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Older persons with HIV (PWH) experience high rates of cognitive impairment and frailty, and accelerated decline in physical function compared with the general population. Metformin use has been associated with beneficial effects on cognitive and physical function among older adults without HIV. The relationship between metformin use on these outcomes in PWH has not been evaluated. AIDS Clinical Trials Group (ACTG) A5322 is an observational cohort study of older PWH with annual assessments for cognition and frailty, including measures of physical function (e.g., gait speed and grip strength). Participants with diabetes who were prescribed antihyperglycemic medications were included in this analysis to evaluate the association between metformin and functional outcomes. Cross-sectional, longitudinal, and time-to-event models were used to evaluate the relationship between metformin exposure with cognitive, physical function, and frailty outcomes. Ninety-eight PWH met inclusion criteria and were included in at least one model. No significant associations between metformin use, frailty, physical, or cognitive function were noted in unadjusted or adjusted cross-sectional, longitudinal, or time-to-event models (p > .1 for all models). This study is the first to examine the association between metformin use on functional outcomes among older PWH. Although it did not ascertain significant associations between metformin use and functional outcomes, our small sample size, restriction to persons with diabetes, and lack of randomization to metformin therapy were limitations. Larger randomized studies are needed to determine whether metformin use has beneficial effects on cognitive or physical function in PWH. Clinical Trial Registration numbers: 02570672, 04221750, 00620191, and 03733132.

BackgroundPersons with HIV (PWH) have an increased risk of cardiovascular disease (CVD) compared to HIV-seronegative individuals (SN). Inflammation contributes to this risk but the role of lipid mediators, with central roles in inflammation, in HIV infection remain to be established; further aspirin reduces CVD risk in the general population through production of some of these anti-inflammatory lipid mediators, but they have not been studied in PWH.MethodsWe evaluated the relationship between plasma lipid mediators (i.e. 50 lipid mediators including classic eicosanoids and specialized pro-resolving mediators (SPMs)) and HIV status; and the impact of aspirin in PWH on regulating these autacoids. Plasma samples were obtained from 110 PWH receiving antiretroviral therapy (ART) from a randomized trial of aspirin (ACTG-A5331) and 107 matched SN samples (MACS-WIHS Combined Cohort).FindingsPWH had lower levels of arachidonic acid-derived pro-inflammatory prostaglandins (PGs: PGE2 and PGD2) and thromboxanes (Tx: TxB2), and higher levels of select pro-resolving lipid mediators (e.g. RvD4 and MaR2n-3 DPA) compared to SN. At the interval tested, aspirin intervention was observed to reduced PGs and Tx, and while we did not observe an increase in aspirin triggered mediators, we observed the upregulation of other SPM in aspirin treated PWH, namely MaR2n-3 DPA.InterpretationTogether these observations demonstrate that plasma lipid mediators profiles, some with links to systemic inflammation and CVD risk, become altered in PWH. Furthermore, aspirin intervention did not increase levels of aspirin-triggered pro-resolving lipid mediators, consistent with other reports of an impaired aspirin response in PWH.FundingNIH.

BackgroundFeminizing hormonal therapy (FHT) and HIV potentially alter cardiovascular disease (CVD) risk in transgender women (TW).MethodsTW were enrolled in Los Angeles, California and Houston, Texas and frequency-matched to Multicenter AIDS Cohort Study cisgender men (CM) on age, race, substance use, and abacavir use. Biomarkers of CVD risk and inflammation were assessed via ELISA. Wilcoxon rank sum and Fisher's exact tests compared TW and CM. Multivariable linear regression assessed factors associated with biomarker concentrations.ResultsTW (HIV+ n  = 75, HIV- n  = 47) and CM (HIV+ n  = 40, HIV- n  = 40) had mean age 43-45 years; TW/CM were 90%/91% non-Hispanic Black, Hispanic, or Multiracial, 26%/53% obese, and 34%/24% current smokers; 67% of TW were on FHT. Among people with HIV (PWH), TW had higher median extracellular newly-identified receptor for advanced glycation end-products (EN-RAGE), lipoprotein-associated phospholipase A2 (LpPLA2), oxidized low-density lipoprotein (oxLDL), soluble tumor necrosis factor receptor type (sTNFR) I/II, interleukin (IL)-8 and plasminogen activator inhibitor (PAI)-1, but lower soluble CD14, von Willebrand factor (vWF) and endothelin (ET)-1 levels than CM. Findings were similar for participants without HIV (all P

ObjectivesPeople with HIV (PWH) are at increased risk for premature cardiovascular disease (CVD). Clonal hematopoiesis is a common age-related condition that may be associated with increased CVD risk. The goal of this study was to determine the prevalence of clonal hematopoiesis and its association with chronic inflammation and CVD in PWH.DesignCross-sectional study utilizing archived specimens and data from 118 men (86 PWH and 32 HIV-uninfected) from the Baltimore-Washington DC center of the Multicenter AIDS Cohort Study (MACS) who had had coronary computed tomography angiography (CTA) and measurement of 34 serologic inflammatory biomarkers.MethodsClonal hematopoiesis was assessed on peripheral blood mononuclear cells utilizing targeted error-corrected next generation sequencing (NGS) focused on 92 genes frequently mutated in hematologic malignancies. Clinical and laboratory data were obtained from the MACS database.ResultsClonal hematopoiesis with a variant allele frequency (VAF) greater than 1% was significantly more common in PWH [20/86 (23.3%)] than in HIV-uninfected men [2/32 (6.3%)] ( P  = 0.035). PWH with clonal hematopoiesis (VAF > 1%) were more likely to have coronary artery stenosis of at least 50% than those without clonal hematopoiesis [6/20 (30%) vs. 6/64 (9%); P  = 0.021]. Presence of clonal hematopoiesis was not significantly associated with serological inflammatory markers, except for significantly lower serum leptin levels; this was not significant after adjustment for abdominal or thigh subcutaneous fat area.ConclusionClonal hematopoiesis was more common in PWH and among PWH was associated with the extent of coronary artery disease. Larger studies are needed to further examine the biological and clinical consequences of clonal hematopoiesis in PWH.

Background and aimsPeople living with HIV (HIV+) are surviving longer due to effective antiretroviral therapy. Cardiovascular disease is a leading cause of non-AIDS related clinical events. We determined HIV-related factors associated with coronary artery stenosis progression.MethodsWe performed serial coronary CT angiography among HIV+ and HIV-uninfected (HIV-) men in the Multicenter AIDS Cohort Study. The median inter-scan interval was 4.5 years. Stenosis was graded as 0, 1-29, 30-49, 50-69 or ≥70%. Progression was defined as an increase ≥2 categories. Suppressed HIV infection was consistent viral loads 1 viral load >500 copies/ml demonstrated greatest stenosis progression (RR 3.01; 95% CI, 1.53-4.92, p = 0.001 compared with HIV- men). Suppressed HIV+ men with suboptimal antiretroviral adherence had greater stenosis progression (RR 1.91; 95% CI 1.12-3.24, p = 0.02) than HIV + suppressed men with optimal adherence.ConclusionsCoronary artery stenosis progression was associated with suboptimal HIV RNA suppression and antiretroviral therapy adherence. Effective ongoing HIV virologic suppression and antiretroviral therapy adherence may mitigate risk for coronary disease events among people living with HIV.

