Association of Androgen Hormones, Sex Hormone-Binding Globulin, and the Menopausal Transition With Incident Diabetes Mellitus in Women With and Without HIV.

BACKGROUND: HIV is associated with alterations in androgen hormone levels and sex hormone-binding globulin (SHBG) in women. Higher SHBG has been associated with a lower risk of diabetes in the general population, but the contribution of HIV, androgen hormones, SHBG, and menopausal phase to diabetes is unclear. METHODS: From April 2003 through February 2020, 896 women with HIV (WWH) and 343 women without HIV (WWOH) from the Women's Interagency HIV Study with morning total testosterone, dehydroepiandrosterone sulfate (DHEAS), and SHBG levels were followed to assess for incident diabetes. Parametric regression models were used with age as the time scale and relative times (RT) as the measure of association of hormone level and menopausal phase with incident diabetes. Analyses incorporated time-dependent androgen hormone, SHBG levels, and menopausal phase and were adjusted for race/ethnicity, enrollment year, smoking status, BMI, hepatitis C virus status, and HIV-related factors. RESULTS: In total, 128 (14%) WWH and 47 (14%) WWOH developed diabetes. In WWH, a doubling of SHBG and DHEAS were associated with a 7% (RT = 1.07 [95% CI: 0.82 to 1.40] and 15% (RT = 1.15 [95% CI: 0.95 to 1.39]) longer time to diabetes, respectively; in WWOH, a doubling of SHBG and DHEAS were associated with 84% (RT = 1.84 [95% CI: 0.89 to 3.82]) and 41% (RT= 1.41 [95% CI: 0.82 to 2.44]) longer times to diabetes. Total testosterone was not associated. In WWH, later menopausal phase was associated with shorter times to diabetes. CONCLUSIONS: Despite alterations in androgen hormone and SHBG levels in HIV, regardless of HIV status, higher SHBG and DHEAS were associated with nonstatistically significant slower progression to diabetes. The menopausal transition may be a better hormonal indicator of diabetes risk in WWH.

Body Composition Changes Over the Menopausal Transition in Women With and Without Human Immunodeficiency Virus.

BACKGROUND: Women are at risk for weight gain during the transition to menopause, but few have examined the contribution of menopause to weight gain in women with human immunodeficiency virus (WWH). METHODS: From 2000 to 2013, participants (621 WWH; 218 without HIV [WWOH]) from the Women's Interagency HIV Study were categorized by menopausal phase using serial measures of anti-Müllerian hormone (AMH). Multivariable linear mixed models examined the association of menopausal phase with body mass index (BMI) and waist circumference (WC) trajectory, stratified by HIV status. RESULTS: In models controlled for chronologic age, the estimated effects (95% confidence interval) of menopausal phase on annual rate of BMI change across early perimenopause, late perimenopause, and menopause, respectively, compared to premenopause were -0.55% (-.80 to -.30), -0.29% (-.61 to .03), and -0.67% (-1.12 to -.20) in WWH, whereas estimated effects were 0.43% (-.01 to .87) and 0.15% (-.42 to .71) across early and late perimenopause, respectively, and -0.40% (-1.24 to .45) across menopause in WWOH. The estimated effects on rate of WC change were negative across early perimenopause (-0.21% [-.44 to .03]) and menopause (-0.12% [-.5 to .26]) and positive across late perimenopause (0.18% [-.10 to .45]) in WWH, and positive across all 3 menopausal phases in WWOH, but these effects were not statistically significant. CONCLUSIONS: In WWH, the menopausal transition was associated with BMI and WC trajectories that were mostly in a negative direction and opposite from WWOH after adjusting for age, suggesting that HIV blunts weight gain during the menopausal transition.

Bone marrow adipose tissue composition and glycemic improvements after gastric bypass surgery.

