Immunoglobulin G N-glycan markers of accelerated biological aging during chronic HIV infection.

People living with HIV (PLWH) experience increased vulnerability to premature aging and inflammation-associated comorbidities, even when HIV replication is suppressed by antiretroviral therapy (ART). However, the factors associated with this vulnerability remain uncertain. In the general population, alterations in the N-glycans on IgGs trigger inflammation and precede the onset of aging-associated diseases. Here, we investigate the IgG N-glycans in cross-sectional and longitudinal samples from 1214 women and men, living with and without HIV. PLWH exhibit an accelerated accumulation of pro-aging-associated glycan alterations and heightened expression of senescence-associated glycan-degrading enzymes compared to controls. These alterations correlate with elevated markers of inflammation and the severity of comorbidities, potentially preceding the development of such comorbidities. Mechanistically, HIV-specific antibodies glycoengineered with these alterations exhibit a reduced ability to elicit anti-HIV Fc-mediated immune activities. These findings hold potential for the development of biomarkers and tools to identify and prevent premature aging and comorbidities in PLWH.

Influence of Impaired Diffusing Capacity and Sleep-disordered Breathing on Nocturnal Hypoxemia and Health Outcomes in Men with and without HIV.

RATIONALE: Nocturnal hypoxemia is common in sleep-disordered breathing (SDB) and is associated with increased morbidity and mortality. Although impaired diffusing capacity of the lungs for carbon monoxide (DLCO) is associated with daytime hypoxemia, its influence on SDB-related nocturnal hypoxemia is not known. OBJECTIVE: To characterize the effects of DLCO impairment on SDB-related nocturnal hypoxemia and associated health outcomes. METHODS: Data from a multi-center cohort of men with and without HIV, with concomitant measures of DLCO and home-based polysomnography (N=544), were analyzed. Multivariable quantile regression models characterized associations between DLCO and several measures of SDB-related hypoxemia (e.g., total sleep time with oxygen saturation [SpO2]<90% [T90]). Structural equation models assessed associations between impaired DLCO and SDB-related hypoxemia measures with prevalent hypertension and type 2 diabetes. RESULTS: DLCO impairment (<80% predicted) was associated with sleep-related hypoxemia. Participants with severe SDB (apnea-hypopnea index≥30 events/hr) and impaired DLCO had a higher T90 (median difference: 15.0%; [95% CI: 10.3,19.7]) and average SDB-related desaturation (median difference: 1.0; [0.5, 1.5]), and lower nadir SpO2 (median difference: -8.2%; [-11.4, -4.9]) and average SpO2 during sleep (median difference: -1.1%; [-2.1, -0.01]), than those with severe SDB and preserved DLCO. A higher T90 was associated with higher adjusted odds of prevalent hypertension (OR 1.39; [1.14,1.70]) and type 2 diabetes (OR 1.25; [1.07,1.46]). CONCLUSIONS: DLCO impairment in severe SDB was associated with sleep-related hypoxemia, prevalent hypertension and type 2 diabetes. Assessment of SDB should be considered in those with impaired DLCO to guide testing and risk-stratification strategies.

The effect of sexual behavior on HIV-1 seroconversion is mediated by the gut microbiome and proinflammatory cytokines.

The association between HIV-1 seroconversion and gut dysbiosis is well documented, and its association with sexual activity is also widely recognized. However, it is not known whether the gut dysbiosis mediates the effects of high-risk sexual behavior on HIV-1 seroconversion. In this report we focused on men who engaged in high-risk sexual behavior where they had receptive anal intercourse with multiple men. We demonstrate that proinflammatory cytokines, sCD14 and sCD163, and gut microbiota mediate the effects of this high-risk sexual behavior on subsequent HIV seroconversion. We discovered changes in the gut microbial ecology, prior to seroconversion, both in terms of the composition as well as inter-relationships among the commensal species. Furthermore, these changes correlate with future HIV seroconversion. Specifically, as the number of sexual partners increased, we discovered in a "dose-response" manner, a decrease in the abundance of commensal and short-chain fatty acid-producing species, A. muciniphila, B. caccae, B. fragilis, B. uniformis, Bacteroides spp., Butyricimonas spp., and Odoribacter spp, and an increase in proinflammatory species Dehalobacterium spp. and Methanobrevibacter spp. These changes were also observed among subsequent HIV seroconverters. Interestingly, we also discovered a reduction in correlations among these commensal and short-chain fatty acid producing bacteria in a "dose-response" manner with the number of sexual partners. Our mediation analysis not only provides a conceptual model for the disease process but also provides clues for future clinical interventions that will manipulate the gut microbiota to treat high-risk subjects to prevent HIV seroconversion.

