Publications by authors named "Robert Paul"

296 Publications

Plasma Cytokine Levels As Predictors of Global and Domain-Specific Human Immunodeficiency Virus-Associated Neurocognitive Impairment in Treatment-Naive Individuals.

J Interferon Cytokine Res 2021 Apr;41(4):153-160

National Health Laboratory Service (NHLS), Tygerberg Business Unity, Cape Town, South Africa.

Central nervous system dysfunction, associated with human immunodeficiency virus (HIV) infection, remains a significant clinical concern, affecting at least 50% of infected people. Imbalances in cytokine expression levels have been linked to HIV-associated neurocognitive disorders. The aim of this study was to evaluate plasma cytokine levels as predictor neurocognitive impairment in HIV infection using a multiplex profiling kit. Stepwise regression model was used to identify cytokine biomarkers of overall and domain-specific cognitive performance. Higher interleukin (IL)-2 ( = 0.04;  = 0.001) and eotaxin ( = 0.01;  = 0.017) were predictors of global neurocognitive, whereas higher IL-5 ( = 0.005;  = 0.007) was negative predictor of global cognitive deficit. IL-2 was a negative predictor of most cognitive domain functions, including recall ( = 0.24;  = 0.005), recognition ( = 0.04;  = 0.026), mental control ( = 0.38;  = 0.005), symbol search ( = -0.55;  = 0.001), and digital symbol ( = -0.79;  = 0.019). IL-6 was associated with 3 impaired domains, mental processing ( = -0.468;  = 0.027), recognition ( = -0.044;  = 0.012), and learning ( = 0.02668;  = 0.020) These results show that plasma cytokines/chemokines may serve as markers of neurocognitive impairment in HIV infection.
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http://dx.doi.org/10.1089/jir.2020.0251DOI Listing
April 2021

Neurocognitive Trajectories After 72 Weeks of First-Line Anti-retroviral Therapy in Vietnamese Adults With HIV-HCV Co-infection.

Front Neurol 2021 12;12:602263. Epub 2021 Mar 12.

Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.

Long-term neurocognitive outcomes following first-line suppressive anti-retroviral therapy (ART) remain uncertain for individuals with HIV and hepatitis C (HCV) co-infection. The study examined neurocognitive performance before and after 72 weeks of ART using repeated multivariate analyses and latent trajectory models. One hundred and sixty adults with chronic, untreated HIV infection ( = 80 with HCV co-infection and = 80 HIV mono-infected) and 80 demographically similar healthy controls were recruited from the Hospital for Tropical Diseases in Ho Chi Minh City and the surrounding community, respectively. Neurocognitive measures (adapted for use in Vietnam) and liver enzyme tests were compared across groups at baseline. Repeated multivariate and group-based trajectory analyses (GBTA) examined neurocognitive subgroup profiles of the co-infected individuals after 72 weeks of efavirenz- ( = 41) or raltegravir-based ( = 39) ART. Baseline analyses revealed worse motor function in HIV-HCV co-infected individuals compared to both comparison groups. Longitudinal analyses revealed improved neurocognitive performance by week 48 for most participants regardless of treatment arm. GBTA identified a subgroup (35% of HIV-HCV sample) with persistent motor impairment despite otherwise successful ART. Higher HIV viral load and lower CD4 T cell count at baseline predicted persistent motor dysfunction. Liver indices and ART regimen did not predict neurocognitive outcomes in HIV-HCV co-infected individuals. Most HIV-HCV co-infected individuals achieve normative neurocognitive performance after 48 weeks of de novo suppressive ART. However, individuals with more severe HIV disease prior to ART exhibited motor impairment at baseline and 72 weeks after otherwise successful treatment. Interventions aimed at improving motor symptoms at the time of HIV treatment onset may improve long-term clinical outcomes in HIV-HCV co-infected adults.
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http://dx.doi.org/10.3389/fneur.2021.602263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996090PMC
March 2021

Relationships between Viral Load, Neuroimaging and Neuropsychological Performance in Persons Living with HIV.

J Acquir Immune Defic Syndr 2021 Mar 1. Epub 2021 Mar 1.

Department of Neurology, Washington University in Saint Louis, Saint Louis, MO 63110, USA. Department of Psychology, University of Missouri, Saint Louis, Saint Louis, MO 63134, USA Department of Radiology, Washington University in Saint Louis, Saint Louis, MO 63110, USA. Hope Center for Neurological Disorders, Washington University in Saint Louis, Saint Louis, MO 63110, USA.

Background: This study examined whether recommended viral load (VL) classifications by the Department of Health and Human Services map onto changes in brain integrity observed in people living with HIV (PLWH).

Methods: 349 PLWH on combination antiretroviral therapy (cART) meeting criteria for virologic suppression (VS) (VL ≤ 20 copies/mL; n=206), "low-level viremia" (LL; 20-200 copies/mL; n=63) or virologic failure (VF) (> 200 copies/mL; n=80), and 195 demographically similar HIV- controls were compared on cognition and brain volumes from 10 regions of interest that are sensitive to HIV. Changes in cognition and brain volumes were examined in a subset of PLWH (n=132) who completed a follow-up evaluation (mean interval=28 months) and had no change in treatment regimen.

Results: Significant differences in cognition and brain volumes were observed between the HIV- control and VS compared to the VF groups, with few differences observed between the three PLWH subgroups. Longitudinally, PLWH who continued to have VF exhibited a greater decline in cognition and brain volumes compared to PLWH who remained VS. Observed longitudinal changes in cognition correlated with brain volume changes.

Conclusion: PLWH with continued VF (consecutive VL measurements of >200 copies/mL) represent a cause for clinical concern, and may benefit from change in treatment in addition to consideration of other potential etiologies of VF to reduce loss of brain integrity.
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http://dx.doi.org/10.1097/QAI.0000000000002677DOI Listing
March 2021

Accelerated brain aging and cerebral blood flow reduction in persons with HIV.

Clin Infect Dis 2021 Feb 23. Epub 2021 Feb 23.

Department of Neurology, Washington University School of Medicine, St. Louis MO, USA.

Background: Persons with HIV (PWH) are characterized by altered brain structure and function. As they attain normal lifespans, it has become crucial to understand potential interactions between HIV and aging. However, it remains unclear how brain aging varies with viral load (VL).

Methods: In this study, we compare MRI biomarkers amongst PWH with undetectable VL (UVL; ≤50 genomic copies/ml; n=230), PWH with detectable VL (DVL; >50 copies/ml; n=93), and HIV uninfected (HIV-) controls (n=206). To quantify gray matter cerebral blood flow (CBF), we utilized arterial spin labeling. To measure structural aging, we used a publicly available deep learning algorithm to estimate brain age from T1-weighted MRI. Cognitive performance was measured using a neuropsychological battery covering five domains.

Results: Associations between age and CBF varied with VL. Older PWH with DVL had reduced CBF vs. PWH with UVL (p=0.02). Structurally predicted brain aging was accelerated in PWH vs. HIV- controls regardless of VL (p<0.001). Overall, PWH had impaired learning, executive function, psychomotor speed, and language compared to HIV- controls. Structural brain aging was associated with reduced psychomotor speed (p<0.001).

