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IntroductionErectile dysfunction (ED) has been established as a comorbidity among men living with HIV, but comparisons by HIV serostatus of ED incidence in a longitudinal follow-up cohort of men are lacking. We sought to evaluate the incidence of ED spanning a period of 12 years in a longitudinal cohort of sexual minority men (SMM) living with and without HIV.MethodsWe analyzed ED incidence data for 625 participants in the longitudinal Multicenter AIDS Cohort Study from visits spanning October 2006 to April 2019.ResultsSMM living with HIV were more likely to have incident ED compared with those living without HIV (rate ratio: 1.41; 95% CI: 1.14-1.75). Older age, current diabetes, cumulative cigarette use, and cumulative antidepressant use were associated with increased incidence of ED in the entire sample. Self-identifying as Hispanic, current diabetes, and cumulative antidepressant use were positively associated with ED incidence among SMM living with HIV. Cumulative cigarette use was positively associated with greater ED incidence only among SMM living without HIV.DiscussionIn summary, age (full sample/ with HIV), current diabetes (full sample/with HIV), cumulative cigarette use (full sample/without HIV), and cumulative antidepressant use (full sample/with HIV) were associated with increased ED incidence. Skillful management of diabetes and careful titration of antidepressants, along with smoking cessation practices, are recommended to mitigate ED in this population.

ObjectiveMarijuana, tobacco and alcohol use are prevalent among people with HIV and may adversely affect kidney function in this population. We determined the association of use of these substances with estimated glomerular filtration rate (eGFR) among women with HIV (WWH) and women without HIV.DesignWe undertook a repeated measures study of 1043 WWH and 469 women without HIV within the United States Women's Interagency HIV Study, a multicenter, prospective cohort of HIV-seropositive and HIV-seronegative women.MethodsWe quantified substance exposures using semi-annual questionnaires. Using pooled eGFR data from 2009 to 2019, we used linear regression models with multivariable generalized estimating equations to ascertain associations between current and cumulative substance use exposures with eGFR, adjusting for sociodemographics, chronic kidney disease risk factors and HIV-related factors.ResultsMarijuana use of 1-14 days/month versus 0 days/month was associated with 3.34 ml/min per 1.73 m 2 [95% confidence interval (CI) -6.63, -0.06] lower eGFR and marijuana use of >0.02-1.6 marijuana-years versus 0-0.2 marijuana-years was associated with 3.61 ml/min per 1.73 m 2 (95% CI -5.97, -1.24) lower eGFR. Tobacco use was not independently associated with eGFR. Alcohol use of seven or more drinks/week versus no drinks/week was associated with 5.41 ml/min per 1.73 m 2 (95% CI 2.34, 8.48) higher eGFR and alcohol use of >0.7-4.27 drink-years and >4.27 drink-years versus 0-0.7 drink-years were associated with 2.85 ml/min per 1.73 m 2 (95% CI 0.55, 5.15) and 2.26 ml/min per 1.73 m 2 (95% CI 0.33, 4.20) higher eGFR, respectively.ConclusionAmong a large cohort of WWH and women without HIV, marijuana use was associated with a lower eGFR while alcohol use was associated with a higher eGFR.

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.

ObjectiveExamine prospective relationships between erectile dysfunction (ED) drugs EDand CD4 and CD8 T-cells, and immune markers among men who have sex with men (MSM).MethodsData from Multicenter AIDS Cohort Study, an observational prospective cohort study, with semi-annual follow-ups conducted in four U.S. centers from 1998 onwards was used. Marginal structural models using g-computation was fitted to estimate the mean differences for the effects of self-reported ED drug use on CD4 and CD8 T-cell outcomes and immune biomarkers.ResultsTotal of 1,391 men with HIV (MWH) and 307 men without HIV (MWOH) was included. Baseline mean CD4 cell count among MWH and MWOH was 499.9 cells/μL and 966.7 cells/μL, respectively. At baseline, 41.8% of MWH were virally suppressed. ED drug users reported a mean of 44.4 months of exposure to ED drugs. ED drug use was associated with increased CD4 cell outcomes among MWH but not MWOH. Mean differences in CD4 cell counts after 1 year of ED drug use was 57.6 cells/μL and increased to 117.7 after 10 years among MWH. CD8 counts were higher in ED drug users among MWH over 10 years than non-users; no consistent differences were found among MWOH. ED drug use appeared to reduce immune marker levels, such as IL-6 and increase markers, such as IL-10. We observed similar effects of ED drug use on biomarker levels among MWOH.ConclusionLong-term use of ED drugs do not adversely affect immune function among MWH or MWOH. Future studies on the relationships between different types of ED drugs and effects on T-cell subtypes are warranted.

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.

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

ObjectiveTo understand the relationship between cardiovascular disease (CVD) risk and frailty among men (MWH) and women living with HIV (WWH), or at risk for HIV.DesignWe considered 10-year coronary heart disease and atherosclerotic CVD risk by Framingham risk score (FRS, 2001 National Cholesterol Education Program Adult Treatment Program III) and Pooled Cohort Equations (PCE, 2013 American College of Cardiology/American Heart Association) in relation to the Fried Frailty Phenotype (FFP) in the Multicenter AIDS Cohort Study (MACS) and Women's Interagency HIV Study (WIHS).MethodsFFP was ascertained in MACS from 2004 to 2019 and in WIHS from 2005 to 2006 and 2011-2019. FFP score at least three of five components defined frailty. Repeated measures logistic regression (both cohorts) and Cox proportional hazards regression (MACS) were performed, controlled for education, income, cholesterol medication and hepatitis C virus serostatus, and among MWH and WWH, CD4+ cell count/μl, antiretroviral therapy, and HIV viral load.ResultsThere were 5554 participants (1265 HIV seronegative/1396 MWH; 768 seronegative/1924 WWH) included. Among men, high-risk FRS was associated with increased risk of incident frailty among seronegative [adjusted hazard ratio (aHR)) = 2.12, 95% confidence interval (CI):1.22-3.69] and MWH (aHR = 2.19, 95% CI: 1.33-3.61). Similar associations were seen with high-risk PCE and incident frailty among SN (aHR = 1.88, 95% CI: 1.48-2.39) and MWH (aHR = 1.59, 95% CI: 1.26-2.00). Among women, high-risk PCE was associated with frailty in SN [adjusted odds ratio (aOR) = 1.43, 95% CI: 1.02-2.00] and WWH (aOR = 1.36, 95% CI: 1.08-1.71); however, high-risk FRS was not (seronegative: aOR = 1.03, 95% CI: 0.30-3.49; WWH: aOR = 0.86, 95% CI: 0.23-3.20).ConclusionHigher CVD risk was associated with increased frailty regardless of HIV serostatus among men and women. These findings may inform clinical practices of screening for frailty.

