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Introduction: Globally, 7 million people with HIV (PWH) aged over 50 years exist. 5 million of them live in sub-Saharan Africa, the epicenter of the HIV epidemic. In Ghana, every 1 in 6 PWH is aged over 50 years. However, access to geriatric health care is grossly limited in Ghana and the sub-Saharan Africa region. This has resulted in a lack of focus on geriatric syndromes, a multi-factorial clinical condition common in older PWH, that do not fit discrete disease categories. Consequently, this gap threatens the life expectancy for aging PWH, necessitating the need to promptly fill it. The KNUST Aging and HIV Outcomes (KAHO) study will help identify priorities and opportunities for developing an effective integrated model of HIV and geriatric healthcare in Ghana., Methods and Analysis: The KAHO study will recruit 151 PWH aged 50 years and older at the Infectious Disease Unit (IDU) of the University Hospital, Kwame Nkrumah University of Science and Technology (KNUST). The study will be conducted over a 2-year period and participants will be seen at months 0, 6 and 12. Participants at each visit will be taken through assessments and questionnaires on geriatric health, cognition, social vulnerability, HIV-related conditions and they will provide biospecimens for laboratory testing. We will also conduct semi-structured qualitative interviews of PWH, healthcare providers, policy makers and study research assistants. Quantitative data will be analyzed using one sample proportion test and linear regression models appropriately. The Levesque's framework will be used as a guide to analyze qualitative data., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Werekuu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Telomere length (TL) is an important indicator of cellular aging. Shorter TL is associated with several age-related diseases including coronary heart disease, heart failure, diabetes, osteoporosis, and cancer. Recently, a DNA methylation-based TL (DNAmTL) estimator has been developed as an alternative method for directly measuring TL. In this study, we examined the association of DNAmTL with cancer prevalence and mortality risk among people with and without HIV in the Veterans Aging Cohort Study Biomarker Cohort (VACS, N = 1917) and Women's Interagency HIV Study Cohort (WIHS, N = 481). We profiled DNAm in whole blood (VACS) or in peripheral blood mononuclear cells (WIHS) using an array-based method. Cancer prevalence was estimated from electronic medical records and cancer registry data. The VACS Index was used as a measure of physiologic frailty. Models were adjusted for self-reported race and ethnicity, batch, smoking status, alcohol consumption, and five cell types (CD4, CD8, NK, B cell, and monocyte). We found that people with HIV had shorter average DNAmTL than those without HIV infection [beta = -0.25, 95% confidence interval (-0.32, -0.18), p = 1.48E-12]. Greater value of VACS Index [beta = -0.002 (-0.003, -0.001), p = 2.82E-05] and higher cancer prevalence [beta = -0.07 (-0.10, -0.03), p = 1.37E-04 without adjusting age] were associated with shortened DNAmTL. In addition, one kilobase decrease in DNAmTL was associated with a 40% increase in mortality risk [hazard ratio: 0.60 (0.44, 0.82), p = 1.42E-03]. In summary, HIV infection, physiologic frailty, and cancer are associated with shortening DNAmTL, contributing to an increased risk of all-cause mortality., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Background: Delayed CD4 recovery after initiating antiretroviral therapy (ART) is a novel potential mechanism by which alcohol consumption leads to increased morbidity and mortality in people with HIV. We hypothesized that alcohol consumption at ART initiation is associated with slower CD4 recovery., Methods: We retrospectively analyzed 2 pooled longitudinal alcohol/HIV cohorts (2014-2019) in St. Petersburg, Russia. Eligible participants initiated the first ART during parent studies; had alcohol consumption assessed by the blood biomarker, phosphatidylethanol (PEth), at the last research visit before ART initiation; and had ≥1 CD4 count measurement before and after initiating ART. Participants were stratified by low, moderate, and high PEth (<8, 8-80, and >80 ng/mL, respectively). We used random-effects piecewise linear regression models to estimate CD4 recovery, defined as CD4 count change per 30 days after ART initiation, by the alcohol group., Results: Of 60 eligible participants, median age was 34 years and 28% were female. The median pre-ART PEth in the low, moderate, and high PEth groups were <8, 23, and 232 ng/mL, respectively. After starting ART, the CD4 count increased by 13.60 cells/mm3/mo (95% CI: 0.33 to 26.87) with low PEth, 0.93 cells/mm3/mo (95% CI: -6.18 to 8.04) with moderate PEth, and 2.33 cells/mm3/mo (95% CI: -3.44 to 8.09) with high PEth., Conclusions: Among Russians with HIV, we observed faster CD4 recovery after ART initiation in those with low alcohol consumption compared with those with moderate and high alcohol consumption, as assessed by PEth. This analysis provides further evidence for the possible value of alcohol reduction interventions for people with HIV who are initiating ART., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: To include, sustain, and retain HIV-focused early career faculty from groups historically excluded from biomedical research, the Providence/Boston Center for AIDS Research (CFAR) conducted focus groups and individual interviews with early and mid-career faculty to discern their needs., Methods: We conducted focus groups and interviews with 15 faculty at institutions affiliated with Providence/Boston CFAR from groups underrepresented in biomedical research. The discussion was guided using the domains of an Asset Bundle Model encompassing scientific human capital, social capital, and financial capital., Result: Participants' identities, including their race, ethnicity, gender, sexual orientation, and being a parent affected their vision of themselves as scientists. Participants reported confusion or limited training on or access to resources for professional development, hiring staff, meeting NIH reporting requirements, international research, support for working parents, sabbaticals, and addressing workplace conflict or unsupportive work environments. Some described feeling like they were a burden on their mentors who seemed overextended. They identified attributes of effective mentors, such as believing in and investing in the mentee; having the requisite content area expertise and self-confidence; being able to identify mentees needs and meet them where they are; and being consistent, communicative, respectful, and kind. They described a need for additional education and support preresearch and postresearch grant award management., Conclusions: To learn how to equitably serve all interested in HIV research, CFARs should engage and include perspectives from scientists who have historically been excluded from biomedical research. Our future work will test, implement, and disseminate the ideas generated by these focus group discussions., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: There is an urgent need to increase diversity among scientific investigators in the HIV research field to be more reflective of communities highly affected by the HIV epidemic. Thus, it is critical to promote the inclusion and advancement of early-stage scholars from racial and ethnic groups underrepresented in HIV science and medicine., Methods: To widen the HIV research career pathway for early-stage scholars from underrepresented minority groups, the National Institutes of Health supported the development of the Centers for AIDS Research (CFAR) Diversity, Equity, and Inclusion Pathway Initiative (CDEIPI). This program was created through partnerships between CFARs and Historically Black Colleges and Universities and other Minority Serving Institutions throughout the United States., Results: Seventeen CFARs and more than 20 Historically Black Colleges and Universities and Minority Serving Institutions have participated in this initiative to date. Programs were designed for the high school (8), undergraduate (13), post baccalaureate (2), graduate (12), and postdoctoral (4) levels. Various pedagogical approaches were used including didactic seminar series, intensive multiday workshops, summer residential programs, and mentored research internship opportunities. During the first 18 months of the initiative, 257 student scholars participated in CDEIPI programs including 150 high school, 73 undergraduate, 3 post baccalaureate, 27 graduate, and 4 postdoctoral students., Conclusion: Numerous student scholars from a wide range of educational levels, geographic backgrounds, and racial and ethnic minority groups have engaged in CDEIPI programs. Timely and comprehensive program evaluation data will be critical to support a long-term commitment to this unique training initiative., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Hepatic steatosis (fatty liver disease) affects 25% of the world's population, particularly people with HIV (PWH). Pharmacoepidemiologic studies to identify medications associated with steatosis have not been conducted because methods to evaluate liver fat within digitized images have not been developed. We determined the accuracy of a deep learning algorithm (automatic liver attenuation region-of-interest-based measurement [ALARM]) to identify steatosis within clinically obtained noncontrast abdominal CT images compared to manual radiologist review and evaluated its performance by HIV status., Methods: We performed a cross-sectional study to evaluate the performance of ALARM within noncontrast abdominal CT images from a sample of patients with and without HIV in the US Veterans Health Administration. We evaluated the ability of ALARM to identify moderate-to-severe hepatic steatosis, defined by mean absolute liver attenuation <40 Hounsfield units (HU), compared to manual radiologist assessment., Results: Among 120 patients (51 PWH) who underwent noncontrast abdominal CT, moderate-to-severe hepatic steatosis was identified in 15 (12.5%) persons via ALARM and 12 (10%) by radiologist assessment. Percent agreement between ALARM and radiologist assessment of absolute liver attenuation <40 HU was 95.8%. Sensitivity, specificity, positive predictive value, and negative predictive value of ALARM were 91.7% (95%CI, 51.5%-99.8%), 96.3% (95%CI, 90.8%-99.0%), 73.3% (95%CI, 44.9%-92.2%), and 99.0% (95%CI, 94.8%-100%), respectively. No differences in performance were observed by HIV status., Conclusions: ALARM demonstrated excellent accuracy for moderate-to-severe hepatic steatosis regardless of HIV status. Application of ALARM to radiographic repositories could facilitate real-world studies to evaluate medications associated with steatosis and assess differences by HIV status., (© 2023 John Wiley & Sons Ltd.)

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/mm 3 (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., Competing Interests: Disclosures Dr Beckman reports receiving consulting fees from JanOne, Janssen, and Novartis and research funds from Bristol Myers Squibb outside of the current work. Dr Aday reports receiving consulting fees from OptumCare, CRC Oncology, and Aeglea outside of the current work. The other authors report no conflicts.