Conclusions: Brain aging in HIV is multifaceted. CBF depends on age and current VL, and is improved by medication adherence. By contrast, structural aging is an indicator of cognitive function and reflects serostatus rather than current VL.
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http://dx.doi.org/10.1093/cid/ciab169DOI Listing
February 2021

Cognitive trajectories after treatment in acute HIV infection.

AIDS 2021 05;35(6):883-888

Missouri Institute of Mental Health, University of Missouri-St. Louis, Missouri, USA.

Objective: People with HIV continue to exhibit cognitive symptoms after suppressive antiretroviral therapy (ART). It remains unclear if initiating ART during acute HIV-1 infection (AHI) uniformly improves cognitive outcomes.

Methods: Sixty-seven individuals (96% men, median age 28 years) initiated ART immediately after AHI diagnosis and maintained viral suppression for 6 years. They underwent a four-test neuropsychological battery that measured fine motor speed and dexterity, psychomotor speed, and executive functioning at baseline (pre-ART AHI), weeks 12, 24 and 96, and annually thereafter through week 288. Performances were standardized to calculate an overall (NPZ-4) score and frequencies of impaired cognitive performance (≤-1 SD on at least two tests, or ≤-2 SD on at least one test). Group-based trajectory analysis (GBTA) was applied to identify distinct neuropsychological trajectories modelled from baseline to week 288. Posthoc analyses examined HIV-1 and demographic factors that differed between trajectory subgroups.

Results: NPZ-4 scores improved from baseline to week 96 (P < 0.001) and from weeks 96 to 288 (P < 0.001), with frequencies of impaired performance of 30, 6 and 2% at the respective time-points. The amplitude of NPZ-4 improvement throughout the period was more than 0.5 SD and beyond practice effects. GBTA identified three NPZ-4 trajectory subgroups that all showed improvement over-time. The subgroup with lowest baseline performance exhibited worse depressive symptoms at baseline (P = 0.04) and the largest improvement among the three. HIV-1 indices did not differ between the subgroups.

Conclusion: Cognitive performance improved in a sustained and stable manner after initiating ART during AHI. Largest improvements were seen in participants with worst baseline cognitive performance.
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http://dx.doi.org/10.1097/QAD.0000000000002831DOI Listing
May 2021

Impact of Plasma IP-10/CXCL10 and RANTES/CCL5 Levels on Neurocognitive Function in HIV Treatment-Naive Patients.

AIDS Res Hum Retroviruses 2021 Feb 17. Epub 2021 Feb 17.

National Health Laboratory Service (NHLS), Tygerberg Business Unit, Cape Town, South Africa.

Immune activation, which is accompanied by the production of proinflammatory cytokines, is a strong predictor of disease progression in HIV infection. Inflammation is critical in neuronal damage linked to HIV-associated neurocognitive disorders. We examined the relationship between plasma cytokine levels and deficits in neurocognitive function. Multiplex profiling by Luminex technology was used to quantify 27 cytokines/chemokines from 139 plasma samples of people living with HIV (PLWH). The relationship of plasma cytokine markers, clinical parameters, and cognitive impairment, was assessed using Spearman correlations. Partial least squares regression and variable importance in projection scores were used for further evaluation of the association. Forty-nine (35.3%) participants exhibited neurocognitive impairment based on a global deficit score (GDS) of at least 0.5 and 90 (64.7%) were classified as nonimpaired. Twenty-three (16.5%) initiated on combination antiretroviral therapy for 4 weeks before cognitive assessment and 116 (83.5%) were not on treatment. We identified five proinflammatory cytokines that were significant predictors of GDS namely, IP-10 ( = 0.058;  = .007), RANTES ( = 0.049;  = .005), IL-2 ( = 0.047,  = .006), Eotaxin ( = 0.042,  = .003), and IL-7 ( = 0.039,  = .003). IP-10 and RANTES were the strongest predictors of GDS. Both cytokines correlated with plasma viral load and lymphocyte proviral load and were inversely correlated with CD4 T cell counts. IP-10 and RANTES formed a separate cluster with highest proximity. Study findings describe novel associations among IP-10, RANTES, cognitive status, plasma viral load, and cell-associated viral load.
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http://dx.doi.org/10.1089/AID.2020.0203DOI Listing
February 2021

Association of Immunosuppression and Viral Load With Subcortical Brain Volume in an International Sample of People Living With HIV.

JAMA Netw Open 2021 01 4;4(1):e2031190. Epub 2021 Jan 4.

Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey.

Importance: Despite more widely accessible combination antiretroviral therapy (cART), HIV-1 infection remains a global public health challenge. Even in treated patients with chronic HIV infection, neurocognitive impairment often persists, affecting quality of life. Identifying the neuroanatomical pathways associated with infection in vivo may delineate the neuropathologic processes underlying these deficits. However, published neuroimaging findings from relatively small, heterogeneous cohorts are inconsistent, limiting the generalizability of the conclusions drawn to date.

Objective: To examine structural brain associations with the most commonly collected clinical assessments of HIV burden (CD4+ T-cell count and viral load), which are generalizable across demographically and clinically diverse HIV-infected individuals worldwide.

Design, Setting, And Participants: This cross-sectional study established the HIV Working Group within the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) consortium to pool and harmonize data from existing HIV neuroimaging studies. In total, data from 1295 HIV-positive adults were contributed from 13 studies across Africa, Asia, Australia, Europe, and North America. Regional and whole brain segmentations were extracted from data sets as contributing studies joined the consortium on a rolling basis from November 1, 2014, to December 31, 2019.

Main Outcomes And Measures: Volume estimates for 8 subcortical brain regions were extracted from T1-weighted magnetic resonance images to identify associations with blood plasma markers of current immunosuppression (CD4+ T-cell counts) or detectable plasma viral load (dVL) in HIV-positive participants. Post hoc sensitivity analyses stratified data by cART status.

Results: After quality assurance, data from 1203 HIV-positive individuals (mean [SD] age, 45.7 [11.5] years; 880 [73.2%] male; 897 [74.6%] taking cART) remained. Lower current CD4+ cell counts were associated with smaller hippocampal (mean [SE] β = 16.66 [4.72] mm3 per 100 cells/mm3; P < .001) and thalamic (mean [SE] β = 32.24 [8.96] mm3 per 100 cells/mm3; P < .001) volumes and larger ventricles (mean [SE] β = -391.50 [122.58] mm3 per 100 cells/mm3; P = .001); in participants not taking cART, however, lower current CD4+ cell counts were associated with smaller putamen volumes (mean [SE] β = 57.34 [18.78] mm3 per 100 cells/mm3; P = .003). A dVL was associated with smaller hippocampal volumes (d = -0.17; P = .005); in participants taking cART, dVL was also associated with smaller amygdala volumes (d = -0.23; P = .004).