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.

We investigated the longitudinal relationship between erectile dysfunction (ED) drug use with behavioral factors, including substance use and sexual activities in men who have sex with men from the Multicenter AIDS Cohort Study during 1998-2016 (n = 1636). We used a bivariate random-intercept model to evaluate ED drug use along with other behavioral factors to assess relationships between the two outcomes over time on a population level and also at the individual level. Average ED drug use among men who have sex with men (MSM) with HIV was positively correlated with average use of marijuana (r = .19), poppers (r = .27), and stimulants (r = .25). In this group, testosterone use (r = .32), multiple partners (r = .41), insertive anal intercourse with condom (r = .40), and insertive anal intercourse without condom (r = .43) all showed moderate correlations over time with average ED use (p

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.

Background: Chronic inflammation contributes to aging and organ dysfunction in the general population, and is a particularly important determinant of morbidity and mortality among people with HIV (PWH). The effect of cannabis use on chronic inflammation is not well understood among PWH, who use cannabis more frequently than the general population. Materials and Methods: We evaluated participants in the Multicenter AIDS Cohort Study (MACS) beginning in 2004 with available data on cannabis use and inflammatory biomarkers. Associations of current cannabis use with plasma concentrations of inflammatory markers were adjusted for hepatitis C, tobacco smoking, and comorbidities. Markers were analyzed individually and in exploratory factor analysis (EFA). Results: We included 1352 men within the MACS. Twenty-seven percent of HIV-negative men, 41% of HIV viremic men, and 35% of virologically suppressed men reported cannabis use at baseline. Among cannabis users, 20-25% in all groups defined by HIV serostatus were daily users, and the same proportion reported weekly use. The remaining ∼50% of users in all groups reported monthly or less frequent use. Four biomarker groupings were identified by EFA: Factor 1: immune activation markers; Factor 2: proinflammatory cytokines; Factor 3: Th1- and Th2-promoting cytokines; and Factor 4: inflammatory chemokines. In EFA, daily users had 30% higher levels of Factor 2 biomarkers than nonusers (p=0.03); this was the only statistically significant difference by cannabis use status. Among individual markers, concentrations of IL-1β, IL-2, IL-6, and IL-8 (Factor 2); IL-10 (Factor 3); and BAFF (Factor 1) were higher (p

IntroductionWeight gain following antiretroviral therapy (ART) initiation is common, potentially predisposing some persons with HIV (PWH) to cardio-metabolic disease. We assessed relationships between ART drug class and weight change among treatment-naïve PWH initiating ART in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD).MethodsAdult, treatment-naïve PWH in NA-ACCORD initiating integrase strand transfer inhibitor (INSTI), protease inhibitor (PI) or non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based ART on/after 1 January 2007 were followed through 31 December 2016. Multivariate linear mixed effects models estimated weight up to five years after ART initiation, adjusting for age, sex, race, cohort site, HIV acquisition mode, treatment year, and baseline weight, plasma HIV-1 RNA level and CD4+ cell count. Due to shorter follow-up for PWH receiving newer INSTI drugs, weights for specific INSTIs were estimated at two years. Secondary analyses using logistic regression and all covariates from primary analyses assessed factors associated with >10% weight gain at two and five years.ResultsAmong 22,972 participants, 87% were male, and 41% were white. 49% started NNRTI-, 31% started PI- and 20% started INSTI-based regimens (1624 raltegravir (RAL), 2085 elvitegravir (EVG) and 929 dolutegravir (DTG)). PWH starting INSTI-based regimens had mean estimated five-year weight change of +5.9kg, compared to +3.7kg for NNRTI and +5.5kg for PI. Among PWH starting INSTI drugs, mean estimated two-year weight change was +7.2kg for DTG, +5.8kg for RAL and +4.1kg for EVG. Women, persons with lower baseline CD4+ cell counts, and those initiating INSTI-based regimens had higher odds of >10% body weight increase at two years (adjusted odds ratio = 1.37, 95% confidence interval: 1.20 to 1.56 vs. NNRTI).ConclusionsPWH initiating INSTI-based regimens gained, on average, more weight compared to NNRTI-based regimens. This phenomenon may reflect heterogeneous effects of ART agents on body weight regulation that require further exploration.

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

Improvements in life expectancy among people living with human immunodeficiency virus (PLWH) receiving antiretroviral treatment in the United States and Canada might differ among key populations. Given the difference in substance use among key populations and the current opioid epidemic, drug- and alcohol-related deaths might be contributing to the disparities in life expectancy. We sought to estimate life expectancy at age 20 years in key populations (and their comparison groups) in 3 time periods (2004-2007, 2008-2011, and 2012-2015) and the potential increase in expected life expectancy with a simulated 20% reduction in drug- and alcohol-related deaths using the novel Lives Saved Simulation model. Among 92,289 PLWH, life expectancy increased in all key populations and comparison groups from 2004-2007 to 2012-2015. Disparities in survival of approximately a decade persisted among black versus white men who have sex with men and people with (vs. without) a history of injection drug use. A 20% reduction in drug- and alcohol-related mortality would have the greatest life-expectancy benefit for black men who have sex with men, white women, and people with a history of injection drug use. Our findings suggest that preventing drug- and alcohol-related deaths among PLWH could narrow disparities in life expectancy among some key populations, but other causes of death must be addressed to further narrow the disparities.

