Association of HIV Infection and Incident Abdominal Aortic Aneurysm Among 143 001 Veterans.

BACKGROUND: People with HIV (PWH) have an increased risk of cardiovascular disease. Previous cross-sectional data suggest there is a higher prevalence of abdominal aortic aneurysm (AAA) in PWH than in those without HIV. Whether PWH have an increased risk of incident AAA compared with those without HIV is unknown. METHODS: We analyzed data among participants without prevalent AAA from the Veterans Aging Cohort Study, a prospective, observational, longitudinal cohort of veterans with HIV matched 1:2 with veterans without HIV infection. We calculated AAA rates by HIV status and assessed the association between HIV infection and incident AAA using Cox proportional hazards models. We defined AAA using the International Classification of Diseases, 9th or 10th revision, or Current Procedural Terminology codes and adjusted all models for demographic characteristics, cardiovascular disease risk factors, and substance use. Secondary analyses examined the association between time-varying CD4+ T-cell count or HIV viral load and incident AAA. RESULTS: Among 143 001 participants (43 766 with HIV), over a median follow-up of 8.7 years, there were 2431 incident AAA events (26.4% among PWH). Rates of incident AAA per 1000 person-years were similar among PWH (2.0 [95% CI, 1.9-2.2]) and people without HIV (2.2 [95% CI, 2.1-2.3]). There was no evidence that HIV infection increased the risk of incident AAA compared with no HIV infection (adjusted hazard ratio, 1.02 [95% CI, 0.92-1.13]). In adjusted analyses with time-varying CD4+ T-cell counts or HIV viral load, PWH with CD4+ T-cell counts <200 cells/mm3 (adjusted hazard ratio, 1.29 [95% CI, 1.02-1.65]) or HIV viral load ≥500 copies/mL (adjusted hazard ratio, 1.29 [95% CI, 1.09-1.52]) had an increased risk of AAA compared with those without HIV. CONCLUSIONS: HIV infection is associated with an increased risk of AAA among those with low CD4+ T-cell counts or elevated HIV viral load over time.

Healthcare Utilization Among Persons with HIV and Unhealthy Alcohol Use in St. Petersburg, Russia.

Few studies have examined the association between healthcare utilization and heavy alcohol use in Russia among persons with HIV (PWH), a group with high healthcare needs. This study analyzed the association between unhealthy alcohol use (defined as AUDIT score ≥ 8) and healthcare utilization among PWH with heavy alcohol use and daily smoking in St. Petersburg, Russia. This secondary analysis used data from a randomized controlled trial addressing alcohol use. The primary outcome was seeing an infectionist for HIV care in the past year. Outcomes were measured at baseline, 6 months, and 12 months. We assessed the association between unhealthy alcohol use and healthcare utilization outcomes with a repeated measures logistic regression model, controlling for relevant covariates. Nearly all (96.0%) participants had unhealthy alcohol use at baseline, and 90.0% had seen an infectionist for HIV care in the past year. In adjusted analyses, unhealthy alcohol use was associated with a 36% decrease in seeing an infectionist for HIV care (aOR = 0.64, 95% CI 0.43-0.95). Participants reported low levels of emergency department visits and hospitalizations. Understanding how to engage this population in alcohol use disorder treatment and HIV care is an important next step for improving health outcomes for this population.

Is Abstinence from Alcohol and Smoking Associated with Less Anxiety and Depressive Symptoms Among People with HIV?