Fracture risk is increased in type 2 diabetes, which may in part be due to altered bone marrow adiposity. Cross sectional studies have reported that people with type 2 diabetes have lower unsaturated BMAT lipid levels than people without diabetes, although there are limited data on longitudinal changes. We hypothesized that Roux-en-Y gastric bypass (RYGB), which dramatically improves glycemic status, would have differential effects on BMAT composition, with increases in the unsaturated lipid index in people with diabetes. Given reports that axial BMAT is responsive to metabolic stimuli while appendicular BMAT is stable, we hypothesized that BMAT changes would occur at the spine but not the tibia. We enrolled 30 obese women, stratified by diabetes status, and used magnetic resonance spectroscopy to measure BMAT at the spine in all participants, and the tibia in a subset (n = 19). At baseline, BMAT parameters were similar between those with and without diabetes, except tibial marrow fat content was lower in women with diabetes (97.4 % ± 1.0 % versus 98.2 % ± 0.4 %, p = 0.04). Six months after surgery, both groups experienced similar weight loss of 27 kg ± 7 kg. At the spine, there was a significant interaction between diabetes status and changes in both marrow fat content and the unsaturated lipid index (p = 0.02, p < 0.01 for differences, respectively). Women with diabetes had a trend towards a decline in marrow fat content (-4.3 % ± 8.2 %, p = 0.09) and increase in the unsaturated lipid index (+1.1 % ± 1.5 %, p = 0.02). In contrast, BMAT parameters did not significantly change in women without diabetes. In all women, changes in the unsaturated lipid index inversely correlated with hemoglobin A1c changes (r = -0.47, p = 0.02). At the tibia, there was little BMAT change by diabetes status. Our results suggest that vertebral BMAT composition is responsive to changes in glycemic control after RYGB.

Association of Vitamin D Status and COVID-19-Related Hospitalization and Mortality.

BACKGROUND: The relationship between vitamin D status and COVID-19-related clinical outcomes is controversial. Prior studies have been conducted in smaller, single-site, or homogeneous populations limiting adjustments for social determinants of health (race/ethnicity and poverty) common to both vitamin D deficiency and COVID-19 outcomes. OBJECTIVE: To evaluate the dose-response relationship between continuous 25(OH)D and risk for COVID-19-related hospitalization and mortality after adjusting for covariates associated with both vitamin D deficiency and COVID-19 outcomes. DESIGN: Retrospective cohort study. PATIENTS: Veteran patients receiving care in US Department of Veteran Affairs (VA) health care facilities with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test and a blood 25(OH)D test between February 20, 2020, and November 8, 2020, followed for up to 60 days. MAIN MEASURES: Exposure was blood 25(OH)D concentration ascertained closest to and within 15 to 90 days preceding an index positive SARS-CoV-2 test. Co-primary study outcomes were COVID-19-related inpatient hospitalization requiring airborne, droplet, contact, or other isolation and mortality ascertained within 60 days of an index positive SARS-CoV-2 test. KEY RESULTS: Of 4,599 veterans with a positive SARS-CoV-2 test, vitamin D deficiency (< 20 ng/mL) was identified in 665 (14.5%); 964 (21.0%) were hospitalized; and 340 (7.4%) died. After adjusting for all covariates, including race/ethnicity and poverty, there was a significant independent inverse dose-response relationship between increasing continuous 25(OH)D concentrations (from 15 to 60 ng/mL) and decreasing probability of COVID-19-related hospitalization (from 24.1 to 18.7%, p=0.009) and mortality (from 10.4 to 5.7%, p=0.001). In modeling 25(OH)D as a log-transformed continuous variable, the greatest risk for hospitalization and death was observed at lower 25(OH)D concentrations. CONCLUSIONS: Continuous blood 25(OH)D concentrations are independently associated with COVID-19-related hospitalization and mortality in an inverse dose-response relationship in this large racially and ethnically diverse cohort of VA patients. Randomized controlled trials are needed to evaluate the impact of vitamin D supplementation on COVID-19-related outcomes.

The Heart and Cannabis (THC) Cohort: Differences in Baseline Health and Behaviors by Cannabis Use.

BACKGROUND: Evidence on the cardiovascular health effects of cannabis use is limited. We designed a prospective cohort study of older Veterans (66 to 68 years) with coronary artery disease (CAD) to understand the cardiovascular consequences of cannabis use. We describe the cohort construction, baseline characteristics, and health behaviors that were associated with smoking cannabis. OBJECTIVE: To understand the cardiovascular consequences of cannabis use. DESIGN: We designed a prospective cohort study of older Veterans (66 to 68 years) with CAD. PARTICIPANTS: A total of 1,015 current cannabis smokers and 3,270 non-cannabis smokers with CAD. MAIN MEASURES: Using logistic regression, we examined the association of baseline variables with smoking cannabis in the past 30 days. RESULTS: The current cannabis smokers and non-current smokers were predominantly male (97.2% vs 97.1%, p=0.96). Characteristics associated with recent cannabis use in multivariable analyses included lack of a high school education (odds ratio [OR] 2.15, 95% confidence interval [CI]: 1.10 to 4.19), financial difficulty (OR 1.47, 95% CI: 1.02 to 2.11), tobacco use (OR 3.02, 95% CI: 1.66 to 5.48), current drug use (OR 2.82, 95% CI: 1.06 to 7.46), and prior drug use (OR 2.84, 95% CI: 2.11 to 3.82). In contrast, compared to individuals with 0 to 1 comorbid conditions, those with 5 chronic conditions or more (OR 0.43, 95% CI: 0.27 to 0.70) were less likely to smoke cannabis. CONCLUSIONS: In this older high-risk cohort, smoking cannabis was associated with higher social and behavioral risk, but with fewer chronic health conditions.