BackgroundHigh-sensitivity cardiac troponin (hs-cTn) elevations are associated with incident cardiovascular disease events in primary prevention samples. However, the mechanisms underlying this association remain unclear.MethodsWe studied 458 men without known cardiovascular disease who participated in the cardiovascular disease substudy of the Multicenter AIDS Cohort Study and had cardiac CT angiography. We used multivariable linear and logistic regression models to examine the cross-sectional associations between coronary artery stenosis, coronary artery plaque, indexed left ventricular mass (LVMi), and the outcome of hs-cTnI. We also evaluated the associations between HIV serostatus or use of highly active antiretroviral therapy (HAART) and hs-cTnI.ResultsThe mean age was 54 years, 54% were white, and 61% were HIV infected. In multivariable-adjusted logistic models, comparing the highest quartile of LVMi with the lowest quartile, the odds ratio (OR) of hs-cTnI ≥75th percentile was 2.59 (95% CI, 1.20-5.75). There was no significant association between coronary stenosis severity or plaque type and hs-cTnI in linear models; however, in logistic regression models, coronary artery stenosis ≥70% (8% of sample) was marginally associated with a higher likelihood (OR, 2.75 [95% CI, 1.03, 7.27]) of having hs-cTnI ≥75th percentile. There were no associations between HIV serostatus or HAART use and hs-cTnI in either linear or logistic models.ConclusionAmong primary prevention men with or at risk for HIV, hs-cTnI concentrations were strongly associated with LVMi but were not associated with HIV infection or treatment status or with coronary plaque type or stenosis until the extremes of severity (≥70% stenosis).

BackgroundChronic kidney disease (CKD) occurs commonly among HIV-infected persons. Statins may delay CKD onset and progression through their cholesterol-lowering and pleiotropic effects.MethodsAmong 850 HIV-infected men from the Multicenter AIDS Cohort Study with stored urine samples (2009-2011), we evaluated cross-sectional associations of statin use with urine biomarkers of kidney damage [albumin-to-creatinine ratio (ACR), alpha-1-microglobulin, interleukin-18, kidney injury molecule-1, and procollagen type III N-terminal propeptide] using multivariable linear regression. We evaluated the longitudinal associations of statin use with annual change in estimated glomerular filtration rate by creatinine (eGFR) using linear mixed models, and with incident proteinuria and incident CKD (eGFR

HIV infection has been associated with diastolic heart failure and atrial fibrillation. The purpose of this study is to determine whether HIV infection is associated with differences in left ventricular mass (LVM), left ventricular end-diastolic volume (LVEDV), and left atrial volume (LAV) indexed to body surface area (left ventricular mass index, left ventricular end-diastolic volume index [LVEDVI], and left atrial volume index [LAVI], respectively). Cross-sectional study of 721 men [425 HIV-infected (HIV+), 296 HIV-uninfected (HIV-) enrolled in the cardiovascular substudy of the Multicenter AIDS Cohort Study (MACS). Participants underwent cardiac computed tomography imaging. A blinded reader measured LVM, LVEDV, and LAV. We used multivariable linear regression models to evaluate whether LVEDVI, left ventricular mass index (LVMI), and LAVI differed by HIV serostatus, adjusting for demographics and cardiovascular disease risk factors. LVMI was significantly greater in HIV+ compared with HIV- men, with adjusted difference of 2.65 g/m2 (95% confidence interval 0.53-4.77, p

Polypharmacy is the concurrent use of five or more medications. We used group-based trajectory analysis to identify groups of non-HIV medication polypharmacy and investigate associated risk factors among HIV-positive and HIV-negative men in the Multicenter AIDS Cohort Study (MACS) from 2004 to 2016. Each participant was assigned to mutually exclusive groups based on their observed patterns of polypharmacy over time. Risk factors associated with membership with resulting groups were investigated using a multinomial generalized logit model with repeated measures. There were 3160 participants (54.3% HIV positive) included in the study. The overall prevalence of polypharmacy was 33.1% and was higher in HIV-positive than HIV-negative participants (36.2% vs. 30.0%; p

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.

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

ObjectivesUrinary biomarkers of kidney injury may have potential to identify subclinical injury attributable to tenofovir disoproxil fumarate (TDF) toxicity.DesignThis observational study included 198 HIV-infected participants from the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study, who initiated TDF between 2009 and 2015 and had urine samples collected at baseline before and after TDF initiation.MethodsWe used linear mixed-effects models controlling for urine creatinine and time on TDF to evaluate the effects of TDF initiation on changes in 14 urinary biomarkers.ResultsWithin 1 year after TDF initiation, concentrations of trefoil factor 3 [+78%; 95% confidence interval (CI) +38%, +129%), alpha-1 microglobulin (α1m) (+32%; 95% CI +13%, +55%), clusterin (+21%; 95% CI +6%, +38%), uromodulin (+19%; 95% CI +4%, +36%), and kidney injury molecule-1 (KIM-1) (+13%; 95% CI +1%, +26%) significantly increased, whereas interleukin-18 (IL-18) significantly decreased (-13%, 95% CI -7%, -25%). Subsequent to the first year of TDF use, biomarker concentrations stabilized, and these changes were not statistically significant. When stratifying by baseline viremia (HIV-1 RNA < vs. ≥80 copies/ml), concentration changes for most biomarkers during the first year of TDF use were greater among aviremic vs. viremic participants, with significant differences in α1m (+80 vs. +22%), KIM-1 (+43 vs. +10%), beta-2 microglobulin (+83 vs. -10%), YKL-40 (+33 vs. -5%), and IL-18 (+20 vs. -27%).ConclusionsTDF initiation was associated with substantial changes in urinary biomarkers of kidney injury within the first year of use, particularly among aviremic participants. A urinary biomarker panel may be a clinically useful tool to detect and monitor the heterogeneous effects of TDF on the kidney.

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.

