Computationally inferred cell-type specific epigenome-wide DNA methylation analysis unveils distinct methylation patterns among immune cells for HIV infection in three cohorts.

BACKGROUND: Epigenome-wide association studies (EWAS) have identified CpG sites associated with HIV infection in blood cells in bulk, which offer limited knowledge of cell-type specific methylation patterns associated with HIV infection. In this study, we aim to identify differentially methylated CpG sites for HIV infection in immune cell types: CD4+ T-cells, CD8+ T-cells, B cells, Natural Killer (NK) cells, and monocytes. METHODS: Applying a computational deconvolution method, we performed a cell-type based EWAS for HIV infection in three independent cohorts (Ntotal = 1,382). DNA methylation in blood or in peripheral blood mononuclear cells (PBMCs) was profiled by an array-based method and then deconvoluted by Tensor Composition Analysis (TCA). The TCA-computed CpG methylation in each cell type was first benchmarked by bisulfite DNA methylation capture sequencing in a subset of the samples. Cell-type EWAS of HIV infection was performed in each cohort separately and a meta-EWAS was conducted followed by gene set enrichment analysis. RESULTS: The meta-analysis unveiled a total of 2,021 cell-type unique significant CpG sites for five inferred cell types. Among these inferred cell-type unique CpG sites, the concordance rate in the three cohorts ranged from 96% to 100% in each cell type. Cell-type level meta-EWAS unveiled distinct patterns of HIV-associated differential CpG methylation, where 74% of CpG sites were unique to individual cell types (false discovery rate, FDR <0.05). CD4+ T-cells had the largest number of unique HIV-associated CpG sites (N = 1,624) compared to any other cell type. Genes harboring significant CpG sites are involved in immunity and HIV pathogenesis (e.g. CD4+ T-cells: NLRC5, CX3CR1, B cells: IFI44L, NK cells: IL12R, monocytes: IRF7), and in oncogenesis (e.g. CD4+ T-cells: BCL family, PRDM16, monocytes: PRDM16, PDCD1LG2). HIV-associated CpG sites were enriched among genes involved in HIV pathogenesis and oncogenesis that were enriched among interferon-α and -γ, TNF-α, inflammatory response, and apoptotic pathways. CONCLUSION: Our findings uncovered computationally inferred cell-type specific modifications in the host epigenome for people with HIV that contribute to the growing body of evidence regarding HIV pathogenesis.

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

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

Cardiovascular Disease Risk Factor Control in People With and Without HIV.

BACKGROUND: Management of hypertension, dyslipidemia, diabetes and other modifiable factors may mitigate the cardiovascular disease (CVD) risk in people with human immunodeficiency virus (HIV, PWH) compared with people without HIV (PWoH). METHODS: This was a retrospective cohort study of 8285 PWH and 170 517 PWoH from an integrated health system. Risk factor control was measured using a novel disease management index (DMI) accounting for amount/duration above treatment goals (0% to 100% [perfect control]), including 2 DMIs for hypertension (diastolic and systolic blood pressure), 3 for dyslipidemia (low-density lipoprotein, total cholesterol, triglycerides), and 1 for diabetes (HbA1c). CVD risk by HIV status was evaluated overall and in subgroups defined by DMIs, smoking, alcohol use, and overweight/obesity in adjusted Cox proportional hazards models. RESULTS: PWH and PWoH had similar DMIs (80%-100%) except for triglycerides (worse for PWH) and HbA1c (better for PWH). In adjusted models, PWH had an elevated risk of CVD compared with PWoH (hazard ratio [HR], 1.18; 95% confidence interval [CI], 1.07-1.31). This association was attenuated in subgroups with controlled dyslipidemia and diabetes but remained elevated for PWH with controlled hypertension or higher total cholesterol. The strongest HIV status association with CVD was seen in the subgroup with frequent unhealthy alcohol use (HR, 2.13; 95% CI, 1.04-4.34). CONCLUSIONS: Control of dyslipidemia and diabetes, but not hypertension, attenuated the HIV status association with CVD. The strong association of HIV and CVD with frequent unhealthy alcohol use suggests enhanced screening and treatment of alcohol problems in PWH is warranted.

