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.

HIV infection is an independent risk factor for decreased 6-minute walk test distance.

BACKGROUND: Ambulatory function predicts morbidity and mortality and may be influenced by cardiopulmonary dysfunction. Persons living with HIV (PLWH) suffer from a high prevalence of cardiac and pulmonary comorbidities that may contribute to higher risk of ambulatory dysfunction as measured by 6-minute walk test distance (6-MWD). We investigated the effect of HIV on 6-MWD. METHODS: PLWH and HIV-uninfected individuals were enrolled from 2 clinical centers and completed a 6-MWD, spirometry, diffusing capacity for carbon monoxide (DLCO) and St. George's Respiratory Questionnaire (SGRQ). Results of 6-MWD were compared between PLWH and uninfected individuals after adjusting for confounders. Multivariable linear regression analysis was used to determine predictors of 6-MWD. RESULTS: Mean 6-MWD in PLWH was 431 meters versus 462 in 130 HIV-uninfected individuals (p = 0.0001). Older age, lower forced expiratory volume (FEV1)% or lower forced vital capacity (FVC)%, and smoking were significant predictors of decreased 6-MWD in PLWH, but not HIV-uninfected individuals. Lower DLCO% and higher SGRQ were associated with lower 6-MWD in both groups. In a combined model, HIV status remained an independent predictor of decreased 6-MWD (Mean difference = -19.9 meters, p = 0.005). CONCLUSIONS: HIV infection was associated with decreased ambulatory function. Airflow limitation and impaired diffusion capacity can partially explain this effect. Subjective assessments of respiratory symptoms may identify individuals at risk for impaired physical function who may benefit from early intervention.

Predictors of electrocardiographic QT interval prolongation in men with HIV.

OBJECTIVE: HIV-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. METHODS: We 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. RESULTS: After adjusting for demographics and risk factors, QTc was 4.0 ms longer in HIV+ than HIV- men (p<0.001). Use of antiretroviral therapy (ART), specific ART drug class use and other HIV-specific risk factors were not associated with longer QTc. Among the subgroup with inflammatory biomarker measurements, higher interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1) and B-cell activating factor levels were independently associated with longer QTc and their inclusion partially attenuated the HIV effect. CONCLUSIONS: HIV+ men had longer QTc, which was associated with higher levels of systemic inflammatory factors. This longer QTc may contribute to the increased risk for sudden arrhythmic cardiac death in some HIV+ individuals.

Systemic Inflammation Characterizes Lack of Metabolic Health in Nonobese HIV-Infected Men.

BACKGROUND: Increasing body mass index (BMI) is generally associated with loss of metabolic health, although some obese individuals remain metabolically healthy. Among nonobese men, HIV infection has been associated with a lower prevalence of metabolic health. METHODS: We conducted a cross-sectional analysis of 470 HIV-infected and 368 HIV-uninfected men enrolled in the Multicenter AIDS Cohort Study Cardiovascular substudy. Circulating biomarker levels were compared by BMI category and by HIV serostatus. Poisson regression with robust variance determined associations between metabolic health and circulating inflammatory biomarker levels after adjusting for factors previously associated with metabolic health. RESULTS: HIV-infected men were younger and less likely to be obese. Among HIV-infected, normal weight metabolically healthy men (compared to unhealthy) had significantly lower circulating levels of interleukin- (IL-) 6, soluble tumor necrosis factor receptors (sTNFR) I and II, and homeostatic model assessment of insulin resistance (HOMA-IR), higher adiponectin, less visceral fat, and more subcutaneous fat. Among HIV-uninfected normal weight men and obese men (regardless of HIV serostatus), metabolic health was associated only with higher levels of adiponectin, less visceral fat, and lower HOMA-IR values. In multivariate analyses restricted to HIV-infected men, lower hs-CRP, sTNFRI, sTNFRII, and HOMA-IR and higher adiponectin levels were associated with metabolic health. Additional adjustment for visceral adiposity did not alter results. CONCLUSIONS: Among HIV-infected normal weight men, metabolic health was associated with less systemic inflammation, a relationship that, among normal weight men, was unique to HIV+ men and did not exist among obese men of either HIV serostatus.

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.

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.

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.

Circulating mediators of inflammation and immune activation in AIDS-related non-hodgkin lymphoma.

