ABSTRACT
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] ß = 16.66 [4.72] mm3 per 100 cells/mm3; P < .001) and thalamic (mean [SE] ß = 32.24 [8.96] mm3 per 100 cells/mm3; P < .001) volumes and larger ventricles (mean [SE] ß = -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] ß = 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.
Subject(s)
Brain/pathology , CD4 Lymphocyte Count , HIV Infections , Viral Load , Adult , Aged , Aged, 80 and over , Brain/diagnostic imaging , Cross-Sectional Studies , Female , HIV Infections/epidemiology , HIV Infections/immunology , HIV Infections/pathology , HIV Infections/virology , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Young AdultSubject(s)
HIV Infections , Biomarkers , Humans , Neurocognitive Disorders , S100 Calcium Binding Protein beta Subunit , UgandaABSTRACT
We previously reported that galectin-9 (Gal-9), a soluble lectin with immunomodulatory properties, is elevated in plasma during HIV infection and induces HIV transcription. The link between Gal-9 and compromised neuronal function is becoming increasingly evident; however, the association with neuroHIV remains unknown. We measured Gal-9 levels by ELISA in cerebrospinal fluid (CSF) and plasma of 70 HIV-infected (HIV+) adults stratified by age (older > 40 years and younger < 40 years) either ART suppressed or with detectable CSF HIV RNA, including a subgroup with cognitive assessments, and 18 HIV uninfected (HIV-) controls. Gal-9 tissue expression was compared in necropsy brain specimens from HIV- and HIV+ donors using gene datasets and immunohistochemistry. Among older HIV+ adults, CSF Gal-9 was elevated in the ART suppressed and CSF viremic groups compared to controls, whereas in the younger group, Gal-9 levels were elevated only in the CSF viremic group (p < 0.05). CSF Gal-9 positively correlated with age in all groups (p < 0.05). CSF Gal-9 tracked with CSF HIV RNA irrespective of age (ß = 0.33; p < 0.05). Higher CSF Gal-9 in the older viremic HIV+ group correlated with worse neuropsychological test performance scores independently of age and CSF HIV RNA (p < 0.05). Furthermore, CSF Gal-9 directly correlated with myeloid activation (CSF-soluble CD163 and neopterin) in both HIV+ older groups (p < 0.05). Among HIV+ necropsy specimens, Gal-9 expression was increased in select brain regions compared to controls (p < 0.05). Gal-9 may serve as a novel neuroimmuno-modulatory protein that is involved in driving cognitive deficits in those aging with HIV and may be valuable in tracking cognitive abnormalities.
Subject(s)
Antigens, CD/genetics , Antigens, Differentiation, Myelomonocytic/genetics , Central Nervous System/virology , Galectins/genetics , HIV Infections/virology , RNA, Viral/genetics , Receptors, Cell Surface/genetics , Viremia/virology , Adult , Age Factors , Anti-HIV Agents/therapeutic use , Antigens, CD/cerebrospinal fluid , Antigens, Differentiation, Myelomonocytic/cerebrospinal fluid , Antiretroviral Therapy, Highly Active , Biomarkers/cerebrospinal fluid , Case-Control Studies , Central Nervous System/drug effects , Central Nervous System/metabolism , Central Nervous System/physiopathology , Cognition/drug effects , Cognition/physiology , Female , Galectins/cerebrospinal fluid , HIV Infections/cerebrospinal fluid , HIV Infections/drug therapy , HIV Infections/immunology , HIV-1/genetics , HIV-1/pathogenicity , Humans , Male , Middle Aged , Neopterin/cerebrospinal fluid , Neuropsychological Tests , RNA, Viral/cerebrospinal fluid , Viremia/cerebrospinal fluid , Viremia/drug therapy , Viremia/immunologyABSTRACT
