Elevation of cell-associated HIV-1 transcripts in CSF CD4+ T cells, despite effective antiretroviral therapy, is linked to brain injury.

Antiretroviral therapy (ART) can attain prolonged undetectable HIV-1 in plasma and cerebrospinal fluid (CSF), but brain injury remains prevalent in people living with HIV-1 infection (PLHIV). We investigated cell-associated (CA)-HIV-1 RNA transcripts in cells in CSF and blood, using the highly sensitive Double-R assay, together with proton Magnetic Resonance Spectroscopy (1H MRS) of major brain metabolites, in sixteen PLHIV. 14/16 CSF cell samples had quantifiable CA-HIV-1 RNA, at levels significantly higher than in their PBMCs (median 9,266 vs 185 copies /106 CD4+ T-cells; p<0.0001). In individual PLHIV, higher levels of HIV-1 transcripts in CSF cells were associated with greater brain injury in the frontal white matter (Std ß=-0.73; p=0.007) and posterior cingulate (Std ß=-0.61; p=0.03). 18-colour flow cytometry revealed that the CSF cells were 91% memory T-cells, equally CD4+ and CD8+ T-cells, but fewer B cells (0.4 %), and monocytes (3.1%). CXCR3+CD49d+integrin ß7-, CCR5+CD4+ T-cells were highly enriched in CSF, compared with PBMC (p <0.001). However, CA-HIV-1 RNA could not be detected in 10/16 preparations of highly purified monocytes from PBMC, and was extremely low in the other six. Our data show that elevated HIV-1 transcripts in CSF cells were associated with brain injury, despite suppressive ART. The cellular source is most likely memory CD4+ T cells from blood, rather than trafficking monocytes. Future research should focus on inhibitors of this transcription to reduce local production of potentially neurotoxic and inflammatory viral products.

What are the predictors of TOMM failure in clinical TBI populations? A retrospective analysis.

OBJECTIVES: To determine base rates of invalid performance on the Test of Memory Malingering (TOMM) in patients with traumatic brain injury (TBI) undertaking rehabilitation who were referred for clinical assessment, and the factors contributing to TOMM failure. METHODS: Retrospective file review of consecutive TBI referrals for neuropsychological assessment over seven years. TOMM failure was conventionally defined as performance <45/50 on Trial 2 or Retention Trial. Demographic, injury, financial compensation, occupational, and medical variables were collected. RESULTS: Four hundred and ninety one TBI cases (Median age = 40 years [IQR = 26-52], 79% male, 82% severe TBI) were identified. Overall, 48 cases (9.78%) failed the TOMM. Logistic regression analyses revealed that use of an interpreter during the assessment (adjusted odds ratio [aOR] = 8.25, 95%CI = 3.96-17.18), outpatient setting (aOR = 4.80, 95%CI = 1.87-12.31) and post-injury psychological distress (aOR = 2.77, 95%CI = 1.35-5.70) were significant multivariate predictors of TOMM failure. The TOMM failure rate for interpreter cases was 49% (21/43) in the outpatient setting vs. 7% (2/30) in the inpatient setting. By comparison, 9% (21/230) of non-interpreter outpatient cases failed the TOMM vs. 2% (4/188) of inpatient cases. CONCLUSIONS: TOMM failure very rarely occurs in clinical assessment of TBI patients in the inpatient rehabilitation setting. It is more common in the outpatient setting, particularly in non-English-speaking people requiring an interpreter. The findings reinforce the importance of routinely administering stand-alone performance validity tests in assessments of clinical TBI populations, particularly in outpatient settings, to ensure that neuropsychological test results can be interpreted with a high degree of confidence.

Reversible large-scale network disruption correlates with neurocognitive improvement in HIV-associated minor neurocognitive disorder with combined anti-retroviral therapy intensification: a prospective longitudinal resting-state functional magnetic resonance imaging study.