Conclusions And Relevance: In a large-scale international population of HIV-positive individuals, volumes of structures in the limbic system were consistently associated with current plasma markers. Our findings extend beyond the classically implicated regions of the basal ganglia and may represent a generalizable brain signature of HIV infection in the cART era.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.31190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811179PMC
January 2021

Deep Phenotyping of HIV Neurocognitive Complications Among Individuals Residing in High-Income Countries.

Curr Top Behav Neurosci 2021 Jan 14. Epub 2021 Jan 14.

Missouri Institute of Mental Health, St. Louis, MO, USA.

People living with HIV (PLWH) residing in high-income countries (HICs) are, in theory, well positioned to benefit from clinical care strategies that predict optimal neurocognitive and neuropsychiatric outcomes. However, there is substantial inter-individual variability in access to clinical care, prevalence of co-occurring risk factors, and comorbid health conditions that represent barriers to achieving the full potential of antiretroviral therapy (ART). Complex interactions between these variables translate into heterogeneity in HIV clinical phenotypes, including abnormalities in brain structure and function. The growing population of PLWH in HICs who are now reaching advanced age introduces additional causal pathways of neurocognitive variability among PLWH receiving ART. These patterns foreshadow trends expected to develop globally in response to increased access to ART. This chapter reviews the combination of highly dimensional risk factors for neurocognitive complications among PLWH residing in HICs. We begin with a brief description of the neuropathological, neuroimaging, and neurocognitive signatures of HIV, followed by a summary of controversies regarding the clinical presentation of HIV-associated neurocognitive disorders (HAND), including putative synergies between HIV disease dynamics and advanced age. Finally, we introduce innovative research strategies that have potential to advance the existing conceptual framework of HAND and, ideally, catalyze the development and of clinical interventions needed to achieve HIV treatment and eradication efforts.
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http://dx.doi.org/10.1007/7854_2020_185DOI Listing
January 2021

HIV-related enacted stigma and increase frequency of depressive symptoms among Thai and Cambodian adolescents and young adults with perinatal HIV.

Int J STD AIDS 2021 Mar 18;32(3):246-256. Epub 2020 Dec 18.

The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), The Thai Red Cross AIDS Research Center, Bangkok, Thailand.

HIV-related enacted stigma and social problems may increase risk for depression and/or behavioral problems among adolescents and young adults with perinatal HIV(AYA-PHIV), yet few studies have explored stigma in AYA-PHIV residing in low-to-middle income regions, including Southeast Asia. We assessed HIV-related enacted stigma and social problems in AYA-PHIV who participated in the RESILIENCE study (clinicaltrials.gov identification: U19AI53741) in Thailand and Cambodia using specific questions during structured in-person interviews. Depression was measured by the Child Depression Inventory for children <15 years, or the Center for Epidemiologic Studies Depression Scales for youth ≥15 years); behavioral problems were measured by the Child Behavior Checklist (CBCL-caregiver report). Among 195 AYA-PHIV (median age 16.9 years), 25.6% reported a lifetime experience of enacted stigma, while 10.8% experienced social problems due to HIV infection. The frequency of depressive symptoms was nearly two-fold higher among AYA-PHIV with compared to those without HIV-related enacted stigma (34.7% vs. 16.0%, p = 0.005). Caregiver-reported behavioral problems were detected in 14.6% of all AYA-PHIV, with no differences between those with and without HIV-related enacted stigma. Low household income and caregiver mental health problems were independent risk factors for depressive symptoms; HIV-related enacted stigma was also associated with increased risk, warranting targeted services to support AYA-PHIV.
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http://dx.doi.org/10.1177/0956462420960602DOI Listing
March 2021

Minimal detection of cerebrospinal fluid escape after initiation of antiretroviral therapy in acute HIV-1 infection.

AIDS 2021 04;35(5):777-782

Yale School of Medicine, New Haven, Connecticut, USA.

Objective: Despite suppression of HIV-1 replication in the periphery by antiretroviral therapy (ART), up to 10% of treated individuals have quantifiable HIV-1 in the CSF, termed CSF escape. CSF escape may be asymptomatic but has also been linked to progressive neurological disease, and may indicate persistence of HIV in the central nervous system (CNS). CSF escape has not yet been assessed after initiation of ART during acute HIV-1 infection (AHI).

Design: Prospective cohort study.

Setting: Major voluntary counseling and testing site in Bangkok, Thailand.

Participants: Participants identified and initiated on ART during AHI who received an optional study lumbar puncture at pre-ART baseline or after 24 or 96 weeks of ART.

Main Outcome Measures: Paired levels of CSF and plasma HIV-1 RNA, with CSF greater than plasma HIV-1 RNA defined as CSF escape.

Results: Two hundred and four participants had paired blood and CSF sampling in at least one visit at baseline, week 24, or week 96. Twenty-nine participants had CSF sampling at all three visits. CSF escape was detected in 1/90 at week 24 (CSF HIV-1 RNA 2.50 log10 copies/ml, plasma HIV-1 RNA <50 copies/ml), and 0/55 at week 96.

Conclusion: Although levels of CSF HIV-1 RNA in untreated AHI are high, initiating treatment during AHI results in a very low rate of CSF escape in the first 2 years of treatment. Early treatment may improve control of HIV-1 within the CNS compared with treatment during chronic infection, which may have implications for long-term neurological outcomes and CNS HIV-1 persistence.
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http://dx.doi.org/10.1097/QAD.0000000000002786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969409PMC
April 2021

Effects of anticholinergic medication use on brain integrity in persons living with HIV and persons without HIV.

AIDS 2021 03;35(3):381-391

Department of Neurology, Washington University in Saint Louis.

Objective: This study examined relationships between anticholinergic medication burden and brain integrity in people living with HIV (PLWH) and people without HIV (HIV-).

Methods: Neuropsychological performance z-scores (learning, retention, executive function, motor/psychomotor speed, language domains, and global cognition), and neuroimaging measures (brain volumetrics and white matter fractional anisotropy) were analyzed in PLWH (n = 209) and HIV- (n = 95) grouped according to the Anticholinergic Cognitive Burden (ACB) scale (0 = no burden, 1-3 = low burden, >3 = high burden). Neuropsychological performance and neuroimaging outcomes were compared between HIV- and PLWH with high anticholinergic burden. Within a cohort of PLWH (n = 90), longitudinal change in ACB score over ∼2 years was correlated to the rate of change per month of study interval in neuropsychological performance and neuroimaging measures.

Results: A higher number of anticholinergic medications and ACB was observed in PLWH compared with HIV- (P < 0.05). A higher ACB was associated with worse motor/psychomotor performance, smaller occipital lobe, putamen, subcortical gray matter and total gray matter volumes in HIV-; and poorer executive function, retention and global cognition, smaller brain volumes (frontal, parietal and temporal lobes, hippocampus, amygdala, cortex, subcortical gray matter and total gray matter), and reduced fractional anisotropy (posterior corpus callosum, perforant pathway) in PLWH. PLWH with high anticholinergic burden performed worse on tests of learning and executive function compared with HIV- with high anticholinergic burden. Longitudinally, PLWH who reduced their ACB over time had better neuropsychological performance and neuroimaging measures.