BackgroundThe adipokines leptin and adiponectin, produced primarily by adipose tissue, have diverse endocrine and immunologic effects, and circulating levels reflect adipocyte lipid content, local inflammation, and tissue composition. We assessed relationships between changes in regional fat depots, leptin and adiponectin levels, and metabolic and inflammatory markers over 96 weeks in the AIDS Clinical Trials Group (ACTG) A5260s metabolic substudy of the A5257 randomized trial of tenofovir disoproxil fumarate/emtricitabine plus atazanavir/ritonavir, darunavir/ritonavir, or raltegravir among treatment-naive persons with human immunodeficiency virus (PWH).MethodsFat depots were measured using dual-energy absorptiometry and abdominal computed tomographic imaging at treatment initiation and 96 weeks later. Serum leptin and adiponectin, homeostatic model assessment of insulin resistance (HOMA-IR), and high-sensitivity C-reactive protein (hsCRP) were measured at the same timepoints. Multivariable regression models assessed relationships between fat depots, adipokines, HOMA-IR, and hsCRP at week 96.ResultsTwo hundred thirty-four participants maintained viral suppression through 96 weeks (90% male, 29% black, median age 36 years). Serum leptin increased over 96 weeks (mean change 22%) while adiponectin did not (mean change 1%), which did not differ by study arm. Greater trunk, limb, and abdominal subcutaneous and visceral fat were associated with higher HOMA-IR and hsCRP at 96 weeks, but serum leptin level was a stronger determinant of these endpoints using a mediation model approach. A similar mediating effect was not observed for adiponectin.ConclusionsHigher circulating leptin is associated with greater HOMA-IR and hsCRP independent of fat depot size, suggesting that greater adipocyte lipid content may contribute to impaired glucose tolerance and systemic inflammation among PWH starting antiretroviral therapy.

BackgroundTenofovir disoproxil fumarate-containing pre-exposure prophylaxis (PrEP) has been associated with decreases in bone mineral density (BMD), but the bone effects of other non-tenofovir disoproxil fumarate candidate PrEP regimens are not well described.MethodsThe HPTN 069/ACTG A5305 study randomized 406 US cisgender men and transgender women, and 188 cisgender women at risk for HIV infection to one of four double-blinded regimens: (i) maraviroc; (ii) maraviroc + emtricitabine; (iii) maraviroc + tenofovir disoproxil fumarate; or (iv) tenofovir disoproxil fumarate + emtricitabine. BMD was measured in a subset of participants at the lumbar spine (LS) and hip by dual-energy X-ray absorptiometry (DXA) at baseline and 48 weeks. Percentage change in LS and hip BMD was compared between the tenofovir disoproxil fumarate- and non-tenofovir disoproxil fumarate-containing arms by Wilcoxon rank-sum tests and multiple linear regression adjusting for sex, race and baseline BMI.ResultsAt baseline (n = 307), the median age was 33 years, 56% male and 43% black. At the hip, the median percentage change in BMD at 48 weeks was -1.05% in the tenofovir disoproxil fumarate arms and 0.0% in the non-tenofovir disoproxil fumarate arms (between group P = 0.001). No interaction by sex was observed. The median percentage change in LS BMD was not different between arms.ConclusionsTenofovir disoproxil fumarate-containing PrEP was associated with significantly greater bone loss compared with maraviroc ± emtricitabine PrEP at the hip, but not the LS. The BMD changes at the hip were similar in magnitude in men and women.

ObjectiveThe aim of this study was to assess the association of cardiovascular disease (CVD) risk scores and coronary artery plaque (CAP) progression in HIV-infected participants.MethodsWe studied men with and without HIV-infection enrolled in the Multicenter AIDS Cohort Study (MACS) CVD study. CAP at baseline and follow-up was assessed with cardiac computed tomography angiography (CCTA). We examined the association between baseline risk scores including pooled cohort equation (PCE), Framingham risk score (FRS), and Data collect of Adverse effects of anti-HIV drugs equation (D:A:D) and CAP progression.ResultsWe studied 495 men (211 HIV-uninfected, 284 HIV-infected). The adjusted odds ratio (aOR) of total plaque volume (TPV) and noncalcified plaque volume (NCPV) progression in the highest relative to lowest tertile was 9.4 [95% confidence interval (95% CI) 2.4-12.1, P

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) symptoms among people living with HIV (PLWH) are not well described.SettingLongitudinal survey within the MACS/WIHS Combined Cohort Study (MWCCS) of PLWH compared with similar HIV-seronegative (SN) individuals.MethodsTelephone-administered survey of MWCCS participants at 13 clinical research sites across the United States addressing COVID-19 symptoms, SARS-CoV-2 testing, and pandemic impact on social distancing and antiretroviral therapy (ART) use. Primary data collection occurred during May (wave 1), June-July (wave 2), and August-September, 2020 (wave 3).ResultsOne-third of MWCCS participants were tested for SARS-CoV-2 infection; 10% was tested ≥2 times. Similar proportions of PLWH and SN participants were tested, but SARS-CoV-2 positivity was higher among PLWH than among SN individuals (9.4% vs 4.8%, P = 0.003). Odds of SARS-CoV-2 positivity remained higher among PLWH after adjusting for age, sex, race/ethnicity, and study site (adjusted odds ratio = 2.0, 95% confidence interval = 1.2 to 3.2). SARS-CoV-2 positivity was not associated with CD4 cell counts among PLWH. Among SARS-CoV-2 positive participants, 9% had no symptoms, 7% had 1-2 mild symptoms, and 84% had ≥3 symptoms. Most of the (98%) participants reported physical distancing during all survey waves; self-reported ART adherence among PLWH was not adversely affected during the pandemic compared with the previous year (similar adherence in 89% of participants, improved in 9% of participants, and decreased in 2% of participants).ConclusionsDespite similar SARS-CoV-2 testing and physical distancing profiles by HIV serostatus among MWCCS participants, PLWH who reported SARS-CoV-2 testing were more likely to have a positive test result. Additional studies are needed to determine whether and why PLWH are at increased risk of SARS-CoV-2 infection.