BackgroundAdults with HIV have an increased burden of non-AIDS-defining cancers, myocardial infarction, end-stage liver disease, and end-stage renal disease. The objective of this study was to estimate the population attributable fractions (PAFs) of preventable or modifiable HIV-related and traditional risk factors for non-AIDS-defining cancers, myocardial infarction, end-stage liver disease, and end-stage renal disease outcomes.MethodsWe included participants receiving care in academic and community-based outpatient HIV clinical cohorts in the USA and Canada from Jan 1, 2000, to Dec 31, 2014, who contributed to the North American AIDS Cohort Collaboration on Research and Design and who had validated non-AIDS-defining cancers, myocardial infarction, end-stage liver disease, or end-stage renal disease outcomes. Traditional risk factors were tobacco smoking, hypertension, elevated total cholesterol, type 2 diabetes, renal impairment (stage 4 chronic kidney disease), and hepatitis C virus and hepatitis B virus infections. HIV-related risk factors were low CD4 count (400 copies per mL), and history of a clinical AIDS diagnosis. PAFs and 95% CIs were estimated to quantify the proportion of outcomes that could be avoided if the risk factor was prevented.FindingsIn each of the study populations for the four outcomes (1405 of 61 500 had non-AIDS-defining cancer, 347 of 29 515 had myocardial infarctions, 387 of 35 044 had end-stage liver disease events, and 255 of 35 620 had end-stage renal disease events), about 17% were older than 50 years at study entry, about 50% were non-white, and about 80% were men. Preventing smoking would avoid 24% (95% CI 13-35) of these cancers and 37% (7-66) of the myocardial infarctions. Preventing elevated total cholesterol and hypertension would avoid the greatest proportion of myocardial infarctions: 44% (30-58) for cholesterol and 42% (28-56) for hypertension. For liver disease, the PAF was greatest for hepatitis C infection (33%; 95% CI 17-48). For renal disease, the PAF was greatest for hypertension (39%; 26-51) followed by elevated total cholesterol (22%; 13-31), detectable HIV RNA (19; 9-31), and low CD4 cell count (13%; 4-21).InterpretationThe substantial proportion of non-AIDS-defining cancers, myocardial infarction, end-stage liver disease, and end-stage renal disease outcomes that could be prevented with interventions on traditional risk factors elevates the importance of screening for these risk factors, improving the effectiveness of prevention (or modification) of these risk factors, and creating sustainable care models to implement such interventions during the decades of life of adults living with HIV who are receiving care.FundingNational Institutes of Health, US Centers for Disease Control and Prevention, the US Agency for Healthcare Research and Quality, the US Health Resources and Services Administration, the Canadian Institutes of Health Research, the Ontario Ministry of Health and Long Term Care, and the Government of Alberta.

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.

BACKGROUND:HIV-infected (HIV+) persons are at increased risk of chronic kidney disease, but serum creatinine does not detect early losses in kidney function. We hypothesized that urine biomarkers of kidney damage would be associated with subsequent changes in kidney function in a contemporary cohort of HIV+ and HIV-uninfected (HIV-) men. METHODS:In the Multicenter AIDS Cohort Study, we measured baseline urine concentrations of 5 biomarkers from 2009 to 2011 in 860 HIV+ and 337 HIV- men: albumin, alpha-1-microglobulin (α1m), interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), and procollagen type III N-terminal propeptide (PIIINP). We evaluated associations of urine biomarker concentrations with annual changes in estimated glomerular filtration rate (eGFR) using multivariable linear mixed models adjusted for demographics, traditional kidney disease risk factors, HIV-related risk factors, and baseline eGFR. RESULTS:Over a median follow-up of 4.8 years, the average annual eGFR decline was 1.42 mL/min/1.73 m2/year in HIV+ men and 1.22 mL/min/1.73 m2/year in HIV- men. Among HIV+ men, the highest vs. lowest tertiles of albumin (-1.78 mL/min/1.73 m2/year, 95% CI -3.47 to -0.09) and α1m (-2.43 mL/min/1.73 m2/year, 95% CI -4.14 to -0.73) were each associated with faster annual eGFR declines after multivariable adjustment. Among HIV- men, the highest vs. lowest tertile of α1m (-2.49 mL/min/1.73 m2/year, 95% CI -4.48 to -0.50) was independently associated with faster annual eGFR decline. Urine IL-18, KIM-1, and PIIINP showed no independent associations with eGFR decline, regardless of HIV serostatus. CONCLUSIONS:Among HIV+ men, higher urine albumin and α1m are associated with subsequent declines in kidney function, independent of eGFR.

BackgroundNeurocognitive impairment (NCI) is strongly associated with frailty in people living with human immunodeficiency virus (PLWH); the overlap of frailty and NCI and the impact on health outcomes in PLWH are unknown.MethodsPLWH in a longitudinal, observational study of aging completed entry evaluations for frailty and NCI. Outcomes of falls (recurrent) increased limitations in independent activities of daily living (IADL), or mortality were combined. Poisson regression models estimated prevalence ratios (PR) for ≥1 outcome over 2 years.ResultsAmong 987 participants, the median age at entry was 51 years; 19% were female; the median CD4 count was 616 cells/µL; and HIV-1 RNA was

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.

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

BackgroundFactors affecting kidney function and proteinuria among HIV-positive (HIV+) and HIV-negative (HIV-) persons need better characterization.MethodsWe evaluated estimated glomerular filtration rate (eGFR, ml/min per 1.73 m) changes, proteinuria prevalence (a urine protein-to-creatinine ratio of ≥0.2 at two consecutive visits) and associated factors among HIV+ and HIV- men.ResultsThere were 917 HIV+ men receiving HAART, 159 HIV+ men not receiving HAART, and 1305 HIV- men seen from October 2003 to September 2014. Median annual eGFR change was -0.5, -0.8% for HIV+ and -0.3% for HIV- men (P

ObjectiveDespite effective antiretroviral therapy (HAART) and durable viral suppression, many HIV-infected individuals still do not achieve CD4 cell count (CD4) normalization. Vitamin D has immunoregulatory functions, including inducing the development of T cells and higher levels may improve CD4 rebound.DesignLongitudinal study of men from the Multicenter AIDS Cohort Study who virally suppressed following HAART initiation and had pre-HAART and post-HAART 25(OH)D and 1,25(OH)2D measurements and repeated measures of CD4.MethodsCD4 rebound was modeled using a nonlinear mixed effects model. We estimated the adjusted effect (adjusted for pre-HAART antiretroviral exposure, black race, age and CD4 at HAART initiation) of pre-HAART and post-HAART vitamin D metabolite levels on the rate of CD4 increase and final CD4 plateau.ResultsAmong the 263 HIV-infected HAART initiators with pre-HAART vitamin D measurements, a 1-SD higher pre-HAART 25(OH)2D level was associated with a 9% faster rate of rise (P = 0.02) but no gain in final CD4 plateau. In contrast, a 1-SD higher 1,25(OH)2D level was associated with a 43-cell lower final CD4 (P = 0.04). Among 560 men with post-HAART measurements, findings were similar to those for pre-HAART 25(OH)2D with 1-SD higher level associated with faster rate of rise but no improvement in final CD4.ConclusionWe found no evidence that higher vitamin D metabolite levels pre-HAART or post-HAART are associated with better CD4 outcomes among HIV-infected HAART initiators. However, the value of pre-HAART 1,25(OH)2D levels as an indicator of immune response dysregulation could be further explored.