BACKGROUND: Chronic inflammation and immune dysfunction occur in human immunodeficiency virus (HIV)-infection despite stable antiretroviral therapy (ART). Red blood cell distribution width (RDW) has been shown to correlate with markers of inflammation in non-HIV conditions. The study objective was to determine associations between RDW with cellular markers of immune activation and immune dysfunction including soluble inflammatory mediators in ART treated HIV infection. METHODS: We performed a cross-sectional analysis of the Hawaii Aging with HIV-Cardiovascular study. RDW was defined as one standard deviation of RBC size divided by mean corpuscular volume multiplied by 100%. Correlations were analyzed between RDW, soluble inflammatory biomarkers and T cell activation (CD38 + HLA-DR+), senescence (CD28-CD57+), and immune exhaustion (PD-1, TIGIT, TIM-3 expression). RESULTS: Of 158 participants analyzed, median age was 50 years, duration of ART 12.6 years, virally suppressed 84.4%, and CD4 count 503 cells/mm3. Significant positive correlations were identified between RDW and soluble biomarkers including sICAM, IL-8, IL-6, SAA, TNF-α, sE-selection, fibrinogen, D-dimer, CRP, CD4/CD8 ratio, and frequency of multiple CD8 T-cell populations such as CD38 + HLA-DR + T-cells, single TIGIT+, and dual expressing of TIGIT + PD1+, TIGIT + TIM3+, and TIM3 + PD1+ CD8+ T-cell subsets (p < .05). Frequencies of CD38 + HLA-DR + CD8+ T-cells and TIGIT + CD8+ T-cells remained significant adjusting for baseline variables (p < .01). CONCLUSION: Our study revealed correlations between RDW with systemic inflammatory biomarkers and CD8+ T-cell populations related to immune activation and exhaustion in HIV-infected individuals on ART. Further studies are warranted to determine the utility of RDW as a marker of immune dysregulation in HIV.
Subject(s)
Erythrocyte Indices , Erythrocytes/cytology , HIV Infections/drug therapy , Inflammation/pathology , T-Lymphocytes , Anti-Retroviral Agents , Biomarkers/blood , Cross-Sectional Studies , Female , HIV Infections/blood , HIV Infections/epidemiology , Hawaii/epidemiology , Humans , Male , Middle Aged , Viral LoadABSTRACT
The antiretroviral drug efavirenz (EFV) has been linked to disordered sleep and cognitive abnormalities. We examined sleep and cognitive function and subsequent changes following switch to an alternative integrase inhibitor-based regimen. Thirty-two HIV-infected individuals on EFV, emtricitabine, and tenofovir (EFV/FTC/TDF) without traditional risk factors for obstructive sleep apnea (OSA) were randomized 2:1 to switch to elvitegravir/cobicistat/emtricitabine/tenofovir (EVG/COBI/FTC/TDF) or to continue EFV/FTC/TDF therapy for 12 weeks. Overnight polysomnography and standardized sleep and neuropsychological assessments were performed at baseline and at 12 weeks. No significant differences in change over 12 weeks were noted between the two arms in any sleep or neuropsychological test parameter. At entry, however, the rate of sleep disordered breathing (SDB) was substantially higher in study subjects compared to published age-matched norms and resulted in a high assessed OSA rate of 59.4%. Respiratory Disturbance Index (RDI), a measure of SDB, correlated with age- and education-adjusted global neuropsychological Z-score (NPZ) (r = -0.35, p = 0.05). Sleep Maintenance Efficiency, Wake after Sleep Onset, REM Sleep and RDI correlated with domain-specific NPZ for learning and memory (all p-values ≤ 0.05). Among HIV-infected individuals on EFV-based therapy and without traditional risk factors for OSA, sleep and neuropsychological abnormalities do not readily reverse after discontinuation of EFV. High baseline rates of SDB and abnormalities in sleep architecture exist in this population correlating with neuropsychological impairment. The role of HIV immuno-virologic or lifestyle factors as contributing etiologies should be explored. OSA may be an under-recognized etiology for cognitive dysfunction during chronic HIV.
