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Higher exposure to tenofovir (TFV) increases the risk for kidney function decline, but the impact of genetic factors on TFV exposure is largely unknown. We investigated whether single-nucleotide polymorphisms (SNPs, n=211) in 12 genes are potentially involved in TFV exposure. Participants (n=91) from the Women's Interagency HIV Study, underwent a 24 h intensive pharmacokinetic sampling of TFV after witnessed dose and TFV area under the time-concentration curves (AUCs) were calculated for each participant. SNPs were assayed using a combination of array genotyping and Sanger sequencing. Linear regression models were applied to logarithmically transformed AUC. Those SNPs that met an a priori threshold of P

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Proteinuria is associated with adverse clinical outcomes in HIV infection. Here we evaluated whether APOL1 risk alleles, previously associated with advanced kidney disease, are independently associated with proteinuria in HIV infection in a cross-sectional

Statistical approaches for estimating and drawing inference on the correlation between two biomarkers that are repeatedly assessed over time and subject to left-censoring because minimum detection levels are lacking. We propose a linear mixed-effects model and estimate the parameters with the Monte Carlo expectation maximization (MCEM) method. Inferences regarding the model parameters and the correlation between the biomarkers are performed by applying Louis's method and the delta method. Simulation studies were conducted to compare the proposed MCEM method with existing methods including the maximum likelihood estimation method, the multiple imputation method, and two widely used ad hoc approaches: replacing the censored values with the detection limit or with half of the detection limit. The results show that the performance of the MCEM with respect to relative bias and coverage probability for the 95% confidence interval is superior to the detection limit and half of the detection limit approaches and exceeds that of the multiple imputation method at medium to high levels of censoring, and the standard error estimates from the MCEM method are close to ideal. The maximum likelihood estimation method can estimate the parameters accurately; however, a nonpositive definite information matrix can occur so that the variances are not estimable. These five methods are illustrated with data from a longitudinal human immunodeficiency virus study to estimate and draw inference on the correlation between human immunodeficiency virus RNA levels measured in plasma and in cervical secretions at multiple time points. [ABSTRACT FROM AUTHOR]

Background: Human leukocyte antigen (HLA) class I and II genotype is associated with clearance of hepatitis C virus (HCV) infection, but little is known regarding its relation with HCV viral load or risk of liver disease in patients with persistent HCV infection.Methods: High-resolution HLA class I and II genotyping was conducted in a prospective cohort of 519 human immunodeficiency virus (HIV)-seropositive and 100 HIV-seronegative women with persistent HCV infection. The end points were baseline HCV viral load and 2 noninvasive indexes of liver disease, fibrosis-4 (FIB-4), and the aspartate aminotransferase to platelet ratio index (APRI), measured at baseline and prospectively.Results: DQB1*0301 was associated with low baseline HCV load (β = -.4; 95% confidence interval [CI], -.6 to -.3; P < .00001), as well as with low odds of FIB-4-defined (odds ratio [OR], .5; 95% CI, .2-.9; P = .02) and APRI-defined liver fibrosis (OR, .5; 95% CI, .3-1.0; P = .06) at baseline and/or during follow-up. Most additional associations with HCV viral load also involved HLA class II alleles. Additional associations with FIB-4 and APRI primarily involved class I alleles, for example, the relation of B*1503 with APRI-defined fibrosis had an OR of 2.0 (95% CI, 1.0-3.7; P = .04).Conclusions: HLA genotype may influence HCV viral load and risk of liver disease, including DQB1*0301, which was associated with HCV clearance in prior studies. [ABSTRACT FROM AUTHOR]