The forecasted prevalence of comorbidities and multimorbidity in people with HIV in the United States through the year 2030: A modeling study.

BACKGROUND: Estimating the medical complexity of people aging with HIV can inform clinical programs and policy to meet future healthcare needs. The objective of our study was to forecast the prevalence of comorbidities and multimorbidity among people with HIV (PWH) using antiretroviral therapy (ART) in the United States (US) through 2030. METHODS AND FINDINGS: Using the PEARL model-an agent-based simulation of PWH who have initiated ART in the US-the prevalence of anxiety, depression, stage ≥3 chronic kidney disease (CKD), dyslipidemia, diabetes, hypertension, cancer, end-stage liver disease (ESLD), myocardial infarction (MI), and multimorbidity (≥2 mental or physical comorbidities, other than HIV) were forecasted through 2030. Simulations were informed by the US CDC HIV surveillance data of new HIV diagnosis and the longitudinal North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) data on risk of comorbidities from 2009 to 2017. The simulated population represented 15 subgroups of PWH including Hispanic, non-Hispanic White (White), and non-Hispanic Black/African American (Black/AA) men who have sex with men (MSM), men and women with history of injection drug use and heterosexual men and women. Simulations were replicated for 200 runs and forecasted outcomes are presented as median values (95% uncertainty ranges are presented in the Supporting information). In 2020, PEARL forecasted a median population of 670,000 individuals receiving ART in the US, of whom 9% men and 4% women with history of injection drug use, 60% MSM, 8% heterosexual men, and 19% heterosexual women. Additionally, 44% were Black/AA, 32% White, and 23% Hispanic. Along with a gradual rise in population size of PWH receiving ART-reaching 908,000 individuals by 2030-PEARL forecasted a surge in prevalence of most comorbidities to 2030. Depression and/or anxiety was high and increased from 60% in 2020 to 64% in 2030. Hypertension decreased while dyslipidemia, diabetes, CKD, and MI increased. There was little change in prevalence of cancer and ESLD. The forecasted multimorbidity among PWH receiving ART increased from 63% in 2020 to 70% in 2030. There was heterogeneity in trends across subgroups. Among Black women with history of injection drug use in 2030 (oldest demographic subgroup with median age of 66 year), dyslipidemia, CKD, hypertension, diabetes, anxiety, and depression were most prevalent, with 92% experiencing multimorbidity. Among Black MSM in 2030 (youngest demographic subgroup with median age of 42 year), depression and CKD were highly prevalent, with 57% experiencing multimorbidity. These results are limited by the assumption that trends in new HIV diagnoses, mortality, and comorbidity risk observed in 2009 to 2017 will persist through 2030; influences occurring outside this period are not accounted for in the forecasts. CONCLUSIONS: The PEARL forecasts suggest a continued rise in comorbidity and multimorbidity prevalence to 2030, marked by heterogeneities across race/ethnicity, gender, and HIV acquisition risk subgroups. HIV clinicians must stay current on the ever-changing comorbidities-specific guidelines to provide guideline-recommended care. HIV clinical directors should ensure linkages to subspecialty care within the clinic or by referral. HIV policy decision-makers must allocate resources and support extended clinical capacity to meet the healthcare needs of people aging with HIV.

Postoperative Outcomes Associated with the Timing of Surgery After SARS-CoV-2 Infection.