Incident Proteinuria differs by HIV Serostatus among Men with Pre-diabetes: The Multicenter AIDS Cohort Study.

BACKGROUND: Pre-diabetes is associated with proteinuria, a risk factor for chronic kidney disease. While people living with HIV (PWH) have a higher risk of proteinuria than people without HIV (PWOH), it is unknown whether incident proteinuria differs by HIV serostatus among pre-diabetic persons. METHODS: Urine protein-to-creatinine ratio (PCR) was measured at semi-annual visits among men in the Multicenter AIDS Cohort Study since April 2006. Men with pre-DM on or after April 2006 and no prevalent proteinuria or use of anti-diabetic medications were included. Pre-diabetes was defined as fasting glucose (FG) of 100-125 mg/dL confirmed within a year by a repeat FG or hemoglobin A1c 5.7-6.4%. Incident proteinuria was defined as PCR > 200 mg/g, confirmed within a year. We used Poisson regression models to determine whether incident proteinuria in participants with pre-diabetes differed by HIV serostatus and, among PWH, whether HIV-specific factors were related to incident proteinuria. RESULTS: Between 2006 and 2019, among 1276 men with pre-diabetes, 128/613 PWH (21%) and 50/663 PWOH (8%) developed proteinuria over a median 10-year follow-up. After multivariable adjustment, the incidence of proteinuria in PWH with pre-diabetes was 3.3 times [95% CI: 2.3-4.8 times] greater than in PWOH (p < 0.01). Among PWH, current CD4 count <500 cells/mm3 (p < 0.01) and current use of protease inhibitors (p = 0.03) were associated with incident proteinuria, while lamivudine and integrase inhibitor use were associated with a lower risk. CONCLUSION: Among men with pre-DM, the risk of incident proteinuria was 3 times higher in PWH. Strategies to preserve renal function are needed in this population.

Proteomic Signature of HIV-Associated Subclinical Left Atrial Remodeling and Incident Heart Failure.

Background: People living with HIV (PLWH) are at higher risk of heart failure (HF) and preceding subclinical cardiac abnormalities, including left atrial dilation, compared to people without HIV (PWOH). Hypothesized mechanisms include premature aging linked to chronic immune activation. We leveraged plasma proteomics to identify potential novel contributors to HIV-associated differences in indexed left atrial volume (LAVi) among PLWH and PWOH and externally validated identified proteomic signatures with incident HF among a cohort of older PWOH. Methods: We performed proteomics (Olink Explore 3072) on plasma obtained concurrently with cardiac magnetic resonance imaging among PLWH and PWOH in the United States. Proteins were analyzed individually and as agnostically defined clusters. Cross-sectional associations with HIV and LAVi were estimated using multivariable regression with robust variance. Among an independent general population cohort, we estimated associations between identified signatures and LAVi using linear regression and incident HF using Cox regression. Results: Among 352 participants (age 55±6 years; 25% female), 61% were PLWH (88% on ART; 73% with undetectable HIV RNA) and mean LAVi was 29±9 mL/m 2 . Of 2594 analyzed proteins, 439 were associated with HIV serostatus, independent of demographics, hepatitis C virus infection, renal function, and substance use (FDR<0.05). We identified 73 of these proteins as candidate contributors to the independent association between positive HIV serostatus and higher LAVi, enriched in tumor necrosis factor (TNF) signaling and immune checkpoint proteins regulating T cell, B cell, and NK cell activation. We identified one protein cluster associated with LAVi and HIV regardless of HIV viral suppression status, which comprised 42 proteins enriched in TNF signaling, ephrin signaling, and extracellular matrix (ECM) organization. This protein cluster and 30 of 73 individual proteins were associated with incident HF among 2273 older PWOH (age 68±9 years; 52% female; 8.5±1.4 years of follow-up). Conclusion: Proteomic signatures that may contribute to HIV-associated LA remodeling were enriched in immune checkpoint proteins, cytokine signaling, and ECM organization. These signatures were also associated with incident HF among older PWOH, suggesting specific markers of chronic immune activation, systemic inflammation, and fibrosis may identify shared pathways in HIV and aging that contribute to risk of HF.