BACKGROUND: Non-Hodgkin lymphoma (NHL) is the most common AIDS-related malignancy in developed countries. An elevated risk of developing NHL persists among HIV-infected individuals in comparison to the general population despite the advent of effective antiretroviral therapy. The mechanisms underlying the development of AIDS-related NHL (A-NHL) are not fully understood, but likely involve persistent B-cell activation and inflammation. METHODS: This was a nested case-control study within the ongoing prospective Multicenter AIDS Cohort Study (MACS). Cases included 47 HIV-positive male subjects diagnosed with high-grade B-cell NHL. Controls were matched to each case from among participating HIV-positive males who did not develop any malignancy. Matching criteria included time HIV+ or since AIDS diagnosis, age, race and CD4+ cell count. Sera were tested for 161 serum biomarkers using multiplexed bead-based immunoassays. RESULTS: A subset of 17 biomarkers, including cytokines, chemokines, acute phase proteins, tissue remodeling agents and bone metabolic mediators was identified to be significantly altered in A-NHL cases in comparison to controls. Many of the biomarkers included in this subset were positively correlated with HIV viral load. A pathway analysis of our results revealed an extensive network of interactions between current and previously identified biomarkers. CONCLUSIONS: These findings support the current hypothesis that A-NHL develops in the context of persistent immune stimulation and inflammation. Further analysis of the biomarkers identified in this report should enhance our ability to diagnose, monitor and treat this disease.

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.

Lipodystrophy and inflammation predict later grip strength in HIV-infected men: the MACS Body Composition substudy.

Body fat changes in HIV-infected persons are associated with increased systemic inflammation and increased mortality. It is unknown whether lipodystrophy is also associated with declines in physical function. Between 2001 and 2003, 33 HIV-infected men with evidence of lipodystrophy (LIPO⁺), 23 HIV-infected men without lipodystrophy (LIPO⁻), and 33 seronegative men were recruited from the Multicenter AIDS Cohort Study (MACS) for the Body Composition substudy. Visceral adipose tissue (VAT) was assessed by quantitative computed tomography. Lean body mass (LBM) and extremity fat were measured by dual-energy x-ray absorptiometry. Insulin resistance was estimated by Homeostatic Model Assessment (HOMA). Serum interleukin (IL)-6, soluble tumor necrosis factor (TNF)-α receptors I and II (sTNFRI and sTNFRII), and highly sensitive C-reactive protein (hs-CRP) concentrations were quantified from archived serum samples. These measurements were correlated with grip strength measured in 2007 using linear regression. At the substudy visit, the LIPO⁺ group had higher HOMA, sTNFRI, sTNFRII, and IL-6 levels than the LIPO⁻ group. In 2007, the LIPO⁺ group had lower median grip strength than the LIPO⁻ group (34.4 vs. 42.7 kg, p=0.002). Multivariable analysis of HIV⁺ men showed older age, lower LBM, higher sTNFRII concentrations, and LIPO⁺ status [adjusted mean difference -4.9 kg (p=0.045)] at the substudy visit were independently associated with lower subsequent grip strength. Inflammation, lower LBM, and lipodystrophy in HIV-infected men were associated with lower subsequent grip strength. These findings suggest that inflammation may contribute to declines in functional performance, independent of age.

Comparison of QIAsymphony automated and QIAamp manual DNA extraction systems for measuring Epstein-Barr virus DNA load in whole blood using real-time PCR.

Automated and manual extraction systems have been used with real-time PCR for quantification of Epstein-Barr virus [human herpesvirus 4 (HHV-4)] DNA in whole blood, but few studies have evaluated relative performances. In the present study, the automated QIAsymphony and manual QIAamp extraction systems (Qiagen, Valencia, CA) were assessed using paired aliquots derived from clinical whole-blood specimens and an in-house, real-time PCR assay. The detection limits using the QIAsymphony and QIAamp systems were similar (270 and 560 copies/mL, respectively). For samples estimated as having ≥10,000 copies/mL, the intrarun and interrun variations were significantly lower using QIAsymphony (10.0% and 6.8%, respectively), compared with QIAamp (18.6% and 15.2%, respectively); for samples having ≤1000 copies/mL, the two variations ranged from 27.9% to 43.9% and were not significantly different between the two systems. Among 68 paired clinical samples, 48 pairs yielded viral loads ≥1000 copies/mL under both extraction systems. Although the logarithmic linear correlation from these positive samples was high (r(2) = 0.957), the values obtained using QIAsymphony were on average 0.2 log copies/mL higher than those obtained using QIAamp. Thus, the QIAsymphony and QIAamp systems provide similar EBV DNA load values in whole blood.