OBJECTIVE: Examine the association between prior SARS-CoV-2 infection, interval from infection to surgery, and adverse surgical outcomes. SUMMARY BACKGROUND DATA: Earlier series have reported worse outcomes for surgery after COVID-19 illness, and these findings have led to routinely deferring surgery seven weeks after infection. METHODS: We created a retrospective cohort of patients from US Veterans Health Administration facilities nationwide, April 2020-September 2022, undergoing surgical procedures. Primary outcomes were 90-day all-cause mortality and 30-day complications. Within surgical procedure groupings, SARS-CoV-2 infected and uninfected patients were matched in a 1:4 ratio. We categorized patients by two-week intervals from SARS-CoV-2 positive test to surgery. Hierarchical multilevel multivariable logistic regression models were used to estimate the association between infection to surgery interval versus no infection and primary endpoints. RESULTS: We identified 82,815 veterans undergoing eligible operations (33% general, 27% orthopedic, 13% urologic, 9% vascular), of whom 16,563 (20%) had laboratory confirmed SARS-CoV-2 infection prior to surgery. The multivariable models demonstrated an association between prior SARS-CoV-2 infection and increased 90-day mortality (odds ratio (OR) 1.42, 95% CI 1.08, 1.86) and complications (OR 1.32, 95% CI 1.11, 1.57) only for patients having surgery within 14 days of infection. ASA-stratified multivariable models showed that the associations between increased 90-day mortality (OR 1.40, 95% CI 1.12, 1.75) and complications (OR 1.73, 95% CI 1.34, 2.24) for patients having surgery within 14 days of infection were confined to those with ASA 4-5. CONCLUSIONS: In a contemporary surgical cohort, patients with prior SARS-CoV-2 infection only had increased post-operative mortality or complications when they had surgery within 14 days after positive test. These findings support revising timing recommendations between surgery and prior SARS-CoV-2 infection.

Hypertension Control During the Coronavirus Disease 2019 Pandemic: A Cohort Study Among US Veterans.

DESIGN: Retrospective cohort study. OBJECTIVE: We sought to examine whether disruptions in follow-up intervals contributed to hypertension control. BACKGROUND: Disruptions in health care were widespread during the coronavirus disease 2019 pandemic. PATIENTS AND METHODS: We identified a cohort of individuals with hypertension in both prepandemic (March 2019-February 2020) and pandemic periods (March 2020-February 2022) in the Veterans Health Administration. First, we calculated follow-up intervals between the last prepandemic and first pandemic blood pressure measurement during a primary care clinic visit, and between measurements in the prepandemic period. Next, we estimated the association between the maintenance of (or achieving) hypertension control and the period using generalized estimating equations. We assessed associations between follow-up interval and control separately for periods. Finally, we evaluated the interaction between period and follow-up length. RESULTS: A total of 1,648,424 individuals met the study inclusion criteria. Among individuals with controlled hypertension, the likelihood of maintaining control was lower during the pandemic versus the prepandemic (relative risk: 0.93; 95% CI: 0.93, 0.93). Longer follow-up intervals were associated with a decreasing likelihood of maintaining controlled hypertension in both periods. Accounting for follow-up intervals, the likelihood of maintaining control was 2% lower during the pandemic versus the prepandemic. For uncontrolled hypertension, the likelihood of gaining control was modestly higher during the pandemic versus the prepandemic (relative risk: 1.01; 95% CI: 1.01, 1.01). The likelihood of gaining control decreased with follow-up length during the prepandemic but not pandemic. CONCLUSIONS: During the pandemic, longer follow-up between measurements contributed to the lower likelihood of maintaining control. Those with uncontrolled hypertension were modestly more likely to gain control in the pandemic.

Contribution of Potentially Inappropriate Medications to Polypharmacy-Associated Risk of Mortality in Middle-Aged Patients: A National Cohort Study.