Introduction: Unhealthy alcohol use is associated with a range of adverse outcomes among people with HIV (PWH). Testing the efficacy and promoting the availability of effective interventions to address unhealthy alcohol use among PWH is thus a priority. Alcohol use outcomes in intervention studies are often measured by self-report alone, which can lead to spurious results due to information biases (eg, social desirability). Measuring alcohol outcomes objectively through biomarkers, such as phosphatidylethanol (PEth), in addition to self-report has potential to improve the validity of intervention studies. This protocol outlines the methods for a systematic review and individual participant data meta-analysis that will estimate the efficacy of interventions to reduce alcohol use as measured by a combined categorical self-report/PEth variable among PWH and compare these estimates to those generated when alcohol is measured by self-report or PEth alone., Methods and Analysis: We will include randomised controlled trials that: (A) tested an alcohol intervention (behavioural and/or pharmacological), (B) enrolled participants 15 years or older with HIV; (C) included both PEth and self-report measurements, (D) completed data collection by 31 August 2023. We will contact principal investigators of eligible studies to inquire about their willingness to contribute data. The primary outcome variable will be a combined self-report/PEth alcohol categorical variable. Secondary outcomes will include PEth alone, self-report alone and HIV viral suppression. We will use a two-step meta-analysis and random effects modelling to estimate pooled treatment effects; I 2 will be calculated to evaluate heterogeneity. Secondary and sensitivity analyses will explore treatment effects in adjusted models and within subgroups. Funnel plots will be used to explore publication bias., Ethics and Dissemination: The study will be conducted with deidentified data from completed randomised controlled trials and will be considered exempt from additional ethical approval. Results will be disseminated through peer-reviewed publications and international scientific meetings., Prospero Registration Number: CRD42022373640., Competing Interests: Competing interests: JAH received consulting fees from Pear Therapeutics in 2022., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Biomarkers that provide insight into drivers of aging are needed for people with human immunodeficiency virus (PWH). The study objective was to determine if epigenetic age acceleration (EAA) markers are associated with physiologic frailty measured by the Veterans Aging Cohort Study (VACS) Index and predict all-cause mortality for PWH., Methods: Epigenome-wide DNA methylation was profiled in VACS total white blood cell samples collected during 2005-2007 from 531 PWH to generate 6 established markers of EAA. The association of each EAA marker was tested with VACS Index 2.0. All-cause mortality was assessed over 10 years. For each EAA marker, the hazard ratio per increased year was determined using Cox regression. To evaluate mortality discrimination, C-statistics were derived., Results: Participants were mostly men (98.5%) and non-Hispanic Black (84.4%), with a mean age of 52.4 years (standard deviation [SD], 7.8 years). Mean VACS Index score was 59.3 (SD, 16.4) and 136 deaths occurred over a median follow-up of 8.7 years. Grim age acceleration (AA), PhenoAA, HannumAA, and extrinsic epigenetic AA were associated with the VACS Index and mortality. HorvathAA and intrinsic epigenetic AA were not associated with either outcome. GrimAA had the greatest mortality discrimination among EAA markers and predicted mortality independently of the VACS Index. One-year increase in GrimAA was associated with a 1-point increase in VACS Index and a 10% increased hazard for mortality., Conclusions: The observed associations between EAA markers with physiologic frailty and mortality support future research to provide mechanistic insight into the accelerated aging process and inform interventions tailored to PWH for promoting increased healthspan., Competing Interests: Potential conflicts of interest. V. C. M. has received investigator-initiated research grants (paid to institution) and consulting fees (both unrelated to the current work) from Eli Lilly, Bayer, Gilead Sciences, and ViiV; grants or contracts from Gilead (for ACTT2, ACTT3, and ACTT4), ViiV (for DISCO and ASPIRE), and the Centers for Disease Control and Prevention, NIH, and Department of Veterans Affairs (other studies); honorarium in 2019 and support for attending meeting and/or travel from Eli Lilly (Ground Transportation 2019); participation on a data and safety monitoring board (DSMB) for IL-1b inhibitor study sponsored by the NIH and Novartis; and was the Study Section Chair for NIH. K. K. O. is the DSMB chair (1R01AG066562 from NIH, payment in-kind). K. S. reports grants or contracts from NIH. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022.)

Of the 12 million people who inject drugs worldwide, 13% live with HIV. Whether opioid use impacts HIV pathogenesis and latency is an outstanding question. To gain insight into whether opioid use influences the proviral landscape and latent HIV reservoir, we performed intact proviral DNA assays (IPDA) on peripheral blood mononuclear cells (PBMCs) from antiretroviral therapy (ART)-suppressed people living with HIV (PWH) with or without current opioid use. No differences were observed between PWH with and without opioid use in the frequency of HIV intact and defective proviral genomes. To evaluate the latent reservoir, we activated PBMCs from ART-suppressed PWH with or without opioid use and assessed the induction of HIV RNA. PWH using opioids had diminished responses to ex vivo HIV reactivation, suggesting a smaller reversible reservoir of HIV-1 latently infected cells. However, in vitro studies using primary CD4+ T cells treated with morphine showed no effect of opioids on HIV-1 infection, replication or latency establishment. The discrepancy in our results from in vitro and clinical samples suggests that while opioids may not directly impact HIV replication, latency and reactivation in CD4+ T cells, opioid use may indirectly shape the HIV reservoir in vivo by modulating general immune functions.

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., (© Society of Behavioral Medicine 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Human immunodeficiency virus (HIV) infection is associated with subclinical cardiomyopathy, diastolic dysfunction, and increased risk of cardiovascular death. However, the relationship between left atrial (LA) mechanics and left ventricular (LV) diastolic function has not been evaluated in people living with HIV (PLWH) relative to HIV-uninfected (HIV-) controls. This is a multicenter, cross-sectional cohort analysis using the HIV Cardiovascular Disease substudy of the Veterans Aging Cohort Study database, which aimed to examine a cohort of PLWH and HIV- veterans without known cardiovascular disease. A total of 277 subjects (180 PLWH, 97 HIV-) with echocardiograms were identified. LV and LA phasic strain were derived and diastolic function was evaluated. Relationship between LA strain, LV strain, and the degree of diastolic dysfunction were assessed using analysis of variance and ordinal logistic regression with propensity weighting. In the PLWH cohort, 91.7% were on antiretroviral therapy and 86.1% had HIV viral loads <500 copies/ml. The mean (± SD) duration of infection was 9.7 ± 4.9 years. Relative to HIV- veterans, PLWH did not differ in LA mechanics and proportion of diastolic dysfunction (p = 0.31). Using logistic regression with propensity weighting, we found no association between HIV status and degree of diastolic dysfunction. In both cohorts, LA reservoir strain and LA conduit strain were inversely and independently associated with the degree of diastolic dysfunction. Compared with HIV- veterans, PLWH who are primarily virally suppressed and antiretroviral-treated did not differ in LA strain or LV diastolic dysfunction. If confirmed in other cohorts, HIV viral suppression may curtail adverse alterations in cardiac structure and function., (Published by Elsevier Inc.)

