Plasma Glycomic Markers of Accelerated Biological Aging During Chronic HIV Infection.

People with HIV (PWH) experience an increased vulnerability to premature aging and inflammation-associated comorbidities, even when HIV replication is suppressed by antiretroviral therapy (ART). However, the factors that contribute to or are associated with this vulnerability remain uncertain. In the general population, alterations in the glycomes of circulating IgGs trigger inflammation and precede the onset of aging-associated diseases. Here, we investigate the IgG glycomes of cross-sectional and longitudinal samples from 1,216 women and men, both living with virally suppressed HIV and those without HIV. Our glycan-based machine learning models indicate that living with chronic HIV significantly accelerates the accumulation of pro-aging-associated glycomic alterations. Consistently, PWH exhibit heightened expression of senescence-associated glycan-degrading enzymes compared to their controls. These glycomic alterations correlate with elevated markers of inflammatory aging and the severity of comorbidities, potentially preceding the development of such comorbidities. Mechanistically, HIV-specific antibodies glycoengineered with these alterations exhibit reduced anti-HIV IgG-mediated innate immune functions. These findings hold significant potential for the development of glycomic-based biomarkers and tools to identify and prevent premature aging and comorbidities in people living with chronic viral infections.

Association of marijuana, tobacco and alcohol use with estimated glomerular filtration rate in women living with HIV and women without HIV.

OBJECTIVE: Marijuana, 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. DESIGN: We 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. METHODS: We 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. RESULTS: Marijuana 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. CONCLUSION: Among 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.

Short Communication: Plasma Lymphocyte Activation Gene 3 and Subclinical Coronary Artery Disease in the Multicenter AIDS Cohort Study.

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.

Short Communication: Plasma Lymphocyte Activation Gene 3 and Subclinical Coronary Artery Disease in the Multicenter AIDS Cohort Study.

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.

Associations of Urine Biomarkers with Kidney Function Decline in HIV-Infected and Uninfected Men.

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.

Lung Function, Coronary Artery Disease, and Mortality in HIV.

Rationale: Impaired lung function is a potent independent predictor of coronary artery disease (CAD) in individuals without human immunodeficiency virus (HIV) infection; however, the relationship between lung function and CAD in HIV remains undefined. Objectives: To examine the relationship between lung function, CAD, mortality, and circulating biomarkers in HIV. Methods: Spirometry, diffusing capacity of the lung for carbon monoxide (DlCO), emphysema, coronary artery calcium, mortality, cause of death, and biomarkers were examined in HIV-infected and uninfected individuals enrolled in a cohort study at the University of Pittsburgh. Results were then validated in the Multicenter AIDS Cohort Study (MACS) cohort. Results: We examined data on 234 participants in the Pittsburgh cohort. The mean ± standard deviation age was 49.5 ± 10.2 years old, 82.1% were male, and 67.5% were ever smokers. Among the 177 of 234 individuals with HIV infection, lower DlCO (not forced expiratory volume in 1 second or emphysema) was independently associated with greater coronary artery calcium (odds ratio, 1.43 per 10% lower DlCO; 95% confidence interval, 1.14-1.81). HIV-infected individuals with both reduced DlCO and coronary artery calcium had a much higher mortality than those with either low DlCO or coronary calcium alone or with neither condition. Endothelin-1, a circulating biomarker of endothelial dysfunction, was associated with both lower DlCO and greater coronary artery calcium in those with HIV infection. Results were reproducible in 144 individuals enrolled in the MACS cohort; intercellular adhesion molecule 1 was the biomarker of endothelial dysfunction assessed in the MACS cohort. Conclusions: Impaired DlCO and CAD were associated with each other and with higher mortality in individuals with HIV infection.

Association of Urinary Biomarkers of Kidney Injury with Estimated GFR Decline in HIV-Infected Individuals following Tenofovir Disoproxil Fumarate Initiation.