Cytomegalovirus IgG is Associated With Physical Function But Not Muscle Density in People With HIV.

BACKGROUND: Cytomegalovirus (CMV) seropositivity is associated with poor outcomes, including physical function impairment, in people without HIV. We examined associations between CMV IgG titer and physical function in virologically suppressed people with HIV (PWH). METHODS: REPRIEVE is a double-blind randomized trial evaluating pitavastatin for primary prevention of atherosclerotic cardiovascular disease in PWH. This analysis focused on participants enrolled in a substudy with additional biomarker testing, imaging [coronary CT angiography], and physical function measures at entry. CMV IgG was measured using quantitative enzyme immunoassay, physical function by Short Physical Performance Battery, and muscle density and area by CT. Associations between CMV IgG (risk factor) and outcomes were evaluated using the partial Spearman correlation and linear and log-binomial regression. RESULTS: Among 717 participants, 82% male, the median CMV IgG was 2716 (Q1, Q3: 807, 6672) IU/mL, all above the limit of quantification. Among 631 participants with imaging, there was no association between CMV IgG and CT-based muscle density or area, controlling for age (r = -0.03 and r = -0.01, respectively; P ≥ 0.38). Among 161 participants with physical function data, higher CMV IgG was associated with poorer overall modified Short Physical Performance Battery score ( P = 0.02), adjusted for age, nadir CD4, and high-sensitivity C-reactive protein. CONCLUSIONS: Higher CMV IgG titer was associated with poorer physical function, not explained by previous immune compromise, inflammation, or muscle density or area. Further mechanistic studies are needed to understand this association and whether CMV-specific therapy can affect physical function in PWH.

Skeletal muscle DNA methylation: Effects of exercise and HIV.

Aging, human immunodeficiency virus (HIV) infection, and antiretroviral therapy modify the epigenetic profile and function of cells and tissues, including skeletal muscle (SkM). In some cells, accelerated epigenetic aging begins very soon after the initial HIV infection, potentially setting the stage for the early onset of frailty. Exercise imparts epigenetic modifications in SkM that may underpin some health benefits, including delayed frailty, in people living with HIV (PWH). In this first report of exercise-related changes in SkM DNA methylation among PWH, we investigated the impact of 24 weeks of aerobic and resistance exercise training on SkM (vastus lateralis) DNA methylation profiles and epigenetic age acceleration (EAA) in older, virally suppressed PWH (n = 12) and uninfected controls (n = 18), and associations of EAA with physical function at baseline. We identified 983 differentially methylated positions (DMPs) in PWH and controls at baseline and 237 DMPs after training. The influence of HIV serostatus on SkM methylation was more pronounced than that of exercise training. There was little overlap in the genes associated with the probes most significantly differentiated by exercise training within each group. Baseline EAA (mean ± SD) was similar between PWH (-0.4 ± 2.5 years) and controls (0.2 ± 2.6 years), and the exercise effect was not significant (p = 0.79). EAA and physical function at baseline were not significantly correlated (all p ≥ 0.10). This preliminary investigation suggests HIV-specific epigenetic adaptations in SkM with exercise training but confirmation in a larger study that includes transcriptomic analysis is warranted.

Association of urine biomarkers of kidney health with subclinical cardiovascular disease among men with and without HIV.

OBJECTIVE: The aim of this study was to determine whether urine biomarkers of kidney health are associated with subclinical cardiovascular disease among men with and without HIV. DESIGN: A cross-sectional study within the Multicenter AIDS Cohort Study (MACS) among 504 men with and without HIV infection who underwent cardiac computed tomography scans and had urine biomarkers measured within the preceding 2 years. METHODS: Our primary predictors were four urine biomarkers of endothelial (albuminuria), proximal tubule dysfunction (alpha-1-microglobulin [A1 M] and injury (kidney injury molecule-1 [KIM-1]) and tubulointerstitial fibrosis (pro-collagen-III N-terminal peptide [PIIINP]). These were evaluated for association with coronary artery calcium (CAC) prevalence, CAC extent, total plaque score, and total segment stenosis using multivariable regression. RESULTS: Of the 504 participants, 384 were men with HIV (MWH) and 120 were men without HIV. In models adjusted for sociodemographic factors, cardiovascular disease risk factors, eGFR, and HIV-related factors, each two-fold higher concentration of albuminuria was associated with a greater extent of CAC (1.35-fold higher, 95% confidence interval 1.11-1.65), and segment stenosis (1.08-fold greater, 95% confidence interval 1.01-1.16). Associations were similar between MWH and men without HIV in stratified analyses. The third quartile of A1 M showed an association with greater CAC extent, total plaque score, and total segment stenosis, compared with the lowest quartile. CONCLUSION: Worse endothelial and proximal tubule dysfunction, as reflected by higher urine albumin and A1 M, were associated with greater CAC extent and coronary artery stenosis.