Achieving abstinence from alcohol, tobacco, or both may improve mental health, but is understudied in people with HIV (PWH). The St PETER HIV randomized clinical trial compared varenicline, cytisine, and nicotine replacement therapy on alcohol and smoking behavior among 400 PWH in Russia. The primary exposure was thirty-day point prevalence abstinence (PPA) from (1) alcohol, (2) smoking, (3) both, or (4) neither and was assessed at 1, 3, 6 and 12-months as were the study outcomes of anxiety (GAD-7) and depressive (CES-D) symptoms. The primary aim was to examine the association between smoking and/or alcohol abstinence and subsequent symptoms of depression and anxiety. Primary analysis used repeated measures generalized linear modeling to relate PPA with mental health scores across time. In secondary analyses, Kruskal-Wallis tests related PPA with mental health scores at each timepoint. Primary analyses did not identify significant differences in anxiety or depressive symptoms between exposure groups over time. Secondary analyses found CES-D scores across PPA categories were similar at 1-month (11, 10, 11, 11) and 6-months (10, 10, 11, 11) but differed at 3-months (9, 11, 10, 12; p = 0.035) and 12-months (10, 6, 11, 10; p = 0.019). GAD-7 scores did not vary across PPA categories at any time point. While abstinence was associated with fewer depressive symptoms at times, findings were not consistent during follow-up, perhaps reflecting intermittent relapse. PWH with polysubstance use and mental health comorbidity are complex, and larger samples with sustained abstinence would further elucidate effects of abstinence on mental health.

Elevated Pulmonary Arterial Compliance Is Associated with Survival in Pulmonary Hypertension: Results from a Novel Network Medicine Analysis.

Rationale: Predictors of adverse outcome in pulmonary hypertension (PH) are well established; however, data that inform survival are lacking. Objectives: We aim to identify clinical markers and therapeutic targets that inform the survival in PH. Methods: We included data from patients with elevated mean pulmonary artery pressure (mPAP) diagnosed by right heart catheterization in the U.S. Veterans Affairs system (October 1, 2006-September 30, 2018). Network medicine framework was used to subgroup patients when considering an N of 79 variables per patient. The results informed outcome analyses in the discovery cohort and a sex-balanced validation right heart catheterization cohort from Vanderbilt University (September 24, 1998-December 20, 2013). Measurements and Main Results: From an N of 4,737 complete case patients with mPAP of 19-24 mm Hg, there were 21 distinct subgroups (network modules) (all-cause mortality range = 15.9-61.2% per module). Pulmonary arterial compliance (PAC) drove patient assignment to modules characterized by increased survival. When modeled continuously in patients with mPAP ⩾19 mm Hg (N = 37,744; age, 67.2 yr [range = 61.7-73.8 yr]; 96.7% male; median follow-up time, 1,236 d [range = 570-1,971 d]), the adjusted all-cause mortality hazard ratio was <1.0 beginning at PAC ⩾3.0 ml/mm Hg and decreased progressively to ∼7 ml/mm Hg. A protective association between PAC ⩾3.0 ml/mm Hg and mortality was also observed in the validation cohort (N = 1,514; age, 60.2 yr [range = 49.2-69.1 yr]; 48.0% male; median follow-up time, 2,485 d [range = 671-3,580 d]). The association was strongest in patients with precapillary PH at the time of catheterization, in whom 41% (95% confidence interval, 0.55-0.62; P < 0.001) and 49% (95% confidence interval, 0.38-0.69; P < 0.001) improvements in survival were observed for PAC ⩾3.0 versus <3.0 ml/mm Hg in the discovery and validation cohorts, respectively. Conclusions: These data identify elevated PAC as an important parameter associated with survival in PH. Prospective studies are warranted that consider PAC ⩾3.0 ml/mm Hg as a therapeutic target to achieve through proven interventions.

Examining Depression as a Risk Factor for Cardiovascular Disease in People with HIV: A Systematic Review.