To determine prevalence and predictors of complementary and alternative medicine (CAM) use disclosure to health care providers and whether CAM use disclosure is associated with highly active antiretroviral therapy (HAART) adherence among HIV-infected women, we analyzed longitudinal data collected between October 1994 and March 2002 from HIV-infected CAM-using women enrolled in the Women's Interagency HIV Study. Repeated measures Poisson regression models were constructed to evaluate associations of selected predictors with CAM use disclosure and association between CAM use disclosure and HAART adherence. A total of 1,377 HIV-infected women reported CAM use during study follow-up and contributed a total of 4,689 CAM-using person visits. The overall prevalence of CAM use disclosure to health care providers was 36% across study visits. Women over 45 years old, with a college education, or with health insurance coverage were more likely to disclose their CAM use to health care providers, whereas women identified as non-Hispanic Black or other ethnicities were less likely to communicate their CAM usage. More health care provider visits, more CAM domains used, and higher health care satisfaction scores had significant relationships with increased levels of CAM use disclosure. Restricting analysis to use of herbal or nonherbal medications only, similar results were obtained. Compared to other CAM domains, mind-body practice had the lowest prevalence of CAM use disclosure. Additionally, CAM use disclosure was significantly associated with higher HAART adherence. From this study, we showed that a high percentage of HIV-infected women did not discuss their CAM use with health care providers. Interventions targeted towards both physicians and patients may enhance communication of CAM use, avoid potential adverse events and drug interactions, and enhance HAART adherence. [ABSTRACT FROM AUTHOR]

Background: We sought to identify factors associated with newly detected human papillomavirus (HPV) infection in a high-risk cohort of injection drug using women in Baltimore, MD.Methods: We studied 146 HIV-infected and 73 HIV-uninfected female participants in a 5-year prospective HIV natural history study. We examined the association of sexual and nonsexual risk factors and newly detected type-specific HPV infection as determined by consensus PCR between consecutive visits.Results: Newly detected HPV was more common among HIV-infected versus HIV-uninfected women (30% and 6%, respectively; P <0.01). Among the entire cohort, recent crack use (OR, 1.7; 95% CI, 1.1-2.6) and HIV infection/CD4 cell count were independent predictors for new HPV detection (HIV-uninfected as reference, OR, 4.6; 95% CI, 2.3-8.9, OR, 5.4; 95% CI, 2.8-10.3, and OR, 10.9; 95% CI, 5.5-21.7 for HIV-infected CD4 >500, 200-500, and <200, respectively). Among HIV-uninfected women, recent marijuana use was an independent predictor of newly detected HPV infection (OR, 3.5; 95% CI, 1.3-9.5).Conclusions: Newly detected HPV clearly increased with greater immunosuppression in HIV-infected injection drug users. Larger studies of HIV-uninfected and infected high-risk individuals are needed to clarify the independent associations of crack and marijuana use with new (or reactivated) HPV infection. [ABSTRACT FROM AUTHOR]

PURPOSE: To evaluate the association of sexual behavior and recreational drug exposures with T-cell homeostasis failure (TCHF), which corresponds to the onset of a rapid decline in an individual's T lymphocyte count, which occurs on average approximately 1.75 years prior to an initial diagnosis of acquired immunodeficiency syndrome (AIDS). METHODS: A case-crossover design and a case-time-control design, both nested within the Multicenter AIDS Cohort Study of 4954 homosexual and bisexual men initiated in 1983. RESULTS: In the case-crossover analysis, use of both recreational drugs and hashish were found to be protective against TCHF (odds ratios < or = 0.41), based on comparisons with four earlier control periods. However, a significant decreasing trend in the prevalence of these exposures was observed over time, thus motivating the implementation of the case-time-control design. Using the latter approach, the associations of drug use (odds ratio=0.53; 95% confidence interval (CI): 0.22, 1.28) and hashish use (odds ratio=0.46; 95% CI: 0.20, 1.05) with TCHF were no longer statistically significant. CONCLUSIONS: The difference in inferences between these approaches demonstrates the importance of evaluating temporal trends in exposures when using a case-crossover design. [ABSTRACT FROM AUTHOR]