OBJECTIVE: HIV-associated neurocognitive disorder (HAND) affects multiple cognitive domains and currently, the neuropsychological testing is the gold standard to identify these deficits. The aim of this longitudinal 12-month pilot study is to determine the effect of intensified combination antiretroviral therapy (cART) on rs-fMRI in virally suppressed (both in CSF and blood) patients with active HAND (those who have progressive neurocognitive impairment) and correlated with neurocognitive function tests. METHODS: In this pilot study, we have evaluated sixteen patients with active HAND with viral suppression in both blood and CSF to study the effect of cART on functional connectivity. Participants underwent rs-fMRI at the baseline (time point-1 (TP-1) and 12-month visits (time point-2 (TP-2)). Connectivity in the five major networks was measured at TP-1 and TP-2 using the seed-based approach. All the participants underwent a five-domain neuropsychological battery at TP-1 and TP-2. Neurocognitive scores (NC) as well as blood and CSF markers were correlated with functional connectivity (FC). RESULTS: There was a significant increase in the FC between the two time points within the executive, salience, default mode, dorsal attention, and visual networks at voxel level threshold of p < 0.001 and cluster level threshold of p < 0.05 and corrected for false detection rate (FDR). The neurocognitive scores were positively correlated with all the networks at similar cluster and voxel level thresholds. CONCLUSIONS: These results indicate that rs-fMRI can be potentially used as one of the biomarkers for treatment efficacy in HAND.

Lack of cognitive impairment in long-term survivors of colorectal cancer.

BACKGROUND: Our longitudinal study reported cognitive impairment in 43% of people following diagnosis of localised colorectal cancer (CRC) versus 15% in healthy controls (p < 0.001) and 50% versus 13% 1-2 years later (p < 0.001). Here we evaluate cognitive function and neuroimaging in a subgroup at long-term follow-up. PATIENTS AND METHODS: Cancer-free Australian participants in the study, and controls, completed cognitive and functional assessments. Neuroimaging was optional. Blood tests included inflammatory markers, clotting factors, sex hormones and apolipoprotein E genotype. The primary endpoint was demographically and practice effect-corrected cognitive scores comparing CRC survivors with controls over time examined using a linear mixed model, adjusted for baseline performance. Secondary endpoints included cognitive impairment rate using the Global Deficit Score [GDS > 0.5], Functional Deficit Score, blood results and neuroimaging. RESULTS: The study included 25 CRC survivors (60% men, median age 72) at mean 9 years after baseline (9 received adjuvant chemotherapy) and 25 controls (44% men, median age 68) at mean 6 years after baseline. There were no significant differences in cognitive scores or proportion with cognitive impairment (16 vs. 8%) between survivors and controls and no evidence of accelerated ageing in CRC survivors. Baseline cognitive performance predicted for subsequent cognitive function. There were no differences in functional tests or blood tests between groups. In 18 participants undergoing neuroimaging, 10 CRC survivors had higher myoinositol levels than 8 controls, and lower volume in the right amygdala and caudate and left hippocampal regions. CONCLUSIONS: There was no difference in cognitive capacity and function between CRC survivors and controls 6-12 years after diagnosis. Differences in neuroimaging require confirmation in a larger sample. HIGHLIGHTS: • No evidence of long term cognitive impairment in colorectal cancer survivors compared to controls 6-12 years after diagnosis • No evidence of accelerated cognitive ageing in colorectal cancer survivors • No evidence of long-term functional impairment in colorectal cancer survivors.

External causes of death after severe traumatic brain injury in a multicentre inception cohort: clinical description and risk factors.

Objective: To characterize the clinical profile of patients dying from external causes (EC) following severe traumatic brain injury (TBI). Design and Methods: Data from 2545 patients forming the NSW-BIRP inception cohort discharged from post-acute inpatient rehabilitation between 1 July 1990 and 1 October 2007 were retrospectively reviewed. Standardized mortality ratios (SMRs) were calculated for EC sub-categories. Demographic, clinical and rehabilitation service factors were compared between deaths from EC, deaths from other causes (OC), and non-deceased. Clinical profiles of EC sub-categories were analysed descriptively. Results: Overall, patients with TBI were 5.2x more likely to die from EC relative to the general population. Risk of death was elevated in all EC sub-categories examined, with the largest risks relating to other accidental threats to breathing (SMR = 33.0; 95%CI = 13.79-60.45) and falls (SMR = 14.3; 95%CI = 5.01-28.39). The EC group were younger, more likely to have pre-injury psychiatric histories, less severe injuries, greater functional independence, and die earlier than the OC group. There was considerable heterogeneity in the clinical profiles of patients dying from different EC sub-categories. Conclusions: EC constitutes one of the largest causes of mortality following TBI in patients surviving beyond the post-acute phase. Potential implications for risk modification and prevention of premature and avoidable deaths are discussed.

HIV-associated neurocognitive disorder in Australia: a case of a high-functioning and optimally treated cohort and implications for international neuroHIV research.