BackgroundWe have previously shown that the initiation of antiretroviral therapy (ART) is associated with a decrease in skeletal muscle density (greater fat accumulation), suggesting that gains in lean body mass seen in many ART studies may reflect gains in low quality, fatty muscle. Here, we explore whether skeletal muscle density and area are associated with markers of inflammation and immune activation.MethodsART-naïve people with HIV were randomized to raltegravir or ritonavir-boosted atazanavir or darunavir, each with tenofovir disoproxil fumarate/emtricitabine. Abdominal computed tomography scans from baseline and week 96 were reanalyzed for psoas density and area and correlations explored with inflammation [interleukin-6 (IL-6) and high-sensitivity C-reactive protein] and immune activation [soluble CD14 (sCD14), soluble CD163 (sCD163), and %CD38+HLADR+ on CD4+ or CD8+ T cells].ResultsTwo hundred twenty-two participants had available inflammation/immune activation markers and paired computed tomography scans. At baseline, lower psoas density (greater fat) correlated with higher IL-6 (r = -0.26, P < 0.001) and sCD163 (r -0.15, P = 0.03) and lower lean psoas area correlated with higher IL-6, high-sensitivity C-reactive protein, sCD14, sCD163, and %CD38+HLADR+ on CD4+ T cells (r = -0.30-0.13; all P ≤ 0.05). From baseline to week 96, greater percent decrease in total psoas density (more fat) correlated with greater increase in IL-6 (r = -0.14; P = 0.04); greater % decrease in lean psoas area correlated greater increases in IL-6, sCD14, sCD163, and %CD38+HLADR+ on CD8+ T cells (r = -0.15 to -0.18; all P < 0.04).ConclusionsGreater fat infiltration within the psoas muscle (lower density) and greater loss in lean psoas muscle area were associated with higher inflammation and immune activation, which may portend important effects on muscle function and cardiometabolic risk.

The number of people with HIV (PWH) aged 50 years or older continues to steadily increase. The convergence of age- and HIV-related complications in these individuals presents a challenge for both patients and clinicians alike. New findings continue to emerge, as numerous researchers evaluate the combined impact of these two factors on quality of life, physiological systems, and mental health in PWH. Since its first occurrence in 2009, the International Workshop on HIV and Aging has served as a multidisciplinary meeting to share basic biomedical data, clinical trial results, treatment strategies, and epidemiological recommendations, toward better understanding and outcomes among like-minded scientific professionals. In this article, we share a selection of key findings presented in plenary talks at the 11th Annual International Workshop on HIV and Aging, held virtually from September 30, 2020 to October 2, 2020. We will also address the future directions of HIV and aging research, to further assess how the aging process intersects with chronic HIV.

BackgroundDespite advances in antiretroviral therapy (ART), people living with human immunodeficiency virus (HIV) continue to be at increased risk of cardiometabolic complications compared to HIV-uninfected individuals. Advanced glycation end products (AGEs) are implicated in the development and progression of cardiometabolic complications in the general population. Their role in HIV remains unclear.MethodsACTG A5260s is a prospective open-label randomized trial in which ART-naive people living with HIV were randomized to tenofovir disoproxil fumarate /emtricitabine plus atazanavir/ritonavir, darunavir/ritonavir, or raltegravir over 96 weeks. Changes in circulating AGEs with ART initiation were assessed, and linear regression was used to examine the associations between serum AGEs with carotid intima-media thickness (cIMT), visceral and subcutaneous adipose tissue, total fat, lean mass, body mass index, insulin resistance, leptin, and adiponectin.ResultsOverall, 214 participants were included. Ninety percent were male, 48% were White, the median age was 36 years, median HIV-1 RNA was 4.58 log10 copies/mL, and median CD4 count was 338 cells/µL. Most AGEs remained relatively unchanged following 96 weeks of ART initiation, except for methylglyoxal-derived hydroimidazolone 1 (MG-H1), which increased following 96 weeks of ART (mean fold change, 1.15 [95% confidence interval, 1.02-1.30]). No differences were detected across ART regimens. Increases in AGE levels over time were associated with worsening body fat composition measures, insulin resistance, and cIMT, even after adjusting for clinically relevant factors.ConclusionsAGE levels did not decrease following ART initiation. Most AGE levels remained stable, except for MG-H1, which increased. In people with HIV on ART, the accumulation of circulating AGEs over time appears to be independently associated with worsening cardiometabolic biomarkers.Summary: Antiretroviral therapy (ART) does not appear to be effective in reducing advanced glycation end product (AGE) levels. On the contrary, AGE levels seem to increase following ART initiation. Accumulation of AGEs was found to be independently associated with cardiometabolic complications in treated people living with HIV.

Chronic inflammation, including among people with HIV (PWH), elevates immune cell expression of lymphocyte activation gene 3 (LAG3); however, low plasma LAG3 predicts cardiovascular disease (CVD) events in the general population. The associations among LAG3 plasma levels, subclinical atherosclerosis, inflammation, and HIV infection have not been well described. We measured plasma LAG3 in 704 men with and without HIV from the multicenter AIDS cohort study, who underwent coronary computed tomography angiography. HIV serostatus was not independently associated with LAG3 after adjustment for sociodemographic and CVD risk factors. Current smoking status and African American race were associated with lower LAG3, and age and sTNFαRI concentration were associated with greater LAG3. LAG3 was not associated with coronary artery stenosis. Thus, no difference was found in plasma LAG3 concentration by HIV serostatus, and no association between LAG3 and subclinical coronary atherosclerosis in men with and without HIV was observed.

BackgroundNeurocognitive impairment (NCI) and frailty are more prevalent among persons with HIV (PWH) compared to those without HIV. Frailty and NCI often overlap with one another. Whether frailty precedes declines in neurocognitive function among PWH or vice versa has not been well-established.SettingAIDS Clinical Trials Group (ACTG) A5322 is an observational cohort study of older PWH. Participants undergo annual assessments for NCI and frailty.MethodsACTG A5322 participants who developed NCI as indexed by tests of impaired executive functioning and processing speed during the first 3 years were compared to persons who maintained normal cognitive function; those who demonstrated resolution of NCI were compared to those who had persistent NCI. Participants were similarly compared by frailty trajectory. We fit multinomial logistic regression models to assess associations between baseline covariates (including NCI) and frailty, and associations between baseline covariates (including frailty) and NCI.Results929 participants were included with a median age of 51 years (IQR 46-56). At study entry, 16% had NCI and 6% were frail. Over 3 years, 6% of participants developed NCI; 5% developed frailty. NCI was associated with development of frailty (odds ratio [OR]=2.06; 95% confidence interval [CI]=0.94, 4.48; p=0.07). Further adjustment for confounding strengthened this association (OR=2.79; 95% CI=1.21, 6.43; p=0.02). Baseline frailty however was not associated with NCI development.ConclusionsNCI was associated with increased risk of frailty, but frailty was not associated with development of NCI. These findings suggest that the presence of NCI in PWH should prompt monitoring for the development of frailty and interventions to prevent frailty in this population.