Associations of CKD risk factors and longitudinal changes in urine biomarkers of kidney tubules among women living with HIV.

BACKGROUND: Novel urine biomarkers have enabled the characterization of kidney tubular dysfunction and injury among persons living with HIV, a population at an increased risk of kidney disease. Even though several urine biomarkers predict progressive kidney function decline, antiretroviral toxicity, and mortality in the setting of HIV infection, the relationships among the risk factors for chronic kidney disease (CKD) and urine biomarkers are unclear. METHODS: We assessed traditional and infection-related CKD risk factors and measured 14 urine biomarkers at baseline and at follow-up among women living with HIV in the Women's Interagency Health Study (WIHS). We then used simultaneously adjusted multivariable linear regression models to evaluate the associations of CKD risk factors with longitudinal changes in biomarker levels. RESULTS: Of the 647 women living with HIV in this analysis, the majority (67%) were Black, the median age was 45 years and median follow-up time was 2.5 years. Each traditional and infection-related CKD risk factor was associated with a unique set of changes in urine biomarkers. For example, baseline hemoglobin a1c was associated with worse tubular injury (higher interleukin [IL]-18), proximal tubular reabsorptive dysfunction (higher α1-microglobulin), tubular reserve (lower uromodulin) and immune response to injury (higher chitinase-3-like protein-1 [YKL-40]). Furthermore, increasing hemoglobin a1c at follow-up was associated with further worsening of tubular injury (higher kidney injury molecule-1 [KIM-1] and IL-18), as well as higher YKL-40. HCV co-infection was associated with worsening proximal tubular reabsorptive dysfunction (higher ß2-microglobulin [ß2m]), and higher YKL-40, whereas HIV viremia was associated with worsening markers of tubular and glomerular injury (higher KIM-1 and albuminuria, respectively). CONCLUSIONS: CKD risk factors are associated with unique patterns of biomarker changes among women living with HIV, suggesting that serial measurements of multiple biomarkers may help in detecting and monitoring kidney disease in this setting.

Mortality following myocardial infarction among HIV-infected persons: the Center for AIDS Research Network Of Integrated Clinical Systems (CNICS).

BACKGROUND: Persons with human immunodeficiency virus (HIV) have higher risks for myocardial infarction (MI) than the general population. This is driven in part by higher type 2 MI (T2MI, due to coronary supply-demand mismatch) rates among persons with HIV (PWH). In the general population, T2MI has higher mortality than type 1 MI (T1MI, spontaneous and generally due to plaque rupture and thrombosis). PWH have a greater burden of comorbidities and may therefore have an even greater excess risk for complication and death in the setting of T2MI. However, mortality patterns after T1MI and T2MI in HIV are unknown. METHODS: We analyzed mortality after MI among PWH enrolled in the multicenter, US-based Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort (N = 28,186). Incident MIs occurring between January 1, 1996, and December 31, 2014, were centrally adjudicated and classified as T1MI or T2MI. We first compared mortality following T1MI vs. T2MI among PWH. Cox survival analyses and Bayesian model averaging were then used to evaluate pre-MI covariates associated with mortality following T1MI and T2MI. RESULTS: Among the 596 out of 28,186 PWH who experienced MI (2.1%; 293 T1MI and 303 T2MI), mortality rates were significantly greater after T2MI (22.2/100 person-years; 1-, 3-, and 5-year mortality 39%, 52%, and 62%) than T1MI (8.2/100 person-years; 1-, 3-, and 5-year mortality 15%, 22%, and 30%). Significant mortality predictors after T1MI were higher HIV viral load, renal dysfunction, and older age. Significant predictors of mortality after T2MI were low body-mass index (BMI) and detectable HIV viral load. CONCLUSIONS: Mortality is high following MI for PWH and substantially greater after T2MI than T1MI. Predictors of death after MI differed by type of MI, reinforcing the different clinical scenarios associated with each MI type and the importance of considering MI types separately.