Background: Lower CD4 + cell count in people with HIV infection (PWH) is associated with increased cardiovascular disease (CVD) risk. Whether subsets of CD4 + T helper cells are linked with CVD is unclear., Objectives: The aim of this study was to explore the association between peripherally circulating CD4 + T cell subsets and incident CVD., Methods: Data from 1,860 participants (1,270 PWH) without prevalent CVD from the VACS (Veterans Aging Cohort Study), a prospective, observational cohort of veterans with and without HIV infection, were analyzed. T cell subsets were quantified in baseline samples using flow cytometry. Incident CVD events were identified using International Classification of Diseases-9th Revision and International Classification of Diseases-10th Revision diagnosis and procedure codes. Participants were followed from baseline date (2005-2006) to the first of CVD incidence, death, or September 30, 2016. Cox proportional hazards regression was used to model associations between these T cell subsets and the risk for incident CVD while adjusting for demographics and other CVD risk factors., Results: The median participant age at baseline was 51.6 years. Most were male (94%) and of Black race (69.1%). There were 344 incident CVD events (219 in PWH) during follow-up (median 9.8 years). In PWH, higher proportions (per SD increment) of T helper type 17 cells (adjusted HR: 1.19; 95% CI: 1.08-1.31), T effector memory cells re-expressing CD45RA (adjusted HR: 1.19; 95% CI: 1.07-1.34), and CD28 null cells (adjusted HR: 1.18; 95% CI: 1.03-1.34) were significantly associated with an increased risk for incident CVD. Among those without HIV infection, no T cell subsets were significantly associated with CVD., Conclusions: Among PWH, T helper type 17 cells, senescent cells, and CD4 + T effector memory cells re-expressing CD45RA were significantly associated with incident CVD that was not explained by CVD risk factors., Competing Interests: Funding Support and Author Disclosures This material is based upon work supported by the VA, the Veterans Health Administration, and the Office of Research and Development, National Institute on Alcohol Abuse and Alcoholism (grants U24-AA020794, U01-AA020790, U24-AA022001, and U10 AA013566), and grant R01HL125032. Dr So-Armah’s work on this project was supported by National Institutes of Health grants K01HL134147, R61DA047032, and P30AI042853. The funders had no role in the study design or the collection, analyses, and interpretation of data. The views expressed in this paper are those of the authors and do not necessarily reflect the position or policy of the VA. Dr Beckman is a consultant for AstraZeneca, Bristol Myers Squibb, Amgen, Merck, Sanofi, Antidote Pharmaceutical, and Boehringer Ingelheim; and serves on data and safety monitoring committees for Bayer and Novartis. Dr McDonnell is an employee and shareholder of 10x Genomics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Elevated plasma levels of sCD14 predict all-cause mortality in people with HIV (PWH). Epigenetic regulation plays a key role in infection and inflammation. To reveal the epigenetic relationships between sCD14, immune function and disease progression among PWH, we conducted an epigenome-wide association study (EWAS) of sCD14 and investigated the relationship with mortality., Design and Methods: DNA methylation (DNAm) levels of peripheral blood samples from PWH in the Veterans Aging Cohort Study (VACS) were measured using the Illumina Infinium Methylation 450K (n = 549) and EPIC (850K) BeadChip (n = 526). Adjusted for covariates and multiple testing, we conducted an epigenome-wide discovery, replication, and meta-analysis to identify significant associations with sCD14. We then examined and replicated the relationship between the principal epigenetic sites and survival using Cox regression models., Findings: We identified 118 DNAm sites significantly associated with sCD14 in the meta-analysis of 1075 PWH. The principal associated DNAm sites mapped to genes (e.g. STAT1, PARP9, IFITM1, MX1, and IFIT1) related to inflammation and antiviral response. Adjusting for multiple testing, 10 of 118 sCD14-associated DNAm sites significantly predicted survival time conditional on sCD14 levels., Conclusion: The identification of DNAm sites independently predicting survival may improve our understanding of prognosis and potential therapeutic targets among PWH., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: Cigarette smoking and risky alcohol consumption co-occur and are undertreated. Nicotine receptor partial agonists and nicotine replacement therapy (NRT) treat smoking but are unproven for alcohol, and clinical trials rarely include individuals with HIV, substance use, and mental health conditions., Objective: To compare the effects on drinking and smoking of nicotinic acetylcholine receptor partial agonists varenicline and cytisine with those of NRT., Design, Setting, and Participants: This 4-group randomized, double-blinded, placebo-controlled clinical trial was conducted from July 2017 to December 2020 in St Petersburg, Russia. Included participants were 400 individuals with HIV who engaged in risky drinking (≥5 prior-month heavy-drinking days [HDDs]) and daily smoking; they were followed up for 12 months after enrollment. Data were analyzed from May 2021 through June 2022., Interventions: Participants received alcohol and tobacco counseling, 1 active medication, and 1 placebo in 1 of 4 groups: active varenicline and placebo NRT (group 1), placebo varenicline and active NRT (group 2), active cytisine and placebo NRT (group 3), or placebo cytisine and active NRT (group 4)., Main Outcomes and Measures: The primary outcome was number of prior-month HDDs at 3 months. Secondary outcomes included biochemically validated abstinence from alcohol at 3 months and smoking at 6 months., Results: Among 400 participants (263 [65.8%] men; mean [SD] age, 39 [6] years), 97 individuals (24.3%) used opioids and 156 individuals (39.1%) had depressive symptoms. These individuals had a mean (SD) CD4 count of 391 (257) cells/mm3, smoked a mean (SD) of 21 [8] cigarettes/d, and reported a mean (SD) of 9.3 (5.8) HDDs in the prior 30 days. At 3 months, the mean (SD) number of HDDs was decreased vs baseline across all groups (group 1: 2.0 [3.8] HDDs vs. 9.5 [6.1] HDDs; group 2: 2.1 [4.3] HDDs vs 9.3 [5.7] HDDs; group 3: 1.5 [3.3] HDDs vs 8.9 [5.0] HDDs; group 4: 2.4 [5.2] HDDs vs 9.6 [6.3] HDDs). There were no significant differences at 3 months between groups in mean (SD) HDDs, including group 1 vs 2 (incident rate ratio [IRR], 0.94; 95% CI, 0.49-1.79), 3 vs 4 (IRR, 0.60; 95% CI, 0.30-1.18), and 1 vs 3 (IRR, 1.29; 95% CI, 0.65-2.55). There were no significant differences at 6 months between groups in smoking abstinence, including group 1 vs 2 (15 of 100 individuals [15.0%] vs 17 of 99 individuals [17.2%]; odds ratio [OR],0.89; 95% CI, 0.38-2.08), 3 vs 4 (19 of 100 individuals [19.0%] vs 19 of 101 individuals [18.8%]; OR, 1.00; 95% CI, 0.46-2.17), and 1 vs 3 (OR, 0.79; 95% CI, 0.35-1.78). Post hoc analyses suggested lower mean (SD) HDDs (eg, at 3 months: 0.7 [1.8] HDDs vs 2.3 [4.6] HDDs) and higher alcohol abstinence (eg, at 3 months: 30 of 85 individuals [35.3%] vs 54 of 315 individuals [17.1%]) among those who quit vs continued smoking., Conclusions and Relevance: This study found that among individuals with HIV who engaged in risky drinking and smoking, varenicline and cytisine were not more efficacious than NRT to treat risky drinking and smoking but that behavior change rates were high in all groups., Trial Registration: ClinicalTrials.gov Identifier: NCT02797587.

Background: The association between cannabis use and HIV-1 RNA (viral load) among people with HIV (PWH) engaged in care is unclear. Methods: We used data collected from 2002 to 2018 on PWH receiving antiretroviral therapy (ART) enrolled in the Veterans Aging Cohort Study. Generalized estimating equations were used to estimate associations between self-reported past-year cannabis use and detectable viral load (≥500 copies/mL), with and without adjustment for demographics, other substance use, and adherence. Results: Among 2515 participants, 97% were male, 66% were Black, the mean age was 50 years, and 33% had detectable HIV viral load at the first study visit. In unadjusted analyses, PWH with any past-year cannabis use had 21% higher odds of a detectable viral load than those with no past-year use (OR = 1.21; 95% CI, 1.07-1.37). However, there was no significant association between cannabis use and viral load after adjustment. Conclusions: Among PWH engaged in care and receiving ART, cannabis use is associated with decreased adherence in unadjusted analyses but does not appear to directly impact viral control. Future studies are needed to understand other potential risks and benefits of cannabis use among PWH.

Introduction: We hypothesize that illicit opioid use increases bacterial translocation from the gut, which intensifies systemic inflammation., Objective: To investigate the association between opioid use and plasma soluble CD14 [sCD14], interleukin-6 [IL-6] and D-dimer in people living with HIV (PLWH)., Methods: We analyzed data from the Russia ARCH study-an observational cohort of 351 ART-naive PLWH in St. Petersburg, Russia. Plasma levels of sCD14 (primary outcome), IL-6 and D-dimer (secondary outcomes) were evaluated at baseline, 12, and 24 months. Participants were categorized into three groups based on illicit opioid use: current, prior, and never opioid use. Linear mixed effects models were used to evaluate associations., Results: Compared to never opioid use, sCD14 levels were significantly higher for participants with current opioid use (AMD = 197.8 ng/ml [11.4, 384.2], p = 0.04). IL-6 levels were also higher for participants with current vs. never opioid use (ARM = 2.10 [1.56, 2.83], p <0.001). D-dimer levels were higher for current (ARM = 1.95 [1.43, 2.64], p <0.001) and prior (ARM = 1.57 [1.17, 2.09], p = 0.004) compared to never opioid use., Conclusions: Among PLWH, current opioid use compared to never use is associated with increased monocyte activation and systemic inflammation., Competing Interests: The authors have declared that no competing interests exist.

Objective: A higher proportion of circulating memory CD4+ T cells is associated with prevalent diabetes mellitus in persons with HIV (PWH) and HIV-negative persons. We assessed whether circulating T-cell subsets could also identify individuals who will subsequently develop diabetes., Design: This is a longitudinal follow-up study of PWH and similar HIV-negative individuals from the Veterans Aging Cohort Study who provided peripheral mononuclear blood cells between 2005 and 2007., Methods: We quantified T-cell subsets using flow cytometry and functional assays to identify CD4+ and CD8+ naive, activated, senescent, memory (central, effector, and effector RA+), and TH1, TH2, and TH17-phenotype cells. The occurrence of an incident diabetes diagnosis (i.e. after baseline blood draw) was adjudicated by a two-physician chart review. Cox proportional hazards models adjusted for traditional risk factors, cytomegalovirus serostatus, and plasma inflammatory biomarkers assessed the relationship between T-cell subsets and incident diabetes., Results: One thousand, eight hundred and thirty-seven participants (1259 PWH) without diabetes at baseline were included; 69% were black, 95% were men, and median follow-up was 8.6 years. Higher baseline frequencies of CD4+ T effector memory RA+ (TEMRA) cells defined as CD45RA+ CD27- (P = 0.04) and senescent T cells defined as CD4+ CD28- (P = 0.04) were associated with incident diabetes in PWH only., Conclusions: Higher frequencies of CD4+ TEMRA and CD4+ CD28- T cells were associated with incident diabetes in PWH only after adjustment for other factors. Additional studies are necessary to assess whether these cells act in blood via inflammatory mediators or reflect T-cell populations in metabolically active tissues., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Aims: Alcohol is hypothesized to have effects on the kynurenine pathway of tryptophan catabolism, a potential mechanism for alcohol-induced depression and aggression. A biomarker of this pathway, the plasma kynurenine to tryptophan ratio (K/T ratio), has been associated with HIV progression, mortality and depression. Our aim was to assess whether hazardous alcohol consumption is associated higher K/T ratio among people with HIV., Methods: Participants were a subset of the Uganda Alcohol Research Collaboration on HIV/AIDS Cohort. Alcohol consumption was categorized (abstinent, moderate and hazardous alcohol use) using the Alcohol Use Disorders Identification Test-Consumption and phosphatidylethanol (PEth). K/T ratio was the primary outcome. We used linear regression adjusted for age, sex, FIB-4, hepatitis B surface antigen, log (HIV viral load) to estimate the association between alcohol consumption and K/T ratio., Results: Compared to abstinent participants, hazardous drinkers and moderate drinkers had higher K/T ratio but these differences did not reach statistical significance., Conclusions: Our results suggest that hazardous alcohol consumption, in the context of untreated HIV infection, may not significantly alter kynurenine to tryptophan ratio as a measure of activity of the kynurenine pathway of tryptophan metabolism., (© The Author(s) 2021. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Background People living with HIV have higher sudden cardiac death (SCD) rates compared with the general population. Whether HIV infection is an independent SCD risk factor is unclear. Methods and Results This study evaluated participants from the Veterans Aging Cohort Study, an observational, longitudinal cohort of veterans with and without HIV infection matched 1:2 on age, sex, race/ethnicity, and clinical site. Baseline for this study was a participant's first clinical visit on or after April 1, 2003. Participants were followed through December 31, 2014. Using Cox proportional hazards regression, we assessed whether HIV infection, CD4 cell counts, and/or HIV viral load were associated with World Health Organization (WHO)-defined SCD risk. Among 144 336 participants (30% people living with HIV), the mean (SD) baseline age was 50.0 years (10.6 years), 97% were men, and 47% were of Black race. During follow-up (median, 9.0 years), 3035 SCDs occurred. HIV infection was associated with increased SCD risk (hazard ratio [HR], 1.14; 95% CI, 1.04-1.25), adjusting for possible confounders. In analyses with time-varying CD4 and HIV viral load, people living with HIV with CD4 counts <200 cells/mm 3 (HR, 1.57; 95% CI, 1.28-1.92) or viral load >500 copies/mL (HR, 1.70; 95% CI, 1.46-1.98) had increased SCD risk versus veterans without HIV. In contrast, people living with HIV who had CD4 cell counts >500 cells/mm 3 (HR, 1.03; 95% CI, 0.90-1.18) or HIV viral load <500 copies/mL (HR, 0.97; 95% CI, 0.87-1.09) were not at increased SCD risk. Conclusions HIV infection is associated with increased risk of WHO-defined SCD among those with elevated HIV viral load or low CD4 cell counts.