BackgroundSafe and effective long-acting injectable agents for preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection are needed to increase the options for preventing HIV infection.MethodsWe conducted a randomized, double-blind, double-dummy, noninferiority trial to compare long-acting injectable cabotegravir (CAB-LA, an integrase strand-transfer inhibitor [INSTI]) at a dose of 600 mg, given intramuscularly every 8 weeks, with daily oral tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) for the prevention of HIV infection in at-risk cisgender men who have sex with men (MSM) and in at-risk transgender women who have sex with men. Participants were randomly assigned (1:1) to receive one of the two regimens and were followed for 153 weeks. HIV testing and safety evaluations were performed. The primary end point was incident HIV infection.ResultsThe intention-to-treat population included 4566 participants who underwent randomization; 570 (12.5%) identified as transgender women, and the median age was 26 years (interquartile range, 22 to 32). The trial was stopped early for efficacy on review of the results of the first preplanned interim end-point analysis. Among 1698 participants from the United States, 845 (49.8%) identified as Black. Incident HIV infection occurred in 52 participants: 13 in the cabotegravir group (incidence, 0.41 per 100 person-years) and 39 in the TDF-FTC group (incidence, 1.22 per 100 person-years) (hazard ratio, 0.34; 95% confidence interval, 0.18 to 0.62). The effect was consistent across prespecified subgroups. Injection-site reactions were reported in 81.4% of the participants in the cabotegravir group and in 31.3% of those in the TDF-FTC group. In the participants in whom HIV infection was diagnosed after exposure to CAB-LA, INSTI resistance and delays in the detection of HIV infection were noted. No safety concerns were identified.ConclusionsCAB-LA was superior to daily oral TDF-FTC in preventing HIV infection among MSM and transgender women. Strategies are needed to prevent INSTI resistance in cases of CAB-LA PrEP failure. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 083 ClinicalTrials.gov number, NCT02720094.).

BackgroundStudies suggest lower risk of breast cancer in women with HIV versus without HIV. These estimates may be biased by lower life expectancy and younger age distribution of women with HIV. Our analysis evaluated this bias and characterized secular trends in breast cancer among women with HIV initiating antiretroviral therapy. We hypothesized breast cancer risk would increase over time as mortality decreased.SettingWomen with HIV prescribed antiretroviral therapy in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) from 1997 through 2016.MethodsWe estimated breast cancer hazard (cause-specific hazard ratios) and cumulative incidence accounting for competing risks (subdistribution hazard ratios) to assess changes in breast cancer risk over time. This was assessed overall (1997-2016) and within/across calendar periods. Analyses were adjusted for race/ethnicity and inverse probability weighted for cohort. Cumulative incidence was graphically assessed by calendar period and race/ethnicity.ResultsWe observed 11,587 women during 1997-2016, contributing 63 incident breast cancer diagnoses and 1,353 deaths [73,445 person-years (median follow-up = 4.5 years)]. Breast cancer cumulative incidence was 3.2% for 1997-2016. We observed no secular trends in breast cancer hazard or cumulative incidence. There were annual declines in the hazard and cumulative incidence of death (cause-specific hazard ratios and subdistribution hazard ratios: 0.89, 95% confidence interval: 0.87 to 0.91) which remained within and across calendar periods.ConclusionsThese findings contradict the hypothesis of increasing breast cancer risk with declining mortality over time among women with HIV, suggesting limited impact of changing mortality on breast cancer risk. Additional inquiry is merited as survival improves among women with HIV.

IntroductionAge and vitamin D levels may affect symptom burden in chronic obstructive pulmonary disease (COPD). We used the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) to determine independent associations between vitamin D levels and COPD symptoms in different age strata.MethodsSerum 25-hydroxy (OH)-vitamin D levels were modeled continuously and categorically (65 years old), multivariable modeling was performed to identify relationships between 25-OH-vitamin D levels and the COPD Assessment Test (CAT), the modified Medical Research Council score (mMRC), the St George's Respiratory Questionnaire (SGRQ) total and subdomain scores, the Veterans' Specific Activity Questionnaire, and the 6-minute walk test distance.ResultsInIn the middle-aged group, each 5 ng/ml higher 25-OH-vitamin D level was independently associated with more favorable CAT score (-0.35 [-0.67 to -0.03], P=0.03), total SGRQ (-0.91 [-1.65 to -0.17]; P=0.02), and the SGRQ subdomains (Symptoms:-1.07 [-1.96 to -0.18], P=0.02; Impact: -0.77 [-1.53 to -0.003], P=0.049; Activity: -1.07 [-1.96 to -0.18], P=0.02). These associations persisted after the addition of comorbidity score, reported vitamin D supplementation, outdoor time, or season of blood draw to models. No associations were observed between 25-OH-vitamin D levels and symptom scores in the older age group.DiscussionWhen controlled for clinically relevant covariates, higher 25-OH-vitamin D levels are associated with more favorable respiratory-specific symptoms and quality-of-life assessments in middle-age but not older COPD individuals. Study of the role of vitamin D supplementation in the symptom burden of younger COPD patients is needed.

Background We aimed to investigate whether there are differences in cardiac structure and systolic and diastolic function evaluated by 2-dimensional echocardiography among men living with versus without HIV in the era of combination antiretroviral therapy. Methods and Results We performed a cross-sectional analysis of 1195 men from MACS (Multicenter AIDS Cohort Study) who completed a transthoracic echocardiogram examination between 2017 and 2019. Associations between HIV serostatus and echocardiographic indices were assessed by multivariable regression analyses, adjusting for demographics and cardiovascular risk factors. Among men who are HIV+, associations between HIV disease severity markers and echocardiographic parameters were also investigated. Average age was 57.1±11.9 years; 29% of the participants were Black, and 55% were HIV+. Most men who were HIV+ (77%) were virally suppressed; 92% received combination antiretroviral therapy. Prevalent left ventricular (LV) systolic dysfunction (ejection fraction

Background We aimed to investigate whether there are differences in cardiac structure and systolic and diastolic function evaluated by 2-dimensional echocardiography among men living with versus without HIV in the era of combination antiretroviral therapy. Methods and Results We performed a cross-sectional analysis of 1195 men from MACS (Multicenter AIDS Cohort Study) who completed a transthoracic echocardiogram examination between 2017 and 2019. Associations between HIV serostatus and echocardiographic indices were assessed by multivariable regression analyses, adjusting for demographics and cardiovascular risk factors. Among men who are HIV+, associations between HIV disease severity markers and echocardiographic parameters were also investigated. Average age was 57.1±11.9 years; 29% of the participants were Black, and 55% were HIV+. Most men who were HIV+ (77%) were virally suppressed; 92% received combination antiretroviral therapy. Prevalent left ventricular (LV) systolic dysfunction (ejection fraction