Association of Statin Use With Kidney Damage and Function Among HIV-Infected Men.

BACKGROUND: Chronic kidney disease (CKD) occurs commonly among HIV-infected persons. Statins may delay CKD onset and progression through their cholesterol-lowering and pleiotropic effects. METHODS: Among 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 <60 mL/min/1.73 m) using Cox proportional hazards regression. We used inverse probability weighting to address potential confounding related to statin use. RESULTS: Statin users comprised 30% of participants. In adjusted analyses, each year of cumulative statin use was associated with 4.0% higher baseline ACR levels (P = 0.05), but there was no association with baseline levels of other urine biomarkers. Statin use had no overall association with annual eGFR decline. Among participants with baseline proteinuria, statin use was modestly associated with slower annual eGFR decline compared to non-use (adjusted difference: 1.33 mL/min/1.73 m per year; 95% confidence interval: -0.07 to 2.70). Statin use was not associated with risk of incident proteinuria or incident CKD. CONCLUSIONS: Statin use was associated with higher baseline ACR, but not with biomarkers of tubulointerstitial injury. Statin use was associated with modestly slower eGFR decline only among participants with baseline proteinuria. Although these findings may be susceptible to confounding by indication, they suggest a limited effect of statins on CKD risk among HIV-infected men.

Contributions of HIV, hepatitis C virus, and traditional vascular risk factors to peripheral artery disease in women.

OBJECTIVES: HIV and hepatitis C virus (HCV) have been associated with cardiovascular disease (CVD), but it is unclear whether HIV and HCV are also associated with peripheral artery disease (PAD). We examined the association of HIV, HCV, and traditional CVD risk factors with PAD in the Women's Interagency HIV Study, a multicenter US cohort. METHODS: In this cross-sectional study, ankle-brachial index was estimated using Doppler ultrasound and manual sphygmomanometer in 1899 participants aged more than 40 years with HIV/HCV coinfection, HCV or HIV monoinfection, or neither infection. Multivariable logistic regression was used to estimate the odds of PAD (ankle-brachial index ≤0.9) after controlling for demographic, behavioral, and CVD risk factors. RESULTS: Over two-thirds were African-American, median age was 50 years, and PAD prevalence was 7.7% with little difference by infection status. After multivariable adjustment, neither HIV nor HCV infection was associated with greater odds of PAD. Factors associated with PAD included older age [adjusted odds ratio (aOR): 2.01 for age 61-70 vs. 40-50 years; 95% confidence interval (CI): 1.04, 3.87], Black race (aOR: 2.30; 95% CI: 1.15, 4.63), smoking (aOR: 1.27 per 10-pack-year increment; 95% CI: 1.09, 1.48), and higher SBP (aOR: 1.14 per 10 mmHg; 95% CI: 1.01, 1.28). CONCLUSION: The high PAD prevalence in this nationally representative cohort of women with or at risk for HIV is on par with general population studies in individuals a decade older than our study's median age. HIV and HCV infection are not associated with greater PAD risk relative to uninfected women with similar risk factors. Modifiable traditional CVD risk factors may be important early intervention targets in women with and at risk for HIV.

Tenofovir disoproxil fumarate initiation and changes in urinary biomarker concentrations among HIV-infected men and women.

OBJECTIVES: Urinary biomarkers of kidney injury may have potential to identify subclinical injury attributable to tenofovir disoproxil fumarate (TDF) toxicity. DESIGN: This 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. METHODS: We 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. RESULTS: Within 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%). CONCLUSIONS: TDF 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.

Leptinemia is Associated With Peripheral Artery Disease.

