests. A relationship between CPE score and a positive depression screen was tested further using multivariable binary logistic models. 245 of 254 subjects were on ARVs. Complete ARV data was available for 235 patients. 137 of these 235 patients (58.3%) had a CPE score ≤7, and 98 (41.7%) had a score ≥8. 49 patients had chronic pain, and 9 had neuropathic pain. Low CPE score was not associated with chronic pain (p=0.64), neuropathic pain (p=0.56), or frequent pain (p=0.80), nor was it associated with the severity of reported "worst pain" or "average pain" in the last 24 hours (p=0.18 and 0.48, respectively). Post-hoc analysis revealed that higher CPE score was a significant independent risk factor for depression measured by a positive PHQ-2 screen [OR (95% CI) = 1.29 (1.04-1.61), p=0.02]. This relationship was mediated primarily by exposure to zidovudine. CPE score is not associated with chronic pain in PLWH. Post-hoc analysis demonstrated that CPE score, and zidovudine exposure in particular, predicts a positive depression screen. Given the substantial morbidity associated with chronic pain and mood disorders in PLWH, additional studies to determine preventable and treatable factors are imperative.

The Effect of Central Nervous System Penetration Effectiveness of Highly Active Antiretroviral Therapy on Neuropsychological Performance and Neuroimaging in HIV Infected Individuals.

The incidence of HIV-associated dementia has been greatly reduced in the era of highly active antiretroviral therapy (HAART); however milder forms of cognitive impairment persist. It remains uncertain whether HAART regimens with a high degree of central nervous system penetration effectiveness (CPE) exert beneficial neurological outcomes in HIV-infected (HIV+) individuals on stable treatment. Sixty-four HIV-infected adults on HAART were assigned a CPE score using a published ranking system and divided into high (≥7; n = 35) and low (<7; n = 29) CPE groups. All participants completed neuropsychological testing in addition to structural neuroimaging. Neuropsychological tests included measures known to be sensitive to HIV with values converted into standardized scores (NPZ-4) based on published normative scores. A semi-automated methodology was utilized to assess brain volumetrics within cortical (grey and white matter) and subcortical (thalamus, caudate, putamen) regions of interest. Analyses assessed NPZ-4 and brain volumetric differences between HIV+ individuals with high and low CPE scores. No significant differences in brain integrity were observed between the two groups. Long-term HAART regimens with a high degree of CPE were not associated with significantly improved neuropsychological or neuroimaging outcomes in HIV+ adults. Results suggest that alternate mechanisms may potentially contribute to better neurological outcomes in the era of HAART.

Early viral suppression improves neurocognitive outcomes in HIV-infected children.

To estimate the association of age of viral suppression and central nervous system penetration effectiveness (CPE) score with neurocognitive functioning among school-age children with perinatally acquired HIV infection (PHIV+). We analyzed data from two US-based multisite prospective cohort studies. Multivariable general linear regression models were used to evaluate associations of age at viral suppression and CPE scores (of initial antiretroviral therapy regimen and weighted average) with the Wechsler Intelligence Scale for Children, Third or Fourth Edition neurocognitive assessments [Full-Scale Intelligence Quotient (FSIQ); Performance IQ/Perceptual Reasoning Index (PIQ/PRI); and Verbal IQ/Verbal Comprehension Index (VIQ/VCI)], adjusted for demographic and clinical covariates. Sensitivity analyses were stratified by birth cohort (before versus after 1996). A total of 396 PHIV+ children were included. Estimated differences in mean FSIQ (comparing virally suppressed versus unsuppressed children) by each age cutoff were 3.7, 2.2, 3.2, 4.4, and 3.9 points at ages 1, 2, 3, 4, and 5, respectively. For PIQ/PRI, estimated mean differences were 3.7, 2.4, 2.2, 4.6, and 4.5 at ages 1 through 5, respectively. In both cases, these differences were significant only at the age 4 and 5 thresholds. After stratifying by birth cohort, the association between age at suppression and cognitive function persisted only among those born after 1996. Age at viral suppression was not associated with VIQ/VCI; CPE score was not associated with FSIQ, verbal comprehension, or perceptual reasoning indices. Virologic suppression during infancy or early childhood is associated with improved neurocognitive outcomes in school-aged PHIV+ children. In contrast, CPE scores showed no association with neurocognitive outcomes.

Treatment initiation factors and cognitive outcome in youth with perinatally acquired HIV infection.