BackgroundAdipose tissue (AT) alterations are common in people living with human immunodeficiency virus (PLWH). Decreases in AT density suggest disrupted adipocyte function/hypertrophy. We assessed changes in AT density after antiretroviral therapy (ART) initiation and associations with immunometabolic parameters.MethodsIn a prospective randomized clinical trial of ART initiation, L4-L5 abdominal CT scans measured subcutaneous AT (SAT) and visceral AT (VAT) area and density in treatment-naive PLWH randomized to tenofovir-emtricitabine plus ritonavir-boosted atazanavir, ritonavir-boosted darunavir, or raltegravir. Linear regression models compared week 0 and week 96 levels, and 96-week changes, in SAT and VAT density (in Hounsfield units [HU]). Spearman correlations assessed relationships between AT density and immunometabolic parameters.ResultsOf the 228 participants, 89% were male and 44% were white non-Hispanic. Median age was 36 years, baseline HIV-1 RNA was 4.6 log10 copies/mL, and CD4+ T-cell count was 344 cells/μL. Over 96 weeks, SAT and VAT HU decreased significantly in all arms. Less dense week 96 SAT and VAT density correlated with higher high-density lipoprotein (HDL) cholesterol and adiponectin (r = 0.19-0.30) levels and lower interleukin 6, non-HDL cholesterol, triglyceride, leptin, and homeostatic model assessment of insulin resistance (r = -0.23 to -0.68) levels at week 96 after adjusting for baseline CD4+ T-cell count, HIV-1 RNA, and baseline AT area.ConclusionsFollowing virologic suppression, lower SAT and VAT density was associated with greater plasma measures of systemic inflammation, lipid disturbances, and insulin resistance independent of AT area, suggesting that changes in AT density with ART may lead to adverse health outcomes independent of AT quantity.Clinical trials registrationNCT00851799.

BackgroundThe purpose of this study is to determine if a new score calculated with coronary artery calcium (CAC) density and volume is associated with total coronary artery plaque burden and composition on coronary CT angiography (CCTA) compared to the Agatston score (AS).MethodsWe identified 347 men enrolled in the Multicenter AIDS cohort study who underwent contrast and non-contrast CCTs, and had CAC>0. CAC densities (mean Hounsfield Units [HU]) per plaque) and volumes on non-contrast CCT were measured. A Density-Volume Calcium score was calculated by multiplying the plaque volume by a factor based on the mean HU of the plaque (4, 3, 2 and 1 for 130-199, 200-299, 300-399, and ≥400HU). Total Density-Volume Calcium score was determined by the sum of these individual scores. The semi-quantitative partially calcified and total plaque scores (PCPS and TPS) on CCTA were calculated. The associations between Density-Volume Calcium score, PCPS and TPS were examined.ResultsOverall, 2879 CAC plaques were assessed. Multivariable linear regression models demonstrated a stronger association between the log Density-Volume Calcium score and both the PCPS (β 0.99, 95%CI 0.80-1.19) and TPS (β 2.15, 95%CI 1.88-2.42) compared to the log of AS (PCPS: β 0.77, 95%CI 0.61-0.94; TPS: β 1.70, 95%CI 1.48-1.94). Similar results were observed for numbers of PC or TP segments.ConclusionThe new CAC score weighted towards lower density demonstrated improved correlation with semi-quantitative PC and TP burden on CCTA compared to the traditional AS, which suggests it has utility as an alternative measure of atherosclerotic burden.

BackgroundThe relationship between 25-hydroxyvitamin D (25-OH-vitamin D) and COPD outcomes remains unclear. Using the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), we determined associations among baseline 25-OH-vitamin D and cross-sectional and longitudinal lung function and COPD exacerbations.MethodsSerum 25-OH-vitamin D level was measured in stored samples from 1,609 SPIROMICS participants with COPD. 25-OH-vitamin D levels were modeled continuously and dichotomized as deficient (< 20 ng/mL) vs not deficient (≥ 20 ng/mL). Outcomes of interest included % predicted FEV1 (current and 1-year longitudinal decline) and COPD exacerbations (separately any and severe, occurring in prior year and first year of follow-up).ResultsVitamin D deficiency was present in 21% of the cohort and was more prevalent in the younger, active smokers, and blacks. Vitamin D deficiency was independently associated with lower % predicted FEV1 (by 4.11%) at enrollment (95% CI, -6.90% to -1.34% predicted FEV1; P = .004), 1.27% predicted greater rate of FEV1 decline after 1 year (95% CI, -2.32% to -0.22% predicted/y; P = .02), and higher odds of any COPD exacerbation in the prior year (OR, 1.32; 95% CI, 1.00-1.74; P = .049). Each 10-ng/mL decrease in 25-OH-vitamin D was associated with lower baseline lung function (-1.04% predicted; 95% CI, -1.96% to -0.12% predicted; P = .03) and increased odds of any exacerbation in the year before enrollment (OR, 1.11; 95% CI, 1.01-1.22; P = .04).ConclusionsVitamin D deficiency is associated with worse cross-sectional and longitudinal lung function and increased odds of prior COPD exacerbations. These findings identify 25-OH-vitamin D levels as a potentially useful marker of adverse COPD-related outcomes.

IntroductionMarijuana use is common among persons living with HIV, but whether it's use increases the risk of type 2 diabetes in this population has not been explored.ObjectiveTo determine whether self-reported marijuana use is associated with incident type 2 diabetes in women and men living with and at risk for HIV.MethodsWe analyzed data from the Women's Interagency HIV Study (WIHS) and Multicenter AIDS Cohort Study (MACS), between 2000-2017 (WIHS) and 1999-2017 MACS. The association between self-reported marijuana use and incident type 2 diabetes was analyzed using time-dependent Cox regression models among 3578 and 2682 participants in the WIHS and MACS respectively.ResultsOver the follow-up period, 452 (WIHS) and 326 (MACS) incident type 2 diabetes cases occurred. In multivariable models, the hazard ratios, collectively indicate a reduced risk of type 2 diabetes, in marijuana users compared to none users, although all associations were not statistically significant. The results were similar for HIV-positive and HIV-negative participants in both cohorts.ConclusionsIn this prospective analysis of nearly 20 years of data for women and men with and at risk for HIV in the WIHS and MACS, although we found a pattern of reduced risk of type 2 diabetes among self-reported marijuana users, the associations were not statistically significant. To better inform clinical decisions and legal policy regarding marijuana use in this population, further longitudinal investigations that biologically quantify marijuana use to assess risk for incident diabetes is warranted.

BackgroundThe total QT interval comprises both ventricular depolarization and repolarization currents. Understanding how HIV serostatus and other risk factors influence specific QT interval subcomponents could improve our mechanistic understanding of arrhythmias.MethodsTwelve-lead electrocardiograms (ECGs) were acquired in 774 HIV-infected (HIV+) and 652 HIV-uninfected (HIV-) men from the Multicenter AIDS Cohort Study. Individual QT subcomponent intervals were analyzed: R-onset to R-peak, R-peak to R-end, JT segment, T-onset to T-peak, and T-peak to T-end. Using multivariable linear regressions, we investigated associations between HIV serostatus and covariates, including serum concentrations of inflammatory biomarkers such as interleukin-6 (IL-6), and each QT subcomponent.ResultsAfter adjustment for demographics and risk factors, HIV+ versus HIV- men differed only in repolarization phase durations with longer T-onset to T-peak by 2.3 ms (95% CI 0-4.5, p