Conclusion: Anticholinergic medications were associated with worse neuropsychological performance and reduced structural brain integrity, and these effects were more widespread in PLWH. Use of anticholinergic medications should be carefully monitored in older adults with deprescription considered whenever possible.
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http://dx.doi.org/10.1097/QAD.0000000000002768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855412PMC
March 2021

Impact of Cannabis Use on Brain Structure and Function in Suppressed HIV Infection.

J Behav Brain Sci 2020 Aug 21;10(8):344-370. Epub 2020 Aug 21.

Hawaii Center for AIDS, University of Hawaii-Manoa, Honolulu, HI, USA.

Background: Brain atrophy and cognitive deficits persist among individuals with suppressed HIV disease. The impact of cannabis use is unknown.

Methods: HIV+ and HIV- participants underwent cross-sectional magnetic resonance imaging and neuropsychological testing. Lifetime frequency, duration (years), and recency of cannabis use were self-reported. Relationships of cannabis use to resting-state functional connectivity (RSFC) and to 9 regional brain volumes were assessed with corrections for multiple comparisons. Peripheral blood cytokines and monocyte subsets were measured in the HIV+ group and examined in relation to cannabis exposure.

Results: We evaluated 52 HIV+ [50.8 ± 7.1 years old; 100% on antiretroviral therapy ≥ 3 months; 83% with plasma viral load < 50 copies/mL] and 55 HIV- [54.0 ± 7.5 years old] individuals. Among HIV+ participants, recent cannabis use (within 12 months) was associated with diminished RSFC, including of occipital cortex, controlling for age. Duration of use correlated negatively with volumes of all regions (most strikingly the nucleus accumbens) independently of recent use and intracranial volume. Recent use was associated with larger caudate and white matter volumes and lower soluble vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1 concentrations. Duration of use correlated positively with psychomotor speed. Use > 10 times/lifetime was linked to more somatic symptoms, better executive function, and lower CD14CD16 monocyte count.

Conclusion: HIV+ individuals demonstrated opposing associations with cannabis. Recent use may weaken RSFC and prolonged consumption may exacerbate atrophy of the accumbens and other brain regions. More frequent or recent cannabis use may reduce the inflammation and CD14CD16 monocytes that facilitate HIV neuroinvasion. HIV-specific cannabis studies are necessary.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508465PMC
August 2020

Determinants of suboptimal CD4 T cell recovery after antiretroviral therapy initiation in a prospective cohort of acute HIV-1 infection.

J Int AIDS Soc 2020 09;23(9):e25585

Yale School of Medicine, New Haven, CT, USA.

Introduction: Up to 30% of individuals treated with antiretroviral therapy (ART) during chronic HIV fail to recover CD4 counts to >500 cells/mm despite plasma viral suppression. We investigated the frequency and associations of suboptimal CD4 recovery after ART started during acute HIV infection (AHI).

Methods: Participants who started ART in Fiebig I to V AHI with ≥48 weeks of continuous documented HIV-RNA < 50 copies/mL were stratified by CD4 count at latest study visit to suboptimal immune recovery (SIR; CD4 < 350 cells/mm ), intermediate immune recovery (IIR; 350 ≤ CD4 < 500) and complete immune recovery (CIR; CD4 ≥ 500). Clinical and laboratory parameters were assessed at pre-ART baseline and latest study visit. Additional inflammatory and neurobehavioral endpoints were examined at baseline and 96 weeks.

Results: Of 304 participants (96% male, median 26 years old) evaluated after median 144 (range 60 to 420) weeks of ART initiated at median 19 days (range 1 to 62) post-exposure, 3.6% (n = 11) had SIR and 14.5% (n = 44) had IIR. Pre-ART CD4 count in SIR compared to CIR participants was 265 versus 411 cells/mm (p = 0.002). Individuals with SIR or IIR had a slower CD4 rate of recovery compared to those with CIR. Timing of ART initiation by Fiebig stage did not affect CD4 count during treatment. Following ART, the CD8 T cell count (p = 0.001) and CD4/CD8 ratio (p = 0.047) were lower in SIR compared to CIR participants. Compared to the CIR group at week 96, the combined SIR and IIR groups had higher sCD14 (p = 0.008) and lower IL-6 (p = 0.04) in plasma, without differences in neuropsychological or psychiatric indices.

Conclusions: Despite immediate and sustained treatment in AHI, suboptimal CD4 recovery occurs uncommonly and is associated with low pre-ART CD4 count as well as persistent low CD8 count and CD4/CD8 ratio during treatment.
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http://dx.doi.org/10.1002/jia2.25585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507109PMC
September 2020

Mindfulness-based stress reduction for HIV-associated neurocognitive disorder: Rationale and protocol for a randomized controlled trial in older adults.

Contemp Clin Trials 2020 Nov 15;98:106150. Epub 2020 Sep 15.

Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, USA.

The symptom burden of HIV-associated neurocognitive disorder (HAND) is high among older individuals, and treatment options are limited. Mindfulness-based stress reduction (MBSR) has potential to improve neurocognitive performance, psychosocial wellbeing, and quality of life, but empirical studies in this growing vulnerable population are lacking. In this trial, participants (N = 180) age 55 and older who are living with HIV infection, are on combination antiretroviral therapy with suppressed viral loads, and yet continue to experience behavioral and cognitive symptoms of HAND, are randomized to MBSR or to a waitlist control arm that receives MBSR following a 16-week period of standard care. Primary outcomes (attention, executive function, stress, anxiety, depression, everyday functioning, quality of life) and potential mediators (affect, mindfulness) and moderators (social support, loneliness) are assessed at baseline and weeks 8, 16, and 48 in both groups, with an additional assessment at week 24 (post-MBSR) in the crossover control group. Assessments include self-report and objective measures (e.g., neuropsychological assessment, neurological exam, clinical labs). In addition, a subset of participants (n = 30 per group) are randomly selected to undergo fMRI to evaluate changes in functional connectivity networks and their relationship to changes in neuropsychological outcomes. Forthcoming findings from this randomized controlled trial have the potential to contribute to a growing public health need as the number of older adults with HAND is expected to rise.
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http://dx.doi.org/10.1016/j.cct.2020.106150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686285PMC
November 2020

Central nervous system safety during brief analytic treatment interruption of antiretroviral therapy within four HIV remission trials: an observational study in acutely treated people living with HIV.

Clin Infect Dis 2020 Sep 11. Epub 2020 Sep 11.

Yale University, New Haven, Connecticut, USA.

Background: The central nervous system (CNS) is a likely reservoir of HIV, vulnerable to viral rebound, inflammation, and clinical changes upon stopping antiretroviral therapy (ART). It is critical to evaluate the CNS safety of studies using analytic treatment interruption (ATI) to assess HIV remission.