Background: The prognostic value of CD4+ cell counts and HIV-1 RNA levels attained after the initiation of highly active antiretroviral therapy (HAART) compared with before the initiation of HAART has not been well defined.Objective: To determine the prognostic value for clinical outcomes of CD4+ cell counts and HIV-1 RNA levels attained after initiating therapy.Design: Prospective cohort study.Setting: Women's Interagency HIV Study.Patients: 1132 participants in the Women's Interagency HIV Study.Measurements: HIV-1 RNA level, CD+ cell counts, AIDS-defining illness, and death.Results: In multivariate analyses with a median follow-up of 3.9 years, women with CD4+ cell counts of less than 0.200 x 10(9) cells/L compared with women with CD4+ cell counts of greater than 0.350 x 10(9) cells/L after HAART initiation had a relative hazard of death from all causes of 2.66 (95% CI, 1.42 to 4.99) and a relative hazard of death from AIDS of 47.61 (CI, 5.69 to 398.40). The relative hazard of all-cause death was 3.44 (CI, 1.67 to 7.09) in women with RNA levels of more than 10 000 copies/mL compared with women with attained RNA levels of less than 80 copies/mL. The relative hazard of AIDS-related or all-cause death did not increase for women with post-HAART CD4+ cell counts between 0.200 and 0.350 x 10(9) cells/L compared with women with CD4+ cell counts of greater than 0.350 x 10(9) cells/L. Also, the relative hazard did not increase in women with post-HAART HIV-1 RNA levels between 80 and 10 000 copies/mL compared with women with post-HAART HIV-1 RNA levels of less than 80 copies/mL. Of the laboratory markers, only the post-HAART CD4+ cell count and HIV-1 RNA level were predictive of new AIDS-defining illness.Conclusion: Post-HAART laboratory markers predicted death and new AIDS-defining illness. Pre-HAART CD4+ cell count and HIV-1 RNA level were not predictive of clinical outcomes if adjusted for values attained after HAART initiation, suggesting that even advanced immune suppression can be overcome with HAART that results in CD4+ cell counts of greater than 0.200 x 10(9) cells/L and RNA levels of less than 10 000 copies/mL. [ABSTRACT FROM AUTHOR]

Study objective: To describe the impact of highly active antiretroviral therapy (HAART) on mortality, morbidity, and markers of HIV disease progression in HIV infected women.Design: Data collected from the Women's Interagency HIV Study, a prospective cohort study that enrolled women between October 1994 and November 1995.Setting: Six clinical consortia based in five cities in the United States (New York, NY; Washington, DC; Los Angeles, CA; San Francisco, CA; and Chicago, IL).Participants: A total of 1691 HIV seropositive women with a study visit after April 1996.Main results: Beginning in April 1996, the self reported use of HAART increased over time, with more than 50% of the cohort reporting HAART use in 1999. There was a 23% decline per semester in the incidence of AIDS from April 1996 (95% confidence intervals (CI) -29% to -16%). Furthermore, there was a 21% decline of the semiannual mortality rates among those with AIDS at baseline (95% CI -27% to -14%) and an 11% decline among those AIDS free at baseline (95% CI -3% to -18%). CD4+ lymphocyte counts either increased (women with baseline AIDS) or stabilised (women without baseline AIDS) after April 1996, and HIV RNA levels dramatically declined in both groups, although the percentage of women with HIV RNA above 4000 cps/ml remained stable at approximately 40% since mid-1997.Conclusions: Despite concerns regarding the use of antiretroviral therapies in this population, the use of therapies led to improved immunological function, suppressed HIV disease activity, and dramatic declines in morbidity and mortality. [ABSTRACT FROM AUTHOR]

HIV seropositive women are subject to physical and sexual violence over the course of time. Of interest in this paper is (a) whether recent experience of violence predicts STD incidence among HIV-positive women and (b) whether risky sexual behavior and depression mediate such a relation. Results indicated both forced sexual contact and experience of physical violence predicted STD, incidence, number of partners, and depression. Number of partners mediated the relation between physical violence and STD incidence, although only a distinct minority of both abused (7.7%) and nonabused (3.9%) women had incident STDs. Also noteworthy was that women appeared generally able to alleviate conditions of abuse across visits. The pattern of results suggests that HIV caregivers should attend to violence issues among HIV-positive women and the interaction of violence and risky sexual behavior, as well as actual sexual behaviors. [ABSTRACT FROM AUTHOR]