BackgroundThere is persistent confusion as to whether abacavir (ABC) increases the risk of myocardial infarction (MI), and whether such risk differs by type 1 (T1MI) or 2 (T2MI) MI in adults with HIV.MethodsIncident MIs in North American Cohort Collaboration on Research and Design participants were identified from 2001 to 2013. Discrete time marginal structural models addressed channeling biases and time-dependent confounding to estimate crude hazard ratio (HR) and adjusted hazard ratio (aHR) and 95% confidence intervals; analyses were performed for T1MI and T2MI separately. A sensitivity analysis evaluated whether Framingham risk score (FRS) modified the effect of ABC on MI occurrence.ResultsEight thousand two hundred sixty-five adults who initiated antiretroviral therapy contributed 29,077 person-years and 123 MI events (65 T1MI and 58 T2MI). Median follow-up time was 2.9 (interquartile range 1.4-5.1) years. ABC initiators were more likely to have a history of injection drug use, hepatitis C virus infection, hypertension, diabetes, impaired kidney function, hyperlipidemia, low (

BackgroundAge-associated conditions are increasingly common among persons living with human immunodeficiency virus (HIV) (PLWH). A longitudinal investigation of their accrual is needed given their implications on clinical care complexity. We examined trends in the co-occurrence of age-associated conditions among PLWH receiving clinical care, and differences in their prevalence by demographic subgroup.MethodsThis cohort study was nested within the North American AIDS Cohort Collaboration on Research and Design. Participants from HIV outpatient clinics were antiretroviral therapy-exposed PLWH receiving clinical care (ie, ≥1 CD4 count) in the United States during 2000-2009. Multimorbidity was irreversible, defined as having ≥2: hypertension, diabetes mellitus, chronic kidney disease, hypercholesterolemia, end-stage liver disease, or non-AIDS-related cancer. Adjusted prevalence ratios (aPR) and 95% confidence intervals (CIs) comparing demographic subgroups were obtained by Poisson regression with robust error variance, using generalized estimating equations for repeated measures.ResultsAmong 22969 adults, 79% were male, 36% were black, and the median baseline age was 40 years (interquartile range, 34-46 years). Between 2000 and 2009, multimorbidity prevalence increased from 8.2% to 22.4% (Ptrend < .001). Adjusting for age, this trend was still significant (P < .001). There was no difference by sex, but blacks were less likely than whites to have multimorbidity (aPR, 0.87; 95% CI, .77-.99). Multimorbidity was the highest among heterosexuals, relative to men who have sex with men (aPR, 1.16; 95% CI, 1.01-1.34). Hypertension and hypercholesterolemia most commonly co-occurred.ConclusionsMultimorbidity prevalence has increased among PLWH. Comorbidity prevention and multisubspecialty management of increasingly complex healthcare needs will be vital to ensuring that they receive needed care.

Background and aimNon-alcoholic fatty liver disease (NAFLD) is common among HIV-infected (HIV+) adults. The Liver Fat Score (LFS) is a non-invasive, rapid, inexpensive diagnostic tool that uses routine clinical data and is validated against biopsy in HIV-uninfected (HIV-) persons. CT liver-to-spleen (L/S) attenuation ratio is another validated method to diagnose NAFLD. We compared NAFLD prevalence using the LFS versus L/S ratio among Multicenter AIDS Cohort Study participants to assess the LFS's performance in HIV+vs. HIV-men.MethodsIn a cross-sectional analysis of men reporting

BackgroundPrevious studies of cardiovascular disease (CVD) among HIV-infected individuals have been limited by the inability to validate and differentiate atherosclerotic type 1 myocardial infarctions (T1MIs) from other events. We sought to define the incidence of T1MIs and risk attributable to traditional and HIV-specific factors among participants in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) and compare adjusted incidence rates (IRs) to the general population Atherosclerosis Risk in Communities (ARIC) cohort.MethodsWe ascertained and adjudicated incident MIs among individuals enrolled in 7 NA-ACCORD cohorts between 1995 and 2014. We calculated IRs, adjusted incidence rate ratios (aIRRs), and 95% confidence intervals of risk factors for T1MI using Poisson regression. We compared aIRRs of T1MIs in NA-ACCORD with those from ARIC.ResultsAmong 29,169 HIV-infected individuals, the IR for T1MIs was 2.57 (2.30 to 2.86) per 1000 person-years, and the aIRR was significantly higher compared with participants in ARIC [1.30 (1.09 to 1.56)]. In multivariable analysis restricted to HIV-infected individuals and including traditional CVD risk factors, the rate of T1MI increased with decreasing CD4 count [≥500 cells/μL: ref; 350-499 cells/μL: aIRR = 1.32 (0.98 to 1.77); 200-349 cells/μL: aIRR = 1.37 (1.01 to 1.86); 100-199 cells/μL: aIRR = 1.60 (1.09 to 2.34);