The Australian HIV-infected (HIV+) population is largely comprised of high-functioning men who have sex with men (MSM). Like other English-speaking countries, Australia mostly relies on US neuropsychological normative standards to detect and determine the prevalence of neurological disorders. Whether the US neuropsychological (NP) normative standards are appropriate in Australian HIV+ MSM has not been established. Ninety virally suppressed HIV+ and 49 HIV-uninfected (HIV-) men (respectively 86 and 85 % self-reported MSM; mean age 54 and 56 years, mean premorbid verbal IQ estimate 110 and 111) undertook standard NP testing. The raw neuropsychological data were transformed using the following: (1) US standards as uncorrected scaled scores and demographically corrected T scores (US norms); and (2) z scores (without demographic corrections) derived from Australian comparison group scaled scores (local norms). To determine HIV-associated neurocognitive disorder prevalence, we used a standard definition of impairment based upon a battery-wide summary score: the global deficit score (GDS). Impairment classification (GDS ≥ 0.5) based on the local norms was best at discriminating between the two groups (HIV- = 14.3 % vs. HIV+ = 53.3 %; p < 0.0001). This definition was significantly associated with age. Impairment classification based on the US norms yielded much lower impairment rate regardless of the HIV status (HIV- = 4.1 % vs. HIV+ = 14.7 %; p = 0.05), but was associated with historical AIDS, and not age. Both types of summary scores were associated with reduced independence in activities of daily living (p ≤ 0.03). Accurate neuropsychological classifications of high (or low) functioning individuals may need country-specific norms that correct for performance-based (e.g., reading) estimates of premorbid cognition in addition to the traditional demographic factors.

Factors Associated with Device, Internet and Videoconferencing Use Amongst Individuals with Moderate-to-Severe Traumatic Brain Injury.

Videoconferencing (VC) has the potential to improve access to quality healthcare for individuals with traumatic brain injury (TBI) who require intensive and ongoing rehabilitation post-injury. Gaps in information and communication technology (ICT) use, access, and skills, however, may undermine equitable participation in remotely delivered healthcare and rehabilitation. This cross-sectional study sought to identify which demographic, injury-related, and psychological factors are associated with gaps in digital inclusion amongst individuals with a TBI. Between March 2020 and December 2023, 186 adults with a moderate-to-severe TBI who were aged 18-65 years and were within five years post-injury completed a range of self-report measures. The results demonstrated that most individuals with a moderate-to-severe TBI reported high levels of technology skills and access and used the internet from multiple devices daily. While injury severity was unrelated to technology use, this finding may reflect an overestimation of technology use amongst individuals with the most severe injuries, who were excluded from the study. Several demographic and psychological factors were found to predict VC readiness and are presented within a model to guide clinicians considering client suitability for VC rehabilitation. The current findings indicate that the use of VC in clinical settings following a moderate-to-severe TBI is feasible and suggest that individuals with a TBI may benefit from the greater provision of remotely delivered healthcare than is currently offered.

Validation of the work-ability support scale in individuals seeking to return to work after severe acquired brain injury.

PURPOSE: To assess the reliability and validity of the work-ability support scale (WSS) in a severe traumatic/acquired brain injury (TBI/ABI) population seeking to return to work (RTW). MATERIALS AND METHODS: One hundred forty-four clients were enrolled in a vocational rehabilitation (VR) intervention trial through the Brain Injury Rehabilitation Program in New South Wales, Australia. Each client's primary brain injury clinician and VR provider completed the WSS pre- and post-intervention. Validating measures assessing dysexecutive behavior, disability, participation, and work instability were completed. Several aspects of reliability and validity were evaluated. RESULTS: Internal consistency was excellent for Part A (Cronbach's αs > 0.9) but unacceptably low to questionable for Part B (αs < 0.6). Inter-rater reliability between clinicians and VR providers was generally fair to moderate for Part A (κw < 0.6) and worse for Part B (κw < 0.5), with both slightly improving at post-intervention. Strong support was found for predictive and convergent validity, but not divergent validity. Confirmatory factor analysis indicated a poor fit for Part A, whereas most Part B fit indices met criteria. CONCLUSIONS: The WSS can play a useful role in assessing return to work (RTW) potential, planning and evaluation after severe TBI/ABI. Training could improve consistency of administration among staff working across health and VR service sectors.