Subject(s)
Benzoxazines/adverse effects , Benzoxazines/therapeutic use , Central Nervous System Diseases/chemically induced , HIV Infections/drug therapy , HIV-1 , Sleep Wake Disorders/chemically induced , Adult , Alkynes , Anti-HIV Agents/adverse effects , Anti-HIV Agents/therapeutic use , Benzoxazines/administration & dosage , Cobicistat/administration & dosage , Cobicistat/therapeutic use , Cyclopropanes , Emtricitabine/administration & dosage , Emtricitabine/therapeutic use , Female , Humans , Male , Middle Aged , Tenofovir/administration & dosage , Tenofovir/therapeutic useABSTRACT
OBJECTIVE: To evaluate changes in neuropsychological (NP) performance and in plasma and cell surface markers of peripheral monocyte activation/migration after treatment with cenicriviroc (CVC), a dual C-C chemokine receptor type 2 (CCR2) and type 5 (CCR5) antagonist, in treatment-experienced, HIV-infected individuals. SETTING: Single-arm, 24-week, open-label clinical trial. METHODS: HIV-infected individuals on antiretroviral therapy ≥1 year with plasma HIV RNA ≤50 copies per milliliter and below-normal cognitive performance [defined as age-, sex-, and education-adjusted NP performance (NPZ) <-0.5 in a single cognitive domain or in global performance] were enrolled. Changes over 24 weeks were assessed for global and domain-specific NPZ scores, plasma markers of monocyte/macrophage activation [neopterin, soluble (s)CD14, and sCD163] quantified by ELISA, and CCR2 and CCR5 expression on monocytes, and T cells measured by flow cytometry. RESULTS: Seventeen of 20 enrolled participants completed the study. Improvements over 24 weeks were observed in global NPZ [median change (Δ) = 0.24; P = 0.008], and in cognitive domains of attention (Δ0.23; P = 0.011) and working memory (Δ0.44; P = 0.017). Plasma levels of sCD163, sCD14 and neopterin decreased significantly (P's < 0.01). CCR2 and CCR5 monocyte expression remained unchanged; however, CCR5 levels on CD4 and CD8 T cells and CCR2 expression on CD4 T cells increased (P's < 0.01). CONCLUSIONS: CVC given over 24 weeks was associated with improved NP test performance and decreased plasma markers of monocyte immune activation in virally suppressed, HIV-infected participants. These data potentially link changes in monocyte activation to cognitive performance. Further study of CVC for HIV cognitive impairment in a randomized controlled study is warranted.
Subject(s)
Anti-HIV Agents/therapeutic use , Cognition , HIV Infections/drug therapy , Monocytes/immunology , Receptors, CCR2/antagonists & inhibitors , Receptors, CCR5/drug effects , Viral Load , Female , HIV Infections/immunology , HIV Infections/psychology , HIV Infections/virology , Humans , Leukocyte Count , Macrophage Activation , Male , Middle Aged , Neuropsychological Tests , Pilot ProjectsABSTRACT
Waldenström macroglobulinemia (WM) is an indolent B cell lymphoproliferative disorder with monoclonal IgM secretion. We present a patient with WM who presented with multifocal acute cortical ischemic strokes and was found to have central nervous system (CNS) vasculitis. Workup was negative for cryoglobulins and hyperviscosity syndrome. Immunosuppression with intravenous steroids and cyclophosphamide stabilized the patient's mental status and neurologic deficits. On followup over 7 years, patient gained independence from walking aids and experienced no recurrences of CNS vasculitis. To our knowledge, CNS vasculitis in a WM patient, in the absence of cryoglobulins, has not been reported. Immunosuppression is the preferred treatment.
ABSTRACT
Longitudinally extensive transverse myelitis (LETM) may be associated with viral triggers, including both infections and vaccinations. We present a case of a healthy immunocompetent 33-year-old woman who developed a hemorrhagic LETM 2 weeks after seasonal influenza vaccination. Hemorrhagic LETM has not to our knowledge been reported after influenza vaccination. It may represent a forme fruste variant of acute hemorrhagic leukoencephalitis.