BACKGROUND: Leptin, adiponectin, and resistin are in a class of hormones called adipokines that are produced by adipocytes and have been implicated in the causal pathway of atherosclerosis. We examined the association between adipokine levels and peripheral artery disease (PAD), hypothesizing that after adjusting for fat mass, leptin and resistin would be higher, whereas adiponectin would be lower, in patients with PAD. METHODS: A cross-sectional sample of 179 predominately male (97%) vascular surgery outpatients was recruited from the San Francisco Veterans Affairs Medical Center (SFVAMC). PAD was defined as either an ankle-brachial index < 0.9 plus symptoms of claudication or prior revascularization for symptomatic PAD (n = 141). Controls had an ankle-brachial index ≥0.9 and no history of atherosclerotic disease (n = 38). Adipokines were assayed using commercially available ELISA kits and values were log-transformed. Fat mass was measured using bioelectrical impedance. RESULTS: In an analysis adjusting for body mass index (BMI) and atherosclerotic risk factors, higher serum leptin was associated with PAD (OR 2.54, 95% CI 1.07-6.01, P = 0.03), whereas high molecular weight adiponectin was inversely associated, though not significantly (OR 0.60, 95% CI 0.33-1.08, P = 0.09). Resistin was not associated with PAD. Sensitivity analyses using fat mass/height2 rather than BMI yielded similar results. CONCLUSIONS: These results indicate that after adjusting for BMI or fat mass, serum leptin levels are positively and independently associated with PAD, whereas high molecular weight adiponectin might be inversely associated. Using a more representative, nonveteran sample, further investigations should focus on the potential role of adipokines in the pathophysiology of PAD as well as determine whether leptin levels have clinical utility in predicting PAD outcomes.

Kidney disease risk factors associate with urine biomarkers concentrations in HIV-positive persons; a cross-sectional study.

BACKGROUND: HIV-positive persons bear an excess burden of chronic kidney disease (CKD); however, conventional methods to assess kidney health are insensitive and non-specific for detecting early kidney injury. Urinary biomarkers can detect early kidney injury, and may help mitigate the risk of overt CKD. METHODS: Cross-sectional study of HIV-positive persons in the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study. We measured levels of 14 biomarkers, capturing multiple dimensions of kidney injury. We then evaluated associations of known CKD risk factors with urine biomarkers using separate multivariable adjusted models for each biomarker. RESULTS: Of the 198 participants, one third were on HAART and virally suppressed. The vast majority (95%) had preserved kidney function as assessed by serum creatinine, with a median eGFR of 103 ml/min/1.73 m2 (interquartile range (IQR): 88, 116). In our multivariable analyses, the associations of each CKD risk factor with urinary biomarker levels varied in magnitude. For example, HIV viral load was predominantly associated with elevations in interleukin(IL)-18, and albuminuria, while higher CD4 levels were associated with lower monocyte chemoattractant protein-1 (MCP-1) and ß2-microglobulin. In contrast, older age was significantly associated with elevations in α1-microglobulin, kidney injury marker-1, clusterin, MCP-1, and chitinase-3-like protein-1 levels, as well as lower epidermal growth factor, and uromodulin levels. CONCLUSIONS: Among HIV-positive persons, CKD risk factors are associated with unique and heterogeneous patterns of changes in urine biomarkers levels. Additional work is needed to develop parsimonious algorithms that integrate multiple biomarkers and clinical data to discern the risk of overt CKD and its progression.

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.

Association of Biomarker Clusters With Cardiac Phenotypes and Mortality in Patients With HIV Infection.

BACKGROUND: Although individual cardiac biomarkers are associated with heart failure risk and all-cause mortality in HIV-infected individuals, their combined use for prediction has not been well studied. METHODS AND RESULTS: Unsupervised k-means cluster analysis was performed blinded to the study outcomes in 332 HIV-infected participants on 8 biomarkers: ST2, NT-proBNP (N-terminal pro-B-type natriuretic peptide), hsCRP (high-sensitivity C-reactive protein), GDF-15 (growth differentiation factor 15), cystatin C, IL-6 (interleukin-6), D-dimer, and troponin. We evaluated cross-sectional associations of each cluster with diastolic dysfunction, pulmonary hypertension (defined as echocardiographic pulmonary artery systolic pressure ≥35 mm Hg), and longitudinal associations with all-cause mortality. The biomarker-derived clusters partitioned subjects into 3 groups. Cluster 3 (n=103) had higher levels of CRP, IL-6, and D-dimer (inflammatory phenotype). Cluster 2 (n=86) displayed elevated levels of ST2, NT-proBNP, and GDF-15 (cardiac phenotype). Cluster 1 (n=143) had lower levels of both phenotype-associated biomarkers. After multivariable adjustment for traditional and HIV-related risk factors, cluster 3 was associated with a 51% increased risk of diastolic dysfunction (95% confidence interval, 1.12-2.02), and cluster 2 was associated with a 67% increased risk of pulmonary hypertension (95% confidence interval, 1.04-2.68), relative to cluster 1. Over a median 6.9-year follow-up, 48 deaths occurred. Cluster 3 was independently associated with a 3.3-fold higher risk of mortality relative to cluster 1 (95% confidence interval, 1.3-8.1), and cluster 2 had a 3.1-fold increased risk (95% confidence interval, 1.1-8.4), even after controlling for diastolic dysfunction, pulmonary hypertension, left ventricular mass, and ejection fraction. CONCLUSIONS: Serum biomarkers can be used to classify HIV-infected individuals into separate clusters for differentiating cardiopulmonary structural and functional abnormalities and can predict mortality independent of these structural and functional measures.