Objective: To estimate the cumulative incidence of self-reported influenza vaccination ("vaccination coverage") and investigate predictors in HIV-infected women.Methods: In an ongoing cohort study of HIV-infected women in five US cities, data from two influenza seasons (2006-2007 n=1209 and 2007-2008 n=1161) were used to estimate crude and adjusted prevalence ratios (aPR) and 95% confidence intervals ([,]) from Poisson regression with robust variance models using generalized estimating equations (GEE).Results: In our study, 55% and 57% of HIV-infected women reported vaccination during the 2006-2007 and 2007-2008 seasons, respectively. Using data from both seasons, older age, non-smoking status, CD4 T-lymphocyte (CD4) count > or =200 cells/mm(3), and reporting at least one recent healthcare visit was associated with increased vaccination coverage. In the 2007-2008 season, a belief in the protection of the vaccine (aPR=1.38 [1.18, 1.61]) and influenza vaccination in the previous season (aPR=1.66 [1.44, 1.91]) most strongly predicted vaccination status.Conclusion: Interventions to reach unvaccinated HIV-infected women should focus on changing beliefs about the effectiveness of influenza vaccination and target younger women, current smokers, those without recent healthcare visits, or a CD4 count <200 cells/mm(3). [ABSTRACT FROM AUTHOR]

HIV care continuum outcome disparities by health insurance status have been noted among people with HIV (PWH). We therefore examined associations between state Medicaid expansion and HIV outcomes in the United States. Adults (≥18 years) with ≥1 visit in NA-ACCORD clinical cohorts from 2012-2017 contributed person-time annually between first and final visit or death; in each calendar year, clinical retention was ≥2 completed visits > 90 days apart, antiretroviral therapy (ART) receipt was receipt of ≥3 antiretroviral agents, and viral suppression was last measured HIV-1 RNA < 200 copies/mL. CD4 at enrollment was obtained within 6 months of enrollment in cohort. Difference-in-difference (DID) models quantified associations between Medicaid expansion changes (by state of residence) and HIV outcomes. Across 50 states, 87 290 PWH contributed 325 113 person-years of follow-up. Medicaid expansion had a substantial positive effect on CD4 at enrollment (DID = 93.5, 95% CI: 52.9, 134 cells/mm 3 ), a small negative effect on proportions clinically retained (DID = -0.19, 95% CI: -0.037, -0.01), and no effects on ART receipt (DID = 0.001, 95% CI: -0.003, 0.005) or viral suppression (DID = -0.14, 95% CI: -0.34, 0.07). Medicaid expansion had a positive effect on CD4 at entry, suggesting more timely HIV testing and care linkage, but generally null effects on downstream HIV care continuum measures., Competing Interests: Conflicts of interest Please see ICMJE form(s) for author conflicts of interest. These have been provided as supplementary materials. K.N.A. reports service on the scientific review board for TrioHealth, Inc. and consultancy with the All of Us Research Program. P.F.R. reports consulting fees for advising on HIV care continuum and cardiometabolic outcome analyses from Gilead & Janssen. All other authors report no potential COIs., (© The Author(s) 2024. Published by Oxford University Press on behalf of Project HOPE - The People-To-People Health Foundation, Inc.)