ABSTRACT
BACKGROUND: To compare the rate of surgical site infection (SSI) using surgeon versus patient report. MATERIALS AND METHODS: A prospective observational study of surgical patients in four hospitals within one private health-care system was performed. Surgeon report consisted of contacting the surgeon or staff 30 d after procedure to identify infections. Patient report consisted of telephone contact with the patient and confirmation of infections by a trained surgical clinical reviewer. RESULTS: Between February 2011 and June 2012, there were 2853 surgical procedures that met inclusion criteria. Surgeon-reported SSI rate was significantly lower (2.4%, P value < 0.01) compared with patient self-report (4.3%). The rate was lower across most infection subtypes (1.3% versus 3.0% superficial, 0.3% versus 0.5% organ/space) except deep incisional, most procedure types (2.3% versus 4.4% general surgery) except plastics, most patient characteristics (except body mass index < 18.5), and all hospitals. There were disagreements in 3.4% of cases; 74 cases reported by patients but not surgeons and 21 cases vice versa. Disagreements were more likely in superficial infections (59.8% versus 1.0%), C-sections (22.7% versus 17.7%), hospital A (22.7% versus 17.7%), age < 65 y (74.2% versus 68.3%), and body mass index ≥ 30 (54.2% versus 39.9%). CONCLUSIONS: Patient report is a more sensitive method of detection of SSI compared with surgeon report, resulting in nearly twice the SSI rate. Fair and consistent ways of identifying SSIs are essential for comparing hospitals and surgeons, locally and nationally.
Subject(s)
Quality Assurance, Health Care/methods , Quality Indicators, Health Care/statistics & numerical data , Self Report , Surgeons , Surgical Wound Infection/epidemiology , Adult , Aged , Aged, 80 and over , Female , Hawaii/epidemiology , Humans , Male , Middle Aged , Prospective StudiesABSTRACT
BACKGROUND: Inflammation may contribute to cardiovascular disease (CVD) among antiretrovirally suppressed HIV-infected individuals. We assessed relationships of monocyte, CD8 T-cell activation and plasma biomarkers to changes in carotid artery intima-media thickness (CIMT). METHODS: Longitudinal study of HIV-infected subjects ≥40 years and on stable antiretroviral therapy (ART) ≥3 months. Peripheral blood mononuclear cells were immunophenotyped by multiparameteric flow cytometry to quantify classical (CD14(++)CD16(-)), intermediate (CD14(++)CD16(+)), non-classical (CD14(low/+)CD16(++)) and transitional (CD14(+)CD16(-)) monocyte subsets and activated (CD38(+)HLA-DR(+)) CD8(+) T-cells at baseline. Plasma biomarkers were assessed by multiplex Luminex assay. High-resolution B-mode ultrasounds of right carotid arteries were obtained. Changes in CIMT over two years at the right common carotid artery (CIMTCCA) and right bifurcation (CIMTBIF) were outcome variables. RESULTS: We studied 50 subjects: 84% male, median age 49 (Q1, Q3; 46, 56) years, median CD4 count 461 (317, 578) cells/mm(3), and with HIV RNA ≤ 50 copies/mL in 84%. Change in CIMTBIF correlated with log values of baseline absolute count of non-classical monocytes (r = 0.37, p = 0.020), and with MCP-1 (r = 0.42, p = 0.0024) and TNF-α (r = 0.30, p = 0.036) levels. In multivariable linear regression, only non-classical monocytes and MCP-1 predicted the change in CIMTBIF, independent of Framingham Risk Score and baseline CIMTBIF. No correlation was noted between CD8 T-cell activation and CIMTBIF change. Monocyte subsets, CD8 T-cell activation, and biomarker concentrations were not correlated with changes in CIMTCCA. CONCLUSIONS: Our findings highlight the role of non-classical monocytes and MCP-1 in the progression of CIMTBIF in HIV-infected individuals on stable ART independent of traditional cardio-metabolic risk factors.
Subject(s)
Carotid Artery Diseases/diagnosis , Carotid Artery Diseases/etiology , Carotid Intima-Media Thickness , HIV Infections/complications , HIV Infections/immunology , Monocytes/immunology , Antiretroviral Therapy, Highly Active , Biomarkers , CD4 Lymphocyte Count , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Female , HIV Infections/drug therapy , HIV Infections/metabolism , Humans , Immunophenotyping , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Lymphocyte Activation/immunology , Male , Middle Aged , Monocytes/metabolism , Phenotype , PrognosisABSTRACT
Cross-sectional relationships were examined between regional brain volumes and mitochondrial DNA (mtDNA) 8-hydroxy-2-deoxyguanosine (8-oxo-dG) in peripheral blood mononuclear cells (PBMCs) of 47 HIV patients [mean age 51years; 81% with HIV RNA ≤50copies/mL] on combination antiretroviral therapy. The gene-specific DNA damage and repair assay measured mtDNA 8-oxo-dG break frequency. Magnetic resonance imaging was performed at 3T. Higher mtDNA 8-oxo-dG was associated with lateral ventricular enlargement and with decreased volumes of hippocampus, pallidum, and total subcortical gray matter, suggesting the involvement of systemic mitochondrial-specific oxidative stress in chronic HIV-related structural brain changes and cognitive difficulties. Clarification of the mechanism may provide potential therapeutic targets.