Contribution of Liver Fibrosis and Microbial Translocation to Immune Activation in Persons Infected With HIV and/or Hepatitis C Virus.

Background: The independent contributions of microbial translocation and liver fibrosis to immune activation in human immunodeficiency virus (HIV) and/or hepatitis C virus (HCV)-infected persons are unclear. Methods: Multivariable linear regression was used to evaluate whether intestinal fatty acid binding protein (I-FABP: a marker of gut epithelial integrity) and transient elastography-measured liver fibrosis might mediate the association of HIV and HCV with the soluble CD14 (sCD14) level in 120 individuals with HIV and HCV coinfection, 262 with HIV monoinfection, 72 with HCV monoinfection, and 170 without infection. Results: Coinfected individuals, HIV-monoinfected individuals, and HCV-monoinfected individuals had 37%, 21%, and 12% higher sCD14 levels, respectively, than uninfected individuals, after multivariable adjustment. Additional adjustment for I-FABP level modestly attenuated the association of HIV infection, but attenuation occurred to a lesser extent in the HCV-monoinfected group. Adjustment for liver fibrosis substantially attenuated the association of HCV infection, but attenuation occurred to a lesser extent in the HIV-monoinfected group. Relative to the uninfected group, the primary mediator of the sCD14 level was the I-FABP level in the HIV-infected groups and liver fibrosis in the HCV-monoinfected group. Conclusion: HIV and HCV are independently and additively associated with higher a sCD14 level. Our findings suggest that microbial translocation contributes to an increased sCD14 level during HIV infection, whereas liver fibrosis plays a stronger role during HCV monoinfection. Coinfected persons may be at greatest risk for progression, because of the independent effects of microbial translocation and liver fibrosis on immune activation.

CHA2DS2-VASc Score, Warfarin Use, and Risk for Thromboembolic Events Among HIV-Infected Persons With Atrial Fibrillation.

BACKGROUND: The prevalence of atrial fibrillation in the HIV-infected population is growing, but the ability of the CHA2DS2-VASc score to predict thromboembolic (TE) risk is unknown in this population. SETTING: Within the Veterans Affairs HIV Clinical Case Registry, 914 patients had an atrial fibrillation diagnosis between 1997 and 2011 and no previous TE events. METHODS: We compared TE incidence by CHA2DS2-VASc scores and stratified by warfarin use. Using Cox proportional hazards regression with adjustment for competing risks, we modeled associations of CHA2DS2-VASc scores and warfarin use with TE risk. RESULTS: At baseline, the distribution of CHA2DS2-VASc scores was 0 (n = 208), 1 (n = 285), and 2+ (n = 421); 34 patients developed 38 TE events during a median of 3.8 years follow-up. Event rates by CHA2DS2-VASc scores of 0, 1, and 2+ were 5.4, 9.3, and 8.1 per 1000 person years, respectively; multivariate-adjusted hazards ratios (HRs) were 1.70 (95% confidence interval: 0.65 to 4.45) for CHA2DS2-VASc score 1 (P = 0.28) and HR = 1.34 (0.51, 3.48) for score 2+ versus 0 (P = 0.55). Baseline warfarin use was associated with increased TE risk, although not statistically significant [HR 2.06 (0.86, 4.93), P = 0.11] with similar results when modeled as time-updated use and duration of use. CONCLUSION: In this national registry of HIV-infected veterans with atrial fibrillation, CHA2DS2-VASc scores were only weakly associated with TE risk. Furthermore, warfarin did not seem to be effective at preventing TE events. These results should raise concerns about the optimal strategy for TE prevention among HIV-infected persons with atrial fibrillation.

Association of Tenofovir Use With Risk of Incident Heart Failure in HIV-Infected Patients.