The work-ability support scale (WSS) has potential as a screening tool in assisting return to work (RTW) assessment, planning, and evaluation, following severe traumatic brain injury and acquired brain injury.Employment success following a RTW intervention was predicted by the initial WSS Part A total score.The low inter-rater reliability between brain injury clinicians in health settings and vocational rehabilitation providers suggests that training will be important to improve consistency in WSS administration across service sectors.

A vocational intervention that enhances return to work after severe acquired brain injury: A pragmatic trial.

BACKGROUND: Following a severe acquired brain injury, individuals often have low return to work rates. The Vocational Intervention Program (VIP), a partnership of Brain Injury Rehabilitation Program community rehabilitation centres with external vocational rehabilitation providers in New South Wales, Australia, was developed to facilitate a return to competitive employment for working-age people. OBJECTIVES: To evaluate the efficacy of the VIP partnership model, this intervention was compared to outcomes from a health-based brain injury vocational rehabilitation centre (H-VR) or community brain injury rehabilitation centres ("treatment as usual"; TAU). METHODS: A 3-arm non-randomized controlled trial was conducted among the 12 adult rehabilitation centres of the NSW Brain Injury Rehabilitation Program. The VIP arm was delivered by 6 community rehabilitation centres in partnership with 3 external private Vocational Rehabilitation providers. The H-VR arm was delivered by 1 health-based vocational rehabilitation centre and the 5 remaining centres delivered TAU. Competitive employment status ("Yes"/"No") and clinician ratings of disability and participation were collected pre- and post-intervention, and at 3-month follow-up. Multilevel models were conducted to investigate change over time by treatment arm. RESULTS: In total, 148 individuals with severe brain injury were included in the trial: n = 75 (VIP), n = 33 (H-VR) and n = 40 (TAU). Sixty-five people (of 108, 60%) completed the VR intervention. A significant arm-by-time interaction was found, with higher return to work rates from pre- to post-intervention in VIP and H-VR arms compared to TAU (P = 0.0002). Significant arm-by-time interactions also indicated improved work-related participation and independent living skills from pre- to post-intervention in VIP and H-VR compared to the TAU arm (P < 0.05). These improvements were maintained at 3-month follow-up. CONCLUSIONS: The VIP improved return to competitive employment at comparable rates to the specialist H-VR. Larger-scale adoption of the VIP model could provide significant improvements in vocational rehabilition sevices to support people in their return to work following severe brain injury. ANZCTR TRIAL REGISTRY NUMBER: ACTRN12622000769785.

Meaningful cognitive decline is uncommon in virally suppressed HIV, but sustained impairment, subtle decline and abnormal cognitive aging are not.

Background: High antiretroviral therapy (ART) coverage and viral suppression among people with HIV (PWH) in Australia provide a unique context to study individual cognitive trajectories, cognitive aging and factors associated with longitudinal cognitive function during chronic and stable HIV disease. Methods: Participants from the Predictors of Adherence to Antiretroviral Therapy study (n = 457, recruited between September 2013 and November 2015, median age = 52 years, and all with HIV RNA <50 copies mL) completed a cognitive assessment with CogState Computerized Battery (CCB) at baseline, Month-12, and Month-24. Demographics, psycho-social and socioeconomic factors, healthcare seeking behaviors, HIV disease characteristics and comorbidities were assessed. The CCB data were corrected for age, sex and practice effect and averaged into a global z-score (GZS). Cognitive impairment was defined with the global deficit score method (GDS>0.5). Meaningful cognitive change was statistically defined (decline or improvement versus stability, i.e., 90% CI, that is p < 0.05, 2-tailed) using a novel evidence-based change score: the linear mixed-effect regression (LMER)-based GZS change score. A separate LMER model with a top-down variable selection approach identified the independent effects of age and other demographic, HIV disease characteristics, socioeconomic and health-related factors on the demographically corrected GZS. The combined definitions of change and cross-sectional impairment enabled the identification of cognitive trajectories. Findings: At Month-12 and Month-24, 6% and 7% showed meaningful cognitive decline and 4% and 3% improved respectively. Only 1% showed sustained decline. Incident impairment due to subtle cognitive decline (i.e., below the threshold of meaningful cognitive decline) was 31% and 25% at Month-12 and Month-24, while 14% showed sustained impairment (i.e., cognitively impaired at all study visits). Older age (≥50 years) and time interaction was associated with lower demographically corrected GZS (ß = -0.31, p < 0.001). Having a regular relationship, excellent English proficiency, and perceived stigma (avoidance) were associated with higher GZS (all p < 0.05). Relying on government subsidy, severe depression, and lower belief in ART necessity and higher concerns were associated with lower GZS (all p < 0.05). No HIV disease characteristics had a significant effect. Interpretations: Meaningful cognitive decline was not different from normal expectation in chronic stable HIV disease. Despite this, subtle cognitive decline, sustained cognitive impairment, and greater than normative-age cognitive aging were evident. Funding: Funding for the PAART study was provided in part by unrestricted educational grants from Gilead Sciences (www.gilead.com) (Grant Number: IN-AU-264- 0131), the Balnaves Foundation (www.balnavesfoundation.com), the Victorian Department of Health and Human Services (Australia) (www.dhs.vic.gov.au/home), Western Australia Health (www.health.wa.gov.au), the ACT Ministry of Health (Australia) (www.health.act.gov.au), and in-kind support from the Queensland Department of Health (Australia) (www.health.qld.gov.au), and NHMRC Partnership grant APP1058474 (PI: Carr, Andrew).