Subject(s)
Atrophy/pathology , DNA, Mitochondrial/chemistry , Deoxyguanosine/analogs & derivatives , Gray Matter/pathology , HIV Infections/complications , Hippocampus/pathology , Leukocytes, Mononuclear/pathology , 8-Hydroxy-2'-Deoxyguanosine , Adult , Atrophy/diagnostic imaging , Cross-Sectional Studies , DNA Damage , Deoxyguanosine/analysis , Female , Gray Matter/diagnostic imaging , Hippocampus/diagnostic imaging , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Oxidative Stress , Reactive Oxygen Species/toxicityABSTRACT
BACKGROUND: Persistent inflammation and immune activation has been hypothesized to contribute to increased prevalence of subclinical atherosclerosis and cardiovascular disease (CVD) risk in patients with chronic HIV infection. In this study, we examined the correlation of peripheral monocyte subsets and soluble biomarkers of inflammation to coronary artery calcium (CAC) progression, as measured by cardiac computed tomography scan. METHODS: We conducted a longitudinal analysis utilizing baseline data of 78 participants with HIV infection on stable antiretroviral therapy (ART) in the Hawaii Aging with HIV-Cardiovascular study who had available baseline monocyte subset analysis as well as CAC measurement at baseline and at 2-year follow up. Monocyte phenotypes were assessed from cryopreserved blood by flow cytometry and plasma was assayed for soluble biomarkers using antibody-coated beads in a high sensitivity Milliplex Luminex platform. Change in CAC over 2 years was analyzed as the primary outcome variable. RESULTS: Of all monocyte subsets and biomarkers tested, higher non-classical monocyte percentage (ρ = 0.259, p = 0.022), interleukin (IL)-6 (ρ = 0.311, p = 0.012), and monocyte chemoattractant protein (MCP)-1 (ρ = 0.524, p = <0.001) were significantly correlated to higher 2-year CAC progression in unadjusted Spearman's correlation. Non-classical monocyte percentage (ρ = 0.247, p = 0.039), and MCP-1 (ρ = 0.487, p = <0.001), remained significantly correlated to 2-year CAC progression, while IL-6 was not (ρ = 0.209, p = 0.120) after adjustment for age, hypertension, diabetes mellitus, total/HDL cholesterol ratio, smoking history, and BMI. CONCLUSION: The percentage of non-classical monocytes and plasma MCP-1 levels were independently associated with CAC progression and may be related to the progression of atherosclerosis and increased CVD risk associated with chronic HIV infection on stable ART.
Subject(s)
Calcium/metabolism , Cardiovascular Diseases/complications , Chemokine CCL2/blood , Coronary Vessels/physiopathology , HIV Infections/blood , Monocytes/cytology , Adult , Aging , Anti-Retroviral Agents/therapeutic use , Biomarkers/blood , Calcinosis/physiopathology , Cardiovascular Diseases/drug therapy , Comorbidity , Coronary Vessels/pathology , Disease Progression , Female , HIV Infections/complications , HIV Infections/drug therapy , HIV-1 , Hawaii , Humans , Inflammation , Longitudinal Studies , Male , Middle Aged , Phenotype , Tomography, X-Ray ComputedABSTRACT
The goal of early childhood vision screening is to detect subnormal vision and amblyopic risk factors that threaten visual development so that treatment can be initiated early to yield the highest benefit. Hand-held, portable, instrument-based vision screening devices can be used in children as young as 6 months of age. We assessed the feasibility of hand-held photoscreeners to screen for vision disorders in pre-school children in Hawai'i. A total of 137 preschool children on O'ahu in the "Tutu and Me"/Partners in Development program were screened at 6 different locations using the Plusoptix S12 hand-held photoscreener. Once technical issues were resolved, screening was fast and well tolerated. Possible vision abnormalities were found in 11 of the 137 children (8%). Poor compliance for follow-up with formal vision examination limited our ability to confirm these abnormalities. We conclude that photoscreening has the potential to facilitate early childhood vision screening in Hawai'i. The optimal referral criteria for use in Hawai'i will need to be determined after considering the age of the screening population and the available medical resources in Hawai'i. Early detection of treatable eye disorders has far-reaching benefits for the visual development and long term health and well-being of children. A comprehensive early childhood vision screening program in Hawai'i utilizing automated hand-held photoscreeners may have public health value. Such a program should integrate referral to an eye care professional for confirmation and management of vision disorders of at-risk children found on screening.