BACKGROUND AND OBJECTIVES: Tenofovir disoproxil fumarate (tenofovir) is associated with elevated concentrations of biomarkers of kidney damage and dysfunction in individuals with HIV. The relationship of these kidney biomarkers with longitudinal kidney function decline is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We evaluated associations of 14 urinary biomarkers of kidney injury with changes in eGFR among 198 men and women with HIV who initiated tenofovir between 2009 and 2015 in the Multicenter AIDS Cohort Study and Women's Interagency HIV Study. Urinary biomarkers included albumin-to-creatinine ratio, α-1-microglobulin, ß-2-microglobulin, cystatin C, kidney injury molecule-1 (KIM-1), IL-18, neutrophil gelatinase-associated lipocalin (NGAL), clusterin, osteopontin, uromodulin, monocyte chemoattractant protein-1, EGF, trefoil factor 3, and chitinase 3-like protein 1. We used multivariable linear mixed-effect models controlling for demographics, traditional kidney disease risk factors, and HIV-related risk factors to evaluate associations of baseline biomarkers with first-year changes in eGFR, and associations of year 1 and first-year change in biomarkers with changes in eGFR from year 1 to year 3. We used the least absolute shrinkage and selection operator method to identify a parsimonious set of biomarkers jointly associated with changes in eGFR. RESULTS: Median eGFR before tenofovir initiation was 103 (interquartile range, 88-116) ml/min per 1.73 m2. During the first year of tenofovir use, eGFR decreased on average by 9.2 (95% confidence interval, 6.5 to 11.9) ml/min per 1.73 m2 and was stable afterward (decrease of 0.62; 95% confidence interval, -0.85 to 2.1 ml/min per 1.73 m2 per year). After multivariable adjustment, higher baseline ß-2-microglobulin, KIM-1, and clusterin were associated with larger first-year eGFR declines, whereas higher baseline uromodulin was associated with a smaller eGFR decline. First-year increase in urinary cystatin C and higher year 1 IL-18 were associated with larger annual eGFR declines from year 1 to year 3. The parsimonious models identified higher pre-tenofovir clusterin and KIM-1, lower pre-tenofovir uromodulin, and higher year 1 IL-18 as jointly associated with larger eGFR declines. CONCLUSIONS: Urinary biomarkers of kidney injury measured before and after tenofovir initiation are associated with subsequent changes in eGFR in individuals with HIV. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_08_28_CJASNPodcast_18_9_S.mp3.

No reliable gene expression biomarkers of current or impending neurocognitive impairment in peripheral blood monocytes of persons living with HIV.

Events leading to and propagating neurocognitive impairment (NCI) in HIV-1-infected (HIV+) persons are largely mediated by peripheral blood monocytes. We previously identified expression levels of individual genes and gene networks in peripheral blood monocytes that correlated with neurocognitive functioning in HIV+ adults. Here, we expand upon those findings by examining if gene expression data at baseline is predictive of change in neurocognitive functioning 2 years later. We also attempt to validate the original findings in a new sample of HIV+ patients and determine if the findings are HIV specific by including HIV-uninfected (HIV-) participants as a comparison group. At two time points, messenger RNA (mRNA) was isolated from the monocytes of 123 HIV+ and 60 HIV- adults enrolled in the Multicenter AIDS Cohort Study and analyzed with the Illumina HT-12 v4 Expression BeadChip. All participants received baseline and follow-up neurocognitive testing 2 years after mRNA analysis. Data were analyzed using standard gene expression analysis and weighted gene co-expression network analysis with correction for multiple testing. Gene sets were analyzed for GO term enrichment. Only weak reproducibility of associations of single genes with neurocognitive functioning was observed, indicating that such measures are unreliable as biomarkers for HIV-related NCI; however, gene networks were generally preserved between time points and largely reproducible, suggesting that these may be more reliable. Several gene networks associated with variables related to HIV infection were found (e.g., MHC I antigen processing, TNF signaling, interferon gamma signaling, and antiviral defense); however, no significant associations were found for neurocognitive function. Furthermore, neither individual gene probes nor gene networks predicted later neurocognitive change. This study did not validate our previous findings and does not support the use of monocyte gene expression profiles as a biomarker for current or future HIV-associated neurocognitive impairment.