BACKGROUND: The role of potentially inappropriate medications (PIMs) in mortality has been studied among those 65 years or older. While middle-aged individuals are believed to be less susceptible to the harms of polypharmacy, PIMs have not been as carefully studied in this group. OBJECTIVE: To estimate PIM-associated risk of mortality and evaluate the extent PIMs explain associations between polypharmacy and mortality in middle-aged patients, overall and by sex and race/ethnicity. DESIGN: Observational cohort study. SETTING: Department of Veterans Affairs (VA), the largest integrated healthcare system in the US. PARTICIPANTS: Patients aged 41 to 64 who received a chronic medication (continuous use of ≥ 90 days) between October 1, 2008, and September 30, 2017. MEASUREMENT: Patients were followed for 5 years until death or end of study period (September 30, 2019). Time-updated polypharmacy and hyperpolypharmacy were defined as 5-9 and ≥ 10 chronic medications, respectively. PIMs were identified using the Beers criteria (2015) and were time-updated. Cox models were adjusted for demographic, behavioral, and clinical characteristics. RESULTS: Of 733,728 patients, 676,935 (92.3%) were men, 479,377 (65.3%) were White, and 156,092 (21.3%) were Black. By the end of follow-up, 104,361 (14.2%) patients had polypharmacy, 15,485 (2.1%) had hyperpolypharmacy, and 129,992 (17.7%) were dispensed ≥ 1 PIM. PIMs were independently associated with mortality (HR 1.11, 95% CI 1.04-1.18). PIMs also modestly attenuated risk of mortality associated with polypharmacy (HR 1.07, 95% CI 1.03-1.11 before versus HR 1.05, 95% CI 1.01-1.09 after) and hyperpolypharmacy (HR 1.18, 95% CI 1.09-1.28 before versus HR 1.12, 95% CI 1.03-1.22 after). Patterns varied when stratified by sex and race/ethnicity. LIMITATIONS: The predominantly male VA patient population may not represent the general population. CONCLUSION: PIMs were independently associated with increased mortality, and partially explained polypharmacy-associated mortality in middle-aged people. Other mechanisms of injury from polypharmacy should also be studied.

Risk factors for suicide among veterans living with and without HIV: a nested case-control study.

The rate of suicide among people with HIV (PWH) remains elevated compared to the general population. The aim of the study was to examine the association between a broad range of risk factors, HIV-specific risk factors, and suicide. We conducted a nested case-control study using data from the Veterans Aging Cohort Study (VACS) between 2006 and 2015. The risk of suicide was estimated using conditional logistic regression and models were stratified by HIV status. Most risk factors associated with suicide were similar between PWH and people without HIV; these included affective disorders, use of benzodiazepines, and mental health treatment. Among PWH, HIV-specific risk factors were not associated with suicide. A multiplicative interaction was observed between a diagnosis of HIV and a previous suicide attempt. Among PWH, a high prevalence of psychiatric, substance use disorders and multimorbidity contribute to the risk of suicide.

RESUMEN: La tasa de suicidio entre las personas con VIH (PWH) sigue siendo elevada en comparación con la población general. El objetivo del estudio fue examinar la asociación entre un amplio rango de factores de riesgo, los riesgos específicos del VIH y el suicidio. Realizamos un estudio anidado de casos y controles usando datos del Veterans Aging Cohort Study (VACS) entre 2006­2015. El riesgo de suicidio fue estimado mediante regresión logística condicional y los modelos se estratificaron por estado serológico. La mayoría de los factores de riesgo asociados con el suicidio fueron similares entre las PWH y las personas sin VIH; estos incluyeron trastornos afectivos, uso de benzodiazepinas y tratamiento de salud mental. Entre las PWH, los factores de riesgo específicos del VIH no se asociaron con el suicidio. Se observó una interacción multiplicativa entre un diagnóstico de VIH y un intento de suicidio previo. Entre las PWH, una alta prevalencia de trastornos psiquiátricos, por consumo de sustancias y multimorbilidad contribuyen al riesgo de suicidio.

Epigenetic Age Acceleration Markers Are Associated With Physiologic Frailty and All-Cause Mortality in People With Human Immunodeficiency Virus.

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.

Enhanced Identification of Hispanic Ethnicity Using Clinical Data: A Study in the Largest Integrated United States Health Care System.