Subject(s)
Amblyopia/diagnosis , Diagnostic Equipment , Vision Screening/instrumentation , Child, Preschool , Cross-Sectional Studies , Female , Hawaii , Humans , Infant , MaleABSTRACT
This retrospective study evaluated the frequencies of symptoms associated with autonomic dysfunction in human immunodeficiency virus (HIV)-infected patients on stable combined antiretroviral therapy. Patients infected with HIV reported higher frequencies of dysautonomia symptoms compared with HIV-negative patients, particularly in the autonomic domains related to urinary, sleep, gastroparesis, secretomotor, pupillomotor, and male sexual dysfunction.
ABSTRACT
BACKGROUND: Cardiovascular fitness can improve autonomic function (AF) in human immunodeficiency virus (HIV)-infected individuals. METHODS: Cross-sectional study investigating relationship between AF and cardiovascular fitness in HIV+ individuals on antiretroviral therapy. Participants' (n=29) maximal oxygen consumption (VO2MAX) were assessed by graded exercise test and scaled allometrically, then divided into tertiles by fitness level (Unfit, Low-fit, and Moderately-fit). Heart rate variability (HRV) and the Autonomic Reflex Screen were used to assess AF. RESULTS: Median VO2MAX were 104.9, 130.5, and 150.2 mLâ¢kg-.67â¢min-1 for Unfit (n=10), Low-fit (n=10), and Moderately-fit (n= 9) groups respectively (p<0.05). Positive correlations were found between VO2MAX and HRV (Spearman's rho range 0.383 to 0.553) were found. Quantitative Sudomotor Axon Reflex Test (QSART) Distal Leg volumes was lower in Unfit compared to Low-fit (p=0.007) and Moderately-fit groups (p=0.018). Unfit QSART total volumes was lower than Moderately-fit (p=0.014). CONCLUSION: A positive relationship existed between AF and fitness levels. HIV+ individuals could benefit from improved fitness.
ABSTRACT
BACKGROUND: Association of lipoprotein particle size/number and HDL function with mitochondrial oxidative stress and function may underlie the excess cardiovascular (CVD) risk in HIV. METHODS AND RESULTS: Among HIV infected individuals on stable highly active antiretroviral therapy, we related standard and novel lipid measures [plasma total cholesterol, triglycerides, HDL-C, LDL-C, lipoprotein particle (-P) subclass size and number and HDL function (via cholesterol-efflux capacity)] with oxidative stress [peripheral blood mononuclear cell's mitochondrial-specific 8-oxo-deoxyguanine (8-oxo-dG)] and function markers [oxidative phosphorylation (OXPHOS) NADH dehydrogenase (Complex I) and cytochrome c oxidase (Complex IV) enzyme activities]. Multivariable-adjusted logistic and linear regression analyses were employed adjusting for age, gender, CD4 nadir, viral load, smoking, diabetes, HOMA-IR, hypertension and lipid medications. Among 150 HIV-infected persons (mean age 52 years, 12% women, median CD4 count 524 cell/mm3), low HDL-C and high total cholesterol/HDL-C ratio were related to PBMC 8-oxo-deoxyguanine (p = 0.01 and 0.02 respectively). Large HDL-P and HDL-P size were inversely related to PBMC 8-oxo-deoxyguanine (p = 0.04). Small LDL-P (p = 0.01) and total LDL-P (p = 0.01) were related to decreased OXPHOS Complex I activity. LDL-P was related to decreased OXPHOS Complex IV activity (p = 0.02). Cholesterol efflux capacity was associated with increased OXPHOS Complex IV activity. CONCLUSIONS: HDL concentration and particle size and number are related to decreased PBMC mitochondrial oxidative stress whereas HDL function is positively related to mitochondrial oxidative function. The association we find between atherogenic lipoprotein profile and increased oxidative stress and function suggests these pathways may be important in the pathogenesis of cardiometabolic disease in HIV disease.