Coronary artery endothelial function and aging in people with HIV and HIV-negative individuals.

Coronary artery disease (CAD) is a common comorbidity in people with human immunodeficiency virus (HIV) (PWH) and impaired coronary endothelial function (CEF) plays a central role in the pathogenesis of CAD. Age-related impaired CEF among PWH, however, is not well characterized. We investigated the association between CEF and age in males and females with and without HIV using 3-T magnetic resonance imaging (MRI). We measured the changes in coronary cross-sectional area (CSA) and coronary blood flow during isometric handgrip exercise (IHE), an established endothelial-dependent stressor with smaller increases in CSA and coronary blood flow indicative of impaired CEF. We included 106 PWH and 82 individuals without HIV. Differences in demographic and clinical characteristics between PWH and individuals without HIV were explored using Pearson's χ2 test for categorical variables and Welch's t test for continuous variables. Linear regression models were used to examine the association between CEF and age. CEF was significantly lower in PWH as compared with individuals without HIV. Coronary endothelial dysfunction was also present at younger ages in PWH than in the individuals without HIV and there were significant differences in CEF between the PWH and individuals without HIV across age groups. Among the individuals without HIV, the percent changes in CSA were inversely related to age in unadjusted and adjusted models. There was no significant association between CEF and age in PWH. To the best of our knowledge, this is the first study to examine the relationship between age and CEF in PWH, and our results suggest that factors other than age significantly impair CEF in PWH across the life span.NEW & NOTEWORTHY This is the first study to examine the relationship between age and coronary endothelial function (CEF) in people with human immunodeficiency virus (HIV) (PWH). CEF was assessed using magnetic resonance imaging (MRI) in people with and without HIV. Although age and CEF were significantly inversely related in individuals without HIV, there was no association between age and CEF in PWH.

CROI 2023: Metabolic and Other Complications of HIV Infection.

Comorbid conditions have major impacts on the health, quality of life, and survival of people with HIV, particularly as they age. The 2023 Conference on Retroviruses and Opportunistic Infections (CROI) featured excellent science related to specific comorbidities, such as cardiovascular disease (CVD), cancer, and obesity. Studies investigating factors that may contribute to CVD, such as mental health disorders, antiretroviral therapies, and activation of hormonal pathways, were featured prominently. Other studies sought to understand the epidemiology of non-AIDS-defining cancers in people with HIV. As at previous CROI conferences, weight gain attributable to antiretroviral therapies was a major theme, and several abstracts focused on the important question of whether weight decreases after discontinuation of antiretroviral therapy (ART) regimens associated with weight gain. This review focuses on abstracts presented at CROI 2023 in these areas, highlighting those with the most clinical impact.

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.

Aging-Related Comorbidity Burden Among Women and Men With or At-Risk for HIV in the US, 2008-2019.