Methods: Thirty participants who started ART during acute HIV infection underwent CNS assessments across four ATI remission trials. ART resumption occurred with plasma viral load >1000 copies/mL. CNS measures included paired pre- vs. post-ATI measures of mood, cognitive performance, and neurologic examination, with elective cerebrospinal fluid (CSF) sampling, brain diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS).

Results: Median participant age was 30 years old and 29/30 were male. Participants' median time on ART prior to ATI was 3 years, and ATI lasted a median of 35 days. Post-ATI, there were no differences in median mood scores or neurologic findings and cognitive performance improved modestly. During ATI, a low level of CSF HIV-1 RNA was detectable in six of 20 participants with plasma viremia, with no group changes in CSF immune activation markers or brain DTI measures. Mild worsening was identified in post-ATI basal ganglia total choline MRS, suggesting an alteration in neuronal membranes.

Conclusion: No adverse CNS effects were observed with brief, closely-monitored ATI in participants with acutely treated HIV, except a MRS alteration in basal ganglia choline. Further studies are needed to assess CNS ATI safety in HIV remission trials, particularly for studies using higher thresholds to restart ART and longer ATI durations.
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http://dx.doi.org/10.1093/cid/ciaa1344DOI Listing
September 2020

Peripheral blood lymphocyte proviral DNA predicts neurocognitive impairment in clade C HIV.

J Neurovirol 2020 12 31;26(6):920-928. Epub 2020 Jul 31.

Division of Medical Virology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, Francie van Zijl Avenue, P.O. Box 241, Cape Town, 8000, South Africa.

It is not known if proviral DNA in the periphery corresponds to cognitive status in clade C as it does in clade B and recombinant forms. A cross-sectional study was conducted on participants investigated for HIV-associated neurocognitive impairment in South Africa. HIV-1 proviral DNA was quantified using a PCR assay targeting a highly conserved HIV-1 LTR-gag region. Fifty-four (36.7%) participants were cognitively impaired and 93 (63.3%) were not impaired. Forty-three (79.6%) of the cognitively impaired participants were female and 11 (20.4%) were male. There was no significant age difference between cognitively impaired and unimpaired participants (p = 0.42). HIV-1 DNA in cognitively impaired PLWH was significantly higher than in cognitively normal individuals (p = .016). Considering impaired participants, lymphocyte HIV-1 DNA was significantly higher in males than females (p = 0.02). There was a modest positive correlation between lymphocyte HIV-1 DNA and global deficit scores (GDS) r = 0.176; p = 0.03). The two measures of viral load, lymphocyte HIV-1 DNA copies/million and plasma RNA copies/ml, were positively correlated (r = 0.39; p < .001). After adjusting for other covariates, age, sex, treatment status, and the interactions between impairment and treatment, the multivariate regression showed association between proviral load and neurocognitive impairment; omega effect size was 0.04, p value = 0.010. The burden of HIV-1 peripheral blood lymphocyte proviral DNA corresponds to neurocognitive impairment among individuals infected with clade C disease. Therefore, therapeutic strategies to reduce the HIV-1 proviral DNA reservoir in lymphocytes may improve neurocognitive outcomes in PLWH.
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http://dx.doi.org/10.1007/s13365-020-00882-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717048PMC
December 2020

Spectral correlation of four-wave mixing generated in a photonic crystal fiber pumped by a chirped pulse.

Opt Lett 2020 Aug;45(15):4148-4151

We report the spectral distribution of the parametric process generated in a photonic crystal fiber pumped by a chirped pulse. The spectral correlation of four-wave mixing has been measured using the dispersive Fourier transform method. From statistical analysis of multiple shot-to-shot spectral measurements, the spectral correlation between the signal and idler photons reveals physical insights into the particular portion of the pump spectrum responsible for generating the four-wave mixing. Therefore, the shape of the correlation map indicates directly the temporal and spectral links between the signal and the pump, which are highly important to design a four-wave mixing based amplifier.
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http://dx.doi.org/10.1364/OL.398614DOI Listing
August 2020

The association of peripheral immune markers with brain cortical thickness and surface area in South African people living with HIV.

J Neurovirol 2020 12 13;26(6):908-919. Epub 2020 Jul 13.

Department of Psychiatry and Mental Health, Brain Behaviour Unit, University of Cape Town, Cape Town, South Africa.

A spectrum of cognitive impairments known as HIV-associated neurocognitive disorders (HAND) are consequences of the effects of HIV-1 within the central nervous system. Regardless of treatment status, an aberrant chronic neuro-immune regulation is a crucial contributor to the development of HAND. However, the extent to which inflammation affects brain structures critical for cognitive status remains unclear. The present study aimed to determine associations of peripheral immune markers with cortical thickness and surface area. Participants included 65 treatment-naïve HIV-positive individuals and 26 HIV-negative controls. Thickness and surface area of all cortical regions were derived using automated parcellation of T1-weighted images acquired at 3 T. Peripheral immune markers included C-C motif ligand 2 (CCL2), matrix metalloproteinase 9 (MMP9), neutrophil gelatinase-associated lipocalin (NGAL), thymidine phosphorylase (TYMP), transforming growth factor (TGF)-β1, and vascular endothelial growth factor (VEGF), which were measured using enzyme-linked immunosorbent assays. Associations of these markers with thickness and surface area of cortical regions were evaluated. A mediation analysis examined whether associations of inflammatory markers with cognitive functioning were mediated by brain cortical thickness and surface area. After controlling for multiple comparisons, higher NGAL was associated with reduced thickness of the bilateral orbitofrontal cortex in HIV-positive participants. The association of NGAL with worse motor function was mediated by cortical thickness of the bilateral orbitofrontal region. Taken together, this study suggests that NGAL plays a potential role in the neuropathophysiology of neurocognitive impairments of HIV.
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http://dx.doi.org/10.1007/s13365-020-00873-wDOI Listing
December 2020

Comparison of [11C]-PBR28 Binding Between Persons Living With HIV and HIV-Uninfected Individuals.

J Acquir Immune Defic Syndr 2020 10;85(2):244-251

Department of Neurology, Washington University in St. Louis, St. Louis, MO.

Objective: Despite combined antiretroviral therapy, neuroinflammation may persist in persons living with HIV (PLWH) and contribute to cognitive impairment in this population. Positron emission tomography (PET) imaging targeting 18 kDa translocator protein (TSPO) has been used to localize neuroinflammation. We aimed to use TSPO-PET imaging to evaluate neuroinflammation in PLWH.

Design: Twenty-four virologically suppressed PLWH on combined antiretroviral therapy and 13 HIV-negative (HIV-) controls completed TSPO-PET imaging using the radiotracer [C]PBR28. Because of tracer complexity and differing procedures used in previous studies, we employed an expansive methodological approach, using binding potential (BP) and standard uptake value ratio and multiple different reference regions to estimate [C]PBR28 binding.

Methods: [C]PBR28 binding was measured in 30 cortical and subcortical regions and compared between PLWH and HIV- controls. Pearson correlation evaluated the association between [C]PBR28 binding and cognition and clinical measures of HIV.