Abnormal cognitive aging in people with HIV: evidence from data integration between two countries' cohort studies.

OBJECTIVES: Previous research has shown inconsistent results on whether cognitive aging is abnormal in people with HIV (PWH) because of low sample size, cross-sectional design, and nonstandard neuropsychological methods. To address these issues, we integrated data from two longitudinal studies: Australian HIV and Brain Ageing Research Program ( N  = 102) and CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study ( N  = 924) and determined the effect of abnormal aging on neurocognitive impairment (NCI) among PWH. METHODS: Both studies used the same neuropsychological test battery. NCI was defined based on demographically corrected global deficit score (≥0.5 = impaired). Both studies also assessed comorbidities, neuropsychiatric conditions and functional status using similar tools. To determine the cross-sectional and longitudinal effects of age on the risk of NCI, a generalized linear mixed-effect model tested main and interaction effects of age group (young, <50 vs. old, ≥50) and time on NCI adjusting the effects of covariates. RESULTS: Older PWH had 83% higher chance of NCI compared with younger PWH [odds ratio (OR) = 1.83 (1.15-2.90), P  < 0.05]. Older participants also had a greater risk of increases in NCI over the follow-up [OR = 1.66 (1.05-2.64), P  < 0.05] than younger participants. Nonwhite ethnicity ( P  < 0.05), having a contributing ( P  < 0.05) or confounding ( P  < 0.001) comorbidity, greater cognitive symptoms ( P  < 0.001), and abnormal creatinine level ( P  < 0.05), plasma viral load greater than 200 copies/ml ( P  < 0.05), being from the Australian cohort ( P  < 0.05) were also associated with a higher risk of NCI. CONCLUSION: Data integration may serve as a strategy to increase sample size and study power to better assess abnormal cognitive aging effect in PWH, which was significant in the current study.

An examination of reliable change methods for measuring cognitive change with the Cogstate Computerized Battery: Research and clinical implications.

OBJECTIVE: To compare the performance of four reliable change (RC) methods with respect to measuring cognitive change on the Cogstate Computerized Battery (CCB). METHOD: We assessed cognitive change in 57 healthy, urban, well-educated males on the CCB at baseline and 6 months (Median age = 50, 65% university-educated). The study CCB version comprised seven measures covering attention, processing speed, verbal learning, and memory. Raw scores were z-score transformed using age-corrected Cogstate norms (CN) or the sample mean and standard deviation (internal standardization [IS]), and then averaged to create composite z-scores. Composite scores were entered into four RC formulae. RC was defined based on a 90% two-tailed confidence interval. Change scores were compared as continuous (z-scores) and ordinal variables (RC outcomes). RESULTS: CCB composite score reliability (rXY = .78-.79) was replicated in an age- and sex-matched Cogstate database sample of similar size. There was good overall agreement between the four RC methods (Bland-Altman Mdiff = .00; 95% limits of agreement with the mean-CN: z = ± .90; IS: z = ± .93), with each model adhering closely to the 10% rate of RC expected by chance alone (largest χ2 = .86, p = .99). Initial norming strategy (CN or IS) did not affect these outcomes. CONCLUSIONS: Norming strategy and RC method choice did not significantly impact cognitive change predictions on CCB composite scores. A series of example case data are provided to practically demonstrate the steps involved in applying the longitudinal norms generated in this study. Research in more diverse normative samples is warranted.

How all-type dementia risk factors and modifiable risk interventions may be relevant to the first-generation aging with HIV infection?