The Association of Inflammatory Markers With Nonalcoholic Fatty Liver Disease Differs by Human Immunodeficiency Virus Serostatus.

BACKGROUND: We aimed to determine the relationship of circulating adipokines and inflammatory biomarkers with fatty liver among men in the Multicenter AIDS Cohort Study. METHODS: Noncontrast computed tomography was used to assess fatty liver and measure abdominal visceral adipose tissue (VAT) area in 526 participants without history of cardiovascular disease, heavy alcohol use, or viral hepatitis infection. Multivariable logistic regression was used to assess associations of circulating biomarker levels with fatty liver. RESULTS: Three hundred twenty-nine human immunodeficiency virus (HIV)-infected men had higher levels of several inflammatory biomarkers compared with 197 HIV-uninfected men. Among HIV-uninfected men, increased adiponectin was associated with lower odds of fatty liver (odds ratio [OR] = 0.51 per doubling, P = .02), whereas higher odds of fatty liver was observed with increased levels of the proinflammatory markers intercellular adhesion molecule (ICAM)-1 (OR = 5.30, P = .004), C-reactive protein (OR = 1.66, P = .002), interleukin (IL)-6 (OR = 1.67, P = .03), and tumor necrosis factor α receptor 2 (OR = 6.55, P = .003). Among HIV-infected men, ICAM-1 was the only proinflammatory marker associated with greater odds of fatty liver (OR = 2.67, P = .02), whereas higher adiponectin (OR = 0.57, P = .003), and osteoprotegerin levels (OR = 0.48, P = .03) were associated with lower odds. These associations were all independent of VAT. CONCLUSIONS: Fatty liver is associated with a heightened inflammatory state independent of visceral adiposity in HIV-uninfected men but not in HIV-infected men. However, a heightened anti-inflammatory state may protect against fatty liver regardless of HIV serostatus.

Association of Macrophage Inflammation Biomarkers With Progression of Subclinical Carotid Artery Atherosclerosis in HIV-Infected Women and Men.

Background: Monocytes and monocyte-derived macrophages promote atherosclerosis through increased inflammation and vascular remodeling. This may be especially true in chronic human immunodeficiency virus (HIV) infection. Methods: We 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. Results: Marker 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. Conclusions: sCD14 and sCD163 may play important roles in atherogenesis among HIV+ persons.

Inflammatory Markers Associated With Subclinical Coronary Artery Disease: The Multicenter AIDS Cohort Study.

BACKGROUND: Despite evidence for higher risk of coronary artery disease among HIV+ individuals, the underlying mechanisms are not well understood. We investigated associations of inflammatory markers with subclinical coronary artery disease in 923 participants of the Multicenter AIDS Cohort Study (575 HIV+ and 348 HIV- men) who underwent noncontrast computed tomography scans for coronary artery calcification, the majority (n=692) also undergoing coronary computed tomography angiography. METHODS AND RESULTS: Outcomes included presence and extent of coronary artery calcification, plus computed tomography angiography analysis of presence, composition, and extent of coronary plaques and severity of coronary stenosis. HIV+ men had significantly higher levels of interleukin-6 (IL-6), intercellular adhesion molecule-1, C-reactive protein, and soluble-tumor necrosis factor-α receptor (sTNFαR) I and II (all P<0.01) and a higher prevalence of noncalcified plaque (63% versus 54%, P=0.02) on computed tomography angiography. Among HIV+ men, for every SD increase in log-interleukin-6 and log intercellular adhesion molecule-1, there was a 30% and 60% increase, respectively, in the prevalence of coronary stenosis ≥50% (all P<0.05). Similarly, sTNFαR I and II in HIV+ participants were associated with an increase in prevalence of coronary stenosis ≥70% (P<0.05). Higher levels of interleukin-6, sTNFαR I, and sTNFαR II were also associated with greater coronary artery calcification score in HIV+ men (P<0.01). CONCLUSIONS: Higher inflammatory marker levels are associated with greater prevalence of coronary stenosis in HIV+ men. Our findings underscore the need for further study to elucidate the relationships of inflammatory pathways with coronary artery disease in HIV+ individuals.