Although cognitive outcomes among perinatally infected youth have improved with highly active antiretroviral therapy (HAART), the impact of the age of initiation of treatment and the central nervous system (CNS) penetration effectiveness (CPE) of the regimen on cognitive outcomes is unknown. We aimed to describe the association between initiation age/regimen CPE score and cognitive outcomes in perinatally HIV-infected youth. Linear regression was used to retrospectively assess the association between full-scale IQ score (FSIQ) and age of initiation of HAART, regimen CPE, and the presence/absence of an AIDS diagnosis before initiation of HAART in an urban US cohort. A total of 88 of 181 subjects (48.6%) had an AIDS diagnosis. In 69, AIDS preceded the start of HAART. Mean FSIQ (mean age 155.4 months) was 86.3 [standard deviation (SD) 15.6]. Neither age of initiation of HAART (P = 0.45) nor regimen CPE score (P = 0.33) was associated with FSIQ. Mean FSIQ for patients with an AIDS diagnosis before HAART initiation [82 (SD 17.0)] was significantly lower than for patients initiating HAART before an AIDS diagnosis [90 (SD 13)] (P = 0.001). Of the 129 subjects without AIDS by age 5 years, 41 (31.8%) initiated HAART before age 5 years; four of 41 later developed AIDS, compared with 32 of 88 of those who did not initiate HAART before age 5 years. The relative risk of AIDS if HAART was initiated before age 5 years was 0.19 (95% confidence interval 0.05-0.60). Earlier age at HAART initiation and higher CPE score of a regimen did not improve cognitive outcomes. However, initiating HAART prior to AIDS protected against AIDS and was associated with a significantly higher FSIQ.

The brain and HAART: collaborative and combative connections.

To summarize contemporary observations regarding the effects of highly active antiretroviral therapy (HAART) on the brain. The effects of HAART on the structure and function of the brain during HIV/AIDS is currently a subject of intense interest because the brain is one of the most drug-impenetrable organs that is infected by HIV-1 and as such represents an important reservoir for replication-competent virus. The effects of HAART on neurocognitive impairment caused by HIV-1 infection remain uncertain with both beneficial and adverse outcomes reported with different HAART regimens. Similarly, the effects of individual HAART regimens on viral quantity in cerebrospinal fluid as a surrogate indicator of brain virus burden are variable. Indeed, the situation is further complicated by the ranking of antiretroviral therapies (ARTs) by their central nervous system penetration-effectiveness score on the basis of ART concentrations in cerebrospinal fluid. Experimental studies have also yielded equivocal findings depending on the model and individual ART. At the same time, a burgeoning body of experimental data has demonstrated neurotoxic effects of several ARTs, including nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). HAART selection strategies are currently guided by efficacy, resistance testing, toxicity, potential drug interactions and theoretical brain penetration. As improved strategies are developed to target the viral reservoir within the brain, greater knowledge of the effects of ARTs on neural tissues will be needed to operationalize their use in a rational manner that maximizes antiretroviral efficacy and minimizes the neurotoxic complications.

Classification models for neurocognitive impairment in HIV infection based on demographic and clinical variables.

ObjectiveWe used demographic and clinical data to design practical classification models for prediction of neurocognitive impairment (NCI) in people with HIV infection.MethodsThe study population comprised 331 HIV-infected patients with available demographic, clinical, and neurocognitive data collected using a comprehensive battery of neuropsychological tests. Classification and regression trees (CART) were developed to obtain detailed and reliable models to predict NCI. Following a practical clinical approach, NCI was considered the main variable for study outcomes, and analyses were performed separately in treatment-naïve and treatment-experienced patients.ResultsThe study sample comprised 52 treatment-naïve and 279 experienced patients. In the first group, the variables identified as better predictors of NCI were CD4 cell count and age (correct classification [CC]: 79.6%, 3 final nodes). In treatment-experienced patients, the variables most closely related to NCI were years of education, nadir CD4 cell count, central nervous system penetration-effectiveness score, age, employment status, and confounding comorbidities (CC: 82.1%, 7 final nodes). In patients with an undetectable viral load and no comorbidities, we obtained a fairly accurate model in which the main variables were nadir CD4 cell count, current CD4 cell count, time on current treatment, and past highest viral load (CC: 88%, 6 final nodes).ConclusionPractical classification models to predict NCI in HIV infection can be obtained using demographic and clinical variables. An approach based on CART analyses may facilitate screening for HIV-associated neurocognitive disorders and complement clinical information about risk and protective factors for NCI in HIV-infected patients.