Objectives: Timely control of hypertension is vital to prevent comorbidities. We evaluated the association of race/ethnicity and HIV infection with incident hypertension outcomes, including awareness, treatment, and control., Design: We evaluated cisgender women living with HIV and sociodemographically matched women living without HIV recruited into four Southern sites of the Women's Interagency HIV Study (WIHS) (2013-2019)., Methods: We calculated measurements of the time to four events or censoring: incident hypertension, hypertension awareness, hypertension treatment, and hypertension control. Hazard ratios for race/ethnicity and HIV status were calculated for each outcome using Cox proportional-hazards models adjusted for sociodemographic, behavioral, and clinical risk factors., Results: Among 712 women, 56% were hypertensive at baseline. Forty-five percentage of the remaining women who were normotensive at baseline developed incident hypertension during follow-up. Non-Hispanic white and Hispanic women had faster time to hypertension control compared with non-Hispanic black women ( P  = 0.01). In fully adjusted models, women living with HIV who were normotensive at baseline had faster time to treatment compared with normotensive women living without HIV ( P  = 0.04)., Conclusion: In our study of women in the US South, non-Hispanic black women became aware of their hypertension diagnosis more quickly than non-Hispanic white and Hispanic women but were slower to control their hypertension. Additionally, women living with HIV more quickly treated and controlled their hypertension compared with women living without HIV., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: HIV and hepatitis C virus (HCV) are associated with increased risk of carotid artery atherosclerotic plaque and stroke. We examined associations of HIV- and HCV-related factors with echomorphologic features of carotid artery plaque., Methods: This cross-sectional study included participants from the MACS (Multicenter AIDS Cohort Study)/WIHS (Women's Interagency HIV Study) Combined Cohort Study who underwent high-resolution B-mode carotid artery ultrasound. Plaques were characterized from 6 areas of the right carotid artery. Poisson regression controlling for demographic and cardiometabolic risk factors determined adjusted prevalence ratios (aPRs) and 95% CIs for associations of HIV- and HCV-related factors with echomorphologic features., Results: Of 2655 participants (65% women, median age 44 [interquartile range, 37-50] years), 1845 (70%) were living with HIV, 600 (23%) were living with HCV, and 425 (16%) had carotid plaque. There were 191 plaques identified in 129 (11%) women with HIV, 51 plaques in 32 (7%) women without HIV, 248 plaques in 171 (28%) men with HIV, and 139 plaques in 93 (29%) men without HIV. Adjusted analyses showed that people with HIV and current CD4 + count <200 cells/µL had a significantly higher prevalence of predominantly echolucent plaque (aPR, 1.86 [95% CI, 1.08-3.21]) than those without HIV. HCV infection alone (aPR, 1.86 [95% CI, 1.08-3.19]) and HIV-HCV coinfection (aPR, 1.75 [95% CI, 1.10-2.78]) were each associated with higher prevalence of predominantly echogenic plaque. HIV-HCV coinfection was also associated with higher prevalence of smooth surface plaque (aPR, 2.75 [95% CI, 1.03-7.32]) compared with people without HIV and HCV., Conclusions: HIV with poor immunologic control, as well as HCV infection, either alone or in the presence of HIV, were associated with different echomorphologic phenotypes of carotid artery plaque., Competing Interests: Disclosures Dr Rodriguez reports compensation from Merck and Pfizer for other services; reports grants from Amgen, National Heart, Lung, and Blood Institute, and American Heart Association. Dr Tien reports intellectual property; grants from Merck and Gilead Sciences. Dr Palella reports compensation from Janssen Pharmaceuticals, Gilead Sciences, and ViiV Healthcare Company for other services. The other authors report no conflicts.