Results: Analyses conducted using multiple reference regions and measures of tracer uptake revealed no significant differences between [C]PBR28 binding in PLWH compared with HIV- controls. In addition, [C]PBR28 binding in PLWH was not significantly associated with clinical measures of HIV or plasma biomarkers of inflammation. [C]PBR28 binding was not significantly elevated in cognitively impaired PLWH compared with unimpaired PLWH, but there were inverse relationships between cognitive performance (executive and global function) and [C]PBR28 binding in PLWH.

Conclusions: Our results suggest that neuroinflammation may play a role in cognitive deficits, but overall neuroinflammatory levels as measured by TSPO-PET imaging in PLWH are not significantly different from those seen in HIV- controls.
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http://dx.doi.org/10.1097/QAI.0000000000002435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053041PMC
October 2020

Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer's disease model.

J Exp Med 2020 09;217(9)

Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO.

TREM2 is a receptor for lipids expressed in microglia. The R47H variant of human TREM2 impairs ligand binding and increases Alzheimer's disease (AD) risk. In mouse models of amyloid β (Aβ) accumulation, defective TREM2 function affects microglial response to Aβ plaques, exacerbating tissue damage, whereas TREM2 overexpression attenuates pathology. Thus, AD may benefit from TREM2 activation. Here, we examined the impact of an anti-human TREM2 agonistic mAb, AL002c, in a mouse AD model expressing either the common variant (CV) or the R47H variant of TREM2. Single-cell RNA-seq of microglia after acute systemic administration of AL002c showed induction of proliferation in both CV- and R47H-transgenic mice. Prolonged administration of AL002c reduced filamentous plaques and neurite dystrophy, impacted behavior, and tempered microglial inflammatory response. We further showed that a variant of AL002c is safe and well tolerated in a first-in-human phase I clinical trial and engages TREM2 based on cerebrospinal fluid biomarkers. We conclude that AL002 is a promising candidate for AD therapy.
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http://dx.doi.org/10.1084/jem.20200785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478730PMC
September 2020

Machine Learning Analysis Reveals Novel Neuroimaging and Clinical Signatures of Frailty in HIV.

J Acquir Immune Defic Syndr 2020 08;84(4):414-421

Department of Neurology, Washington University School of Medicine, Saint Louis, MO; and.

Background: Frailty is an important clinical concern for the aging population of people living with HIV (PLWH). The objective of this study was to identify the combination of risk features that distinguish frail from nonfrail individuals.

Setting: Machine learning analysis of highly dimensional risk features was performed on a clinical cohort of PLWH.

Methods: Participants included 105 older (average age = 55.6) PLWH, with at least a 3-month history of combination antiretroviral therapy (median CD4 = 546). Predictors included demographics, HIV clinical markers, comorbid health conditions, cognition, and neuroimaging (ie, volumetrics, resting-state functional connectivity, and cerebral blood flow). Gradient-boosted multivariate regressions were implemented to establish linear and interactive classification models. Model performance was determined by sensitivity/specificity (F1 score) with 5-fold cross validation.

Results: The linear gradient-boosted multivariate regression classifier included lower current CD4 count, lower psychomotor performance, and multiple neuroimaging indices (volumes, network connectivity, and blood flow) in visual and motor brain systems (F1 score = 71%; precision = 84%; and sensitivity = 66%). The interactive model identified novel synergies between neuroimaging features, female sex, symptoms of depression, and current CD4 count.

Conclusions: Data-driven algorithms built from highly dimensional clinical and brain imaging features implicate disruption to the visuomotor system in older PLWH designated as frail individuals. Interactions between lower CD4 count, female sex, depressive symptoms, and neuroimaging features suggest potentiation of risk mechanisms. Longitudinal data-driven studies are needed to guide clinical strategies capable of preventing the development of frailty as PLWH reach advanced age.
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http://dx.doi.org/10.1097/QAI.0000000000002360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903919PMC
August 2020

The Karolinska Institutet Prize for Research in Medical Education: A history.

Med Teach 2020 06 12;42(6):657-662. Epub 2020 Mar 12.

Executive Vice President Education and Chief Medical Officer, University Health Network, Toronto, Canada.

This article presents a history of the Karolinska Institutet Prize for Medical Education (KIPRIME), highlighting the history of, and influences on, its funders Drs. Gunnar Höglund and Anna-Stina Malmborg. Historic analysis of an archive of documents developed by the authors in a prior study exploring philanthropy in medical education research. Documents in the archive were drawn from publicly available Internet sources, media reports about the KIPRIME and its winners and an interview with Drs. Höglund's and Malmborg. The latter interview was conducted with Ethics Board approval in non-anonymous fashion and with the explicit permission of the interviewees to present their personal information and to cite their words. Finally, observations were shaped iteratively by the authors on multiple trips to the Karolinska Institutet with input from the KIPRIME prize committee leaders. The results of this analysis present a history of the prize situating it in the personal histories of, and influences acting upon, Drs. Höglund and Malmborg. Special attention is given to the potential influence of the Nobel Prizes and the culture of philanthropy in Sweden.
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http://dx.doi.org/10.1080/0142159X.2020.1731441DOI Listing
June 2020

Resting-state neural signatures of depressive symptoms in acute HIV.

J Neurovirol 2020 04 27;26(2):226-240. Epub 2020 Jan 27.

Department of Psychological Sciences, University of Missouri-St. Louis, St. Louis, MO, USA.

Depressive symptoms are often elevated in acute and chronic HIV. Previous neuroimaging research identifies abnormalities in emotion-related brain regions in depression without HIV, including the anterior cingulate cortex (ACC) and amygdala. However, no studies have examined the neural signatures of depressive symptoms in acute HIV infection (AHI). Seed-based voxelwise resting-state functional connectivity (rsFC) for affective seed regions of interest (pregenual ACC, subgenual ACC [sgACC], bilateral amygdala) was computed for 74 Thai males with AHI and 30 Thai HIV-uninfected controls. Group analyses compared rsFC of ACC and amygdala seed regions between AHI and uninfected control groups. Within the AHI group, voxelwise regression analyses investigated the relationship between depressive symptoms and rsFC for these affective seed regions. Group analyses revealed alterations in rsFC of the amygdala in AHI versus uninfected controls. Depressive symptoms associated with decreased rsFC between ACC regions and posterior cingulate/precuneus, medial temporal, and lateral parietal regions in AHI. Symptoms of depression also correlated to increased rsFC between ACC regions and lateral prefrontal cortex, sgACC, and cerebellum in AHI. Similar to the ACC, depressive symptoms associated with decreased rsFC between amygdala and precuneus. Of blood biomarkers, only HIV RNA inversely correlated with rsFC between posterior sgACC and left uncus. We found that depressive symptoms in AHI associate with altered rsFC of ACC and amygdala regions previously implicated in depression. Longitudinal research in this cohort will be necessary to determine whether these early alterations in rsFC of affective network regions are related to persistent depressive symptoms after combination antiretroviral therapy.
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http://dx.doi.org/10.1007/s13365-020-00826-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261250PMC
April 2020

Medication management abilities are reduced in older persons living with HIV compared with healthy older HIV- controls.