BackgroundPeople living with human immunodeficiency virus (HIV+) have greater risk for sudden arrhythmic death than HIV-uninfected (HIV-) individuals. HIV-associated abnormal cardiac repolarization may contribute to this risk. We investigated whether HIV serostatus is associated with ventricular repolarization lability by using the QT variability index (QTVI), defined as a log measure of QT-interval variance indexed to heart rate variance.MethodsWe studied 1123 men (589 HIV+ and 534 HIV-) from MACS (Multicenter AIDS Cohort Study), using the ZioXT ambulatory electrocardiography patch. Beat-to-beat analysis of up to 4 full days of electrocardiographic data per participant was performed using an automated algorithm (median analyzed duration [quartile 1-quartile 3]: 78.3 [66.3-83.0] hours/person). QTVI was modeled using linear mixed-effects models adjusted for demographics, cardiac risk factors, and HIV-related and inflammatory biomarkers.ResultsMean (SD) age was 60.1 (11.9) years among HIV- and 54.2 (11.2) years among HIV+ participants (P

BackgroundNonalcoholic fatty liver disease (NAFLD) is a leading cause of liver disease worldwide. Elevated sex hormone-binding globulin (SHBG) levels have been observed in the setting of HIV and may protect against some metabolic disorders. We aimed to investigate whether higher SHBG levels may protect against NAFLD in men with/without HIV.MethodsNAFLD was assessed using noncontrast computed tomography in 530 men in the Multicenter AIDS Cohort Study (MACS) who drank

ObjectiveLow HDL cholesterol (HDL-C) is common in people living with HIV infection, which is associated with inflammation, and correlates with greater cardiovascular disease (CVD) risk. Particles of HDL are HDL subfractions, and in some general population studies, higher small HDL particle number (HDL-P) has been associated with lower CVD risk. The objective of this study was to determine whether HIV serostatus and systemic inflammation were associated with small HDL-P in the Multicenter AIDS Cohort Study (MACS).MethodThe MACS is composed of HIV-infected and HIV-uninfected men. Separate linear regression analyses were conducted to evaluate the associations between outcomes (small HDL-P, large HDL-P, total HDL-P, and HDL size) and variables of interest (interleukin-6 [IL-6], D-dimer, and intercellular adhesion molecule-1 [ICAM-1] levels), with adjustment for other CVD risk factors.ResultsThe study population included 553 HIV-infected (88.1% on current ART) and 319 HIV-uninfected men. The mean age was 52.7 years for HIV-infected men and 55.3 years for HIV-uninfected men. In separate models of the study population, higher log IL-6 was associated with lower total and small HDL-P (P < .01 for both), independent of HIV serostatus and CVD risk factors. Similar results were seen with ICAM-1. Positive HIV serostatus was associated with lower small and total HDL-P, adjusted for inflammatory markers.ConclusionsGreater systemic inflammation and HIV infection both were associated with lower atheroprotective small HDL-P. This may be a potential mechanism contributing to increased cardiovascular risk among HIV-infected people.

Gait speed declines at a faster rate in persons with HIV (PWH) than in the general population but the risk factors associated with this decline are not well understood. In the AIDS Clinical Trials Group (ACTG) A5322 (HAILO, HIV Infection, Aging, and Immune Function Long-term Observational Study), an observational cohort study of PWH ≥40 years of age, those who developed slow gait during the first 3 years of follow-up were compared with persons who maintained normal speed. Associations with demographic and clinical covariates were assessed using multivariable logistic regression. Of 929 participants, 81% were men, 31% Black, and 20% Hispanic. Median age was 51 years [interquartile range (IQR) = 46-56]. At study entry, 92% had plasma HIV RNA

BackgroundBacterial translocation in HIV is associated with inflammation and metabolic complications; few data exist on the role of fungal translocation.MethodsA5260s was a substudy of A5257, a prospective open label randomized trial in which treatment-naïve people with HIV (PWH) were randomized to tenofovir-emtricitabine (TDF/FTC) plus atazanavir-ritonavir (ATV/r), darunavir-ritonavir (DRV/r), or raltegravir (RAL) over 96 weeks. Baseline was assessed, and changes in β-D-glucan (BDG) were assessed at weeks 4, 24, and 96. Wilcoxon rank-sum tests were used to compare distribution shifts in the changes from baseline between treatment arms and linear regression models to assess associations between BDG and measures of inflammation, body composition, and insulin resistance.ResultsTwo hundred thirty-one participants were randomized; 90% were male, the median age was 36 years, HIV-1 RNA was 4.56 log10c/mL, and CD4 cell count was 338 cells/mm3. There was an overall increase in BDG over 96 weeks (1.57 mean fold-change; 95% confidence interval, 1.39 to 1.77) with no differences between arms. Twofold higher BDG levels at week 96 were associated with increases in trunk fat (8%) and total fat (7%) over 96 weeks (P ≤ .035). At week 4, BDG correlated with I-FABP, a marker of enterocyte damage, and zonulin, a marker of intestinal permeability (r = .19-.20; P < .01).ConclusionsIn treatment-naïve participants initiating antiretroviral therapy (ART) with TDF/FTC and either RAL or ATV/r, DRV/r, BDG, a marker of fungal translocation, increased similarly in all arms over 96 weeks. This may represent continued intestinal damage during ART and resulting fungal translocation. Higher BDG was associated with larger fat gains on ART.

ObjectiveObesity is a common, modifiable cardiovascular and cerebrovascular risk factor. Among people with HIV, obesity may contribute to multisystem dysregulation including cognitive impairment. We examined body mass index (BMI) and central obesity (waist circumference [WC]) in association with domain-specific cognitive function and 10-year cognitive decline in men with HIV infection (MWH) vs HIV-uninfected (HIV-) men.MethodsA total of 316 MWH and 656 HIV- Multicenter AIDS Cohort Study participants ≥40 years at baseline, with neuropsychological testing every 2 years and concurrent BMI and WC measurements, were included. MWH were included if taking ≥2 antiretroviral agents and had HIV-1 RNA 80% of visits. Mixed-effects models included all visits from 1996 to 2015, stratified by HIV serostatus, and adjusted for sociodemographic, behavioral, and clinical characteristics. At baseline and follow-up, 8% of MWH and 15% of HIV- men and 41% of MWH and 56% of HIV- men were ≥60 years, respectively.ResultsCross-sectionally, higher BMI was inversely associated with motor function in MWH and HIV- men, and attention/working memory in HIV- men. WC was inversely associated with motor function in MWH and HIV- men. Longitudinal associations indicated an obese BMI was associated with a less steep decline in motor function in MWH whereas in HIV- men, obesity was associated with a greater decline in motor function, learning, and memory. WC, or central obesity, showed similar patterns of associations.ConclusionHigher adiposity is associated with lower cognition cross-sectionally and greater cognitive decline, particularly in HIV- men. Overweight and obesity may be important predictors of neurologic outcomes and avenues for prevention and intervention.