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., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This study describes the self-reported prevalence of hepatitis C virus (HCV) coinfection and the HCV care continuum among persons enrolled in the St PETER HIV Study, a randomized controlled trial of medications for smoking and alcohol cessation in HIV-positive heavy drinkers and smokers in St. Petersburg, Russia. Baseline health questionnaire data were used to calculate proportions and 95% confidence intervals for self-reported steps along the HCV continuum of care. The cohort included 399 HIV-positive persons, of whom 387 [97.0% (95% CI 95.3-98.7%)] reported a prior HCV test and 315 [78.9% (95% CI 74.9-82.9%)] reported a prior diagnosis of HCV. Among those reporting a diagnosis of HCV, 43 [13.7% (95% CI 9.9-17.4%)] had received treatment for HCV, and 31 [9.8% (95% CI 6.6-13.1%)] had been cured. Despite frequent HCV testing in this HIV-positive Russian cohort, the proportion reporting prior effective HCV treatment was strikingly low. Increased efforts are needed to scale-up HCV treatment among HIV-positive Russians in St. Petersburg.

Background HIV infection and depression are each associated with increased ischemic stroke risk. Whether depression is a risk factor for stroke within the HIV population is unknown. Methods and Results We analyzed data on 106 333 (33 528 HIV-positive; 72 805 HIV-negative) people who were free of baseline cardiovascular disease from an observational cohort of HIV-positive people and matched uninfected veterans in care from April 1, 2003 through December 31, 2014. International Classification of Diseases, Ninth Revision ( ICD-9 ) codes from medical records were used to determine baseline depression and incident stroke. Depression occurred in 19.5% of HIV-positive people. After a median of 9.2 years of follow-up, stroke rates were highest among people with both HIV and depression and lowest among those with neither condition. In Cox proportional hazard models, depression was associated with an increased risk of stroke for HIV-positive people after adjusting for sociodemographic characteristics and cerebrovascular risk factors (hazard ratio [HR], 1.18; 95% CI: 1.03-1.34; 0.014). The depression-stroke relationship was attenuated by alcohol use disorders, cocaine use, and baseline antidepressant use, and unaffected by combined antiretroviral therapy use or individual antiretroviral agents. A numerically higher HR of depression on stroke was found among those younger than 60 years. Conclusions Depression is associated with an increased risk of stroke among HIV-positive people after adjusting for sociodemographic characteristics, traditional cerebrovascular risk factors, and HIV-specific factors. Alcohol use disorders, cocaine use, and baseline antidepressant use accounted for some of the observed stroke risk. Depression may be a novel, independent risk factor for ischemic stroke in HIV, particularly among younger people.

Background: Pulmonary hypertension incidence based on echocardiographic estimates of pulmonary artery systolic pressure in people living with HIV remains unstudied. We aimed to determine whether people living with HIV have higher incidence and risk of pulmonary hypertension than uninfected individuals., Methods: In this retrospective cohort study, we evaluated data from participants in the Veterans Aging Cohort Study (VACS) referred for echocardiography with baseline pulmonary artery systolic pressure measures of 35 mm Hg or less. Incident pulmonary hypertension was defined as pulmonary artery systolic pressure higher than 35 mm Hg on subsequent echocardiogram. We used Poisson regression to estimate incidence rates (IRs) of pulmonary hypertension by HIV status. We then estimated hazard ratios (HRs) by HIV status using Cox proportional hazards regression. We further categorised veterans with HIV by CD4 count or HIV viral load to assess the association between pulmonary hypertension risk and HIV severity. Models included age, sex, race or ethnicity, prevalent heart failure, chronic obstructive pulmonary disease, hypertension, smoking status, diabetes, body-mass index, estimated glomerular filtration rate, hepatitis C virus infection, liver cirrhosis, and drug use as covariates., Findings: Of 21 314 VACS participants with at least one measured PASP on or after April 1, 2003, 13 028 VACS participants were included in the analytic sample (4174 [32%] with HIV and 8854 [68%] without HIV). Median age was 58 years and 12 657 (97%) were male. Median follow-up time was 3·1 years (IQR 0·9-6·8) spanning from April 1, 2003, to Sept 30, 2017. Unadjusted IRs per 1000 person-years were higher in veterans with HIV (IR 28·6 [95% CI 26·1-31·3]) than in veterans without HIV (IR 23·4 [21·9-24·9]; p=0·0004). The risk of incident pulmonary hypertension was higher among veterans with HIV than among veterans without HIV (unadjusted HR 1·25 [95% CI 1·12-1·40], p<0·0001). After multivariable adjustment, this association was slightly attenuated but remained significant (HR 1·18 [1·05-1·34], p=0·0062). Veterans with HIV who had a CD4 count lower than 200 cells per μL or of 200-499 cells per μL had a higher risk of pulmonary hypertension than did veterans without HIV (HR 1·94 [1·49-2·54], p<0·0001, for those with <200 cell μL and HR 1·29 [1·08-1·53], p=0·0048, for those with 200-499 cells per μL). Similarly, veterans with HIV who had HIV viral loads of 500 copies per mL or more had a higher risk of pulmonary hypertension than did veterans without HIV (HR 1·88 [1·46-2·42], p<0·0001)., Interpretation: HIV is associated with pulmonary hypertension incidence, adjusting for risk factors. Low CD4 cell count and high HIV viral load contribute to increased pulmonary hypertension risk among veterans with HIV. Thus, as with other cardiopulmonary diseases, suppression of HIV should be prioritised to lessen the burden of pulmonary hypertension in people living with HIV., Funding: National Heart, Lung, and Blood Institute (National Institutes of Health, USA); National Institute on Alcohol Abuse and Alcoholism (National Institutes of Health, USA)., Competing Interests: Declaration of interests We declare no competing interests. MSF, KS-A, OVP, and ELB declare grants to their institutions from the National Heart, Lung, and Blood Institute. VLR III is the president-elect of the International Society for Pharmacoepidemiology. AAB received grant funding from Gilead Science through the Veterans Health Foundation of Pittsburgh. Funders had no role in the content of the manuscript or the decision to submit for publication.