J Neurovirol 2020 04 27;26(2):264-269. Epub 2020 Jan 27.

Department of Neurology, Washington University School of Medicine in Saint Louis, 660 S Euclid Ave, Campus Box 8111, St. Louis, MO, 63110, USA.

Although combination antiretroviral therapy (cART) has simplified over the past decade, polypharmacy is increasing for older people living with HIV (PLWH) due to the emergence of multiple health comorbidities. This study examined predictors of, and relationships between, objective (Medication Management Test-Revised (MMT-R)) and self-reported medication management ability in older (≥ 50 years) PLWH (n = 146) compared with HIV-uninfected (HIV-) individuals (n = 60). PLWH scored worse on the MMT-R and had a higher pill burden compared with HIV- individuals. MMT-R failure was predicted by HIV status, race, reading level, and worse executive functioning, as well as history of Hepatitis C and detectable viral load in PLWH. Self-reported ability to manage medications did not relate to MMT-R score. Older PLWH may not self-describe concerns regarding their ability to manage complex medication regimens. Our results emphasize the need for objective measurements of medication management ability.
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http://dx.doi.org/10.1007/s13365-020-00827-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261252PMC
April 2020

Neuropsychiatric outcomes before and after switching to dolutegravir-based therapy in an acute HIV cohort.

AIDS Res Ther 2020 01 7;17(1). Epub 2020 Jan 7.

Missouri Institute of Mental Health, University of Missouri-St. Louis, St. Louis, MO, USA.

Introduction: Dolutegravir (DTG)-based antiretroviral therapy (ART) is currently the first-line treatment for people living with HIV. Neuropsychiatric adverse events (NP-AEs) have been reported with DTG but neuropsychiatric symptoms have not been systemically quantified using structured scales. This study examined mood and cognitive parameters before and after a planned transition from non-DTG to DTG-based ART within a longitudinal study of acute HIV infection (AHI).

Methods: RV254 AHI cohort participants on ≥ 24 weeks of ART initiated at AHI underwent sequential assessments before and after the switch including: (1) Patient Health Questionnaire-9 (PHQ-9), a 9-item survey (scores 0-27) that evaluates somatic and affective/cognitive symptoms of depression; (2) a 2-Questions screening that has been validated locally for depression; (3) Distress Thermometer (scores 0-10); and 4) administration of a 4-test neurocognitive battery sensitive to HIV.

Results: 254 individuals (95% male, median age 30) switched to a DTG-based regimen after a median 144 weeks of ART. Serial assessments were completed at a median of 19 weeks before and 37 weeks after DTG. There was a modest but statistically significant increase in PHQ-9 scores after DTG (pre-switch: 5 [IQR 1-7] vs. Post-switch: 5 [IQR 2-8], p = 0.009). The percentage of participants with at least moderate depression (PHQ-9 ≥ 10) increased from 10 to 16% (p = 0.006), but the frequency of moderate-severe depression (PHQ-9 ≥ 15) remained unchanged (3%). No volunteer reported NP-AEs within the study period. Somatic symptoms of depression increased more than cognitive/affective symptoms. Plasma viral suppression (HIV-1 RNA < 50; p = 0.005) and PHQ-9 ≥ 10 (p < 0.001) before switch were linked to lower PHQ-9 scores after DTG in multivariable analysis. Performance on all neuropsychological tests, except grooved pegboard test, improved modestly after DTG (all p < 0.05).

Conclusion: After a median duration of 37 weeks of DTG use, there was a modest increase in the higher quartile of PHQ-9. This increase was associated with a rise in moderate depression symptoms but not the more severe forms of depression on PHQ-9. No clinically relevant NP-AEs were reported. Pre-existing depression was not associated with subsequent worsening of symptoms after DTG. Cognitive test performance improved post-DTG but could be due to practice effect.
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http://dx.doi.org/10.1186/s12981-019-0257-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945418PMC
January 2020

Frequency and Predictors of HIV-Related Cognitive Impairment in East Africa: The Africa Cohort Study (AFRICOS).

J Acquir Immune Defic Syndr 2020 02;83(2):157-164

Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA.

Background: Medication adherence is a critical issue in achieving viral suppression targets, particularly in resource-limited countries. As HIV-related cognitive impairment (CI) impacts adherence, we examined frequency and predictors of CI in the African Cohort Study.

Setting: Cross-sectional examination of enrollment data from President's Emergency Plan for AIDS Relief supported clinic sites.

Methods: In a 30-minute cognitive assessment, CI was defined as -1SD on 2 tests or -2SD on one, as compared with 429 controls. We performed univariable and multivariable logistic and linear models examining clinical and demographic factors associated with CI and global neuropsychological performance (NP-6).

Results: Two thousand four hundred seventy-two HIV+ participants from Kenya (n = 1503), Tanzania (n = 469), and Uganda (n = 500). The mean (SD) age was 39.7 (10.7) years, and 1452 (59%) were women. The majority reported completing or partially completing primary school (n = 1584, 64%). Mean (SD) current and nadir CD4 count were 463 (249) and 204 (221) cells/mm, respectively; 1689 (68%) were on combination antiretroviral therapy. Nine hundred thirty-nine (38%) HIV+ versus 113 (26%) HIV- individuals showed CI: (P < 0.001). We found significant effects of literacy [odds ratio (OR): 0.3; 95% CI: 0.2 to 0.4; P < 0.001] and World Health Organization stage 4 (OR: 1.5; 95% CI: 1.0 to 2.q; P = 0.046) on CI. Tanzanians (OR: 3.2; 95% CI: 2.4 to 4.3; P < 0.001) and Kenyans (OR: 2.0; 95% CI: 1.6 to 2.6; P < 0.001) had higher risk of CI compared with Ugandans. Results were relatively unchanged in predictive models of NP-6, with the only difference being an additional significant effect of current CD4 cell count (coeff: 0.0; 95% CI: 0.0 to 0.0; P = 0.005).

Conclusions: Literacy, country, World Health Organization stage, and current CD4 cell count were associated with increased risk of cognitive dysfunction. Our findings help optimize care practices in Africa, illustrating the importance of strategies for early and effective viral-immunological control.
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http://dx.doi.org/10.1097/QAI.0000000000002242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316185PMC
February 2020

Machine-learning classification of neurocognitive performance in children with perinatal HIV initiating de novo antiretroviral therapy.

AIDS 2020 04;34(5):737-748

HIV Netherlands Australia Thailand (HIV-NAT) Research Collaboration, Thai Red Cross AIDS Research Center.

Objective: To develop a predictive model of neurocognitive trajectories in children with perinatal HIV (pHIV).

Design: Machine learning analysis of baseline and longitudinal predictors derived from clinical measures utilized in pediatric HIV.