BACKGROUND: Collection of accurate Hispanic ethnicity data is critical to evaluate disparities in health and health care. However, this information is often inconsistently recorded in electronic health record (EHR) data. OBJECTIVE: To enhance capture of Hispanic ethnicity in the Veterans Affairs EHR and compare relative disparities in health and health care. METHODS: We first developed an algorithm based on surname and country of birth. We then determined sensitivity and specificity using self-reported ethnicity from the 2012 Veterans Aging Cohort Study survey as the reference standard and compared this to the research triangle institute race variable from the Medicare administrative data. Finally, we compared demographic characteristics and age-adjusted and sex-adjusted prevalence of conditions in Hispanic patients among different identification methods in the Veterans Affairs EHR 2018-2019. RESULTS: Our algorithm yielded higher sensitivity than either EHR-recorded ethnicity or the research triangle institute race variable. In 2018-2019, Hispanic patients identified by the algorithm were more likely to be older, had a race other than White, and foreign born. The prevalence of conditions was similar between EHR and algorithm ethnicity. Hispanic patients had higher prevalence of diabetes, gastric cancer, chronic liver disease, hepatocellular carcinoma, and human immunodeficiency virus than non-Hispanic White patients. Our approach evidenced significant differences in burden of disease among Hispanic subgroups by nativity status and country of birth. CONCLUSIONS: We developed and validated an algorithm to supplement Hispanic ethnicity information using clinical data in the largest integrated US health care system. Our approach enabled clearer understanding of demographic characteristics and burden of disease in the Hispanic Veteran population.

Genome-wide association study in individuals of European and African ancestry and multi-trait analysis of opioid use disorder identifies 19 independent genome-wide significant risk loci.

Despite the large toll of opioid use disorder (OUD), genome-wide association studies (GWAS) of OUD to date have yielded few susceptibility loci. We performed a large-scale GWAS of OUD in individuals of European (EUR) and African (AFR) ancestry, optimizing genetic informativeness by performing MTAG (Multi-trait analysis of GWAS) with genetically correlated substance use disorders (SUDs). Meta-analysis included seven cohorts: the Million Veteran Program, Psychiatric Genomics Consortium, iPSYCH, FinnGen, Partners Biobank, BioVU, and Yale-Penn 3, resulting in a total N = 639,063 (Ncases = 20,686;Neffective = 77,026) across ancestries. OUD cases were defined as having a lifetime OUD diagnosis, and controls as anyone not known to meet OUD criteria. We estimated SNP-heritability (h2SNP) and genetic correlations (rg). Based on genetic correlation, we performed MTAG on OUD, alcohol use disorder (AUD), and cannabis use disorder (CanUD). A leave-one-out polygenic risk score (PRS) analysis was performed to compare OUD and OUD-MTAG PRS as predictors of OUD case status in Yale-Penn 3. The EUR meta-analysis identified three genome-wide significant (GWS; p ≤ 5 × 10-8) lead SNPs-one at FURIN (rs11372849; p = 9.54 × 10-10) and two OPRM1 variants (rs1799971, p = 4.92 × 10-09; rs79704991, p = 1.11 × 10-08; r2 = 0.02). Rs1799971 (p = 4.91 × 10-08) and another OPRM1 variant (rs9478500; p = 1.95 × 10-08; r2 = 0.03) were identified in the cross-ancestry meta-analysis. Estimated h2SNP was 12.75%, with strong rg with CanUD (rg = 0.82; p = 1.14 × 10-47) and AUD (rg = 0.77; p = 6.36 × 10-78). The OUD-MTAG resulted in a GWAS Nequivalent = 128,748 and 18 independent GWS loci, some mapping to genes or gene regions that have previously been associated with psychiatric or addiction phenotypes. The OUD-MTAG PRS accounted for 3.81% of OUD variance (beta = 0.61;s.e. = 0.066; p = 2.00 × 10-16) compared to 2.41% (beta = 0.45; s.e. = 0.058; p = 2.90 × 10-13) explained by the OUD PRS. The current study identified OUD variant associations at OPRM1, single variant associations with FURIN, and 18 GWS associations in the OUD-MTAG. The genetic architecture of OUD is likely influenced by both OUD-specific loci and loci shared across SUDs.

Spironolactone as a potential new pharmacotherapy for alcohol use disorder: convergent evidence from rodent and human studies.