Importance: Despite aging-related comorbidities representing a growing threat to quality-of-life and mortality among persons with HIV (PWH), clinical guidance for comorbidity screening and prevention is lacking. Understanding comorbidity distribution and severity by sex and gender is essential to informing guidelines for promoting healthy aging in adults with HIV. Objective: To assess the association of human immunodeficiency virus on the burden of aging-related comorbidities among US adults in the modern treatment era. Design, Setting, and Participants: This cross-sectional analysis included data from US multisite observational cohort studies of women (Women's Interagency HIV Study) and men (Multicenter AIDS Cohort Study) with HIV and sociodemographically comparable HIV-seronegative individuals. Participants were prospectively followed from 2008 for men and 2009 for women (when more than 80% of participants with HIV reported antiretroviral therapy use) through last observation up until March 2019, at which point outcomes were assessed. Data were analyzed from July 2020 to April 2021. Exposures: HIV, age, sex. Main Outcomes and Measures: Comorbidity burden (the number of total comorbidities out of 10 assessed) per participant; secondary outcomes included individual comorbidity prevalence. Linear regression assessed the association of HIV status, age, and sex with comorbidity burden. Results: A total of 5929 individuals were included (median [IQR] age, 54 [46-61] years; 3238 women [55%]; 2787 Black [47%], 1153 Hispanic or other [19%], 1989 White [34%]). Overall, unadjusted mean comorbidity burden was higher among women vs men (3.4 [2.1] vs 3.2 [1.8]; P = .02). Comorbidity prevalence differed by sex for hypertension (2188 of 3238 women [68%] vs 2026 of 2691 men [75%]), psychiatric illness (1771 women [55%] vs 1565 men [58%]), dyslipidemia (1312 women [41%] vs 1728 men [64%]), liver (1093 women [34%] vs 1032 men [38%]), bone disease (1364 women [42%] vs 512 men [19%]), lung disease (1245 women [38%] vs 259 men [10%]), diabetes (763 women [24%] vs 470 men [17%]), cardiovascular (493 women [15%] vs 407 men [15%]), kidney (444 women [14%] vs 404 men [15%]) disease, and cancer (219 women [7%] vs 321 men [12%]). In an unadjusted model, the estimated mean difference in comorbidity burden among women vs men was significantly greater in every age strata among PWH: age under 40 years, 0.33 (95% CI, 0.03-0.63); ages 40 to 49 years, 0.37 (95% CI, 0.12-0.61); ages 50 to 59 years, 0.38 (95% CI, 0.20-0.56); ages 60 to 69 years, 0.66 (95% CI, 0.42-0.90); ages 70 years and older, 0.62 (95% CI, 0.07-1.17). However, the difference between sexes varied by age strata among persons without HIV: age under 40 years, 0.52 (95% CI, 0.13 to 0.92); ages 40 to 49 years, -0.07 (95% CI, -0.45 to 0.31); ages 50 to 59 years, 0.88 (95% CI, 0.62 to 1.14); ages 60 to 69 years, 1.39 (95% CI, 1.06 to 1.72); ages 70 years and older, 0.33 (95% CI, -0.53 to 1.19) (P for interaction = .001). In the covariate-adjusted model, findings were slightly attenuated but retained statistical significance. Conclusions and Relevance: In this cross-sectional study, the overall burden of aging-related comorbidities was higher in women vs men, particularly among PWH, and the distribution of comorbidity prevalence differed by sex. Comorbidity screening and prevention strategies tailored by HIV serostatus and sex or gender may be needed.

Sleep-Disordered Breathing and Prevalent Hypertension in Men With and Without HIV.

BACKGROUND: Sleep-disordered breathing (SDB) is a known risk factor for hypertension. Despite the well-established link between HIV infection and hypertension, it remains to be determined whether HIV infection modifies the association between SDB and hypertension. SETTING: The Multicenter AIDS Cohort Study. METHODS: SDB was assessed using in-home polysomnography in 779 men (436 with and 343 without HIV). The apnea-hypopnea index (AHI) based on oxyhemoglobin desaturation threshold of ≥3% or arousal (AHI 3a ) and ≥4% (AHI 4 ) along with oxygen desaturation index (ODI) were used to quantify SDB severity. Hypertension was defined as a blood pressure ≥140/90 mm Hg, use of antihypertensive medication, or self-report of a clinical diagnosis. The associations between HIV, SDB, and hypertension were characterized using multivariable logistic regression. RESULTS: The prevalence of hypertension and SDB (AHI 3a ≥ 5 events/hr) was high, with estimates of 53.8% and 82.8%, respectively. Among men without SDB, HIV was independently associated with hypertension, with an adjusted odds ratio (OR) of 3.05 [95% confidence interval (CI): 1.33 to 7.01]. In men without HIV, SDB was associated with hypertension (OR: 2.93; 95% CI: 1.46 to 5.86). No significant increase in the odds of hypertension was noted in men with both HIV and SDB compared with men with either factor alone, with an OR of 3.24 (95% CI: 1.62 to 6.47). These results were consistent across different measures used to define SDB (AHI 3a , AHI 4 , ODI 3 , and ODI 4 ). CONCLUSIONS: Predictors of hypertension differed by HIV status. SDB was associated with hypertension in men without HIV, but not in men with HIV. Among men with HIV, SDB did not affect the odds of hypertension.