BackgroundChronic kidney disease (CKD) is common among HIV-infected individuals but serum creatinine is insensitive for detecting kidney damage at early stages. We hypothesized that HIV infection would be associated with elevations in subclinical markers of kidney injury and fibrosis in a contemporary cohort of men.MethodsIn this cross-sectional study, we measured urine levels of interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), pro-collagen type III N-terminal pro-peptide (PIIINP) and albumin-creatinine ratio (ACR) in 813 HIV-infected and 331 uninfected men enrolled in the Multicenter AIDS Cohort Study.ResultsMedian eGFR was 95 ml/min/1.73 m2 among African-Americans (n=376) and 87 ml/min/1.73 m2 among Caucasians (n=768). Among HIV-infected men, the median CD4 lymphocyte count was 572 cells/mm3 and 76% of men had undetectable HIV RNA levels. After multivariable adjustment for traditional CKD risk factors including eGFR, HIV infection was associated with 52% higher urine IL-18 (95% CI, 33%, 73%), 44% higher KIM-1 (27%, 64%), 30% higher PIIINP (15%, 47%) and 84% higher ACR (54%, 120%), with similar effect sizes among African-Americans and Caucasians (P>0.2 for tests of interaction by race). These associations remained statistically significant in analyses that excluded persons with detectable HIV RNA levels and in models that adjusted for cumulative exposure to tenofovir disoproxil fumarate.ConclusionsCompared with uninfected men, HIV-infected men had more extensive glomerular and tubulointerstitial damage, as assessed by urine biomarkers. Future studies should evaluate whether combinations of biomarkers can be used to monitor stages of kidney injury and to predict CKD risk in HIV-infected individuals.

BackgroundOlder human immunodeficiency virus (HIV)-infected adults may experience higher rates of frailty and disability than the general population. Improved understanding of the prevalence, risk factors, and types of impairment can better inform providers and the healthcare system.MethodsHIV-infected participants within the AIDS Clinical Trials Group A5322 HAILO study self-reported disability by the Lawton-Brody Instrumental Activities of Daily Living (IADL) Questionnaire. Frailty was measured by 4-m walk time, grip strength, self-reported weight loss, exhaustion, and low activity. Logistic regression models identified characteristics associated with any IADL impairment. Agreement between IADL impairment and frailty was assessed using the weighted kappa statistic.ResultsOf 1015 participants, the median age was 51 years, 15% were aged ≥60 years, 19% were female, 29% black, and 20% Hispanic. At least 1 IADL impairment was reported in 18% of participants, most commonly with housekeeping (48%) and transportation (36%) and least commonly with medication management (5%). In multivariable models, greater disability was significantly associated with neurocognitive impairment, lower education, Medicare/Medicaid insurance (vs private/other coverage), smoking, and low physical activity. Although a greater proportion of frail participants had IADL impairment (52%) compared to non-frail (11%) persons, agreement was poor (weighted kappa

BackgroundOsteoporosis is common among HIV-infected persons and contributes to risk of fragility fracture. While ART initiation is associated with decreases in bone mineral density and increases in bone turnover, the impact of HIV on bone metabolism is unclear.MethodsWe identified men at the Chicago site of the Multicenter AIDS Cohort Study who HIV seroconverted while under observation. Concentrations of 25-OH vitamin D, bone turnover markers [procollagen type 1 N terminal propeptide (P1NP), osteocalcin (OC), C-telopeptide (CTX)] and sclerostin were measured from stored serum obtained at pre-HIV infection, pre-ART and post-ART initiation timepoints. Mixed models, with each biomarker as an outcome, were fitted. Timepoint, age, CD4 count (cells/mm 3 ), HIV-viral suppression, season and an age by timepoint interaction term were considered as fixed effects.ResultsData from 52 participants revealed that median duration between HIV seroconversion and ART initiation was 8.7 years (IQR 3.7-11.6). Median CD4 and plasma HIV-RNA concentrations were 445 (IQR 298.5-689) and 20 184 copies/mL (IQR 6237-64 340), respectively, at the pre-ART timepoint. Multivariate analyses demonstrated pre-HIV infection levels of OC that were higher than pre-ART levels (6.8 versus 5.7 ng/mL, P  =   0.04); and pre-ART levels of sclerostin that were higher than post-ART levels (0.033 versus 0.02 ng/mL, P

BackgroundMonocytes and monocyte-derived macrophages promote atherosclerosis through increased inflammation and vascular remodeling. This may be especially true in chronic human immunodeficiency virus (HIV) infection.MethodsWe examined 778 women (74% HIV+) in the Women's Interagency HIV Study and 503 men (65% HIV+) in the Multicenter AIDS Cohort Study who underwent repeated B-mode carotid artery ultrasound imaging in 2004-2013. We assessed baseline associations of the serum macrophage inflammation markers soluble (s)CD163, sCD14, galectin-3 (Gal-3), and Gal-3 binding protein (Gal-3BP) with carotid plaque formation (focal intima-media thickness >1.5 mm) over 7 years.ResultsMarker levels were higher in HIV+ persons versus HIV- persons. Presence of focal plaque increased over time: from 8% to 15% in women, and 24% to 34% in men. After adjustment for demographic, behavioral, and cardiometabolic factors, and CRP and interleukin-6, each standard deviation increase in sCD14 was associated with increased plaque formation (risk ratio [RR] 1.24, 95% confidence interval [CI] 1.07-1.43). This pattern was consistentby sex. sCD163 was associated with plaque formation in virally suppressed HIV+ men (RR 1.52, 95% CI 1.04-2.22); Gal-3BP and Gal-3 were not associated with increased plaque.ConclusionssCD14 and sCD163 may play important roles in atherogenesis among HIV+ persons.

BackgroundDecreased kidney function and greater albuminuria are associated with increased incidence and extent of coronary artery calcium (CAC). We investigated whether the associations between kidney function and urine protein-to-creatinine ratio (UPCR) with CAC differ by HIV serostatus.MethodsUsing data from the Multicenter AIDS Cohort Study, a prospective multicenter US study of men who have sex with men, we carried out a cross-sectional study comprised of 592 HIV-infected (HIV+) and 378 uninfected (HIV-) men who underwent noncontrast computed tomography to measure CAC. Logistic and linear regression models were used to determine whether HIV infection modified associations of estimated glomerular filtration rate and UPCR with the presence and extent of CAC, adjusting for age, race, and cardiovascular risk factors.ResultsEvery 10 U decrease in estimated glomerular filtration rate below 90 ml/min/1.73 m was significantly associated with 1.3-fold [95% confidence interval (CI): 1.06-1.51] higher odds of CAC presence and was similar by HIV serostatus (Pinteraction=0.37). Greater UPCR was associated with more extensive CAC, with a change in log CAC score of 0.32 (95% CI: 0.10-0.55) per 1% increase in UPCR. There was a strong trend for effect modification by HIV serostatus for this association [HIV-: 0.75 (95% CI: 0.26-1.25); HIV+: 0.22 (95% CI: -0.03 to 0.47), Pinteraction=0.06].ConclusionGreater CAC burden is apparent among individuals with early kidney disease, irrespective of HIV serostatus. Increased UPCR is associated with a greater extent of CAC with a trend for differences by HIV serostatus; a clearer proteinuria/CAC extent relationship was apparent among HIV- patients.