Asymptomatic primary Merkel cell polyomavirus infection among adults.

Merkel cell polyomavirus (MCV) is a recently discovered virus that causes 80% of Merkel cell carcinomas. We examined data for 564 gay/bisexual male participants >18 years of age in the Multicenter AIDS Cohort Study in Pittsburgh, Pennsylvania, USA, and found that 447 (79.3%) were MCV-antibody positive at initial enrollment. Of the 117 MCV-seronegative men, 31 subsequently seroconverted over a 4-year follow-up period, corresponding to a 6.6% annual conversion rate. MCV immunoglobulin G levels remained detectable up to 25 years after exposure. No signs, symptoms, or routine diagnostic test results were associated with MCV infection, and no correlation between HIV infection or AIDS progression and MCV infection was noted. An initial correlation between chronic hepatitis B virus infection and MCV prevalence could not be confirmed among MCV seroconverters or in studies of a second hepatitis B virus-hyperendemic cohort from Qidong, China. In adults, MCV is typically an asymptomatic, common, and commensal viral infection that initiates rare cancers after virus (rather than host cell) mutations.

Pulse wave analysis and prevalent cardiovascular disease in type 1 diabetes.

OBJECTIVE: Type 1 diabetes (T1D) is associated with a high risk for and mortality from premature coronary artery disease (CAD), including coronary artery calcification (CAC), a subclinical marker, and lower extremity arterial disease (LEAD). Pulse wave analysis (PWA) arterial stiffness indices have been associated with cardiovascular disease (CVD) risk factors and outcomes in various populations, but little is known regarding these relationships in T1D. METHODS: PWA was performed using the SphygmoCor Px device on 144 participants in the Pittsburgh EDC Study of childhood-onset T1D. The cross-sectional associations between arterial stiffness indices, augmentation index (AIx) and augmentation pressure (AP), and subendocardial viability ratio (SEVR), an estimate of myocardial perfusion, with prevalent CAD, electron beam computed tomography-measured CAC and low (<0.90) ankle-brachial index (ABI) were examined. RESULTS: Higher AP (but not AIx) and lower SEVR were univariately associated with prevalent CAD, high CAC score, and low ABI. AP and SEVR's association with CAD and CAC did not, however, remain significant after adjustment for age. In individuals not using nitrates, which profoundly affect PWA measures, AP was significantly higher in those with CAD events and explained more of the variance than either age or brachial blood pressure measures. SEVR was associated with low ABI in multivariable models. CONCLUSIONS: Greater augmentation pressure is independently associated with prevalent CAD and estimated myocardial perfusion with low ABI in type 1 diabetes. These measures may thus help to better characterize CVD risk in type 1 diabetes and need to be examined prospectively.

Augmentation pressure and subendocardial viability ratio are associated with microalbuminuria and with poor renal function in type 1 diabetes.

In this report we explore the hypothesis that arterial stiffness indices, which predict cardiovascular disease, might also correlate with microalbuminuria (MA) in type 1 diabetes (T1D), and thus have potential for risk assessment. Three pulse wave analysis (PWA) indices, measured using the SphygmoCor device, were evaluated on 144 participants with childhood-onset T1D. These variables, augmentation index (AIx), augmentation pressure (AP) and subendocardial viability ratio (SEVR, an estimate of myocardial perfusion) (an estimate of myocardial perfusion), were each analysed cross-sectionally in relation to both prevalent MA (defined as albuminuria excretion rate (AER) = 20-199 microg/min) and renal function (assessed by both eGFR and serum cystatin C). AP and SEVR were each univariately associated with AER, estimated glomerular filtration rate (eGFR) and cystatin C. Lower SEVR was also independently related to the presence of MA and degree of albuminuria within normo- and microalbuminuric participants. SEVR, not AP, was independently and negatively associated with both measures of renal function. SEVR is a better predictor of AER than brachial blood pressure measures in those without clinical proteinuria, indicating a potential use for PWA in the early detection of individuals at risk for cardiovascular and renal complications of T1D.

Cardiovascular autonomic neuropathy, HDL cholesterol, and smoking correlate with arterial stiffness markers determined 18 years later in type 1 diabetes.