Extra-coronary calcification (aortic valve calcification, mitral annular calcification, aortic valve ring calcification and thoracic aortic calcification) in HIV seropositive and seronegative men: Multicenter AIDS Cohort Study.

INTRODUCTION: Previous 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). METHODS: We 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. RESULTS: Among 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. CONCLUSION: HIV infection is an independent predictor of MAC and AVC. Whether these calcifications predict mortality in HIV+ patients deserves further investigation.

Associations between Tobacco, Alcohol, and Drug Use with Coronary Artery Plaque among HIV-Infected and Uninfected Men in the Multicenter AIDS Cohort Study.

BACKGROUND: We characterized associations between smoking, alcohol, and recreational drug use and coronary plaque by HIV serostatus within the Multicenter AIDS Cohort Study (MACS). METHODS: MACS 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. RESULTS: Among 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. CONCLUSION: Smoking 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.

Incidence and progression of coronary artery calcium in HIV-infected and HIV-uninfected men.

OBJECTIVE: The 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. DESIGN: Prospective observational study. SETTING: Multicenter study in four US academic research centers: University of Pittsburgh, Johns Hopkins University, University of California Los Angeles, and Northwestern University. PARTICIPANTS: Eight 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 MEASURES: Incidence and progression of CAC assessed by cardiac CT. RESULTS: During 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. CONCLUSION: In 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.

Incident Hepatitis B Virus Infection in HIV-Infected and HIV-Uninfected Men Who Have Sex With Men From Pre-HAART to HAART Periods: A Cohort Study.

BACKGROUND: Men who have sex with men (MSM) are at high risk for hepatitis B virus (HBV) infection. Data on the effect of highly active antiretroviral therapy (HAART) on incident HBV infection in HIV-infected and HIV-uninfected MSM are limited. OBJECTIVE: To determine predictors of incident HBV infection in MSM during pre-HAART and HAART periods. DESIGN: Observational cohort study. SETTING: Cohort of MSM who have, or are at risk for, HIV infection. PATIENTS: 2375 HBV-uninfected MSM in the Multicenter AIDS Cohort Study. MEASUREMENTS: Poisson regression was used to compare incidence rates of HBV infection in the pre-HAART and HAART eras and to identify factors associated with incidence of HBV infection. RESULTS: In 25,322 person-years of follow-up, 244 incident HBV infections occurred. The unadjusted incidence rate was higher in HIV-infected MSM than in HIV-uninfected MSM (incidence rate ratio [IRR], 1.9 [95% CI, 1.5 to 2.4]) and was significantly lower in the HAART era than in the pre-HAART era among HIV-infected (IRR, 0.2 [CI, 0.1 to 0.4]) and HIV-uninfected (IRR, 0.3 [CI, 0.2 to 0.4]) MSM. Age younger than 40 years (IRR, 2.3 [CI, 1.7 to 3.0]), more than 1 recent sexual partner (IRR, 3.1 [CI, 2.3 to 4.2]), and HIV infection (IRR, 2.4 [CI, 1.8 to 3.1]) were independently associated with higher incidence of HBV infection, whereas HBV vaccination was protective (IRR, 0.3 [CI, 0.2 to 0.4]). Highly active antiretroviral therapy with HIV RNA levels less than 400 copies/mL was associated with protection (IRR, 0.2 [CI, 0.1 to 0.5]), but HAART in those with HIV RNA levels of 400 copies/mL or greater was not. LIMITATION: The observational nature limits inferences about causality. CONCLUSION: Effective HAART is associated with lower incidence of HBV infection; however, even in the HAART era, incidence of HBV infection remains high among MSM. PRIMARY FUNDING SOURCE: National Institute of Allergy and Infectious Diseases.