BACKGROUND: The antiretroviral medication, tenofovir disoproxil fumarate (TDF), is used by most human immunodeficiency virus-infected persons in the United States despite higher risks of chronic kidney disease. Although chronic kidney disease is a strong risk factor for heart failure (HF), the association of TDF with incident HF is unclear. METHODS AND RESULTS: We identified 21 435 human immunodeficiency virus-infected patients in the United States Veterans Health Administration actively using antiretrovirals between 2002 and 2011. We excluded patients with a prior diagnosis of HF. TDF was analyzed categorically (current, past, or never use) and continuously (per year of use). Proportional hazards regression and fully adjusted marginal structural models were used to determine the association of TDF exposure with risk of incident HF after adjustment for demographic, human immunodeficiency virus-related, and cardiovascular risk factors. During follow-up, 438 incident HF events occurred. Unadjusted 5-year event rates for current, past, and never users of TDF were 0.9 (95%CI 0.7-1.1), 1.7 (1.4-2.2), and 4.5 (3.9-5.0), respectively. In fully adjusted analyses, HF risk was markedly lower in current TDF users (HR=0.68; 95%CI 0.53-0.86) compared with never users. Among current TDF users, each additional year of TDF exposure was associated with a 21% lower risk of incident HF (95%CI: 0.68-0.92). When limited to antiretroviral-naive patients, HF risk remained lower in current TDF users (HR=0.53; 95%CI 0.36-0.78) compared to never users. CONCLUSIONS: Among a large national cohort of human immunodeficiency virus-infected patients, TDF use was strongly associated with lower risk of incident HF. These findings warrant confirmation in other populations, both with TDF and the recently approved tenofovir alafenamide fumarate.

Higher CD163 levels are associated with insulin resistance in hepatitis C virus-infected and HIV-infected adults.

OBJECTIVES: HIV/hepatitis C virus (HCV) coinfection is associated with insulin resistance, but the mechanism is unclear. We hypothesized that intestinal epithelial damage and the consequent monocyte/macrophage activation and inflammation explain this perturbation. DESIGN: Cross-sectional study of 519 adults (220 HIV+/HCV-; 64 HIV-/HCV+; 89 HIV+/HCV+; 146 HIV-/HCV-). METHODS: We used multivariable linear regression to evaluate associations of HIV and HCV with the homeostasis model assessment of insulin resistance (HOMA-IR) and if intestinal fatty (FA) acid binding protein (I-FABP, a marker of gut epithelial integrity), soluble CD14 (sCD14) and soluble CD163 (sCD163) (markers of monocyte/macrophage activation), and IL-6 (an inflammatory cytokine) mediated this association. RESULTS: HIV+/HCV+ and HIV-/HCV+ had greater demographic-adjusted HOMA-IR [mean (95% confidence interval (CI)): 1.96 (1.51, 2.54) and 1.65 (1.22, 2.24)] than HIV+/HCV- and HIV-/HCV-[1.41 (1.18, 1.67) and 1.44 (1.17, 1.75), respectively]. After additional adjustment for lifestyle and metabolic factors, HIV+/HCV+ remained associated with 36% (95% CI: 4, 80%) greater HOMA-IR relative to HIV-/HCV-, whereas HIV-/HCV+ and HIV+/HCV- had smaller differences. Adjustment for sCD163 substantially attenuated the difference between HIV+/HCV+ and HIV-/HCV-; adjustment for I-FABP, sCD14, and IL-6 had little effect. Higher sCD163 was independently associated with 19% (95% CI: 7, 33%), 26% (95% CI: 15, 39%), 25% (95% CI: 14, 37%), and 23% (95% CI: 11, 36%) greater HOMA-IR in HIV+/HCV+, HIV-/HCV+, HIV+/HCV-, and HIV-/HCV- (all estimates per doubling of sCD163). I-FABP, sCD14, and IL-6 were not associated with HOMA-IR. CONCLUSION: HIV/HCV coinfection is associated with greater HOMA-IR, even after controlling for demographic, lifestyle, and metabolic factors. sCD163, which appears independent of intestinal epithelial damage and inflammation, partly explains this association. Our findings that the association of sCD163 with HOMA-IR occurred even in the absence of HIV and HCV, indicate that viral and nonviral factors affect sCD163 levels. Its role in insulin resistance needs elucidation.

Associations Between At-Risk Alcohol Use, Substance Use, and Smoking with Lipohypertrophy and Lipoatrophy Among Patients Living with HIV.