Evidence suggests that spironolactone, a nonselective mineralocorticoid receptor (MR) antagonist, modulates alcohol seeking and consumption. Therefore, spironolactone may represent a novel pharmacotherapy for alcohol use disorder (AUD). In this study, we tested the effects of spironolactone in a mouse model of alcohol drinking (drinking-in-the-dark) and in a rat model of alcohol dependence (vapor exposure). We also investigated the association between spironolactone receipt for at least 60 continuous days and change in self-reported alcohol consumption, using the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), in a pharmacoepidemiologic cohort study in the largest integrated healthcare system in the US. Spironolactone dose-dependently reduced the intake of sweetened or unsweetened alcohol solutions in male and female mice. No effects of spironolactone were observed on drinking of a sweet solution without alcohol, food or water intake, motor coordination, alcohol-induced ataxia, or blood alcohol levels. Spironolactone dose-dependently reduced operant alcohol self-administration in dependent and nondependent male and female rats. In humans, a greater reduction in alcohol consumption was observed among those who received spironolactone, compared to propensity score-matched individuals who did not receive spironolactone. The largest effects were among those who reported hazardous/heavy episodic alcohol consumption at baseline (AUDIT-C ≥ 8) and those exposed to ≥ 50 mg/day of spironolactone. These convergent findings across rodent and human studies demonstrate that spironolactone reduces alcohol use and support the hypothesis that this medication may be further studied as a novel pharmacotherapy for AUD.

Treating Hepatitis C in Individuals With Previous Incarceration: The Veterans Health Administration, 2012-2019.

To determine whether the Veterans Health Administration's (VHA) hepatitis C (HCV) treatment campaign reached marginalized populations, we compared HCV care by previous incarceration status with Veterans Aging Cohort Study data. Of those with and those without previous incarceration, respectively, 40% and 21% had detectable HCV, 59% and 65% underwent treatment (P = .07); 92% and 94% of those who completed treatment achieved sustained virologic response. The VHA HCV treatment effort was successful and other systems should replicate those efforts. (Am J Public Health. 2023;113(2):162-165. https://doi.org/10.2105/AJPH.2022.307152).

Factors Associated with Bothersome Symptoms in Individuals With and Without HIV Who Report Alcohol Use.

Bothersome symptoms potentially related to drinking are commonly reported by people with and without HIV (PWH/PWoH). However, the relationship between bothersome symptoms and level of alcohol use is often not appreciated by patients or providers. Therefore, among persons reporting prior-year alcohol use, we assessed whether alcohol use level (AUDIT-C score), HIV status, and demographic covariates influenced the likelihood of the patient reporting a bothersome symptom. We used the Veterans Aging Cohort Study (VACS) surveys (2002-2018), including a validated symptoms index. Among 3679 PWH and 3830 PWoH currently drinking alcohol, the most commonly reported symptoms were muscle/joint pain (52%), sleep disturbance (51%), and fatigue (50%). Level of alcohol use was independently associated with 18 of 20 bothersome symptoms, including seven symptoms more common among PWH. Results can help inform PWH/PWoH who drink alcohol about the strong relationship between level of alcohol use and bothersome symptoms, potentially motivating reduced use.

Performance of an automated deep learning algorithm to identify hepatic steatosis within noncontrast computed tomography scans among people with and without HIV.

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.

Discrimination and Calibration of the Veterans Aging Cohort Study Index 2.0 for Predicting Mortality Among People With Human Immunodeficiency Virus in North America.