Osteoprotegerin, but Not Receptor Activator for Nuclear Factor-κB Ligand, is Associated With Subclinical Coronary Atherosclerosis in HIV-Infected Men.

CONTEXT: Abnormalities 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. OBJECTIVE: To determine associations of serum OPG and RANKL concentrations with HIV infection and subclinical atherosclerosis. DESIGN: Cross-sectional study nested within the Multicenter AIDS Cohort Study. SETTING: Four US academic medical centers. PARTICIPANTS: There were 578 HIV-infected and 344 HIV-uninfected men. MAIN OUTCOME MEASURES: Coronary 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. RESULTS: OPG 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. CONCLUSIONS: OPG 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.

Low-Density Lipoprotein Cholesterol Levels and Statin Treatment by HIV Status Among Multicenter AIDS Cohort Study Men.

Treating cardiovascular disease (CVD) risk factors, including dyslipidemia, is important in HIV care. Low-density lipoprotein cholesterol (LDL-c) target achievement is a readily available benchmark for dyslipidemia control, although use of this target is not uniformly endorsed by professional societies. We examined whether HIV serostatus is associated with not achieving LDL-c target. Among Multicenter AIDS Cohort Study (MACS) participants completing visit 56 (10/1/2011-3/31/2012), we categorized each man as on or off statin therapy and used NCEP ATP III guidelines to determine if each man was at LDL-c target or not at target. We compared proportions of men not at target and determined predictors using multivariate logistic regression. Sixty of 543 (11.1%) HIV-infected men and 87 of 585 (14.9%) HIV-uninfected men not receiving statin therapy were not at target (p=0.07), while 31 of 230 (13.5%) HIV-infected and 29 of 204 (14.2%) HIV-uninfected men receiving statin therapy were not at target (p=0.82). Factors associated with not being at target (among men not receiving statin therapy) included current smoking (OR=2.31, 95% CI 1.31, 4.06) and a diagnosis of hypertension (OR=4.69, 95% CI 2.68, 8.21). Factors associated with not being at target (among men receiving statin therapy) included current smoking (OR=2.72, 95% CI 1.30, 5.67) and diabetes (OR=5.31, 95% CI 2.47, 11.42). HIV-infected and HIV-uninfected men receiving statin therapy demonstrated similar nonachievement of LDL-c targets. Comorbidities (e.g., diabetes) lowered targets and may explain why goals were less likely to be met.

Comparison of racial differences in plaque composition and stenosis between HIV-positive and HIV-negative men from the Multicenter AIDS Cohort Study.

Previous studies demonstrated that blacks have less coronary artery calcification (CAC) than whites. We evaluated racial differences in plaque composition and stenosis in the Multicenter AIDS Cohort Study. HIV-positive and HIV-negative men underwent noncontrast cardiac computed tomography (CT) if they were aged 40 to 70 years, weighed <136 kg, and had no history of cardiac surgery or revascularization and, if eligible, coronary CT angiography (CTA). There were 1,001 men who underwent CT scans and 759 men CTA. We measured CAC on noncontrast CT and identified total plaque, noncalcified plaque, calcified plaque, mixed plaque, and coronary stenosis >50% on CTA. The association of presence and extent of plaque with race was determined after adjustment for HIV serostatus, cardiovascular risk factors, and measures of socioeconomic status. The prevalences of any plaque on CTA and noncalcified plaque were not different between black and white men; however, black men had lower prevalences of CAC (prevalence ratio [PR] 0.79, p = 0.01), calcified plaque (PR 0.69, p = 0.002), and stenosis >50% (PR 0.59, p = 0.009). There were no associations between black race and extent of plaque in fully adjusted models. Using log-linear regression, black race was associated with a lower extent of any plaque on CTA in HIV-positive men (estimate = -0.24, p = 0.051) but not in HIV-negative men (0.12, p = 0.50, HIV interaction p = 0.005). In conclusion, a lower prevalence of CAC in black compared with white men appears to reflect less calcification of plaque and stenosis rather than a lower overall prevalence of plaque.