BACKGROUND: People with human immunodeficiency virus (HIV) have an increased risk of cardiovascular disease (CVD) not fully accounted for by traditional or HIV-specific risk factors. Successful management of HIV does not eliminate this excess risk. Thus, there is a need to identify novel risk factors for CVD among people with HIV (PWH). PURPOSE: Our objective was to systematically review the literature on one such candidate CVD risk factor in PWH-depression. METHODS: A systematic literature search of PubMed, PsycINFO, EMBASE, Web of Science, and CINAHL was performed to identify published English-language studies examining associations of depression with clinical CVD, subclinical CVD, and biological mechanisms (immune activation, systemic inflammation, altered coagulation) among PWH between the earliest date and June 22, 2021. RESULTS: Thirty-five articles were included. For clinical CVD (k = 8), findings suggests that depression is consistently associated with an increased risk of incident CVD. For subclinical CVD (k = 5), one longitudinal analysis reported a positive association, and four cross-sectional analyses reported null associations. For immune activation (k = 13), systemic inflammation (k = 17), and altered coagulation (k = 5), findings were mixed, and there was considerable heterogeneity in sample characteristics and methodological quality across studies. CONCLUSIONS: Depression may be an independent risk factor for CVD among PWH. Additional research is needed to confirm depression's association with clinical CVD and to determine whether depression is consistently and meaningfully associated with subclinical CVD and biological mechanisms of CVD in HIV. We propose a research agenda for this emerging area.

Can Treatment Support Mitigate Nicotine Metabolism-Based Disparities in Smoking Abstinence? Secondary Analysis of the Helping HAND 4 Trial.

INTRODUCTION: The nicotine metabolite ratio (NMR), a biomarker of CYP2A6-mediated nicotine metabolism, predicts the efficacy of nicotine replacement therapy (NRT), with fast metabolizers benefiting less than slow metabolizers. Whether treatment support to optimize NRT use (henceforth "treatment support") modifies this pharmacogenetic relationship is unknown. METHODS: Hospitalized adult daily smokers were assigned to one of two post-discharge smoking cessation interventions offering NRT and counseling: (1) Transitional Tobacco Care Management, which delivered enhanced treatment support via free combination NRT at discharge and automated counseling, and (2) a quitline-based approach representing usual care (UC). The primary outcome was biochemically verified 7-day point prevalence abstinence 6 months after discharge. Secondary outcomes were the use of NRT and counseling during the 3-month intervention period. Logistic regression models tested for interactions between NMR and intervention, controlling for sex, race, alcohol use, and BMI. RESULTS: Participants (N = 321) were classified as slow (n = 80) or fast (n = 241) metabolizers relative to the first quartile of NMR (0.012-0.219 vs. 0.221-3.455, respectively). Under UC, fast (vs. slow) metabolizers had lower odds of abstinence at 6 months (aOR 0.35, 95% CI 0.13-0.95) and similar odds of NRT and counseling use. Compared to UC, enhanced treatment support increased abstinence (aOR 2.13, 95% CI 0.98-4.64) and use of combination NRT (aOR 4.62, 95% CI 2.57-8.31) in fast metabolizers, while reducing abstinence in slow metabolizers (aOR 0.21, 95% CI 0.05-0.87; NMR-by-intervention interaction p = .004). CONCLUSIONS: Treatment support increased abstinence and optimal use of NRT among fast nicotine metabolizers, thereby mitigating the gap in abstinence between fast and slow metabolizers. IMPLICATIONS: In this secondary analysis of two smoking cessation interventions for recently hospitalized smokers, fast nicotine metabolizers quit at lower rates than slow metabolizers, but providing fast metabolizers with enhanced treatment support doubled the odds of quitting in this group and mitigated the disparity in abstinence between fast and slow metabolizers. If validated, these findings could lead to personalized approaches to smoking cessation treatment that improve outcomes by targeting treatment support to those who need it most.

Mendelian Randomization Analysis of Hemostatic Factors and Their Contribution to Peripheral Artery Disease-Brief Report.

BACKGROUND AND OBJECTIVE: Peripheral artery disease (PAD) is the third most common form of atherosclerotic vascular disease and is characterized by significant functional disability and increased cardiovascular mortality. Recent genetic data support a role for a procoagulation protein variant, the factor V Leiden mutation, in PAD. The role of other hemostatic factors in PAD remains unknown. We evaluated the role of hemostatic factors in PAD using Mendelian randomization. Approach and Results: Two-sample Mendelian randomization to evaluate the roles of FVII (factor VII), FVIII (factor VIII), FXI (factor XI), VWF (von Willebrand factor), and fibrinogen in PAD was performed using summary statistics from GWAS for hemostatic factors performed within the Cohorts for Heart and Aging Research in the Genome Epidemiology Consortium and from GWAS performed for PAD within the Million Veteran Program. Genetically determined FVIII and VWF, but not FVII, FXI, or fibrinogen, were associated with PAD in Mendelian randomization experiments (FVIII: odds ratio, 1.41 [95% CI, 1.23-1.62], P=6.0×10-7, VWF: odds ratio, 1.28 [95% CI, 1.07-1.52], P=0.0073). In single variant sensitivity analysis, the ABO locus was the strongest genetic instrument for both FVIII and VWF. CONCLUSIONS: Our results suggest a role for hemostasis, and by extension, thrombosis in PAD. Further study is warranted to determine whether VWF and FVIII independently affect the biology of PAD.