Background: Insomnia may be a risk factor for cardiovascular disease in HIV (HIV-CVD); however, mechanisms have yet to be elucidated., Methods: We examined cross-sectional associations of insomnia symptoms with biological mechanisms of HIV-CVD (immune activation, systemic inflammation, and coagulation) among 1,542 people with HIV from the Veterans Aging Cohort Study (VACS) Biomarker Cohort. Past-month insomnia symptoms were assessed by the item, "Difficulty falling or staying asleep?," with the following response options: "I do not have this symptom" or "I have this symptom and…" "it doesn't bother me," "it bothers me a little," "it bothers me," "it bothers me a lot." Circulating levels of the monocyte activation marker soluble CD14 (sCD14), inflammatory marker interleukin-6 (IL-6), and coagulation marker D-dimer were determined from blood specimens. Demographic- and fully-adjusted (CVD risk factors, potential confounders, HIV-related factors) regression models were constructed, with log-transformed biomarker variables as the outcomes. We present the exponentiated regression coefficient (exp[b]) and its 95% confidence interval (CI)., Results: We observed no significant associations between insomnia symptoms and sCD14 or IL-6. For D-dimer, veterans in the "Bothers a Lot" group had, on average, 17% higher D-dimer than veterans in the "No Difficulty Falling or Staying Asleep" group in the demographic-adjusted model (exp[b] = 1.17, 95%CI = 1.01-1.37, p = .04). This association was nonsignificant in the fully-adjusted model (exp[b] = 1.09, 95%CI = 0.94-1.26, p = .27)., Conclusion: We observed little evidence of relationships between insomnia symptoms and markers of biological mechanisms of HIV-CVD. Other mechanisms may be responsible for the insomnia-CVD relationship in HIV; however, future studies with comprehensive assessments of insomnia symptoms are warranted., Competing Interests: The authors have read the journal’s policy and the authors of this manuscript have the following competing interests: RB reports funding from ViiV Healthcare and service on scientific advisory boards for Merck & Co, and ViiV Healthcare. SG reports funding from Gilead Sciences, travel support from Gilead Sciences and Bristol-Myers Squibb, and receipt of advisory board fees from Gilead Sciences and GlaxoSmithKline/ViiV Healthcare. MB reports funding from General Electric. AB reports funding from Gilead Sciences. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Aim: This study aimed to analyze the association between any past-month cannabis use and advanced liver fibrosis., Background: Cannabinoid receptors play a role in acute and chronic liver injury, but human studies addressing the impact of cannabis use on liver fibrosis have shown mixed results., Objective: The objective of this study was to explore and estimate the association between pastmonth cannabis use and advanced liver fibrosis (ALF) in a cohort of Russian HIV-positive individuals with heavy alcohol use and a high prevalence of hepatitis C virus (HCV) coinfection., Methods: Baseline data were analyzed from participants of the ZINC study, a trial that enrolled HIV-positive Russian patients without prior antiretroviral therapy. Cannabis use during the prior month was assessed at study entry. ALF was defined as FIB-4>3.25 and APRI>1.5. Transient elastography was used to detect advanced liver fibrosis among participants with FIB-4 values in the intermediate range (between 1.45 and 3.25)., Results: Participants (n=248) were mostly male (72.6%), young (median age of 33.9 years), infected with HCV (87.9%), and did not have advanced immunosuppression (median CD4 count 465). Cannabis use was uncommon (12.4%), and the prevalence of advanced liver disease was 21.7%. The prevalence of ALF was similar among those who used cannabis compared to those who did not (25.8% vs. 21.7%). We were unable to detect an association between cannabis use and ALF (adjusted odds ratio: 1.28, 95% confidence interval: 0.53-3.12, p=0.59) in logistic regression models adjusting for age, sex, heavy drinking, BMI, and CD4 cell count., Conclusion: In this exploratory study among HIV-positive heavy drinking Russians, we did not detect an association between recent cannabis use and ALF. Larger scale studies, including more participants with cannabis use, are needed to examine this relationship further., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background Hospitalization with community-acquired pneumonia (CAP) is associated with an increased risk of cardiovascular disease (CVD) events in patients uninfected with HIV. We evaluated whether people living with HIV (PLWH) have a higher risk of CVD or mortality than individuals uninfected with HIV following hospitalization with CAP. Methods and Results We analyzed data from the Veterans Aging Cohort Study on US veterans admitted with their first episode of CAP from April 2003 through December 2014. We used Cox regression analyses to determine whether HIV status was associated with incident CVD events and mortality from date of admission through 30 days after discharge (30-day mortality), adjusting for known CVD risk factors. We included 4384 patients (67% [n=2951] PLWH). PLWH admitted with CAP were younger, had less severe CAP, and had fewer CVD risk factors than patients with CAP who were uninfected with HIV. In multivariable-adjusted analyses, CVD risk was similar in PLWH compared with HIV-uninfected (hazard ratio [HR], 0.89; 95% CI, 0.70-1.12), but HIV infection was associated with higher mortality risk (HR, 1.49; 95% CI, 1.16-1.90). In models stratified by HIV status, CAP severity was significantly associated with incident CVD and 30-day mortality in PLWH and patients uninfected with HIV. Conclusions In this study, the risk of CVD events during or after hospitalization for CAP was similar in PLWH and patients uninfected with HIV, after adjusting for known CVD risk factors and CAP severity. HIV infection, however, was associated with increased 30-day mortality after CAP hospitalization in multivariable-adjusted models. PLWH should be included in future studies evaluating mechanisms and prevention of CVD events after CAP.

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.

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., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

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.

Importance: Zinc supplementation can reduce alcohol-related microbial translocation and inflammation., Objective: To assess whether zinc supplementation reduces markers of mortality and risk of cardiovascular disease, reduces levels of inflammation and microbial translocation, and slows HIV disease progression in people with heavy alcohol use who are living with HIV/AIDS., Design, Setting, and Participants: This study is a double-blinded placebo-controlled randomized clinical trial of zinc supplementation among participants recruited from 2013 to 2015. Participants were recruited from HIV and addiction clinical and nonclinical care sites in St Petersburg, Russia. Participants were adults (aged 18-70 years) with documented HIV infection who were antiretroviral therapy-naive at baseline and had past 30-day heavy alcohol consumption. Data analysis was performed from February 2017 to February 2020., Intervention: Pharmacy-grade zinc gluconate supplementation (15 mg for men and 12 mg for women, taken daily by mouth for 18 months) was compared with a placebo., Main Outcomes and Measures: The primary outcome was mortality risk measured as a change in Veterans Aging Cohort Study (VACS) Index score between baseline and 18 months. The VACS Index scores range from 0 to 164, with higher scores indicating higher mortality risk. Secondary outcomes were change in CD4 cell count between baseline and 18 months, the assessment of cardiovascular disease risk (Reynolds Risk Score, which ranges from 0% to 100%, with higher scores indicating higher risk), and changes in inflammatory or microbial translocation biomarkers at 18 months. Adjusted linear regression analyses were performed., Results: A total of 254 participants (184 men [72%]; mean [SD] age, 34 [6] years) were enrolled in the trial; 126 were randomized to receive zinc, and 128 were randomized to receive placebo. Participants had high CD4 cell counts (mean [SD], 521 [292] cells/mm3), and 188 (74%) reported heavy drinking in the past week. In the main analyses, zinc supplementation did not affect changes in the VACS Index score at 18 months (change for zinc, mean [SD], 0.49 [14.6]; median [interquartile range], 0.0 [-7.0 to 6.0]; change for placebo, mean [SD], 5.5 [17.2]; median [interquartile range], 6.0 [-6.0 to 14.0]; adjusted mean difference [AMD], -4.68; 95% CI, -9.62 to 0.25; P = .06) or any secondary outcomes, including change in CD4 cell count (AMD, 41.8 cells/mm3; 95% CI, -20.3 to 103.8 cells/mm3; P = .19), Reynolds Risk Score (AMD, -0.014; 95% CI, -0.167 to 0.139; P = .85), interleukin-6 level (AMD, -0.13 pg/mL; 95% CI, -0.38 to 0.11 pg/mL; P = .30), dimerized plasmin fragment D level (AMD, -0.21 μg/mL fibrinogen equivalent units; 95% CI, -0.48 to 0.07 μg/mL fibrinogen equivalent units; P = .14), soluble CD14 level (AMD, -38.01 ng/mL; 95% CI, -166.90 to 90.88 ng/mL; P = .56), intestinal fatty acid binding protein level (AMD, 0.08 pg/mL; 95% CI, -0.07 to 0.22 pg/mL; P = .32), and lipopolysaccharide binding protein level (AMD, -0.09 ng/mL; 95% CI, -0.23 to 0.06 ng/mL; P = .24). In the per-protocol analyses, zinc supplementation statistically significantly affected changes in the VACS Index score at 18 months (AMD, -7.49; 95% CI, -13.74 to -1.23; P = .02); however, the adherence rate to zinc supplementation was 51%., Conclusions and Relevance: Zinc supplementation did not reduce mortality risk, CD4 cell counts, cardiovascular disease risk, and levels of inflammation or microbial translocation in people with heavy alcohol use who are living with HIV/AIDS. Zinc supplementation did not change the VACS Index score but may have been limited by low adherence., Trial Registration: ClinicalTrials.gov Identifier: NCT01934803.

HIV-related cardiovascular disease research is predominantly from Europe and North America. Of the estimated 37·9 million people living with HIV worldwide, 25·6 million live in sub-Saharan Africa. Although mechanisms for HIV-related cardiovascular disease might be the same in all people with HIV, the distribution of cardiovascular disease risk factors varies by geographical location. Sub-Saharan Africa has a younger population, higher prevalence of elevated blood pressure, lower smoking rates, and lower prevalence of elevated cholesterol than western Europe and North America. These variations mean that the profile of cardiovascular disease differs between low-income and high-income countries. Research in, implementation of, and advocacy for risk reduction of cardiovascular disease in the global context of HIV should account for differences in the distribution of traditional cardiovascular disease risk factors (eg, hypertension, smoking), consider non-traditional cardiovascular disease risk factors (eg, access to antiretroviral therapy with more benign cardiovascular disease side effect profiles, indoor air pollution), and encourage the inclusion of relevant risk reduction approaches for cardiovascular disease in HIV-care guidelines. Future research priorities include implementation science to scale up and expand integrated HIV and cardiovascular disease care models, which have shown promise in sub-Saharan Africa; HIV and cardiovascular disease epidemiology and mechanisms in women; and tobacco cessation for people living with HIV., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Liver fibrosis, is independently associated with incident heart failure (HF). Investigating the association between liver fibrosis and type of HF, specifically HF with reduced ejection fraction (EF; HFrEF) or HF with preserved ejection fraction (HFpEF), may provide mechanistic insight into this association. We sought to determine the association between liver fibrosis score (FIB-4) and type of HF, and to assess whether HIV or hepatitis C status modified this association., Methods: We included patients alive on or after 4/1/2003 from the Veterans Aging Cohort Study. We followed patients without prevalent cardiovascular disease until their first HF event, death, last clinic visit, or 9/30/2015. We defined liver fibrosis as: likely advanced fibrosis (FIB-4 > 3.25), indeterminate (FIB-4 range 1.45-3.25), unlikely advanced fibrosis (FIB-4 < 1.45). Primary outcomes were HFrEF and HFpEF (defined using ICD-9 diagnoses for HF, and EF extracted from electronic medical records using natural language processing). Cox proportional hazards models were adjusted for potential confounders and used to estimate hazard ratios (HR)., Results: Among 108,708 predominantly male (96%) participants mean age was 49 years. Likely advanced fibrosis was present in 4% at baseline and was associated with an increased risk of HFpEF [HR (95% confidence interval)] [1.70 (1.3-2.3)]; and non-significantly with HFrEF [1.20 (0.9-1.7)]. These associations were not modified by HIV or hepatitis C status., Conclusion: Likely advanced fibrosis was independently associated with incident HFpEF but not HFrEF. This suggests that risk factors and/or mechanisms for liver fibrosis may have greater overlap with those for HFpEF than HFrEF., (Copyright © 2020. Published by Elsevier Inc.)