BACKGROUND:Proteinuria has been associated with bone loss and fractures in general population, but data in HIV-infected population are lacking. SETTING:Prospective, multicenter cohort study of men with or at risk of HIV infection. METHODS:Between 2006 and 2015, urine protein measurements and bone fracture histories were ascertained semiannually in 947 HIV-infected (HIV+) and 969 HIV-uninfected (HIV-) men aged 40 years or older. Proteinuria was defined as protein-to-creatinine ratio ≥200 mg/g at ≥2 consecutive visits. Outcome measures (1) all fractures (excluding fractures of skull, face, and digits) and (2) fragility fractures (fractures of vertebral column, femur, wrist, and humerus). Multivariable Cox proportional hazards models assessed the association between proteinuria and fracture after adjusting for additional risk factors. RESULTS:The overall period prevalence of proteinuria was higher among HIV+ than HIV- (29% vs 6%, P < 0.001). Men with proteinuria had a significantly higher risk of fragility fracture compared with men without proteinuria [adjusted hazard ratio (aHR) = 2.29 (1.12-4.66)] and did not differ by HIV serostatus (p-interaction = 0.83). The risk of all fractures was not statistically different between men with or without proteinuria [aHR = 1.31 (0.84-2.05)]. Among HIV+ men, the association between confirmed proteinuria and fragility fracture was attenuated [aHR = 2.12 (0.95-4.73)] after additional adjustment for CD4 T-cell count/mm, history of AIDS, the presence of detectable plasma HIV-1 RNA, and cumulative exposure to tenofovir disoproxil fumarate. CONCLUSIONS:Proteinuria was more common in HIV+ than in HIV- men and was a strong independent risk factor for fragility fracture regardless of HIV serostatus. Proteinuria should prompt consideration of a thorough evaluation for bone disease among HIV+ persons.

ObjectiveWhether HIV modifies the relationship of serum lipids with coronary atherosclerosis and coronary plaque subtypes is uncertain. We examined the associations between traditional lipids and coronary atherosclerosis among HIV-infected (HIV+) and HIV-uninfected (HIV-) men.DesignThe Multicenter AIDS Cohort Study is an observational cohort with a total of 429 HIV+ and 303 HIV- men who had non-contrast cardiac computed tomography performed to measure coronary artery calcium and coronary computed tomography angiography to measure coronary stenosis, coronary plaque presence, and composition.MethodsWe used multivariable adjusted prevalence ratios to examine the relationship between the SD difference in each lipid parameter and coronary atherosclerosis.ResultsTotal cholesterol (TC)/HDL-cholesterol had the strongest associations with coronary atherosclerosis regardless of HIV status. Overall, lipid parameters were most strongly associated with the presence of mixed plaque, stenosis more than 50%, and coronary artery calcium for both HIV+ and HIV- men. HIV+ men had similar, but weaker associations, between lipid parameters and coronary atherosclerosis compared with HIV- men. The strongest association was between the TC/HDL-cholesterol and stenosis more than 50% for both HIV+ [prevalence ratios 1.25 per SD (95% confidence interval 1.07-1.43)] and HIV- men [prevalence ratios 1.46 per SD (95% confidence interval 1.08-1.85)].ConclusionThe associations between lipids and coronary atherosclerosis tended to be weaker for HIV+ compared with HIV- men, although TC/HDL had the strongest association for both HIV+ and HIV- men. A weaker association between lipid levels and coronary atherosclerosis for HIV+ men may contribute to the decreased discrimination of cardiovascular disease risk observed in HIV+ individuals.

BackgroundFat accumulation and insulin resistance remain a threat to the success of antiretroviral therapy (ART). The role of gut dysfunction in metabolic complications associated with ART initiation is unclear.MethodsHuman immunodeficiency virus (HIV)-infected ART-naive participants were randomized to tenofovir disoproxil fumarate/emtricitabine plus atazanavir/ritonavir, darunavir/ritonavir, or raltegravir (RAL). Changes in the gut integrity markers zonulin, lipopolysaccharide-binding protein (LBP), and intestinal fatty acid and ileal bile acid binding proteins (I-FABP and I-BABP) were assessed over 96 weeks. Wilcoxon rank-sum tests were used to compare changes between groups and linear regression models to quantify associations between gut markers, insulin resistance, body mass index (BMI), and visceral, subcutaneous, and total adipose tissue (VAT, SAT, and TAT).Results: 90% were male and 48% were White non-Hispanic. The median age was 36 years, HIV-1 ribonucleic acid was 4.56 log10 copies/mL, and CD4 count was 338 cells/µL. An overall 1.7-fold increase in I-FABP was observed throughout 96 weeks, with no difference between arms. Zonulin levels increased with RAL compared to protease inhibitor-based regimens (week 96, P = .02); minimal changes in I-BABP or LBP levels were observed. Higher baseline I-FABP levels were associated with increases in VAT, TAT, and BMI (16%, 9%, and 2.5%, respectively; P < .04) over 96 weeks.ConclusionsWhile ART induces changes in the markers of gut barrier dysfunction, the extent to which they improve or worsen the gut barrier function remains unclear. Nevertheless, markers of gut barrier dysfunction in ART-naive individuals predict increases in total and visceral abdominal fat with treatment initiation.

ObjectiveHIV-infected (HIV+) individuals may be at increased risk for sudden arrhythmic cardiac death. Some studies have reported an association between HIV infection and prolongation of the electrocardiographic QT interval, a measure of ventricular repolarisation, which could potentiate ventricular arrhythmias. We aimed to assess whether HIV+ men have longer QT intervals than HIV-uninfected (HIV-) men and to determine factors associated with QT duration.MethodsWe performed resting 12-lead ECGs in 774 HIV+ and 652 HIV- men in the Multicenter AIDS Cohort Study (MACS). We used multivariable linear and logistic regression analyses to assess associations between HIV serostatus and Framingham corrected QT interval (QTc), after accounting for potential confounders. We also determined associations among QTc interval and HIV-related factors in HIV+ men. In a subgroup of participants, levels of serum markers of inflammation were also assessed.ResultsAfter adjusting for demographics and risk factors, QTc was 4.0 ms longer in HIV+ than HIV- men (p

BackgroundMitochondrial DNA (mtDNA) copy number varies by cell type and energy demands. Blood mtDNA copy number has been associated with neurocognitive function in persons without HIV. Low mtDNA copy number may indicate disordered mtDNA replication; high copy number may reflect a response to mitochondrial dysfunction. We hypothesized that blood mtDNA copy number estimated from genome-wide genotyping data is related to neurocognitive impairment (NCI) in persons with HIV.MethodsIn the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study, peripheral blood mtDNA copy number was obtained from genome-wide genotyping data as a ratio of mtDNA single-nucleotide polymorphism probe intensities relative to nuclear DNA single-nucleotide polymorphisms. In a multivariable regression model, associations between mtDNA copy number and demographics, blood cell counts, and HIV disease and treatment characteristics were tested. Associations of mtDNA copy number with the global deficit score (GDS), GDS-defined NCI (GDS ≥ 0.5), and HIV-associated neurocognitive disorder (HAND) diagnosis were tested by logistic regression, adjusting for potential confounders.ResultsAmong 1010 CHARTER participants, lower mtDNA copy number was associated with longer antiretroviral therapy duration (P < 0.001), but not with d-drug exposure (P = 0.85). mtDNA copy number was also associated with GDS (P = 0.007), GDS-defined NCI (P < 0.001), and HAND (P = 0.002). In all analyses, higher mtDNA copy number was associated with poorer cognitive performance.ConclusionsHigher mtDNA copy number estimated from peripheral blood genotyping was associated with worse neurocognitive performance in adults with HIV. These results suggest a connection between peripheral blood mtDNA and NCI, and may represent increased mtDNA replication in response to mitochondrial dysfunction.