Tenofovir disoproxil fumarate (TDF) can cause kidney damage, but current clinical tests are insensitive for detecting toxicity. Among 884 HIV-infected men enrolled in the Multicenter AIDS Cohort Study, we measured urine biomarkers specific for tubular damage (interleukin-18, kidney injury molecule-1, procollagen type III N-terminal propeptide) and albuminuria. In adjusted analyses, each year of TDF exposure was independently associated with 3.3% higher interleukin-18 (95% CI: 0.8% to 5.8%), 3.4% higher kidney injury molecule-1 (1.1% to 5.7%), and 3.1% higher procollagen type III N-terminal propeptide (0.8% to 5.5%), but not with albuminuria (2.8%; -0.6% to 6.2%). Biomarkers of tubular damage may be more sensitive than albuminuria for detecting toxicity from TDF and other medications.

BackgroundTenofovir disoproxil fumarate (TDF) can cause proximal tubular damage and chronic kidney disease in human immunodeficiency virus (HIV)-infected individuals. Urine α1-microglobulin (A1M), a low-molecular-weight protein indicative of proximal tubular dysfunction, may enable earlier detection of TDF-associated tubular toxicity.Study designCross-sectional.Setting & participants883 HIV-infected and 350 -uninfected men enrolled in the Multicenter AIDS Cohort Study.PredictorsHIV infection and TDF exposure.OutcomeUrine A1M level.ResultsUrine A1M was detectable in 737 (83%) HIV-infected and 202 (58%) -uninfected men (P

IntroductionPrevious studies have demonstrated an association between HIV infection and coronary artery disease (CAD); little is known about potential associations between HIV infection and extra-coronary calcification (ECC).MethodsWe analyzed 621 HIV infected (HIV+) and 384 HIV uninfected (HIV-) men from the Multicenter AIDS Cohort Study who underwent non-contrast computed tomography (CT) from 2010-2013. Agatston scores were calculated for mitral annular calcification (MAC), aortic valve calcification (AVC), aortic valve ring calcification (AVRC), and thoracic aortic calcification (TAC). The associations between HIV infection and the presence of each type of ECC (score > 0) were evaluated by multivariable logistic regression. We also evaluated the association of ECC with inflammatory biomarker levels and coronary plaque morphology.ResultsAmong HIV+ and HIV- men, the age-standardized prevalences were 15% for TAC (HIV+ 14%/HIV- 16%), 10% for AVC (HIV+ 11%/HIV- 8%), 24% for AVRC (HIV+ 23% HIV- 24%), and 5% for MAC (HIV+ 7%/HIV- 3%). After adjustment, HIV+ men had 3-fold greater odds of MAC compared to HIV- men (OR = 3.2, 95% CI: 1.5-6.7), and almost twice the odds of AVC (1.8, 1.1-2.9). HIV serostatus was not associated with TAC or AVRC. AVRC was associated with higher Il-6 and sCD163 levels. TAC was associated with higher ICAM-1, TNF-α RII, and Il-6 levels. AVC and AVRC calcification were associated with presence of non-calcified plaque in HIV+ but not HIV- men.ConclusionHIV infection is an independent predictor of MAC and AVC. Whether these calcifications predict mortality in HIV+ patients deserves further investigation.

BackgroundHepatitis C virus (HCV) infection may increase the risk of cardiovascular disease (CVD). We evaluated the association of chronic HCV infection and coronary atherosclerosis among participants in the Multicenter AIDS Cohort Study.MethodsWe assessed 994 men with or without human immunodeficiency virus (HIV) infection (87 of whom had chronic HCV infection) for coronary plaque, using noncontrast coronary computed tomography (CT); 755 also underwent CT angiography. We then evaluated the associations of chronic HCV infection and HIV infection with measures of plaque prevalence, extent, and stenosis.ResultsAfter adjustment for demographic characteristics, HIV serostatus, behaviors, and CVD risk factors, chronic HCV infection was significantly associated with a higher prevalence of coronary artery calcium (prevalence ratio, 1.29; 95% confidence interval [CI], 1.02-1.63), any plaque (prevalence ratio, 1.26; 95% CI, 1.09-1.45), and noncalcified plaque (prevalence ratio, 1.42; 95% CI, 1.16-1.75). Chronic HCV infection and HIV infection were independently associated with the prevalence of any plaque and of noncalcified plaque, but there was no evidence of a synergistic effect due to HIV/HCV coinfection. The prevalences of coronary artery calcium, any plaque, noncalcified plaque, a mixture of noncalcified and calcified plaque, and calcified plaque were significantly higher among men with an HCV RNA load of ≥2 × 10(6) IU/mL, compared with findings among men without chronic HCV infection.ConclusionsChronic HCV infection is associated with subclinical CVD, suggesting that vigilant assessments of cardiovascular risk are warranted for HCV-infected individuals. Future research should determine whether HCV infection duration or HCV treatment influence coronary plaque development.