Subject(s)
Cholesterol/chemistry , HIV Infections/blood , Lipoproteins, HDL/blood , Lipoproteins, LDL/blood , Mitochondria/metabolism , Oxidative Stress , Adult , Aged , Atherosclerosis/blood , Blood Glucose , Cholesterol/blood , Cohort Studies , Female , HIV Infections/physiopathology , Humans , Inflammation , Leukocytes, Mononuclear/cytology , Lipoproteins/chemistry , Magnetic Resonance Spectroscopy , Male , Middle Aged , Oxygen/chemistry , Particle Size , PhosphorylationABSTRACT
There is an increase in the cardiovascular disease (CVD) morbidity in individuals infected with HIV that may be due to inflammatory lipid modulation not captured by traditional lipid measures. The objective of this study was to perform advanced lipoprotein phenotyping inclusive of the high-density lipoprotein (HDL) cholesterol efflux capacity and lipoprotein particle concentration and size in a well-phenotyped group of 118 patients infected with HIV. We used simple and multivariable analyses to determine the associations between advanced lipoprotein parameters and known cardiometabolic risk factors. Participants were on stable antiretroviral therapy (ART) and had benign traditional lipid panels [median total cholesterol, low-density lipoprotein (LDL)-C, HDL-C, and triglycerides of 178 mg/dl, 108 mg/dl, 44 mg/dl, and 122.5 mg/dl, respectively]. However, advanced lipoprotein phenotyping demonstrated an elevation of LDL particle number (median of 1,233 nmol/liter) and a decrease in LDL size (median of 20.4 nm), along with a decrease in protective, large HDL particles (median of 3.15 µmol/liter) and reduced HDL cholesterol efflux capacity in comparison to controls of other studies. HDL cholesterol efflux capacity was associated with HDL levels (ß=0.395, p<0.001), small LDL particle concentration (ß=-0.198, p=0.031), insulin sensitivity by the Matsuda index (ß=0.218, p=0.029), and the Framingham Risk Score (ß=-0.184, p=0.046). We demonstrate an atherogenic lipoprotein profile by NMR spectroscopy and HDL efflux measurement in a group of HIV-infected patients on stable ART with normal lipid panels.
Subject(s)
Anti-Retroviral Agents/therapeutic use , HIV Infections/drug therapy , HIV Infections/pathology , Lipoproteins/blood , Atherosclerosis/epidemiology , Cohort Studies , Female , HIV Infections/complications , Humans , Longitudinal Studies , Magnetic Resonance Spectroscopy , Male , Middle Aged , Risk AssessmentABSTRACT
BACKGROUND: Rates of insulin resistance are increased in HIV-infected patients on stable antiretroviral therapy (ART). Such increase may partially be due to HIV-induced immune dysregulation involving monocytes (MO) and its subsets. MATERIALS AND METHODS: Cross-sectional analysis of 141 HIV-infected subjects age ≥ 40 years on stable ART. Homeostatic model assessment-insulin resistance (HOMA-IR) and rates of metabolic syndrome were calculated. Subjects were classified by fasting glucose and oral glucose tolerance test (OGTT) into clinical diabetes categories. Multi-parametric flow cytometry was used to determine MO subset percentages: [classical (CD14(++)CD16(-)), intermediate (CD14(++)CD16(+)), non-classical (CD14(low/+)CD16(++)), and a recently identified fourth (CD14(low/+)CD16(-)) 'transitional' MO subset] and percentage of activated (CD38(+)HLA-DR(+)) CD8 T cells. Absolute levels of cells were calculated using clinical CBC and T cell subset data. Multiple plasma soluble biomarkers were assessed by Luminex technology. RESULTS: Median age 50 years, CD4 count (percent) 505 cells/µL (29%), and 89% male. Total MO (r=-0.23, p=0.006) and classical and non-classical MO subsets correlated negatively with CD4 percent. No correlations were seen with CD4 count as absolute values. Log-total MO and log-classical MO predicted HOMA-IR independently of HIV immuno-virologic and diabetes risk factors (ß=0.42, p=0.02 and ß=0.35, p=0.02, respectively) and were increased in subjects with metabolic syndrome (p=0.03 and p=0.05 respectively). Total and/or subset MO levels correlated with multiple soluble plasma biomarkers including CRP, IL-6, MMP-9, MPO, SAA, SAP and tPAI-1, with tPAI-1 independently predicting HOMA-IR (ß=0.74, p<0.001). CONCLUSIONS: MO levels increase with worsening HIV immune dysregulation as assessed by CD4 percent. CD4 percent may provide additional information about MO and metabolic risk in this population beyond absolute values. MO, and specifically classical MO, may contribute to insulin resistance and metabolic syndrome during chronic HIV infection. Multiple soluble plasma biomarkers including tPAI-1 increase with increase in MO. Levels of tPAI-1 independently predict the development of insulin resistance.