OBJECTIVE: To examine associations between lipohypertrophy and lipoatrophy and illicit drug use, smoking, and at-risk alcohol use among a large diverse cohort of persons living with HIV (PLWH) in clinical care. METHODS: 7,931 PLWH at six sites across the United States completed 21,279 clinical assessments, including lipohypertrophy and lipoatrophy, drug/alcohol use, physical activity level, and smoking. Lipohypertrophy and lipoatrophy were measured using the FRAM body morphology instrument and associations were assessed with generalized estimating equations. RESULTS: Lipohypertrophy (33% mild, 4% moderate-to-severe) and lipoatrophy (20% mild, 3% moderate-to-severe) were common. Older age, male sex, and higher current CD4 count were associated with more severe lipohypertrophy (p values <.001-.03). Prior methamphetamine or marijuana use, and prior and current cocaine use, were associated with more severe lipohypertrophy (p values <.001-.009). Older age, detectable viral load, and low current CD4 cell counts were associated with more severe lipoatrophy (p values <.001-.003). In addition, current smoking and marijuana and opiate use were associated with more severe lipoatrophy (p values <.001-.03). Patients with very low physical activity levels had more severe lipohypertrophy and also more severe lipoatrophy than those with all other activity levels (p values <.001). For example, the lipohypertrophy score of those reporting high levels of physical activity was on average 1.6 points lower than those reporting very low levels of physical activity (-1.6, 95% CI: -1.8 to -1.4, p < .001). CONCLUSIONS: We found a high prevalence of lipohypertrophy and lipoatrophy among a nationally distributed cohort of PLWH. While low levels of physical activity were associated with both lipohypertrophy and lipoatrophy, associations with substance use and other clinical characteristics differed between lipohypertrophy and lipoatrophy. These results support the conclusion that lipohypertrophy and lipoatrophy are distinct, and highlight differential associations with specific illicit drug use.

Types of Myocardial Infarction Among Human Immunodeficiency Virus-Infected Individuals in the United States.

Importance: The Second Universal Definition of Myocardial Infarction (MI) divides MIs into different types. Type 1 MIs result spontaneously from instability of atherosclerotic plaque, whereas type 2 MIs occur in the setting of a mismatch between oxygen demand and supply, as with severe hypotension. Type 2 MIs are uncommon in the general population, but their frequency in human immunodeficiency virus (HIV)-infected individuals is unknown. Objectives: To characterize MIs, including type; identify causes of type 2 MIs; and compare demographic and clinical characteristics among HIV-infected individuals with type 1 vs type 2 MIs. Design, Setting, and Participants: This longitudinal study identified potential MIs among patients with HIV receiving clinical care at 6 US sites from January 1, 1996, to March 1, 2014, using diagnoses and cardiac biomarkers recorded in the centralized data repository. Sites assembled deidentified packets, including physician notes and electrocardiograms, procedures, and clinical laboratory tests. Two physician experts adjudicated each event, categorizing each definite or probable MI as type 1 or type 2 and identifying the causes of type 2 MI. Main Outcomes and Measures: The number and proportion of type 1 vs type 2 MIs, demographic and clinical characteristics among those with type 1 vs type 2 MIs, and the causes of type 2 MIs. Results: Among 571 patients (median age, 49 years [interquartile range, 43-55 years]; 430 men and 141 women) with definite or probable MIs, 288 MIs (50.4%) were type 2 and 283 (49.6%) were type 1. In analyses of type 1 MIs, 79 patients who underwent cardiac interventions, such as coronary artery bypass graft surgery, were also included, totaling 362 patients. Sepsis or bacteremia (100 [34.7%]) and recent use of cocaine or other illicit drugs (39 [13.5%]) were the most common causes of type 2 MIs. A higher proportion of patients with type 2 MIs were younger than 40 years (47 of 288 [16.3%] vs 32 of 362 [8.8%]) and had lower current CD4 cell counts (median, 230 vs 383 cells/µL), lipid levels (mean [SD] total cholesterol level, 167 [63] vs 190 [54] mg/dL, and mean (SD) Framingham risk scores (8% [7%] vs 10% [8%]) than those with type 1 MIs or who underwent cardiac interventions. Conclusions and Relevance: Approximately half of all MIs among HIV-infected individuals were type 2 MIs caused by heterogeneous clinical conditions, including sepsis or bacteremia and recent use of cocaine or other illicit drugs. Demographic characteristics and cardiovascular risk factors among those with type 1 and type 2 MIs differed, suggesting the need to specifically consider type among HIV-infected individuals to further understand MI outcomes and to guide prevention and treatment.