ObjectiveGlycA, a novel NMR biomarker of inflammation, has been associated with incident cardiovascular disease (CVD) in the general population, but its association with CVD among HIV-infected individuals is unknown. We examined the associations between GlycA and subclinical coronary plaque among HIV-infected and HIV-uninfected men participating in Multicenter AIDS Cohort Study (MACS).DesignCross-sectional analysis of 935 men with plasma measurement of GlycA and noncontrast cardiac computed tomography (CT) and/or coronary CT angiography.MethodsWe used multivariable Poisson and linear regression to assess associations of GlycA with prevalent coronary atherosclerosis and plaque extent, respectively.ResultsMean ± SD age was 54 ± 7 years; 31% were black; 63% HIV-infected. GlycA levels were higher in HIV-infected compared with HIV-uninfected men (397 ± 68 vs. 380 ± 60 μmol/l, P = 0.0001) and higher for men with detectable viral load vs. undetectable (413 ± 79 vs. 393 ± 65 μmol/l, P = 0.004). After adjusting for HIV serostatus, demographic and CVD risk factors, every 1SD increment in GlycA level was associated with a higher prevalence of coronary artery calcium (CAC >0) [prevalence ratio 1.09 (95% CI 1.03-1.15)] and coronary stenosis at least 50% [1.20 (1.02-1.41)]. These associations were not significantly altered after adjusting for traditional inflammatory biomarkers or differ by HIV serostatus. Among men with plaque, GlycA was positively associated with the extent of CAC and total plaque.ConclusionHIV infection was associated with higher GlycA levels. In both HIV-infected and HIV-uninfected individuals, GlycA was significantly associated with several measures of subclinical coronary atherosclerosis, independent of other CVD risk factors and inflammatory biomarkers. These findings suggest the potential role of GlycA in CVD risk stratification among HIV patients.

BackgroundIn the Multicenter AIDS Cohort Study, we examined whether fibroblast growth factor-23 (FGF-23), a bone-derived phosphaturic hormone involved in bone metabolism, is associated with incident frailty. Furthermore, we examined whether this association differs by HIV serostatus and race.MethodsOf 715 men assessed for frailty and selected for FGF-23 measurements using stored blood samples (2007-2011), 512 men were nonfrail at/before the baseline visit. Frailty was defined by the presence of ≥3 of the following on 2 consecutive 6-month visits within 1 year: unintentional weight loss ≥10 pounds, weakness, slowness, low energy, and low physical activity. We determined the association of FGF-23 levels with incident frailty using proportional hazards models adjusting for sociodemographics, comorbidities, and kidney function.ResultsSixty-five percent were HIV-infected; 29% were black. Median baseline FGF-23 levels were lower in HIV-infected vs. HIV-uninfected men (33.7 vs. 39.9 rU/mL, P = 0.006) but similar by race. During a median follow-up of 6.6 years, 32 men developed frailty; they had higher baseline FGF-23 levels vs. men who remained nonfrail (45 vs. 36 rU/mL, P = 0.02). FGF-23 (per doubling) was associated with a 1.63-fold risk of frailty [95% confidence interval (CI): 1.19 to 2.23]; results did not differ by HIV serostatus. Conversely, FGF-23 was associated with a 2.72-fold risk of frailty among blacks (95% CI: 1.51 to 4.91) but had minimal association among nonblacks (hazard ratio = 1.26, 95% CI: 0.77 to 2.05; p-interaction = 0.024).ConclusionsAmong men with or at-risk of HIV infection, higher FGF-23 was associated with greater risk of frailty, particularly in blacks. The mechanisms by which FGF-23 may contribute to frailty warrant further study.

BackgroundThis study investigates the association of clinical and demographic predictors with abdominal fat gain, measured using waist circumference (WC) and self-reported abdominal size.MethodsWe analyzed data from ACTG A5257, a clinical trial that randomized treatment-naïve HIV-infected participants to 1 of 3 antiretroviral regimens: raltegravir (RAL) or the protease inhibitors (PIs) atazanavir/ritonavir (ATV/r) or darunavir/ritonavir (DRV/r), each in combination with tenofovir disoproxil fumarate/emtricitabine. Associations of treatment and baseline/demographic characteristics with 96-week WC change were assessed using repeated-measures models. Ordinal logistic regression was used to examine the associations of predictors with week 96 self-reported abdominal changes.ResultsThe study population (n = 1809) was 76.0% male and predominantly black non-Hispanic (41.9%) and white non-Hispanic (34.1%). Mean baseline WC was 90.6 cm, with an average 96-week increase of 3.4 cm. WC increases were higher in the RAL arm compared with DRV/r (P = .0130). Females experienced greater increases in WC on RAL vs ATV/r than males (P = .0065). Similarly, a larger difference in WC change was found for RAL vs DRV/r for black vs nonblack individuals (P = .0043). A separate multivariable model found that in addition to the treatment regimen, higher baseline viral load and lower CD4+ were also associated with WC increases.ConclusionsWith antiretroviral therapy initiation, higher WC increases in the RAL arm compared with PIs were more pronounced in female and black participants, and a more advanced baseline HIV disease state was a strong predictor of larger abdominal increases. Understanding factors predisposing individuals to abdominal fat gain could inform health management after therapy initiation.

ObjectiveSleep disturbance is a known risk factor for depression, but it is not known whether sleep disturbance contributes to greater risk of depression in those infected with human immunodeficiency virus (HIV+) as compared to those uninfected with HIV (HIV-).MethodsUsing data from the Multicenter AIDS Cohort Study, a population-based prospective study of men who have sex with men (MSM), self-reported sleep disturbance (>2 weeks) and depressive symptoms (Clinical Epidemiologic Scale for Depression, CES-D) were assessed every 6 months over 12 years of follow-up. Adjusted mixed effects logistic regression analyses tested whether sleep disturbance predicted depression (CES-D ≥ 16) at the immediate subsequent visit, and so on over 12 years, in non-depressed HIV+(N = 1054; 9556 person-visits) and non-depressed HIV- (N = 1217; 12,680 person-visits). In HIV+ vs. HIV- MSM, linearly estimated average incidence of depression and normalized cumulative rate of depression over 12 years were compared.ResultsIn the HIV+ MSM, sleep disturbance was associated with a significant increase in depression 6 months later (OR = 1.6; 95% CI, 1.30, 1.96), which was significantly greater (P