OBJECTIVE To examine the relationship between cardiovascular autonomic neuropathy and pulse waveform analysis (PWA) measures of arterial stiffness in a childhood-onset type 1 diabetes population. RESEARCH DESIGN AND METHODS Cardiac autonomic nerve function was measured in the baseline examination of the Pittsburgh Epidemiology of Diabetes Complications Study of childhood-onset type 1 diabetes by heart rate variability (R-R interval) during deep breathing and expressed as expiration-to-inspiration (E/I) ratio. Other cardiovascular and diabetes factors were also assessed. PWA was performed using SphgymoCor Px on 144 participants at the 18-year follow-up examination. Univariate and multivariate analyses for associations between baseline nerve function and other cardiovascular and diabetes-related factors were performed for augmentation index (AIx), augmentation pressure (AP), and subendocardial viability ratio (SEVR), a surrogate marker of myocardial perfusion. RESULTS E/I ratio correlated negatively with both AIx (r = -0.18, P = 0.03) and AP (r = -0.32, P < 0.001) and positively with SEVR (r = 0.47, P < 0.001) univariately. Lower baseline E/I ratio, HDL cholesterol, and a history of smoking were associated with higher follow-up (18 years later) AIx and AP and lower SEVR in multivariate analyses. Higher baseline HbA(1) was also associated with higher AP and lower SEVR multivariately. CONCLUSIONS Cardiovascular autonomic neuropathy is associated with increased arterial stiffness measures and decreased estimated myocardial perfusion in those with type 1 diabetes some 18 years later. This association persists after adjustment for potential confounders as well as for baseline HbA(1), HDL cholesterol, and smoking history, which were also associated with these PWA measures.

Subclinical coronary atherosclerosis, HIV infection and antiretroviral therapy: Multicenter AIDS Cohort Study.

OBJECTIVE: To evaluate the association of HIV infection and cumulative exposure to highly active antiretroviral therapy (HAART) with the presence and extent of coronary artery calcification (CAC). DESIGN: A cross-sectional study of 947 male participants (332 HIV-seronegative, 84 HAART-naive and 531 HAART-experienced HIV-infected) from the Multicenter AIDS Cohort Study. METHODS: The main outcome was CAC score calculated as the geometric mean of the Agatston scores of two computed tomography replicates. Presence of CAC was defined as calcification score above 10, and extent of CAC by the score for those with CAC present. Multivariable regression was used to evaluate the association between HIV infection and HAART and presence and extent of calcification. RESULTS: Increasing age was most strongly associated with both prevalence and extent of CAC for all study groups. After adjustment for age, race, family history, smoking, high-density lipoprotein-C, low-density lipoprotein-C and hypertension, HIV infection (odds ratio, 1.35; 95% confidence interval, 0.70, 2.61) and long-term HAART use (odds ratio, 1.33; 95% confidence interval, 0.87, 2.05) increased the odds for presence of CAC. In contrast, after adjustment for these covariates, the extent of CAC was lower among HAART users. Among those not taking lipid-lowering therapy, HAART usage of at least 8 years was associated with significantly reduced CAC scores (relative CAC score, 0.43; 95% confidence interval, 0.24, 0.79). CONCLUSION: HAART use may have different effects on the presence and extent of coronary calcification. Although prevalence of calcification was marginally increased among long-term HAART users, the extent of calcification was significantly reduced among HAART users compared with HIV-seronegative controls.

Low CD4+ T-cell count as a major atherosclerosis risk factor in HIV-infected women and men.

OBJECTIVE: To assess the association of HIV infection, HIV disease parameters (including CD4+ T-cell counts, HIV viral load, and AIDS) and antiretroviral medication use with subclinical carotid artery atherosclerosis. DESIGN: Cross-sectional study nested within a prospective cohort study. METHODS: Among participants in the Women's Interagency HIV Study (1331 HIV-infected women, 534 HIV-uninfected women) and Multicenter AIDS Cohort Study (600 HIV-infected men, 325 HIV-uninfected men), we measured subclinical carotid artery lesions and common carotid artery intima-media thickness using B-mode ultrasound. We estimated adjusted mean carotid artery intima-media thickness differences and prevalence ratios for carotid lesions associated with HIV-related disease and treatments, with multivariate adjustment to control for possible confounding variables. RESULTS: Among HIV-infected individuals, a low CD4+ T-cell count was independently associated with an increased prevalence of carotid lesions. Compared with the reference group of HIV-uninfected individuals, the adjusted prevalence ratio for lesions among HIV-infected individuals with CD4+ T-cell count less than 200 cells/mul was 2.00 (95% confidence interval, 1.22-3.28) in women and 1.74 (95% confidence interval, 1.04-2.93) in men. No consistent association of antiretroviral medications with carotid atherosclerosis was observed, except for a borderline significant association between protease inhibitor use and carotid lesions in men (with no association among women). History of clinical AIDS and HIV viral load were not significantly associated with carotid atherosclerosis. CONCLUSION: Beyond traditional cardiovascular disease risk factors, low CD4+ T-cell count is the most robust risk factor for increased subclinical carotid atherosclerosis in HIV-infected women and men.