Antiretroviral penetration into the CNS and incidence of AIDS-defining neurologic conditions.

The link between CNS penetration of antiretrovirals and AIDS-defining neurologic disorders remains largely unknown. HIV-infected, antiretroviral therapy-naive individuals in the HIV-CAUSAL Collaboration who started an antiretroviral regimen were classified according to the CNS Penetration Effectiveness (CPE) score of their initial regimen into low (<8), medium (8-9), or high (>9) CPE score. We estimated "intention-to-treat" hazard ratios of 4 neuroAIDS conditions for baseline regimens with high and medium CPE scores compared with regimens with a low score. We used inverse probability weighting to adjust for potential bias due to infrequent follow-up. A total of 61,938 individuals were followed for a median (interquartile range) of 37 (18, 70) months. During follow-up, there were 235 cases of HIV dementia, 169 cases of toxoplasmosis, 128 cases of cryptococcal meningitis, and 141 cases of progressive multifocal leukoencephalopathy. The hazard ratio (95% confidence interval) for initiating a combined antiretroviral therapy regimen with a high vs low CPE score was 1.74 (1.15, 2.65) for HIV dementia, 0.90 (0.50, 1.62) for toxoplasmosis, 1.13 (0.61, 2.11) for cryptococcal meningitis, and 1.32 (0.71, 2.47) for progressive multifocal leukoencephalopathy. The respective hazard ratios (95% confidence intervals) for a medium vs low CPE score were 1.01 (0.73, 1.39), 0.80 (0.56, 1.15), 1.08 (0.73, 1.62), and 1.08 (0.73, 1.58). We estimated that initiation of a combined antiretroviral therapy regimen with a high CPE score increases the risk of HIV dementia, but not of other neuroAIDS conditions.

Changes in PINCH levels in the CSF of HIV+ individuals correlate with hpTau and CD4 count

Several studies report associations between the particularly interesting new cysteine histidine-rich (PINCH) protein and HIV-associated CNS disease. PINCH is detected in the CSF of HIV patients, and changes in levels during disease may be indicative of changes in disease status over time. PINCH binds hyperphosphorylated Tau (hpTau) in the brain and CSF, but little is known about the relevance of these interactions to HIV CNS disease. In this study, PINCH and hpTau levels were assessed in three separate CSF samples collected longitudinally from 20 HIV+ participants before and after initiating antiretroviral therapy or before and after a change in the treatment regimen. The intervals were approximately 1 (T2) and 3-7 (T3) months from the initial visit (baseline, T1). Correlational analyses were conducted for CSF levels of PINCH and hpTau and other variables including blood CD4 T-cell count, plasma and CSF viral burden, CSF neopterin, white blood cell (WBC) count, and antiretroviral CNS penetration effectiveness (CPE). Values for PINCH and hpTau were determined for each patient by calculating the fold changes between the second (T2) and third measurements (T3) from the baseline measurement (T1). Statistical analyses showed that the fold changes in CSF PINCH protein from T1 to T2 were significantly higher in participants with CD4 counts >200 cells/mm(3) at T2 compared to those with CD4 counts <200 cells/mm(3) at T2. This trend persisted irrespective of plasma or CSF viral burden or antiretroviral therapy CPE scores. The fold changes in PINCH levels between T1 and T2, and T1 and T3 were highly correlated to the fold changes in hpTau at T2/T1 and T3/T1 (correlation coefficient = 0.69, p < 0.001; correlation coefficient = 0.83, p < 0.0001, respectively). In conclusion, in these HIV participants, changes in CSF levels of PINCH appear to correlate with changes in blood CD4 count and with changes in CSF hpTau levels, but not with plasma or CSF viral burden, neopterin, WBC, or antiretroviral regimen CPE.

Antiretroviral neuropenetration scores better correlate with cognitive performance of HIV-infected patients after accounting for drug susceptibility.