Association of cumulative social risk and gestational diabetes mellitus in the US, 2007-2018.

AIMS: Little is known regarding the association of multiple social risk factors and gestational diabetes mellitus (GDM). METHODS: We analyzed the 2007-2018 National Health and Nutrition Examination Surveys including 10,439 women aged ≥20 years (8 % with history of GDM). We created a cumulative social risk score (CSR) by adding scores assigned to each of the following: race/ethnicity, citizenship status and country of birth, education, and family income (score of 0 used as reference group). Using logistic regression, we assessed the associations of individual social risk factors (education, income, race/ethnicity and citizenship status) and CSR score with GDM, adjusting for age, parity, insurance status, care access, smoking, diet, physical activity, and body mass index. RESULTS: Among individual social risk factors, being a non-U.S. citizen (OR:1.51, 95% CI: 1.06-2.15) or belonging to a minority racial/ethnic group (OR:1.30, 95% CI: 1.04-1.59) was significantly associated with a greater odds of GDM. When examining the combined effects of social risk factors, a CSR score ≥3 was associated with an increased odds of GDM (OR:1.64, 95% CI: 1.22-2.1). CONCLUSIONS: Women with a greater burden of social risk factors are more likely to have GDM, thus should be the focus of interventions to prevent and treat GDM.

Estrogen-Based Gender-Affirming Hormone Therapy and Subclinical Cardiovascular Disease in Transgender Women with HIV.

Purpose: Transgender women (TW) are disproportionately affected by HIV infection and cardiovascular disease (CVD). This study evaluated whether estrogen-based gender-affirming hormone therapy (GAHT) in TW with HIV (TWH-GAHT) is associated with indices of subclinical CVD. Methods: Of the 40 HIV-seropositive persons enrolled, 20-60 years of age, on antiretroviral treatment with undetectable viral load, assessments were performed on 15 TWH; of these persons, 11 were GAHT treated. These TWH-GAHT were matched with HIV+ cisgender men and women based on age, ethnicity/race, body mass index, and antihypertensive medication use. Sex hormones, and cardiometabolic (waist circumference, blood pressure, insulin resistance, lipid profile, and C-reactive protein), vascular (flow-mediated dilation [FMD] and arterial stiffness), and proinflammatory measures were obtained. Results: TWH-GAHT displayed elevated estradiol and suppressed testosterone levels relative to normative ranges. Analyses indicated the TWH-GAHT displayed lower low-density lipoprotein compared with cisgender groups (p < 0.05). Although no difference was seen on FMD, the central augmentation index of aortic stiffness was higher in cisgender HIV+ women than cisgender HIV+ men (p < 0.05). No other group difference on subclinical CVD markers was observed. For TWH, partial correlations indicated associations of certain sex hormones with selected cardiometabolic outcomes and the inflammatory cytokine, interleukin-8. Conclusion: When well matched to HIV+ cisgender men and women, subclinical CVD pathophysiology did not appear elevated in TWH-GAHT, although tendencies emerged suggesting that some subclinical CVD indices may be higher, but others lower than cisgender groups. Longitudinal studies of TWH are needed to more precisely evaluate the moderating effect of GAHT on cardiometabolic pathophysiology.

Pulmonary Function and Quality of Life in Aging Men With and Without HIV from the Multicenter AIDS Cohort Study.