PURPOSE: The purpose of this review is to provide an overview of established risk factors for all-type dementia and results of interventions on dementia modifiable risk factors, all with relevance to aging people living with HIV (PLHIV). METHODS: Narrative literature review. RESULTS: Our review identifies a high prevalence of risk factors for dementia in the global HIV population that is entering dementia age range (60 +), in relation to both traditional and HIV-specific risk factors. This includes age (HIV-related premature aging and possibly HIV-related accelerated brain aging and cerebrovascular injury), HIV-related and non-HIV-related cardiovascular diseases burden with related-vascular brain damage, HIV-associated neurocognitive disorders, high mental health burden, low educational/socio-economic status, historical immune compromise, and persistent immune activation with consequent augmented immune senescence. Our review highlights that the results of interventions on all-type dementia modifiable factors show discrepancies between positive observational study results and inconclusive clinical trials. The main reasons for such discrepancies relate to the preventative framework that complex interventions' trials have difficulty to emulate and the suboptimal measurement of cognitive change. Multi-domain intervention trials are now advocated to concomitantly tackle complex age-related comorbid profiles. CONCLUSIONS: The burden of dementia risk in aging PLHIV is higher than that in the general population, particularly in the most vulnerable clusters. Epidemiological studies are urgently needed to provide accurate estimates. Lessons from interventions trials in all-type dementia on modifiable factors need to be carefully considered for enhancing trials' potential in aging PLHIV. A comprehensive and preventative neurogeriatric healthcare response linked with HIV communities and dementia associations should be urgently put in place.

Imaging correlates of the blood-brain barrier disruption in HIV-associated neurocognitive disorder and therapeutic implications.

OBJECTIVE: HIV-associated neurocognitive disorders (HANDs) in the context of suppressive combination antiretroviral therapy (cART) still occur. We explored the role of blood-brain barrier (BBB) disruption in the pathogenesis of HAND in the context of fully suppressive cART using dynamic contrast enhanced perfusion (DCE-P) MRI. DCE-P is a new MRI technique that measures capillary permeability as an indicator for BBB integrity. We hypothesized that virally suppressed incident HAND would be associated with an impaired BBB as determined by DCE-P. DESIGN: A cross sectional study. METHODS: K-trans, a metric derivative of DCE-P, was obtained from different regions of the brain in a cohort of 20 patients with HAND who were virally suppressed in both cerebrospinal fluid (CSF) and blood compared with CSF and blood markers of neuroinflammation as well as with neurometabolites derived from magnetic resonance (MR) spectroscopy. RESULTS: The K-trans data showed significantly impaired BBB in HAND patients when compared with the controls in the regions of the basal ganglia and anterior frontal white matter (both P < 0.0001). CSF neopterin and CSF/serum albumin ratio correlated positively with K-trans but not with blood levels. CONCLUSION: This study indicates that HAND in the context of viral suppression is associated with BBB disruption and the DCE MR derived K-trans metric is a very sensitive parameter to identify the BBB disruption. The finding of region-specific BBB disruption rather than globally and the lack of correlation with blood markers of neuroinflammation suggest that HIV and not systemic inflammation is driving the BBB disturbance and that the BBB disruption is a consequence of HIV already in the brain as opposed to HIV first causing BBB disruption then brain disease.

HIV brain latency as measured by CSF BcL11b relates to disrupted brain cellular energy in virally suppressed HIV infection.

OBJECTIVE: We investigated whether HIV brain latency was associated with brain injury in virally suppressed HIV infection. DESIGN: Observational cross-sectional and longitudinal study. METHODS: The study included 26 virally suppressed HIV-infected men (61.5% with HIV-associated neurocognitive disorder) who undertook cerebrospinal fluid (CSF) analyses at baseline. They also completed a proton magnetic resonance spectroscopy (1H MRS) and neuropsychological assessments at baseline and 18 months. To quantify whether there was residual brain HIV transcription, we measured CSF HIV-tat. As an HIV brain latency biomarker, we used concentrations of CSF BcL11b - a microglia transcription factor that inhibits HIV transcription. Concurrently, we assessed neuroinflammation with CSF neopterin, neuronal injury with CSF neurofilament light-chain (NFL), and in-vivo neurochemistry with 1H MRS of N-acetyl aspartate (NAA), choline (Cho), creatine, myo-inositol (MI), glutamine/glutamate (Glx) in the frontal white matter (FWM), posterior cingulate cortex (PCC), and caudate nucleus area. RESULTS: Baseline adjusted regression models for neopterin, NFL, and tat showed that a higher CSF BcL11b was consistently associated with lower FWM creatine (when adjusted for neopterin: ß = -0.30, P = 0.15; when adjusted for NFL: ß = -0.47, P = 0.04; and when adjusted for tat: ß = -0.47, P = 0.02). In longitudinal analyses, we found no time effect, but a consistent BcL11b altering effect on FWM creatine. The effect reached a significant moderate effect size range when corrected for CSF NFL (ß = -0.36, P = 0.02) and CSF tat (ß = -0.34, P = 0.02). CONCLUSIONS: Reduced frontal white matter total creatine may indicate subclinical HIV brain latency-related injury. H MRS may offer a noninvasive option to measure HIV brain latency.