BACKGROUND: The updated Veterans Aging Cohort Study (VACS) Index 2.0 combines general and human immunodeficiency virus (HIV)-specific biomarkers to generate a continuous score that accurately discriminates risk of mortality in diverse cohorts of persons with HIV (PWH), but a score alone is difficult to interpret. Using data from the North American AIDS Cohort Collaboration (NA-ACCORD), we translate VACS Index 2.0 scores into validated probability estimates of mortality. METHODS: Because complete mortality ascertainment is essential for accurate calibration, we restricted analyses to cohorts with mortality from the National Death Index or equivalent sources. VACS Index 2.0 components were ascertained from October 1999 to April 2018. Mortality was observed up to March 2019. Calibration curves compared predicted (estimated by fitting a gamma model to the score) to observed mortality overall and within subgroups: cohort (VACS/NA-ACCORD subset), sex, age <50 or ≥50 years, race/ethnicity, HIV-1 RNA ≤500 or >500 copies/mL, CD4 count <350 or ≥350 cells/µL, and years 1999-2009 or 2010-2018. Because mortality rates have decreased over time, the final model was limited to 2010-2018. RESULTS: Among 37230 PWH in VACS and 8061 PWH in the NA-ACCORD subset, median age was 53 and 44 years; 3% and 19% were women; and 48% and 39% were black. Discrimination in NA-ACCORD (C-statistic = 0.842 [95% confidence interval {CI}, .830-.854]) was better than in VACS (C-statistic = 0.813 [95% CI, .809-.817]). Predicted and observed mortality largely overlapped in VACS and the NA-ACCORD subset, overall and within subgroups. CONCLUSIONS: Based on this validation, VACS Index 2.0 can reliably estimate probability of all-cause mortality, at various follow-up times, among PWH in North America.

Epidemiology of HIV in the USA: epidemic burden, inequities, contexts, and responses.

The HIV epidemic in the USA began as a bicoastal epidemic focused in large cities but, over nearly four decades, the epidemiology of HIV has changed. Public health surveillance data can inform an understanding of the evolution of the HIV epidemic in terms of the populations and geographical areas most affected. We analysed publicly available HIV surveillance data and census data to describe: current HIV prevalence and new HIV diagnoses by region, race or ethnicity, and age; trends in HIV diagnoses over time by HIV acquisition risk and age; and the distribution of HIV prevalence by geographical area. We reviewed published literature to explore the reasons for the current distribution of HIV cases and important disparities in HIV prevalence. We identified opportunities to improve public health surveillance systems and uses of data for planning and monitoring public health responses. The current US HIV epidemic is marked by geographical concentration in the US South and profound disparities between regions and by race or ethnicity. Rural areas vary in HIV prevalence; rural areas in the South are more likely to have a high HIV prevalence than rural areas in other US Census regions. Ongoing disparities in HIV in the South are probably driven by the restricted expansion of Medicaid, health-care provider shortages, low health literacy, and HIV stigma. HIV diagnoses overall declined in 2009-18, but HIV diagnoses among individuals aged 25-34 years increased during the same period. HIV diagnoses decreased for all risk groups in 2009-18; among men who have sex with men (MSM), new diagnoses decreased overall and for White MSM, remained stable for Black MSM, and increased for Hispanic or Latino MSM. Surveillance data indicate profound and ongoing disparities in HIV cases, with disproportionate impact among people in the South, racial or ethnic minorities, and MSM.

Dexamethasone in hospitalised COVID-19 patients not on intensive respiratory support.

BACKGROUND: Dexamethasone decreases mortality in coronavirus disease 2019 (COVID-19) patients on intensive respiratory support (IRS) but is of uncertain benefit if less severely ill. We determined whether early (within 48 h) dexamethasone was associated with mortality in patients hospitalised with COVID-19 not on IRS. METHODS: We included patients admitted to US Veterans Affairs hospitals between 7 June 2020 and 31 May 2021 within 14 days after a positive test for severe acute respiratory syndrome coronavirus 2. Exclusions included recent prior corticosteroids and IRS within 48 h. We used inverse probability of treatment weighting (IPTW) to balance exposed and unexposed groups, and Cox proportional hazards models to determine 90-day all-cause mortality. RESULTS: Of 19 973 total patients (95% men, median age 71 years, 27% black), 15 404 (77%) were without IRS within 48 h. Of these, 3514 out of 9450 (34%) patients on no oxygen received dexamethasone and 1042 (11%) died; 4472 out of 5954 (75%) patients on low-flow nasal cannula (NC) only received dexamethasone and 857 (14%) died. In IPTW stratified models, patients on no oxygen who received dexamethasone experienced 76% increased risk for 90-day mortality (hazard ratio (HR) 1.76, 95% CI 1.47-2.12); there was no association with mortality among patients on NC only (HR 1.08, 95% CI 0.86-1.36). CONCLUSIONS: In patients hospitalised with COVID-19, early initiation of dexamethasone was common and was associated with no mortality benefit among those on no oxygen or NC only in the first 48 h; instead, we found evidence of potential harm. These real-world findings do not support the use of early dexamethasone in hospitalised COVID-19 patients without IRS.