Pharmacoepidemiology, Machine Learning, and COVID-19: An Intent-to-Treat Analysis of Hydroxychloroquine, With or Without Azithromycin, and COVID-19 Outcomes Among Hospitalized US Veterans.

Hydroxychloroquine (HCQ) was proposed as an early therapy for coronavirus disease 2019 (COVID-19) after in vitro studies indicated possible benefit. Previous in vivo observational studies have presented conflicting results, though recent randomized clinical trials have reported no benefit from HCQ among patients hospitalized with COVID-19. We examined the effects of HCQ alone and in combination with azithromycin in a hospitalized population of US veterans with COVID-19, using a propensity score-adjusted survival analysis with imputation of missing data. According to electronic health record data from the US Department of Veterans Affairs health care system, 64,055 US Veterans were tested for the virus that causes COVID-19 between March 1, 2020 and April 30, 2020. Of the 7,193 veterans who tested positive, 2,809 were hospitalized, and 657 individuals were prescribed HCQ within the first 48-hours of hospitalization for the treatment of COVID-19. There was no apparent benefit associated with HCQ receipt, alone or in combination with azithromycin, and there was an increased risk of intubation when HCQ was used in combination with azithromycin (hazard ratio = 1.55; 95% confidence interval: 1.07, 2.24). In conclusion, we assessed the effectiveness of HCQ with or without azithromycin in treatment of patients hospitalized with COVID-19, using a national sample of the US veteran population. Using rigorous study design and analytic methods to reduce confounding and bias, we found no evidence of a survival benefit from the administration of HCQ.

Cardiovascular Effects of Androgen Deprivation Therapy in Prostate Cancer: Contemporary Meta-Analyses.

Androgen deprivation therapy is a cornerstone of prostate cancer treatment. Pharmacological androgen deprivation includes gonadotropin-releasing hormone agonism and antagonism, androgen receptor inhibition, and CYP17 (cytochrome P450 17A1) inhibition. Studies in the past decade have raised concerns about the potential for androgen deprivation therapy to increase the risk of adverse cardiovascular events such as myocardial infarction, stroke, and cardiovascular mortality, possibly by exacerbating cardiovascular risk factors. In this review, we summarize existing data on the cardiovascular effects of androgen deprivation therapy. Among the therapies, abiraterone stands out for increasing risk of cardiac events in meta-analyses of both randomized controlled trials and observational studies. We find a divergence between observational studies, which show consistent positive associations between androgen deprivation therapy use and cardiovascular disease, and randomized controlled trials, which do not show these associations reproducibly.

Association of Syndemic Unhealthy Alcohol Use, Smoking, and Depressive Symptoms on Incident Cardiovascular Disease among Veterans With and Without HIV-Infection.