Subject(s)
HIV Infections/immunology , HIV Infections/metabolism , Insulin Resistance/immunology , Monocytes/immunology , Age Factors , Biomarkers/blood , Biomarkers/metabolism , Blood Glucose , Cross-Sectional Studies , Diabetes Mellitus/diagnosis , Diabetes Mellitus/immunology , Diabetes Mellitus/metabolism , Female , Humans , Immunophenotyping , Lymphocyte Count , Male , Metabolic Syndrome/immunology , Metabolic Syndrome/metabolism , Middle Aged , Monocytes/metabolism , Risk Factors , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolismABSTRACT
Background. Given the dementia epidemic and the increasing cost of healthcare, there is a need to assess the economic benefit of community based dementia screening programs. Materials and Methods. Markov model simulations were generated using data obtained from a community based dementia screening program over a one-year period. The models simulated yearly costs of caring for patients based on clinical transitions beginning in pre dementia and extending for 10 years. Results. A total of 93 individuals (74 female, 19 male) were screened for dementia and 12 meeting clinical criteria for either mild cognitive impairment (n = 7) or dementia (n = 5) were identified. Assuming early therapeutic intervention beginning during the year of dementia detection, Markov model simulations demonstrated 9.8% reduction in cost of dementia care over a ten-year simulation period, primarily through increased duration in mild stages and reduced time in more costly moderate and severe stages. Discussion. Community based dementia screening can reduce healthcare costs associated with caring for demented individuals through earlier detection and treatment, resulting in proportionately reduced time in more costly advanced stages.
ABSTRACT
HIV infection causes systemic immune inflammation, and increases the risk for cardiovascular (CVD) disease even among those on virologically suppressive anti-retroviral treatment (ART). We performed a biostatistical analysis and screen of candidate cellular and plasma biomarkers for association with carotid artery intima-media thickness (CIMT), independent of traditional CVD risk factors such as age, gender, systolic blood pressure (SBP), lipid levels, smoking and diabetes. We conducted a multi-stage analysis based on a cross-sectional study of CVD risk in HIV-infected subjects age >45 years on ART for >6 months. The goal of this analysis was to identify candidate cellular and plasma biomarkers of CIMT in HIV-1 infected adults. We further sought to determine if these candidate biomarkers were independent of traditional CVD risk factors previously identified in HIV negative adults. High-resolution B-mode ultrasound images of the right common carotid common artery (CCA) were obtained. Plasma soluble inflammatory mediators, cytokines and chemokines were detected. Monocytes were defined by CD14/CD16 expression, and CD8+ T-cell activation by CD38/HLA-DR expression. Subjects were a median of 49.5 years old, 87% male, had a CIMT of 0.73 mm, FRS of 6%, a median viral load of 48 copies/mL, and CD4+ T cell count of 479 cells/µL. Soluble VCAM-1, and expansion of CD14dimCD16- monocytes each associated with higher CIMT independently of age and SBP. These factors are distinct components of a shared atherogenic process; 1) vascular endothelial molecular expression and 2) vascular monocytes that enter into the vascular endothelium and promote atherosclerotic plaque.