People living with HIV have greater pulmonary function impairments and decreased health-related quality of life (HRQoL) compared to uninfected peers. We examined whether pulmonary impairment was associated with HRQoL or respiratory health status. Using Multicenter AIDS Cohort Study data (2017-2019), associations between outcomes [HRQoL (36-Item Short Form Survey) and respiratory health status (St. George's Respiratory Questionnaire)] with pulmonary impairment [diffusing capacity for carbon monoxide (DLCO) and forced expiratory volume in 1 s (FEV1), defined as <80% predicted for both] were examined. Adjusted analyses utilized linear and zero-inflated beta regression, the latter summarized by odds ratio (OR) and quotient ratios (QRs). We also considered whether the subset of adjustment variables age, HIV serostatus, or smoking modified the relationships examined. Of 1048 men, 55% had HIV, with median age 57 [interquartile range (IQR) = 48, 64] years and 1.2 (IQR = 0, 18.1) smoking pack-years. Impaired DLCO, but not impaired FEV1, was significantly associated with lower physical HRQoL [-2.71 (-4.09, -1.33); -1.46 (-3.45, 0.54), respectively]. Pulmonary impairment was associated with higher odds of any St. George's Respiratory Questionnaire (SGRQ) (total score) limitation [DLCO OR = 1.53 (1.15, 2.04); FEV1 OR = 2.48 (1.16, 5.30)] and was elevated in individuals with more severe SGRQ limitations [DLCO QR = 1.13 (0.94, 1.36); FEV1 QR = 1.27 (0.98, 1.64)]. HIV did not modify any associations examined. Age modified the DLCO and any respiratory limitation (SGRQ symptom score) association for every 10 mL CO/min/mmHg decrease in DLCO [age 30 OR = 1.03 (0.51, 2.08); age 50 OR = 1.85 (1.27, 3.85); and age 70 OR = 3.45 (2.00, 5.88)]. Similarly, age modified the DLCO and any respiratory limitation (SGRQ total score) association. FEV1 associations with SGRQ and HRQoL scores were similar across all ages. Impaired pulmonary function was associated with lower HRQoL and greater respiratory impairments. Future studies can determine if interventions aimed at preserving pulmonary function are effective in improving HRQoL and respiratory health among aging men with and without HIV.

Associations of Muscle Density and Area With Coronary Artery Plaque and Physical Function.

OBJECTIVE: Skeletal muscle quality and mass are important for maintaining physical function during advancing age. We leveraged baseline data from Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) to evaluate whether paraspinal muscle density and muscle area are associated with cardiac or physical function outcomes in people with HIV (PWH). METHODS: REPRIEVE is a double-blind randomized trial evaluating the effect of pitavastatin for primary prevention of major adverse cardiovascular events in PWH. This cross-sectional analysis focuses on participants who underwent coronary computed tomography at baseline. Lower thoracic paraspinal muscle density (Hounsfield units [HU]) and area (cm 2 ) were assessed on noncontrast computed tomography. RESULTS: Of 805 PWH, 708 had paraspinal muscle measurements. The median age was 51 years and 17% were natal female patients. The median muscle density was 41 HU (male) and 30 HU (female); area 13.2 cm 2 /m (male) and 9.9 cm 2 /m (female). In adjusted analyses, greater density (less fat) was associated with a lower prevalence of any coronary artery plaque, coronary artery calcium score >0, and high plaque burden ( P = 0.06); area was not associated with plaque measures. Among 139 patients with physical function measures, greater area (but not density) was associated with better performance on a short physical performance battery and grip strength. CONCLUSIONS: Among PWH, greater paraspinal muscle density was associated with a lower prevalence of coronary artery disease while greater area was associated with better physical performance. Whether changes in density or area are associated with changes in CAD or physical performance will be evaluated through longitudinal analyses in REPRIEVE.

Beyond Undetectable: Modeling the Clinical Benefit of Improved Antiretroviral Adherence in Persons With Human Immunodeficiency Virus With Virologic Suppression.

Background: Incomplete antiretroviral therapy (ART) adherence has been linked to deleterious immunologic, inflammatory, and clinical consequences, even among virally suppressed (<50 copies/mL) persons with human immunodeficiency virus (PWH). The impact of improving adherence in the risk of severe non-AIDS events (SNAEs) and death in this population is unknown. Methods: We estimated the reduction in the risk of SNAEs or death resulting from an increase in ART adherence by (1) applying existing data on the association between adherence with high residual inflammation/coagulopathy in virally suppressed PWH, and (2) using a Cox proportional hazards model derived from changes in plasma interleukin 6 (IL-6) and D-dimer from 3 randomized clinical trials. Comparatively, assuming 100% ART adherence in a PWH who achieves viral suppression, we estimated the number of persons in whom a decrease in adherence to <100% would need to be observed for an additional SNAE or death event to occur during 3- and 5-year follow-up. Results: Increasing ART adherence to 100% in PWH who are suppressed on ART despite imperfect adherence translated into a 6%-37% reduction in the risk of SNAEs or death. Comparatively, based on an anticipated 12% increase in IL-6, 254 and 165 PWH would need to decrease their adherence from 100% to <100% for an additional event to occur over 3- and 5-year follow-up, respectively. Conclusions: Modest gains in ART adherence could have clinical benefits beyond virologic suppression. Increasing ART adherence (eg, via an intervention or switch to long-acting ART) in PWH who remain virally suppressed despite incomplete adherence should be evaluated.