Unhealthy alcohol use, smoking, and depressive symptoms are risk factors for cardiovascular disease (CVD). Little is known about their co-occurrence - termed a syndemic, defined as the synergistic effect of two or more conditions-on CVD risk in people with HIV (PWH). We used data from 5621 CVD-free participants (51% PWH) in the Veteran's Aging Cohort Study-8, a prospective, observational study of veterans followed from 2002 to 2014 to assess the association between this syndemic and incident CVD by HIV status. Diagnostic codes identified cases of CVD (acute myocardial infarction, stroke, heart failure, peripheral artery disease, and coronary revascularization). Validated measures of alcohol use, smoking, and depressive symptoms were used. Baseline number of syndemic conditions was categorized (0, 1, ≥ 2 conditions). Multivariable Cox Proportional Hazards regressions estimated risk of the syndemic (≥ 2 conditions) on incident CVD by HIV-status. There were 1149 cases of incident CVD (52% PWH) during the follow-up (median 10.1 years). Of the total sample, 64% met our syndemic definition. The syndemic was associated with greater risk for incident CVD among PWH (Hazard Ratio [HR] 1.87 [1.47-2.38], p < 0.001) and HIV-negative veterans (HR 1.70 [1.35-2.13], p < 0.001), compared to HIV-negative with zero conditions. Among those with the syndemic, CVD risk was not statistically significantly higher among PWH vs. HIV-negative (HR 1.10 [0.89, 1.37], p = .38). Given the high prevalence of this syndemic combined with excess risk of CVD, these findings support linked-screening and treatment efforts.

T Lymphocyte Subsets Associated With Prevalent Diabetes in Veterans With and Without Human Immunodeficiency Virus.

BACKGROUND: A higher proportion of circulating memory CD4+ T cells is associated with prevalent diabetes mellitus in the general population. Given the broad changes in adaptive immunity, including memory T-cell expansion, and rising prevalence of diabetes in the human immunodeficiency virus (HIV) population, we assessed whether similar relationships were present in persons with HIV (PWH). METHODS: Multiple CD4+ and CD8+ T-cell subsets were measured by flow cytometry, and prevalent diabetes cases were adjudicated by 2 physicians for PWH and HIV-negative participants in the Veterans Aging Cohort Study. Multivariable logistic regression models evaluated the association of T-cell subsets and diabetes stratified by HIV status, adjusted for cytomegalovirus serostatus and traditional risk factors. RESULTS: Among 2385 participants (65% PWH, 95% male, 68% African American), higher CD45RO+ memory CD4+ T cells and lower CD38+ CD4+ T cells were associated with prevalent diabetes, and had a similar effect size, in both the PWH and HIV-negative (P ≤ .05 for all). Lower CD38+CD8+ T cells were also associated with diabetes in both groups. CONCLUSIONS: The CD4+ and CD8+ T-cell subsets associated with diabetes are similar in PWH and HIV-negative individuals, suggesting that diabetes in PWH may be related to chronic immune activation.

Characteristics, Prevention, and Management of Cardiovascular Disease in People Living With HIV: A Scientific Statement From the American Heart Association.

As early and effective antiretroviral therapy has become more widespread, HIV has transitioned from a progressive, fatal disease to a chronic, manageable disease marked by elevated risk of chronic comorbid diseases, including cardiovascular diseases (CVDs). Rates of myocardial infarction, heart failure, stroke, and other CVD manifestations, including pulmonary hypertension and sudden cardiac death, are significantly higher for people living with HIV than for uninfected control subjects, even in the setting of HIV viral suppression with effective antiretroviral therapy. These elevated risks generally persist after demographic and clinical risk factors are accounted for and may be partly attributed to chronic inflammation and immune dysregulation. Data on long-term CVD outcomes in HIV are limited by the relatively recent epidemiological transition of HIV to a chronic disease. Therefore, our understanding of CVD pathogenesis, prevention, and treatment in HIV relies on large observational studies, randomized controlled trials of HIV therapies that are underpowered to detect CVD end points, and small interventional studies examining surrogate CVD end points. The purpose of this document is to provide a thorough review of the existing evidence on HIV-associated CVD, in particular atherosclerotic CVD (including myocardial infarction and stroke) and heart failure, as well as pragmatic recommendations on how to approach CVD prevention and treatment in HIV in the absence of large-scale randomized controlled trial data. This statement is intended for clinicians caring for people with HIV, individuals living with HIV, and clinical and translational researchers interested in HIV-associated CVD.

Microvascular Disease, Peripheral Artery Disease, and Amputation.