Atrophic brain signatures of mild forms of neurocognitive impairment in virally suppressed HIV infection.

OBJECTIVE: There is a lack of evidence for the neurobiological underpinning of asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorders (MNDs) in virally suppressed HIV-positive persons. We hypothesized that such mild impairment would be associated with focal brain atrophy. DESIGN: A cross-sectional observational study. METHODS: Eighty-five virally suppressed HIV-positive and 44 geographically, demographically and lifestyle comparable HIV-negative men underwent anatomical MRI, neuropsychological evaluation and HIV laboratory tests. Volumes of interest (VOI) from magnetic resonance (MR) images were extracted using FreeSurfer to yield grey and white matter volumes in regions associated with HIV-related brain injury. HIV-associated neurocognitive disorder (HAND) [ANI = 38%, MND = 13%, HIV-associated dementia (HAD) = 3% vs. neuropsychologically-normal] was classified using Global Deficit Score (GDS ≥0.5) and functional decline. Effects of HIV status on VOI were assessed with multivariate analyses controlling for family-wise error. HAND categories and HIV biomarker effects on VOI were assessed with multiple regression. RESULTS: Relative to the HIV-negative group, the HIV-positive group demonstrated subcortical grey (d = 0.50-0.60) and white matter (d = 0.43-0.69) atrophy, with relative cortical sparing (d = 0.23). ANI showed reduced medial-orbitofrontal white matter compared with NP-normal cases (P = 0.04). MND showed enlarged lateral ventricles (P = 0.02) and reduced caudal-middle-frontal white matter (P = 0.04), caudal-anterior-cingulate white matter (P = 0.006) and inferior-parietal white matter (P = 0.04) compared with neuropsychologically normal. Across the HIV-positive group, lower CD4+/CD8 ratio was the strongest predictor of atrophy in subcortical regions. Across HAND categories, HIV disease duration uniquely predicted greater medial-orbitofrontal white matter atrophy only in ANI (P = 0.002). CONCLUSION: ANI shows specific frontal white matter atrophy to which HIV disease duration is a unique contributor. MND is characterized by more widespread subcortical atrophy.

Socioeconomic factors explain suboptimal adherence to antiretroviral therapy among HIV-infected Australian adults with viral suppression.

BACKGROUND: Missing more than one tablet of contemporary antiretroviral therapy (ART) per month increases the risk of virological failure. Recent studies evaluating a comprehensive range of potential risk factors for suboptimal adherence are not available for high-income settings. METHODS: Adults on ART with undetectable viral load (UDVL) were recruited into a national, multi-centre cohort, completing a comprehensive survey assessing demographics, socio-economic indicators, physical health, well-being, life stressors, social supports, HIV disclosure, HIV-related stigma and discrimination, healthcare access, ART regimen, adherence, side effects, costs and treatment beliefs. Baseline data were assessed, and suboptimal adherence was defined as self-reported missing ≥1 ART dose/month over the previous 3-months; associated factors were identified using bivariate and multivariate binary logistic regression. RESULTS: We assessed 522 participants (494 [94.5%] men, mean age = 50.8 years, median duration UDVL = 3.3 years [IQR = 1.2-6.8]) at 17 sexual health, hospital, and general practice clinics across Australia. Seventy-eight participants (14.9%) reported missing ≥1 dose/month over the previous three months, which was independently associated with: being Australian-born (AOR [adjusted odds ratio] = 2.4 [95%CI = 1.2-4.9], p = 0.014), not being in a relationship (AOR = 3.3 [95%CI = 1.5-7.3], p = 0.004), reaching the "Medicare safety net" (capping annual medical/pharmaceutical costs) (AOR = 2.2 [95%CI = 1.1-4.5], p = 0.024), living in subsidised housing (AOR = 2.5 [95%CI = 1.0-6.2], p = 0.045), receiving home-care services (AOR = 4.4 [95%CI = 1.0-18.8], p = 0.046), HIV community/outreach services linkage (AOR = 2.4 [95%CI = 1.1-5.4], p = 0.033), and starting ART following self-request (AOR = 3.0 [95%CI = 1.3-7.0], p = 0.012). CONCLUSIONS: In this population, 15% reported recent suboptimal ART adherence at levels associated in prospective studies with subsequent virological failure, despite all having an undetectable viral load. Associations were with social/economic/cultural/patient engagement factors, but not ART regimen/clinical factors. These associations may help identify those at higher risk of future virological failure and guide patient education and support.