Ten-year predicted coronary heart disease risk in HIV-infected men and women.

BACKGROUND: Highly active antiretroviral therapy (HAART), in addition to traditional vascular risk factors, may affect coronary heart disease (CHD) risk in individuals with human immunodeficiency virus (HIV) infection. METHODS: Among HIV-infected (931 men and 1455 women) and HIV-uninfected (1099 men and 576 women) adults, the predicted risk of CHD was estimated on the basis of age, sex, lipid and blood pressure levels, the presence of diabetes, and smoking status. RESULTS: Among HIV-infected men, 2% had moderate predicted risk of CHD (10-year CHD risk, 15%-25%), and 17% had high predicted risk (10-year CHD risk of > or = 25% or diabetes). Among HIV-infected women, 2% had moderate predicted CHD risk, and 12% had high predicted CHD risk. Compared with users of protease inhibitor-based HAART, the adjusted odds ratio (OR) for moderate-to-high risk of CHD was significantly lower among HAART-naive individuals (OR, 0.57; 95% confidence interval [CI], 0.36-0.89). Users of HAART that was not protease inhibitor based (OR, 0.74; 95% CI, 0.53-1.01) and former HAART users (OR, 0.68; 95% CI, 0.46-1.03) were also less likely than users of protease inhibitor-based HAART to have moderate-to-high CHD risk, although 95% CIs overlapped the null. Low income was associated with increased likelihood of moderate-to-high CHD risk (for annual income < $10,000 vs. > $40,000: OR, 2.32; 95% CI, 1.51-3.56 ). Elevated body mass index (calculated as weight in kilograms divided by the square of height in meters) predicted increased likelihood of moderate-to-high CHD risk (for BMI of 18.5-24.9 vs. BMI of 25-30: OR, 1.41 [95% CI, 1.03-1.93]; for BMI of 18.5-24.9 vs. BMI > or = 30: OR, 1.79 [95% CI, 1.25-2.56]). CONCLUSIONS: Among HIV-infected adults, in addition to antiretroviral drug exposures, being overweight and having a low income level were associated with increased predicted CHD risk. This suggests a need to target HIV-infected men and women with these characteristics for vascular risk factor screening.

Use of a multiantigen detection algorithm for diagnosis of Kaposi's sarcoma-associated herpesvirus infection.

The ability to readily and accurately diagnose Kaposi's sarcoma-associated herpesvirus (KSHV, or human herpesvirus 8) infection in individuals remains a demanding task. Among the available diagnostic methods, sensitivities and specificities range widely, and many are inadequate for large-scale screening studies. We examined a serological algorithm for detecting KSHV in human sera having high sensitivity and specificity. This method uses previously described open reading frame (ORF) K8.1 and ORF65 peptide-based enzyme-linked immunosorbent assays and a novel purified recombinant full-length LANA1 protein. We generated two multiantigen algorithms: one that maximized sensitivity and one that maximized specificity. These serological algorithms were then used to evaluate seroprevalence rates among populations of clinical and epidemiological importance. The serological algorithms yielded sensitivities of 96% and 93% and specificities of 94% and 98% for the more sensitive and specific algorithms, respectively. Among kidney donors, seroprevalence was low, 4.0% (2/50), and similar to that of blood donors (P = 0.46; odds ratio [OR], 1.4; confidence interval [CI], 0.14 to 7.9) using the highly specific algorithm. Using the sensitive algorithm, 8.0% (4/50) were infected compared to 6.4% (16/250) observed among blood donors (OR, 1.3; CI, 0.41 to 4.0; P = 0.43). Among subjects requiring bone marrow transplantation, seroprevalence rates were not elevated compared to those of blood donors (OR, 2.0; 95% CI, 0.10 to 122.9; P = 0.50). Because the need for high-quality KSHV detection methods are warranted and because questions remain about the optimal methods for assessing KSHV infection in individuals, we propose a systematic approach to standardize and optimize the assessment of KSHV infection rates using a combination of established and novel serological assays and methods.