Maraviroc intensification in patients with suppressed HIV viremia has limited effects on CD4+ T cell recovery and gene expression.

Addition of the CCR5 inhibitor Maraviroc (MVC) to ongoing antiretroviral therapy increases CD4+ T cell counts in some virologically suppressed patients with suboptimal CD4+ T cell recovery. To understand the mechanisms by which MVC elicits increases in CD4+ T cell counts, the present study was undertaken to identify host factors (i.e. genes) that are modulated and are correlated with CD4+ T cell recovery during the 24weeks of MVC intensification in 32 subjects. Median changes of CD4+ T cell counts over 24weeks of MVC compared to baseline were 38cells/mm(3) (p<0.001). The median slope of CD4+ T cell recovery was 39cells/mm(3) per year before initiation of MVC and 76cells/mm(3) per year during MVC intensification, however, this increase was not statistically significant (p=0.33). Microarray analysis (N=31,426 genes) identified a single differentially expressed gene, tumor necrosis factor alpha (TNF), which was modestly (1.44-fold, p<0.001) downregulated by MVC at week 24 compared to baseline. TNF differential expression was evaluated using an independent method of droplet digital PCR, but the difference was not significant (p=0.6). Changes in gene expression did not correlate with CD4+ T cell recovery or any changes in the CD4+ T cell maturation, proliferation and activation phenotypes. In summary, our data suggest that modest improvements of CD4+ T cell counts during MVC intensification cannot be explained by changes in gene expression elicited by MVC. However, the modest changes in T cell composition, including reduction of the percentages of Tregs, proliferating CD4+ T cells and senescent CD8+ T cells, suggest immunologically favorable effects of MVC.

The impact of age on the prognostic capacity of CD8+ T-cell activation during suppressive antiretroviral therapy.

OBJECTIVE: To assess whether CD8 T-cell activation predicts risk of AIDS and non-AIDS morbidity during suppressive antiretroviral treatment (ART). DESIGN: Post-hoc analyses of ART-naive participants in prospective ART studies. Participants with HIV-RNA levels 200 copies/ml or less and CD8 T-cell activation data (%CD38HLA-DR) at year-1 of ART were selected to determine years 2-5 incidence of AIDS and non-AIDS events. METHODS: We censored data at time of ART interruption or virologic failure. Inverse probability of censoring-weighted logistic regression was used to correct for informative censoring. RESULTS: We included 1025 participants; 82% were men, median age 38 years, pre-ART CD4 cell count 255 cells/µl, and year-1-activated CD8 T cells 24%. Of these, 752 had 5 years of follow-up; 379 remained on ART and had no confirmed plasma HIV-RNA more than 200 copies/ml. The overall probability of an AIDS or non-AIDS event in years 2-5 was estimated at 13% [95% confidence interval (CI) 10-15%] had everyone remained on suppressive ART. Higher year-1-activated CD8 T-cell percentage increased the probability of subsequent events [odds ratio 1.22 per 10% higher (95% CI 1.04-1.44)]; this effect was not significant after adjusting for age. Among those age 50 years at least (n=108 at year 1), the probability of an event in years 2-5 was 37% and the effect of CD8 T-cell activation was more apparent (odds ratio=1.42, P=0.02 unadjusted and adjusted for age). CONCLUSION: CD8 T-cell activation is prognostic of clinical events during suppressive ART, although this association is confounded by age. The consequences of HIV-associated immune activation may be more important in patients 50 years and older.