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., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The multifactorial mechanisms driving negative health outcomes among risky drinkers with HIV may include immunosenescence. Immunosenescence, aging of the immune system, may be accentuated in HIV and leads to poor outcomes. The liver regulates innate immunity and adaptive immune tolerance. HIV-infected people have high prevalence of liver-related comorbidities. We hypothesize that advanced liver fibrosis/cirrhosis is associated with alterations in T-cell subsets consistent with immunosenescence., Methods: ART-naïve people with HIV with a recent history of heavy drinking were recruited into a clinical trial of zinc supplementation. Flow cytometry was used to characterize T-cell subsets. The two primary dependent variables were CD8+ and CD4+ T-cells expressing CD28-CD57+ (senescent cell phenotype). Secondary dependent variables were CD8+ and CD4+ T-cells expressing CD45RO + CD45RA- (memory phenotype), CD45RO-CD45RA+ (naïve phenotype), and the naïve phenotype to memory phenotype T-cell ratio (lower ratios associated with immunosenescence). Advanced liver fibrosis/cirrhosis was defined as FIB-4 > 3.25, APRI≥1.5, or Fibroscan measurement ≥10.5 kPa. Analyses were conducted using multiple linear regression adjusted for potential confounders., Results: Mean age was 34 years; 25% female; 88% hepatitis C. Those with advanced liver fibrosis/cirrhosis (N = 25) had higher HIV-1 RNA and more hepatitis C. Advanced liver fibrosis/cirrhosis was not significantly associated with primary or secondary outcomes in adjusted analyses., Conclusions: Advanced liver fibrosis/cirrhosis was not significantly associated with these senescent T-cell phenotypes in this exploratory study of recent drinkers with HIV. Future studies should assess whether liver fibrosis among those with HIV viral suppression and more advanced, longstanding liver disease is associated with changes in these and other potentially senescent T-cell subsets.

Background: Biomarkers of monocyte activation (soluble CD14 [sCD14]), inflammation (interleukin-6 [IL-6]), and altered coagulation (D-dimer) are associated with increased mortality risk in people with HIV. The objective of the Russia Alcohol Research Collaboration on HIV/AIDS (ARCH) study was to evaluate the association between heavy alcohol use and inflammatory biomarkers over time., Methods: The study sought antiretroviral therapy naive participants with HIV (n = 350) and assessed them at baseline, 12 and 24 months. Linear mixed effects models were used to determine whether heavy drinking (self-report augmented by phosphatidylethanol [PEth], an alcohol biomarker) was longitudinally associated with IL-6, sCD14 and D-dimer adjusting for potential confounders (e.g., demographics, HIV factors, comorbid conditions)., Results: Participants' baseline characteristics were as follows: 71% male; mean age of 34 years; 87% self-reported hepatitis C; and 86% current smokers. Mean log10 (HIV RNA) was 4.3 copies/mL. Heavy alcohol use, based on National Institute of Alcohol Abuse and Alcoholism risky drinking criteria and PEth (versus non-heavy alcohol use) was associated with higher sCD14 (adjusted mean difference 125 ng/mL [95% CI: 42, 209]), IL-6 (ratio of means 1.35 [95% CI: 1.17, 1.55] pg/mL), and D-dimer (ratio of means 1.20 [95% CI: 1.06, 1.37] ug/mL) across the two-year follow-up., Conclusion: Among HIV+ adults, current heavy alcohol use is associated with higher sCD14, IL-6 and D-dimer over time. Since these biomarkers are associated with mortality, interventions to mitigate effects of heavy drinking on these immune processes merit consideration., Competing Interests: An employee of the funder (K. Bryant) is a co-author on this manuscript and helped guide analysis, interpretation and presentation of data and participated in the decision to submit the manuscript for publication. Debbie Cheng serves on Data Safety Monitoring Boards for Janssen Research & Development. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The remaining authors report no declarations of interest.

Background and Aims: Liver disease in people living with HIV co-infected with hepatitis C virus is a source of morbidity and mortality in Russia. HIV accelerates liver fibrosis in the setting of HCV co-infection and alcohol use. Zinc deficiency is common among people living with HIV and may be a factor that facilitates the underlying mechanisms of liver fibrosis. We investigated the association between zinc deficiency and advanced liver fibrosis in a cohort of HIV/HCV co-infected persons reporting heavy drinking in Russia., Methods: This is a secondary data analysis of baseline data from 204 anti-retroviral treatment naïve HIV/HCV co-infected Russians with heavy drinking that were recruited into a clinical trial of zinc supplementation. The primary outcome of interest in this cross-sectional study was advanced liver fibrosis. Zinc deficiency, the main independent variable, was defined as plasma zinc <0.75 mg/L. Exploratory analyses were performed examining continuous zinc levels and fibrosis scores. Analyses were conducted using multivariable regression models adjusted for potential confounders., Results: The prevalence of advanced liver fibrosis was similar for those with zinc deficiency compared to those with normal zinc levels, (27.7% vs. 23.0%, respectively). We did not detect an association between zinc deficiency and advanced liver fibrosis in the adjusted regression model (aOR: 1.28, 95% CI: 0.62-2.61, p = 0.51) nor in exploratory analyses., Conclusions: In this cohort of Russians with HIV/HCV co-infection, who are anti-retroviral treatment naïve and have heavy alcohol use, we did not detect an association between zinc deficiency or zinc levels and advanced liver fibrosis., Competing Interests: The authors have declared that no competing interests exist.

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 β-cell function, and T2DM pathogenesis., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Insomnia is associated with increased cardiovascular disease (CVD) risk in the general population and is highly prevalent in people with HIV. The CVD risk conferred by insomnia in the HIV population is unknown., Methods: Using the Veterans Aging Cohort Study Survey Cohort, insomnia symptoms were measured and dummy coded with the item, "Difficulty falling or staying asleep?" (5-point scale from no difficulty to bothers a lot). Incident CVD event ICD-9 codes (acute myocardial infarction, stroke, or coronary artery revascularization) were identified with the Department of Veterans Affairs (VA) and Medicare administrative data and VA fee-for-service data. Those with baseline CVD were excluded., Results: HIV-infected (N = 3108) veterans had a median follow-up time of 10.8 years, during which 267 CVD events occurred. Compared to HIV-infected veterans with no difficulty falling or staying asleep, HIV-infected veterans bothered a lot by insomnia symptoms had an increased risk of incident CVD after adjusting for demographics [hazard ratio (HR) = 1.64, 95% confidence interval (CI): 1.16 to 2.31, P = 0.005], CVD risk factors (HR = 1.62, 95% CI: 1.14 to 2.30, P = 0.007), additional potential confounders (hepatitis C infection, renal disease, anemia, alcohol use, and cocaine use; HR = 1.70, 95% CI: 1.19 to 2.43, P = 0.003), and HIV-specific factors (HIV-1 RNA, CD4 T-cell count, and antiretroviral therapy; HR = 1.66, 95% CI: 1.16 to 2.37, P = 0.005). Additional adjustment for nonbenzodiazepine sleep medication (HR = 1.62, 95% CI: 1.13 to 2.32, P = 0.009) did not attenuate the association; however, it fell short of significance at P < 0.01 after adjustment for depressive symptoms (HR = 1.51, 95% CI: 0.98 to 2.32, P = 0.060) or antidepressant medication (HR = 1.51, 95% CI: 1.04 to 2.19, P = 0.031)., Conclusions: Highly bothersome insomnia symptoms were significantly associated with incident CVD in HIV-infected veterans, suggesting that insomnia may be a novel, modifiable risk factor for CVD in HIV.

Background: Hepatic steatosis is prevalent in Western countries, but few studies have evaluated whether the frequency and severity of steatosis are greater in the setting of HIV infection. We compared the prevalence and severity of hepatic steatosis between HIV-infected (HIV+) and uninfected persons and identified factors associated with greater steatosis severity within both groups., Methods: We performed a cross-sectional study among participants without cardiovascular disease who participated in a substudy of the Veterans Aging Cohort Study. Hepatic steatosis was defined by noncontrast computed tomography (CT) liver-to-spleen (L/S) attenuation ratio < 1.0. Multivariable linear regression was used to: 1) evaluate the association between HIV infection and severity of hepatic steatosis, as measured by absolute liver attenuation, and 2) identify factors associated with greater severity of steatosis, by HIV status., Results: Among 268 participants (median age, 55 years; 99% male; 79% black; 23% obese; 64% HIV+ [91% on antiretroviral therapy]), the overall prevalence of steatosis was 7.8% and was similar between HIV+ and uninfected individuals (13 [7.6%] versus 8 [8.2%], respectively; p = 0.85). Participants with HIV, the majority of whom received antiretroviral therapy, had a higher mean absolute liver attenuation (mean difference, 5.68 Hounsfield units; p < 0.001), correlating with lesser hepatic steatosis severity, compared to uninfected participants. After adjusting for covariates, only advanced hepatic fibrosis was associated with greater severity of steatosis in HIV+ persons (p = 0.03) and uninfected individuals (p < 0.001)., Conclusions: In this sample of participants without cardiovascular disease, the prevalence of hepatic steatosis by noncontrast abdominal CT was not different by HIV status. Increasing severity of steatosis was independently associated with advanced hepatic fibrosis in both groups.