BACKGROUND: The mechanism of adverse limb events associated with peripheral artery disease remains incompletely understood. We investigated whether microvascular disease is associated with amputation in a large cohort of veterans to determine whether microvascular disease diagnosed in any location increases the risk of amputation alone and in concert with peripheral artery disease. METHODS: Participants in the Veterans Aging Cohort Study were recruited from April 1, 2003 through December 31, 2014. We excluded participants with known prior lower limb amputation. Using time-updated Cox proportional hazards regression, we analyzed the effect of prevalent microvascular disease (retinopathy, neuropathy, and nephropathy) and peripheral artery disease status on the risk of incident amputation events after adjusting for demographics and cardiovascular risk factors. RESULTS: Among 125 674 veterans without evidence of prior amputation at baseline, the rate of incident amputation over a median of 9.3 years of follow-up was 1.16 per 1000 person-years, yielding a total of 1185 amputations. In time-updated multivariable-adjusted analyses, compared with those without peripheral artery disease or microvascular disease, microvascular disease alone was associated with a 3.7-fold (95% CI, 3.0-4.6) increased risk of amputation; peripheral artery disease alone conferred a 13.9-fold (95% CI, 11.3-17.1) elevated risk of amputation; and the combination of peripheral artery disease and microvascular disease was associated with a 22.7-fold (95% CI, 18.3-28.1) increased risk of amputation. CONCLUSIONS: Independent of traditional risk factors, the presence of microvascular disease increases the risk of amputation alone and synergistically increases risk in patients with peripheral artery disease. Further research is needed to understand the mechanisms by which this occurs.

Epigenetic Associations With Estimated Glomerular Filtration Rate Among Men With Human Immunodeficiency Virus Infection.

BACKGROUND: People living with human immunodeficiency virus (HIV) infection have higher risk for chronic kidney disease (CKD), defined by a reduced estimated glomerular filtration rate (eGFR). Previous studies have implicated epigenetic changes related to CKD; however, the mechanism of HIV-related CKD has not been thoroughly investigated. METHODS: We conducted an epigenome-wide association study of eGFR among 567 HIV-positive and 117 HIV-negative male participants in the Veterans Aging Cohort Study to identify epigenetic signatures of kidney function. RESULTS: By surveying more than 400 000 cytosine guanine dinucleotide (CpG) sites measured from peripheral blood mononuclear cells, we identified 15 sites that were significantly associated with eGFR (false discovery rate Q value < 0.05) among HIV-positive participants. The most significant CpG sites, located at MAD1L1, TSNARE1/BAI1, and LTV1, were all negatively associated with eGFR (cg06329547, P = 5.25 × 10-9; cg23281907, P = 1.37 × 10-8; cg18368637, P = 5.17 × 10-8). We also replicated previously reported eGFR-associated CpG sites including cg17944885 (P = 2.5 × 10-5) located between ZNF788 and ZNF20 on chromosome 19 in the pooled population. CONCLUSIONS: In this study we uncovered novel epigenetic associations with kidney function among people living with HIV and suggest potential epigenetic mechanisms linked with HIV-related CKD risk.

Patterns of COVID-19 testing and mortality by race and ethnicity among United States veterans: A nationwide cohort study.