The aim of the study was to explore how viral resistance and antiretroviral central nervous system (CNS) penetration could impact on cognitive performance of HIV-infected patients. We performed a multicentre cross-sectional study enrolling HIV-infected patients undergoing neuropsychological testing, with a previous genotypic resistance test on plasma samples. CNS penetration-effectiveness (CPE) scores and genotypic susceptibility scores (GSS) were calculated for each regimen. A composite score (CPE-GSS) was then constructed. Factors associated with cognitive impairment were investigated by logistic regression analysis. A total of 215 patients were included. Mean CPE was 7.1 (95% CI 6.9, 7.3) with 206 (95.8%) patients showing a CPE≥6. GSS correction decreased the CPE value in 21.4% (mean 6.5, 95% CI 6.3, 6.7), 26.5% (mean 6.4, 95% CI 6.1, 6.6) and 24.2% (mean 6.4, 95% CI 6.2, 6.6) of subjects using ANRS, HIVDB and REGA rules, respectively. Overall, 66 (30.7%) patients were considered cognitively impaired. No significant association could be demonstrated between CPE and cognitive impairment. However, higher GSS-CPE was associated with a lower risk of cognitive impairment (CPE-GSSANRS odds ratio 0.75, P=0.022; CPE-GSSHIVDB odds ratio 0.77, P=0.038; CPE-GSSREGA odds ratio 0.78, P=0.038). Overall, a cutoff of CPE-GSS≥5 seemed the most discriminatory according to each different interpretation system. GSS-corrected CPE score showed a better correlation with neurocognitive performance than the standard CPE score. These results suggest that antiretroviral drug susceptibility, besides drug CNS penetration, can play a role in the control of HIV-associated neurocognitive disorders.

Central nervous system antiretroviral penetration and cognitive functioning in largely pretreated HIV-infected patients

Prolonged time on effective antiretroviral therapy (ART) should be associated with a low incidence of neurocognitive impairment (NCI). We investigated the rate of NCI in 162 largely pretreated patients with HIV RNA suppression according to CNS antiretroviral drug penetration in comparison with 67 patients on their first ART line. Cognitive performance (Trailmaking A, B, Digit Symbol, Grooved Pegboard; demographically adjusted and converted to Z scores, NPZ4) was evaluated, and CNS penetration effectiveness (CPE) ranks of 1 to 4 were assigned and summed per regimen. After a median of 173.2 months on therapy (1,909.3 patients-year), the rate of NCI was similar in both groups (mean NPZ4, -0.24 vs -0.2). Pretreated patients received regimens with a CPE <7 in a large proportion (30 vs 9 %; p < 0.01). Patients in monotherapy had worse NPZ4 score than patients receiving triple therapy (-0.78 vs -0.18; p = 0.02; effect sizes 1.38), and a lower CPE score was observed in patients with a CD4+ count nadir <200 cells/ml with NCI (6.5 vs 7.3, p = 0.04). In the multivariate model, only the lowest CD4+ count and hepatitis C virus coinfection were associated with NPZ4, whereas CPE <7 showed a trend to association (p = 0.06) probably due to patients on monotherapy (estimate -0.33, p < 0.01). In conclusion, the rate of NCI in largely pretreated patients was similar to that observed in patients on their first regimen, and nadir CD4+ count continue to be critical. CNS drug penetration should be considered in cases of high risk for NCI.

HIV-associated neurocognitive disorders: Antiretroviral regimen, central nervous system penetration effectiveness, and cognitive outcomes

The human immunodeficiency virus (HIV) can give rise to a spectrum of neuropsychological impairments known collectively as HIV-associated neurocognitive disorders (HAND). Although antiretroviral therapy (ART) has reduced the incidence of HIV dementia, the prevalence of milder forms of HAND has increased. It has been postulated that incomplete central nervous system (CNS) viral suppression or potential drug toxicity, both of which could be related to the CNS penetration effectiveness (CPE) of ART regimens, may contribute to this phenomenon. This study compared cognitive outcomes in clade C-infected HIV patients in South Africa treated for 1 year with ART regimens with differing CPE scores. We assessed 111 HIV-positive patients with varying levels of cognitive function at baseline (pre-ART) and then a year later. A neuropsychological battery was administered at both visits to derive global deficit scores. ART regimen data were collected at the follow-up visit. Some participants remained ART-naïve during this period, thus providing a non-treatment control group. Significantly more ART recipients maintained or improved cognitive function compared with patients not on ART (p=0.017). There was no significant difference in cognitive outcomes between higher and lower CPE regimen groups (p=0.473). ART preserves or improves cognition in HIV-infected patients after 1 year, irrespective of the regimen's CPE. South Africa's current low CPE-scored first-line regimen performed as well as higher CPE-scored regimens. These findings are reassuring for South Africa, but larger, longer-term studies would be more definitive.