BackgroundAging in males is associated with lower testosterone levels and a decrease in diurnal variation of testosterone secretion. Cross-sectional studies have shown lower than expected testosterone levels among HIV-infected men, but whether age-related changes in serum testosterone differ by HIV serostatus are not known.MethodsHIV-infected men from the Multicenter AIDS Cohort Study (MACS), age ≥ 45 years at highly active antiretroviral therapy initiation, who had ≥ 2 samples from the subsequent 10 years, were matched to HIV-uninfected men by age, race, MACS site, and calendar time of samples. Linear mixed-effects regression models were used to determine whether free testosterone (FT) and its rate of change differed by HIV serostatus.ResultsOne hundred eighty-two HIV-infected and 267 HIV-uninfected men were included, median age: 48.8 years (interquartile range: 45.8-53.4), median numbers of FT measurements per participant 4 (interquartile range: 3-5), 65% were drawn in the adjusted morning (AM). Mean-adjusted FT levels were lower among HIV-infected than HIV-uninfected men in AM samples {-6.1 ng/dL [95% confidence interval (CI): -9.8 to -2.4], P = 0.001}, but not in afternoon samples [-1.7 ng/dL (-6.0 to 2.6), P = 0.441]. The rate of FT decline with age did not differ by HIV serostatus: 9.2 ng/dL (95% CI: -13.4 to -5.0) per 10 years for HIV-infected vs. 7.9 ng/dL (95% CI: -10.2 to -5.5) for HIV-uninfected men, P = 0.578.ConclusionsFT decreased similarly with increasing age regardless of HIV serostatus. The lower AM, but not adjusted afternoon, FT levels among HIV-infected men compared with HIV-uninfected men suggest a loss of diurnal variation in FT levels among HIV-infected men.

BackgroundWe characterized associations between smoking, alcohol, and recreational drug use and coronary plaque by HIV serostatus within the Multicenter AIDS Cohort Study (MACS).MethodsMACS participants (N = 1005, 621 HIV+ and 384 HIV-) underwent non-contrast CT scanning to measure coronary artery calcium; 764 underwent coronary CT angiograms to evaluate plaque type and extent. Self-reported use of alcohol, tobacco, smoked/inhaled cocaine, methamphetamine, ecstasy, marijuana, inhaled nitrites, and erectile dysfunction drugs was obtained at semi-annual visits beginning 10 years prior to CT scanning. Multivariable logistic and linear regression models were performed, stratified by HIV serostatus.ResultsAmong HIV+ men, current smoking, former smoking, and cumulative pack years of smoking were positively associated with multiple coronary plaque measures (coronary artery calcium presence and extent, total plaque presence and extent, calcified plaque presence, and stenosis >50%). Smoking was significantly associated with fewer plaque measures of comparable effect size among HIV- men; current smoking and calcified plaque extent was the only such association. Heavy alcohol use (>14 drinks/week) was associated with stenosis >50% among HIV+ men. Among HIV- men, low/moderate (1-14 drinks/week) and heavy alcohol use were inversely associated with coronary artery calcium and calcified plaque extent. Few significant associations between other recreational drug use and plaque measures were observed.ConclusionSmoking is strongly associated with coronary plaque among HIV+ men, underscoring the value of smoking cessation for HIV+ persons. Alcohol use may protect against coronary artery calcium and calcified plaque progression in HIV- (but not HIV+) men. Few positive associations were observed between recreational drug use and coronary plaque measures.

ContextAbnormalities in the osteoprotegerin (OPG)/receptor activator of nuclear factor-κB ligand (RANKL) axis have been observed in HIV-infected persons and have been implicated in cardiovascular disease (CVD) pathogenesis in the general population.ObjectiveTo determine associations of serum OPG and RANKL concentrations with HIV infection and subclinical atherosclerosis.DesignCross-sectional study nested within the Multicenter AIDS Cohort Study.SettingFour US academic medical centers.ParticipantsThere were 578 HIV-infected and 344 HIV-uninfected men.Main outcome measuresCoronary artery calcium (CAC) was measured by noncontrast cardiac computed tomography, and coronary stenosis and plaque characteristics (composition, presence, and extent) were measured by coronary computed tomography angiography. All statistical models were adjusted for traditional CVD risk factors.ResultsOPG concentrations were higher, and RANKL concentrations were lower among HIV-infected men compared with HIV-uninfected men (P < 0.0001 each). Among HIV-infected men, higher OPG concentrations were associated with the presence of CAC, mixed plaque, and coronary stenosis >50%, but not with plaque extent. In contrast, among HIV-uninfected men, higher OPG concentrations were associated with the extent of both CAC and calcified plaque, but not with their presence. RANKL concentrations were not associated with plaque presence or the extent among HIV-infected men, but among HIV-uninfected men, lower RANKL concentrations were associated with greater extent of CAC and total plaque.ConclusionsOPG and RANKL are dysregulated in HIV-infected men, and their relationship to the presence and extent of subclinical atherosclerosis varies by HIV status. The role of these biomarkers in CVD pathogenesis and risk prediction may be different in HIV-infected men.

ObjectiveThe aim of this article is to determine whether HIV-infected (HIV+) men have either higher incidence or more rapid progression of coronary artery calcium (CAC) compared with HIV-uninfected (HIV-) controls.DesignProspective observational study.SettingMulticenter study in four US academic research centers: University of Pittsburgh, Johns Hopkins University, University of California Los Angeles, and Northwestern University.ParticipantsEight hundred and twenty-five men (541 HIV+ and 284 HIV-) enrolled in the cardiovascular substudy of the Multicenter AIDS Cohort Study who underwent serial cardiac computed tomography (CT) imaging during a mean follow-up of 5 years (range, 2-8 years).Main outcome measuresIncidence and progression of CAC assessed by cardiac CT.ResultsDuring follow-up, 21% of HIV+ men developed incident CAC compared with 16% of HIV- men. This association persisted after adjustment for traditional and HIV-associated risk factors: hazard ratio 1.64 (1.13-3.14). However, there was no association between HIV serostatus and CAC progression among men with CAC present at baseline. Current smoking and increased insulin resistance, both modifiable risk factors, were independently associated with increased incidence of CAC. No evidence supporting an elevated risk for either CAC progression or incidence was found for either dyslipidemia or long-term usage of antiretroviral therapy.ConclusionIn this large study of HIV+ and HIV- men who underwent serial cardiac CT scan imaging, HIV+ men were at significantly higher risk for development of CAC: hazard ratio 1.64 (1.13-3.14). In addition, two important and modifiable risk factors were identified for increased incidence of CAC. Taken together, these findings underscore the potential importance for smoking cessation and interventions to improve insulin resistance among HIV+ men.