BACKGROUND: There is growing concern that racial and ethnic minority communities around the world are experiencing a disproportionate burden of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19). We investigated racial and ethnic disparities in patterns of COVID-19 testing (i.e., who received testing and who tested positive) and subsequent mortality in the largest integrated healthcare system in the United States. METHODS AND FINDINGS: This retrospective cohort study included 5,834,543 individuals receiving care in the US Department of Veterans Affairs; most (91%) were men, 74% were non-Hispanic White (White), 19% were non-Hispanic Black (Black), and 7% were Hispanic. We evaluated associations between race/ethnicity and receipt of COVID-19 testing, a positive test result, and 30-day mortality, with multivariable adjustment for a wide range of demographic and clinical characteristics including comorbid conditions, health behaviors, medication history, site of care, and urban versus rural residence. Between February 8 and July 22, 2020, 254,595 individuals were tested for COVID-19, of whom 16,317 tested positive and 1,057 died. Black individuals were more likely to be tested (rate per 1,000 individuals: 60.0, 95% CI 59.6-60.5) than Hispanic (52.7, 95% CI 52.1-53.4) and White individuals (38.6, 95% CI 38.4-38.7). While individuals from minority backgrounds were more likely to test positive (Black versus White: odds ratio [OR] 1.93, 95% CI 1.85-2.01, p < 0.001; Hispanic versus White: OR 1.84, 95% CI 1.74-1.94, p < 0.001), 30-day mortality did not differ by race/ethnicity (Black versus White: OR 0.97, 95% CI 0.80-1.17, p = 0.74; Hispanic versus White: OR 0.99, 95% CI 0.73-1.34, p = 0.94). The disparity between Black and White individuals in testing positive for COVID-19 was stronger in the Midwest (OR 2.66, 95% CI 2.41-2.95, p < 0.001) than the West (OR 1.24, 95% CI 1.11-1.39, p < 0.001). The disparity in testing positive for COVID-19 between Hispanic and White individuals was consistent across region, calendar time, and outbreak pattern. Study limitations include underrepresentation of women and a lack of detailed information on social determinants of health. CONCLUSIONS: In this nationwide study, we found that Black and Hispanic individuals are experiencing an excess burden of SARS-CoV-2 infection not entirely explained by underlying medical conditions or where they live or receive care. There is an urgent need to proactively tailor strategies to contain and prevent further outbreaks in racial and ethnic minority communities.

Direct-Acting Antiviral Therapy for HCV Infection Is Associated With a Reduced Risk of Cardiovascular Disease Events.

BACKGROUND & AIMS: Infection with hepatitis virus C (HCV) is associated with an increased risk of cardiovascular disease (CVD) events. It is not clear whether treatment with direct-acting antiviral (DAA) agents affects risk of CVD. METHODS: We searched the Electronically Retrieved Cohort of HCV-Infected Veterans database for patients with chronic HCV infection (n = 242,680) and identified patients who had been treated with a pegylated interferon and ribavirin regimen (n = 4436) or a DAA-containing regimen (n = 12,667). Treated patients were matched for age, race, sex, and baseline values with patients who had never received treatment for HCV infection (controls). All subjects were free of any CVD event diagnosis of HCV infection at baseline. The primary outcome was incident CVD events, identified by International Classification of Diseases, Ninth Edition, Clinical Modification or International Classification of Diseases, Tenth Edition code, in the different groups and in patients with vs without a sustained virologic response to therapy. RESULTS: There were 1239 (7.2%) incident CVD events in the treated groups and 2361 (13.8%) events in the control group. Incidence rates were 30.9 per 1000 patient-years (95% CI 29.6-32.1) in the control group and 20.3 per 1000 patient-years (95% CI 19.2-21.5) in the treated groups (P < .0001). Treatment with pegylated interferon and ribavirin (hazard ratio 0.78; 95% CI 0.71-0.85) or a DAA regimen (hazard ratio 0.57; 95% CI 0.51-0.65) was associated with a significantly lower risk of a CVD event compared with no treatment (controls). Incidence rates for CVD events were 23.5 per 1000 patient-years (95% CI 21.8-25.3) in the group treated with the pegylated interferon and ribavirin regimen, 16.3 per 1000 patient-years (95% CI 14.7-18.0) in the group treated with a DAA regimen, and 30.4 (95% CI 29.2-31.7) in the control group. A sustained virologic response was associated with a lower risk of incident CVD events (hazard ratio 0.87; 95% CI 0.77-0.98). CONCLUSIONS: In an analysis of a cohort of HCV-infected veterans, treatment of HCV infection was associated with a significant decrease in risk of CVD events. Patients treated with a DAA regimen and patients who achieved sustained virologic responses had the lowest risk for CVD events.

Associations of Total, Cognitive/Affective, and Somatic Depressive Symptoms and Antidepressant Use With Cardiovascular Disease-Relevant Biomarkers in HIV: Veterans Aging Cohort Study.