Methods: Two hundred and eighty-five children (ages 2-14 years at baseline; Mage = 6.4 years) with pHIV in Southeast Asia underwent neurocognitive assessment at study enrollment and twice annually thereafter for an average of 5.4 years. Neurocognitive slopes were modeled to establish two subgroups [above (n = 145) and below average (n = 140) trajectories). Gradient-boosted multivariate regressions (GBM) with five-fold cross validation were conducted to examine baseline (pre-ART) and longitudinal predictive features derived from demographic, HIV disease, immune, mental health, and physical health indices (i.e. complete blood count [CBC]).

Results: The baseline GBM established a classifier of neurocognitive group designation with an average AUC of 79% built from HIV disease severity and immune markers. GBM analysis of longitudinal predictors with and without interactions improved the average AUC to 87 and 90%, respectively. Mental health problems and hematocrit levels also emerged as salient features in the longitudinal models, with novel interactions between mental health problems and both CD4 cell count and hematocrit levels. Average AUCs derived from each GBM model were higher than results obtained using logistic regression.

Conclusion: Our findings support the feasibility of machine learning to identify children with pHIV at risk for suboptimal neurocognitive development. Results also suggest that interactions between HIV disease and mental health problems are early antecedents to neurocognitive difficulties in later childhood among youth with pHIV.
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http://dx.doi.org/10.1097/QAD.0000000000002471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072001PMC
April 2020

Regional brain volumetric changes despite 2 years of treatment initiated during acute HIV infection.

AIDS 2020 03;34(3):415-426

University of California at San Francisco, San Francisco, California, USA.

Objective: To assess changes in regional brain volumes after 24 months among individuals who initiated combination antiretroviral therapy (cART) within weeks of HIV exposure.

Design: Prospective cohort study of Thai participants in the earliest stages of HIV-1infection.

Methods: Thirty-four acutely HIV-infected individuals (AHI; Fiebig I-V) underwent brain magnetic resonance (MR) imaging and MR spectroscopy at 1.5 T and immediately initiated cART. Imaging was repeated at 24 months. Regional brain volumes were quantified using FreeSurfer's longitudinal pipeline. Voxel-wise analyses using tensor-based morphometry (TBM) were conducted to verify regional assessments. Baseline brain metabolite levels, blood and cerebrospinal fluid biomarkers assessed by ELISA, and peripheral blood monocyte phenotypes measured by flow cytometry were examined as predictors of significant volumetric change.

Results: Participants were 31 ± 8 years old. The estimated mean duration of infection at cART initiation was 15 days. Longitudinal analyses revealed reductions in volumes of putamen (P < 0.001) and caudate (P = 0.006). TBM confirmed significant atrophy in the putamen and caudate, and also in thalamic and hippocampal regions. In exploratory post-hoc analyses, higher baseline frequency of P-selectin glycoprotein ligand-1 (PSGL-1)-expressing total monocytes correlated with greater caudate volumetric decrease (ρ = 0.67, P = 0.017), whereas the baseline density of PSGL-1-expressing inflammatory (CD14CD16) monocytes correlated with putamen atrophy (ρ = 0.65, P = 0.022).

Conclusion: Suppressive cART initiated during AHI may not prevent brain atrophy. Volumetric decrease appears greater than expected age-related decline, although examination of longitudinal change in demographically similar HIV-uninfected Thai individuals is needed. Mechanisms underlying progressive HIV-related atrophy may include early activation and enhanced adhesive and migratory capacity of circulating monocyte populations.
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http://dx.doi.org/10.1097/QAD.0000000000002436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994348PMC
March 2020

Deep Learning Analysis of Cerebral Blood Flow to Identify Cognitive Impairment and Frailty in Persons Living With HIV.

J Acquir Immune Defic Syndr 2019 12;82(5):496-502

Department of Neurology, Washington University School of Medicine, St. Louis, MI.

Background: Deep learning algorithms of cerebral blood flow were used to classify cognitive impairment and frailty in people living with HIV (PLWH). Feature extraction techniques identified brain regions that were the strongest predictors.

Setting: Virologically suppressed (<50 copies/mL) PLWH (n = 125) on combination antiretroviral therapy were enrolled. Participants averaged 51.4 (11.4) years of age and 13.7 (2.8) years of education. Participants were administered a neuropsychological battery, assessed for frailty, and completed structural neuroimaging.

Methods: Deep neural network (DNN) models were trained to classify PLWH as cognitively unimpaired or impaired based on neuropsychological tests (Hopkins Verbal Learning Test-Revised and Brief Visuospatial Memory Test-Revised, Trail making, Letter-Number Sequencing, Verbal Fluency, and Color Word Interference), as well as frail, prefrail, or nonfrail based on the Fried phenotype criteria (at least 3 of the following 5: weight loss, physical inactivity, exhaustion, grip strength, walking time).

Results: DNNs classified individuals with cognitive impairment in the learning, memory, and executive domains with 82%-86% accuracy (0.81-0.87 AUC). Our model classified nonfrail, prefrail, and frail PLWH with 75% accuracy. The strongest predictors of cognitive impairment were cortical (parietal, occipital, and temporal) and subcortical (amygdala, caudate, and hippocampus) regions, whereas the strongest predictors of frailty were subcortical (amygdala, caudate, hippocampus, thalamus, pallidum, and cerebellum).

Conclusions: DNN models achieved high accuracy in classifying cognitive impairment and frailty status in PLWH. Feature selection algorithms identified predictive regions in each domain and identified overlapping regions between cognitive impairment and frailty. Our results suggest frailty in HIV is primarily subcortical, whereas cognitive impairment in HIV involves subcortical and cortical brain regions.
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http://dx.doi.org/10.1097/QAI.0000000000002181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857844PMC
December 2019

New directions in clinical trials for frontotemporal lobar degeneration: Methods and outcome measures.

Alzheimers Dement 2020 01 6;16(1):131-143. Epub 2020 Jan 6.

Department of Neurology, AbbVie, Chicago, IL, USA.

Introduction: Frontotemporal lobar degeneration (FTLD) is the most common form of dementia for those under 60 years of age. Increasing numbers of therapeutics targeting FTLD syndromes are being developed.

Methods: In March 2018, the Association for Frontotemporal Degeneration convened the Frontotemporal Degeneration Study Group meeting in Washington, DC, to discuss advances in the clinical science of FTLD.

Results: Challenges exist for conducting clinical trials in FTLD. Two of the greatest challenges are (1) the heterogeneity of FTLD syndromes leading to difficulties in efficiently measuring treatment effects and (2) the rarity of FTLD disorders leading to recruitment challenges.

Discussion: New personalized endpoints that are clinically meaningful to individuals and their families should be developed. Personalized approaches to analyzing MRI data, development of new fluid biomarkers and wearable technologies will help to improve the power to detect treatment effects in FTLD clinical trials and enable new, clinical trial designs, possibly leveraged from the experience of oncology trials. A computational visualization and analysis platform that can support novel analyses of combined clinical, genetic, imaging, biomarker data with other novel modalities will be critical to the success of these endeavors.
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http://dx.doi.org/10.1016/j.jalz.2019.06.4956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949386PMC
January 2020