Background: The effect of human immunodeficiency virus (HIV) on the development of peripheral artery disease (PAD) remains unclear. We investigated whether HIV infection is associated with an increased risk of PAD after adjustment for traditional atherosclerotic risk factors in a large cohort of HIV-infected (HIV+) and demographically similar HIV-uninfected veterans., Methods: We studied participants in the Veterans Aging Cohort Study from April 1, 2003 through December 31, 2014. We excluded participants with known prior PAD or prevalent cardiovascular disease (myocardial infarction, stroke, coronary heart disease, and congestive heart failure) and analyzed the effect of HIV status on the risk of incident PAD events after adjusting for demographics, PAD risk factors, substance use, CD4 cell count, HIV-1 ribonucleic acid, and antiretroviral therapy. The primary outcome is incident peripheral artery disease events. Secondary outcomes include mortality and amputation in subjects with incident PAD events by HIV infection status, viral load, and CD4 count., Results: Among 91 953 participants, over a median follow up of 9.0 years, there were 7708 incident PAD events. Rates of incident PAD events per 1000 person-years were higher among HIV+ (11.9; 95% confidence interval [CI], 11.5-12.4) than uninfected veterans (9.9; 95% CI, 9.6-10.1). After adjustment for demographics, PAD risk factors, and other covariates, HIV+ veterans had an increased risk of incident PAD events compared with uninfected veterans (hazard ratio [HR], 1.19; 95% CI, 1.13-1.25). This risk was highest among those with time-updated HIV viral load >500 copies/mL (HR, 1.51; 95% CI, 1.38-1.65) and CD4 cell counts <200 cells/mm 3 (HR, 1.91; 95% CI, 1.71-2.13). In contrast, HIV+ veterans with time updated CD4 cell count ≥500 cells/mm 3 had no increased risk of PAD (HR, 1.03; 95% CI, 0.96-1.11). Mortality rates after incident PAD events are high regardless of HIV status. HIV infection did not affect rates of amputation after incident PAD events., Conclusions: Infection with HIV is associated with a 19% increased risk of PAD beyond that explained by traditional atherosclerotic risk factors. However, for those with sustained CD4 cell counts <200 cells/mm 3 , the risk of incident PAD events is nearly 2-fold higher whereas for those with sustained CD4 cell counts ≥500 cells/mm 3 there is no excess risk of incident PAD events compared with uninfected people., (© 2018 American Heart Association, Inc.)

Purpose of Review: The objective of this review is to provide an update on the link between HIV infection and cardiovascular disease (CVD). We will focus our review mainly on literature describing clinical CVD events and understudied topics of importance., Recent Findings: Heart failure, peripheral artery disease, and stroke are CVD modalities deserving more attention in the context of HIV infection in the highly active antiretroviral therapy era. Incidence data on clinical CVD from HIV populations in low- and middle-income countries are limited. Multisubstance use is common in HIV, but understudied as a moderator or mediator of the association between HIV and CVD. CVD risk assessment in HIV remains challenging, but new research into novel biomarkers may provide further insights. There is also a need for inclusion of non-biologic factors in our attempts to understand, quantify, and predict CVD risk among PLWHA. Significant attention has been paid to generating and testing hypotheses to understand the mechanisms of myocardial infarction in HIV. Similar attention is deserving for heart failure, PAD, stroke, and cardiovascular disease risk in resource-limited settings and among substance users with HIV.

Background: Bilirubin may protect against cardiovascular disease (CVD) by reducing oxidative stress. Whether elevated bilirubin reduces the risk of CVD events among HIV + individuals and if this differs from uninfected individuals remain unclear. We assessed whether bilirubin independently predicted the risk of CVD events among HIV + and uninfected participants in VACS (Veterans Aging Cohort Study)., Methods and Results: We conducted a prospective cohort study using VACS participants free of baseline CVD. Total bilirubin was categorized by quartiles. CVD as well as acute myocardial infarction, heart failure, and ischemic stroke events were assessed. Cox regression was used to evaluate hazard ratios of outcomes associated with quartiles of total bilirubin in HIV + and uninfected people after adjusting for multiple risk factors. There were 96 381 participants (30 427 HIV + ); mean age was 48 years, 48% were black, and 97% were men. There were 6603 total incident CVD events over a mean of 5.7 years. In adjusted models, increasing quartiles of baseline total bilirubin were associated with decreased hazards of all outcomes (hazard ratio, 0.86; 95% confidence interval, 0.80-0.91). Among HIV + participants, results persisted for heart failure, ischemic stroke, and total CVD, but nonsignificant associations were observed for acute myocardial infarction., Conclusions: VACS participants (regardless of HIV status) with elevated bilirubin levels had a lower risk of incident total CVD, acute myocardial infarction, heart failure, and ischemic stroke events after adjusting for known risk factors. Future studies should investigate how this apparently protective effect of elevated bilirubin could be harnessed to reduce CVD risk or improve risk estimation among HIV + individuals., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: D-dimer blood levels in persons with HIV infection are associated with risk of serious non-AIDS conditions and death. Black race has been correlated with higher D-dimer levels in several studies. We examined the effects of race and HIV on D-dimer over time and the impact of viral load suppression by longitudinally comparing changes in levels among healthy young adult male African Americans and whites before HIV seroconversion and before and after initiation of antiretroviral therapy (ART)., Methods: We analyzed D-dimer levels and clinical and laboratory data of 192 participants enrolled in the US Military HIV Natural History Study, a 30-year cohort of military personnel infected with HIV. D-dimer levels were measured on stored sera from each participant at 3 time points: (1) before HIV seroconversion (Pre-SC), (2) ≥6 months after HIV seroconversion but before ART initiation (Post-SC), and (3) ≥6 months after ART with documented viral suppression (Post-ART). Levels were compared at each time point using nonparametric and logistic regression analysis., Results: Compared with whites (n = 106), African Americans (n = 86) had higher D-dimer levels post-SC (P = 0.007), but in the same individuals, pre-SC baseline and post-ART levels were similar (P = 0.40 and P = 0.99, respectively). There were no racial differences in CD4 cell counts, HIV RNA viral load, time from estimated seroconversion to ART initiation, and duration on ART., Conclusions: Observed longitudinally, racial differences in D-dimer levels were seen only during HIV viremia. Higher levels of D-dimer commonly observed in African Americans are likely due to factors in addition to race.

Rationale: The epidemiology and prognostic impact of increased pulmonary pressure among HIV-infected individuals in the antiretroviral therapy era is not well described., Objectives: To examine the prevalence, clinical features, and outcomes of increased echocardiographic pulmonary pressure in HIV-infected and -uninfected individuals., Methods: This study evaluated 8,296 veterans referred for echocardiography with reported pulmonary artery systolic pressure (PASP) estimates from the Veterans Aging Cohort study, an observational cohort of HIV-infected and -uninfected veterans matched by age, sex, race/ethnicity, and clinical site. The primary outcome was adjusted mortality by HIV status., Measurements and Main Results: PASP was reported in 2,831 HIV-infected and 5,465 HIV-uninfected veterans (follow-up [mean ± SD], 3.8 ± 2.6 yr). As compared with uninfected veterans, HIV-infected veterans with HIV viral load greater than 500 copies/ml (odds ratio, 1.27; 95% confidence interval [CI], 1.05-1.54) and those with CD4 cell count less than 200 cells/μl (odds ratio, 1.28; 95% CI, 1.02-1.60) had a higher prevalence of PASP greater than or equal to 40 mm Hg. As compared with uninfected veterans with a PASP less than 40 mm Hg, HIV-infected veterans with a PASP greater than or equal to 40 mm Hg had an increased risk of death (adjusted hazard ratio, 1.78; 95% CI, 1.57-2.01). This risk persisted even among participants without prevalent comorbidities (adjusted hazard ratio, 3.61; 95% CI, 2.17-6.01). The adjusted risk of mortality in HIV-infected veterans was higher at all PASP values than in uninfected veterans, including at values currently considered to be normal., Conclusions: HIV-infected people with high HIV viral loads or low CD4 cell counts have a higher prevalence of increased PASP than uninfected people. Mortality risk in HIV-infected veterans increases at lower values of PASP than previously recognized and is present even among those without prevalent comorbidities. These findings may inform clinical decision-making regarding screening and surveillance of pulmonary hypertension in HIV-infected individuals.