OBJECTIVE: We sought to determine the associations of total, cognitive/affective, and somatic depressive symptoms and antidepressant use with biomarkers of processes implicated in cardiovascular disease in HIV (HIV-CVD). METHODS: We examined data from 1546 HIV-positive and 843 HIV-negative veterans. Depressive symptoms were assessed using the Patient Health Questionnaire-9, and past-year antidepressant use was determined from Veterans Affair pharmacy records. Monocyte (soluble CD14 [sCD14]), inflammatory (interleukin-6 [IL-6]), and coagulation (D-dimer) marker levels were determined from previously banked blood specimens. Linear regression models with multiple imputation were run to estimate the associations between depression-related factors and CVD-relevant biomarkers. RESULTS: Among HIV-positive participants, greater somatic depressive symptoms were associated with higher sCD14 (exp[b] = 1.02, 95% confidence interval [CI] = 1.00-1.03) and D-dimer (exp[b] = 1.06, 95% CI = 1.00-1.11) after adjustment for demographics and potential confounders. Further adjustment for antidepressant use and HIV factors slightly attenuated these relationships. Associations were also detected for antidepressant use, as selective serotonin reuptake inhibitor use was related to lower sCD14 (exp[b] = 0.95, 95% CI = 0.91-1.00) and IL-6 (exp[b] = 0.86, 95% CI = 0.76-0.96), and tricyclic antidepressant use was related to higher sCD14 (exp[b] = 1.07, 95% CI = 1.03-1.12) and IL-6 (exp[b] = 1.14, 95% CI = 1.02-1.28). Among HIV-negative participants, total, cognitive/affective, and somatic depressive symptoms were associated with higher IL-6, and tricyclic antidepressant use was related to higher sCD14. CONCLUSIONS: Our novel findings suggest that a) monocyte activation and altered coagulation may represent two pathways through which depression increases HIV-CVD risk and that b) tricyclic antidepressants may elevate and selective serotonin reuptake inhibitors may attenuate HIV-CVD risk by influencing monocyte and inflammatory activation.

Contribution of Behavioral Health Factors to Non-AIDS-Related Comorbidities: an Updated Review.

PURPOSE OF REVIEW: We summarize recent literature on the contribution of substance use and depression to non-AIDS-related comorbidities. Discussion of recent randomized clinical trials and implementation research to curtail risk attributed to each behavioral health issue is provided. RECENT FINDINGS: Smoking, unhealthy alcohol use, opioid use, and depression are common among PWH and individually contribute to increased risk for non-AIDS-related comorbidities. The concurrence of these conditions is notable, yet understudied, and provides opportunity for linked-screening and potential treatment of more than one behavioral health factor. Current results from randomized clinical trials are inconsistent. Investigating interventions to reduce the impact of these behavioral health conditions with a focus on implementation into clinical care is important. Non-AIDS-defining cancers, cardiovascular disease, liver disease, and diabetes are leading causes of morbidity in people with HIV. Behavioral health factors including substance use and mental health issues, often co-occurring, likely contribute to the excess risk of non-AIDS-related comorbidities.

DNA Methylation Markers of Type 2 Diabetes Mellitus Among Male Veterans With or Without Human Immunodeficiency Virus Infection.

Epigenetic modifications such as DNA methylation are associated with both human immunodeficiency virus (HIV) infection and type 2 diabetes mellitus (T2DM). We investigated epigenetic associations with T2DM according to HIV infection status and assessed interaction effects among 681 male participants of the Veterans Aging Cohort Study. Methylation at previously reported sites, cg1963031 (TXNIP), cg18181703 (SOCS3), and cg09152259 (PROC), was significantly associated with T2DM in HIV-infected individuals. We identified 3 novel associations with suggestive statistical significance: cg1231141 (ADAMTS2), cg19534769 (HGFAC), and cg13163919 (TLE3). Suggestive interaction with HIV infection status was found at cg17862404 (TSC22D1). The implicated genes are involved in inflammation, pancreatic ß-cell function, and T2DM pathogenesis.