The Chronicity of HIV Infection Should Drive the Research Strategy of NeuroHIV Treatment Studies: A Critical Review.

HIV infection has become a chronic illness when successfully treated with combined antiretroviral therapy (cART). The long-term health prognosis of aging with controlled HIV infection and HIV-associated neurocognitive disorder (HAND) remains unclear. In this review, we propose that, almost 20 years after the introduction of cART, a change in research focus is needed, with a greater emphasis on chronicity effects driving our research strategy. We argue that pre-emptive documentation of episodes of mild neurocognitive dysfunction is needed to determine their long-term prognosis. This strategy would also seek to optimally represent the entire HAND spectrum in therapeutic trials to assess positive and/or negative treatment effects on brain functions. In the first part of the paper, to improve the standard implementation of the Frascati HAND diagnostic criteria, we provide a brief review of relevant quantitative neuropsychology concepts to clarify their appropriate application for a non-neuropsychological audience working in HIV research and wanting to conduct randomized clinical trials on brain functions. The second part comprises a review of various antiretroviral drug classes and individual agents with respect to their effects on HAND, while also addressing the question of when cART should be initiated to potentially reduce HAND incidence. In each section, we use recent observational studies and randomized controlled trials to illustrate our perspective while also providing relevant statistical comments. We conclude with a discussion of the neuroimaging methods that could be combined with neuropsychological approaches to enhance the validity of HIV neurology (neuroHIV) treatment effect studies.

Maraviroc-intensified combined antiretroviral therapy improves cognition in virally suppressed HIV-associated neurocognitive disorder.

OBJECTIVE: To investigate whether intensification of combined antiretroviral therapy (cART) with the CC chemokine receptor type 5 (CCR5) entry inhibitor maraviroc leads to improvement in global neurocognitive functioning in virally suppressed men with HIV-associated neurocognitive disorder (HAND). DESIGN: Prospective, double observer-blinded, open-label pilot randomized-controlled trial. Participants were randomized to remain on their existing cART regimen (control arm; n = 8) or receive maraviroc-intensification (maraviroc arm; n = 9). METHODS: Participants completed a five-domain neuropsychological battery at baseline, 6- and 12-month visits. Raw scores were transformed into age-corrected z-scores and averaged into a global z-score. Single voxel (H)-magnetic resonance spectroscopy (MRS) major cerebral metabolite concentrations were collected at baseline and 12 months in the basal ganglia and frontal white matter and quantified using jMRUI. Neuroinflammatory biomarkers cerebrospinal fluid neopterin and ß2-microglobulin were also measured. RESULTS: Fourteen of the 17 participants completed the study: nine maraviroc arm and five control. We found medium to large effect sizes in favour of improved global neurocognitive performance in the maraviroc arm over time {arm*time interaction: P < 0.05; 6 month: [ß=-0.10, standard error (SE)= 0.04, 90% confidence interval (90%CI)= -0.18,.03; P < 0.03] yielding a large effect-size d = 0.77 (90%CI = -0.19,1.71); 12 month: [ß=-0.01; SE = 0.05; 90%CI = -0.09, 0.06; P < 0.77] yielding a moderate effect-size d = 0.55 (90%CI = -0.47,1.55)}. No treatment-related changes were detected for H-MRS metabolites or cerebrospinal fluid biomarkers. CONCLUSION: This pilot study provides feasibility, tolerability, proof-of-concept and preliminary evidence for clinically relevant neurocognitive improvement in cART enhancement with maraviroc in virally suppressed HAND patients. Lack of concomitant brain metabolite and biomarker change may be related to complex dynamics of brain repair.