Liver fibrosis is common, particularly in individuals who are infected with human immunodeficiency virus (HIV). HIV-infected individuals have excess congestive heart failure (CHF) risk compared with uninfected people. It remains unknown whether liver fibrosis stage influences the CHF risk or if HIV or hepatitis C virus (HCV) infection modifies this association. Our objectives were to assess whether 1) stage of liver fibrosis is independently associated with incident CHF and 2) the association between stage of liver fibrosis and incident CHF is modified by HIV/HCV status. Participants alive on or after April 1, 2003, in the Veterans Aging Cohort Study were included. Those without prevalent cardiovascular disease were followed until their first CHF event, death, last follow-up date, or December 31, 2011. Liver fibrosis was measured using the fibrosis 4 index (FIB-4), which is calculated using age, aminotransferases, and platelets. Cox proportional hazards regression models were adjusted for cardiovascular disease risk factors. Among 96,373 participants over 6.9 years, 3844 incident CHF events occurred. FIB-4 between 1.45 and 3.25 (moderate fibrosis) and FIB-4 > 3.25 (advanced fibrosis/cirrhosis) were associated with CHF (hazard ratio [95% confidence interval], 1.17 [1.07-1.27] and 1.65 [1.43-1.92], respectively). The association of advanced fibrosis/cirrhosis and incident CHF persisted regardless of HIV/HCV status., Conclusion: Moderate and advanced liver fibrosis/cirrhosis are associated with an increased risk of CHF. The association for advanced fibrosis/cirrhosis persists even among participants without hepatitis C and/or HIV infection. Assessing liver health may be important for reducing the risk of future CHF events, particularly among HIV and hepatitis C infected people among whom cardiovascular disease risk is elevated and liver disease is common. (Hepatology 2017;66:1286-1295)., (© 2017 by the American Association for the Study of Liver Diseases.)

Objectives: Obesity prevalence among people living with HIV (HIV+) is rising. HIV and obesity are proinflammatory states, but their combined effect on inflammation (measured by interleukin 6, IL-6), altered coagulation (D-dimer), and monocyte activation (soluble CD14, sCD14) is unknown. We hypothesized inflammation increases when obesity and HIV infection co-occur., Methods: The Veterans Aging Cohort Study survey cohort is a prospective, observational study of predominantly male HIV+ veterans and veterans uninfected with HIV; a subset provided blood samples. Inclusion criteria for this analysis were body mass index ≥ 18.5 kg/m and biomarker measurement. Dependent variables were IL-6, sCD14, and D-dimer quartiles. Obesity/HIV status was the primary predictor. Unadjusted and adjusted logistic regression models were constructed., Results: Data were analyzed for 1477 HIV+ and 823 uninfected participants. Unadjusted median IL-6 levels were significantly higher and sCD14 levels significantly lower in obese/HIV+ compared with nonobese/uninfected (P <0.01 for both). In adjusted analyses, the odds ratio for increased IL-6 in obese/HIV+ patients was 1.76 (95% confidence interval: 1.18 to 2.47) compared with nonobese/uninfected, and obesity/HIV+ remained associated with lower odds of elevated sCD14. We did not detect a synergistic association of co-occurring HIV and obesity on IL-6 or sCD14 elevation. D-dimer levels did not differ significantly between body mass index/HIV status groups., Conclusions: HIV-obesity comorbidity is associated with elevated IL-6, decreases in sCD14, and no significant difference in D-dimer. These findings are clinically significant, as previous studies associated these biomarkers with mortality. Future studies should assess whether other biomarkers show similar trends and potential mechanisms for unanticipated sCD14 and D-dimer findings.

Objectives: Opioids have immunosuppressive properties, yet opioid effects on T cell abnormalities consistent with the immune risk phenotype among HIV-infected individuals are understudied., Methods: To assess associations between illicit opioid use and T cell characteristics (CD4/CD8 ratio, memory profiles based on CD45RO and CD28 expression, and senescence based on CD57 expression), we conducted an exploratory cross-sectional analysis of Russia ARCH, a cohort of antiretroviral therapy (ART)-naïve HIV-infected individuals recruited 11/2012 to 10/2014 in St. Petersburg, Russia. The main independent variable was past 30 day illicit opioid use (yes vs. no). Secondary analyses evaluated none (0 days), intermittent (1 to 7 days), and persistent (8 to 30 days) opioid use. Outcomes were determined with flow cytometry. Analyses were conducted using linear regression models., Results: Among 186 participants, 38% reported any illicit opioid use (18% intermittent and 20% persistent). Any illicit opioid use was not significantly associated with T cell characteristics. Intermittent opioid use appeared to be associated with decreased memory CD8+ T cells proportion (CD45RO+CD45RA- CD8+ T cells: adjusted mean difference [AMD] [95% CI] = -6.15 [-11.50, -0.79], p = 0.02) and borderline significant increased senescent T cells (%CD57+ of total CD28-CD8+ T cells (AMD [95% CI] = 7.70 [-0.06, 15.46], p = 0.05)., Conclusions: Among ART-naïve HIV-infected Russians, any illicit opioid use was not significantly associated with T cell abnormalities although intermittent illicit opioid use may be associated with CD8 T cell abnormalities. Longitudinal studies are warranted to confirm these findings given increased risk of infections and comorbidities seen among HIV-infected individuals with illicit opioid use.

Importance: With improved survival, heart failure (HF) has become a major complication for individuals with human immunodeficiency virus (HIV) infection. It is unclear if this risk extends to different types of HF in the antiretroviral therapy (ART) era. Determining whether HIV infection is associated with HF with reduced ejection fraction (HFrEF), HF with preserved ejection fraction (HFpEF), or both is critical because HF types differ with respect to underlying mechanism, treatment, and prognosis., Objectives: To investigate whether HIV infection increases the risk of future HFrEF and HFpEF and to assess if this risk varies by sociodemographic and HIV-specific factors., Design, Setting, and Participants: This study evaluated 98 015 participants without baseline cardiovascular disease from the Veterans Aging Cohort Study, an observational cohort of HIV-infected veterans and uninfected veterans matched by age, sex, race/ethnicity, and clinical site, enrolled on or after April 1, 2003, and followed up through September 30, 2012. The dates of the analysis were October 2015 to November 2016., Exposure: Human immunodeficiency virus infection., Main Outcomes and Measures: Outcomes included HFpEF (EF≥50%), borderline HFpEF (EF 40%-49%), HFrEF (EF<40%), and HF of unknown type (EF missing)., Results: Among 98 015 participants, the mean (SD) age at enrollment in the study was 48.3 (9.8) years, 97.0% were male, and 32.2% had HIV infection. During a median follow-up of 7.1 years, there were 2636 total HF events (34.6% were HFpEF, 15.5% were borderline HFpEF, 37.1% were HFrEF, and 12.8% were HF of unknown type). Compared with uninfected veterans, HIV-infected veterans had an increased risk of HFpEF (hazard ratio [HR], 1.21; 95% CI, 1.03-1.41), borderline HFpEF (HR, 1.37; 95% CI, 1.09-1.72), and HFrEF (HR, 1.61; 95% CI, 1.40-1.86). The risk of HFrEF was pronounced in veterans younger than 40 years at baseline (HR, 3.59; 95% CI, 1.95-6.58). Among HIV-infected veterans, time-updated HIV-1 RNA viral load of at least 500 copies/mL compared with less than 500 copies/mL was associated with an increased risk of HFrEF, and time-updated CD4 cell count less than 200 cells/mm3 compared with at least 500 cells/mm3 was associated with an increased risk of HFrEF and HFpEF., Conclusions and Relevance: Individuals who are infected with HIV have an increased risk of HFpEF, borderline HFpEF, and HFrEF compared with uninfected individuals. The increased risk of HFrEF can manifest decades earlier than would be expected in a typical uninfected population. Future research should focus on prevention, risk stratification, and identification of the mechanisms for HFrEF and HFpEF in the HIV-infected population.

Importance: With the advent of highly effective antiretroviral therapy and improved survival, human immunodeficiency virus (HIV)-infected people are living longer and are now at an increased risk for cardiovascular disease (CVD). There is an urgent need to identify novel risk factors and primary prevention approaches for CVD in HIV. Although depression is prevalent in HIV-infected adults and is associated with future CVD in the general population, its association with CVD events has not been examined in the HIV-infected population., Objective: To examine whether depressive disorders are prospectively associated with incident acute myocardial infarction (AMI) in a large cohort of adults with HIV., Design, Setting, and Participants: Included in this cohort study were 26 144 HIV-infected veterans without CVD at baseline (1998-2003) participating in the US Department of Veterans Affairs Veterans Aging Cohort Study from April 1, 2003, through December 31, 2009. At baseline, 4853 veterans (19%) with major depressive disorder (MDD; International Classification of Diseases, Ninth Revision [ICD-9] codes 296.2 and 296.3) and 2296 (9%) with dysthymic disorder (ICD-9 code 300.4) were identified. The current analysis was conducted from January 2015 to November 2015., Main Outcomes and Measures: Incident AMI (defined by discharge summary documentation, enzyme/electrocardiography evidence of AMI, inpatient ICD-9 code for AMI (410), or AMI as underlying cause of death [International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code 121]) between the enrollment date and December 31, 2009., Results: The mean (SD) age of those with MDD was 47.3 (7.9) years and for those without MDD was 48.2 (9.7) years. During 5.8 years of follow-up, 490 AMI events (1.9%) occurred. Baseline MDD was associated with incident AMI after adjusting for demographics (hazard ratio [HR], 1.31; 95% CI, 1.05-1.62), CVD risk factors (HR, 1.29; 95% CI, 1.04-1.60), and HIV-specific factors (HR, 1.30; 95% CI, 1.05-1.62). Further adjustment for hepatitis C, renal disease, substance abuse, and hemoglobin level (HR, 1.25; 95% CI, 1.00-1.56) and antidepressant use (HR, 1.12; 95% CI, 0.87-1.42) attenuated associations. Baseline dysthymic disorder was not associated with incident AMI., Conclusions and Relevance: We report novel evidence that HIV-infected adults with MDD have a 30% increased risk for AMI than HIV-infected adults without MDD after adjustment for many potential confounders. Our findings raise the possibility that MDD may be independently associated with incident atherosclerotic CVD in the HIV-infected population.