Prostate Cancer Screening and Incidence among Aging Persons Living with HIV.

PURPOSE: The risk of prostate cancer among persons living with human immunodeficiency virus (PWH) is not well understood and may be obscured by different opportunities for detection. MATERIALS AND METHODS: We identified 123,472 (37,819 PWH and 85,653 comparators) men enrolled in the Veterans Aging Cohort Study, a prospective national cohort of PWH and demographically matched, uninfected comparators in 2000-2015. We calculated rates of prostate specific antigen (PSA) testing by human immunodeficiency virus (HIV) status and fit multivariable Poisson models comparing the rates of PSA testing, prostate biopsy, and cancer incidence. RESULTS: The mean age at enrollment was 52 years. Rates of PSA testing were lower in PWH versus uninfected comparators (0.58 versus 0.63 tests per person-year). Adjusted rates of PSA screening and prostate biopsy were lower among PWH (incidence rate ratio [IRR] 0.87, 95% CI 0.75-0.84 and IRR 0.79 95% CI 0.74-0.83, respectively). The crude IRR for prostate cancer was lower in PWH versus controls (IRR 0.90, 95% CI 0.83-0.97). However, in a multivariable model adjusting for PSA testing, cancer incidence was similar by HIV status (IRR=0.93, 95% CI 0.86-1.01, p=0.08). Among patients who received a prostate biopsy, incidence of prostate cancer did not differ significantly by HIV status (IRR 1.06, 95% CI 0.98-1.15, p=0.15). Among incident cancers, there were significant differences in the distributions of Gleason grade (p=0.05), but not cancer stage (p=0.14) by HIV status. CONCLUSIONS: When accounting for less PSA testing among PWH, the incidence of prostate cancer was similar by HIV status. These findings suggest that less screening contributed to lower observed incidence of prostate cancer in PWH.

DNA methylation signature on phosphatidylethanol, not on self-reported alcohol consumption, predicts hazardous alcohol consumption in two distinct populations.

The process of diagnosing hazardous alcohol drinking (HAD) is based on self-reported data and is thereby vulnerable to bias. There has been an interest in developing epigenetic biomarkers for HAD that might complement clinical assessment. Because alcohol consumption has been previously linked to DNA methylation (DNAm), we aimed to select DNAm signatures in blood to predict HAD from two demographically and clinically distinct populations (Ntotal = 1,549). We first separately conducted an epigenome-wide association study (EWAS) for phosphatidylethanol (PEth), an objective measure of alcohol consumption, and for self-reported alcohol consumption in Cohort 1. We identified 83 PEth-associated CpGs, including 23 CpGs previously associated with alcohol consumption or alcohol use disorder. In contrast, no CpG reached epigenome-wide significance on self-reported alcohol consumption. Using a machine learning approach, two CpG subsets from EWAS on PEth and on self-reported alcohol consumption from Cohort 1 were separately tested for the prediction of HAD in Cohort 2. We found that a subset of 143 CpGs selected from the EWAS on PEth showed an excellent prediction of HAD with the area under the receiver operating characteristic curve (AUC) of 89.4% in training set and 73.9% in validation set of Cohort 2. However, CpGs preselected from the EWAS on self-reported alcohol consumption showed a poor prediction of HAD with AUC 75.2% in training set and 57.6% in validation set. Our results demonstrate that an objective measure for alcohol consumption is a more informative phenotype than self-reported data for revealing epigenetic mechanisms. The PEth-associated DNAm signature in blood could serve as a robust biomarker for alcohol consumption.