Background: Hypertension-related diseases are major causes of morbidity among women living with HIV. We evaluated cross-sectional associations of race/ethnicity and HIV infection with hypertension prevalence, awareness, treatment, and control., Methods: Among women recruited into Southern sites of the Women's Interagency HIV Study (2013-2015), hypertension was defined as (1) systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg according to clinical guidelines when data were collected, (2) self-report of hypertension, or (3) use of antihypertensive medication. Awareness was defined as self-report of hypertension, and treatment was self-report of any antihypertensive medication use. Blood pressure control was defined as <140/90 mm Hg at baseline. Prevalence ratios for each hypertension outcome were estimated through Poisson regression models with robust variance estimators adjusted for sociodemographic, behavioral, and clinical risk factors., Results: Among 712 women, 56% had hypertension and 83% were aware of their diagnosis. Of those aware, 83% were using antihypertensive medication, and 63% of those treated had controlled hypertension. In adjusted analyses, non-Hispanic White and Hispanic women had 31% and 48% lower prevalence of hypertension than non-Hispanic Black women, respectively. Women living with HIV who had hypertension were 19% ( P = .04) more likely to be taking antihypertension medication when compared with women living without HIV., Conclusions: In this study population of women living with and without HIV in the US South, the prevalence of hypertension was lowest among Hispanic women and highest among non-Hispanic Black women. Despite similar hypertension prevalence, women living with HIV were more likely to be taking antihypertensive medication when compared with women living without HIV., Competing Interests: Potential conflicts of interest. E. B. L. receives research funding from Amgen unrelated to the current work. All other authors report no potential conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Prior studies have found that human immunodeficiency virus (HIV) infection is associated with impaired lung function and increased risk of chronic lung disease, but few have included large numbers of women. In this study, we investigate whether HIV infection is associated with differences in lung function in women., Methods: This was a cross-sectional analysis of participants in the Women's Interagency HIV Study, a racially and ethnically diverse multicenter cohort of women with and without HIV. In 2018-2019, participants at 9 clinical sites were invited to perform spirometry. Single-breath diffusing capacity for carbon monoxide (DLCO) was also measured at selected sites. The primary outcomes were the post-bronchodilator forced expiratory volume in 1 second (FEV1) and DLCO. Multivariable regression modeling was used to analyze the association of HIV infection and lung function outcomes after adjustment for confounding exposures., Results: FEV1 measurements from 1489 women (1062 with HIV, 427 without HIV) and DLCO measurements from 671 women (463 with HIV, 208 without HIV) met standards for quality and reproducibility. There was no significant difference in FEV1 between women with and without HIV. Women with HIV had lower DLCO measurements (adjusted difference, -0.73 mL/min/mm Hg; 95% confidence interval, -1.33 to -.14). Among women with HIV, lower nadir CD4 + cell counts and hepatitis C virus infection were associated with lower DLCO measurements., Conclusions: HIV was associated with impaired respiratory gas exchange in women. Among women with HIV, lower nadir CD4 + cell counts and hepatitis C infection were associated with decreased respiratory gas exchange., Competing Interests: Potential conflicts of interest . K. M. K. reports consulting fees from Allergan, personal fees for co-chairing a drug safety monitoring board from Nuvaira, and unpaid leadership roles for the American Thoracic Society planning and programming committees. P. C. T. reports grants from Merck, Gilead, and Eli Lilly and royalties from UpToDate. S. P. B. reports consulting fees from Boehringer Ingelheim, Sanofi, Regeneron, and Sunovion; royalties from Springer Humana; honoraria from GlaxoSmithKline; and stock or stock options from Vigor Medical Systems. H. B. reports grants from ViiV Healthcare Limited. M. N. reports grants or contracts from NHLBI/NIH outside of the submitted work. K. A. reports support for attending meetings and/or travel from NIH grants paid to their institution. D. L. reports support for the present article for interpretation of pulmonary function test results. A. M. reports grants or contracts from the NIH outside of the submitted work. 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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

Objective: Alterations in glucocorticoid receptor (GCR) function may be a risk factor for cognitive complications among older people with human immunodeficiency virus (HIV). We evaluated whether HIV serostatus and age modify the GCR function-cognition association among women., Methods: Eighty women with HIV ( n = 40, <40 years of age [younger]; n = 40, >50 years of age [older]) and 80 HIV-uninfected women ( n = 40 older, n = 40 younger) enrolled in the Women's Interagency HIV Study completed a comprehensive neuropsychological test battery. Peripheral blood mononuclear cells collected concurrent with neuropsychological testing were assessed for GCR function. Multivariable linear regression analyses were conducted to examine whether a) HIV serostatus and age were associated with GCR function, and b) GCR function-cognition associations are moderated by HIV serostatus and age adjusting for relevant covariates., Results: Among older women, higher baseline FKBP5 expression level was associated with lower attention/working memory performance among women with HIV ( B = 6.4, standard error = 1.7, p = .0003) but not in women without HIV infection ( B = -1.7, standard error = 1.9, p = .37). There were no significant HIV serostatus by age interactions on dexamethasone (DEX)-stimulated expression of the genes regulated by the GCR or lipopolysaccharide-stimulated tumor necrosis factor α levels (with or without DEX stimulation; p values > .13). HIV serostatus was associated with GC target genes PER1 ( p = .006) and DUSP1 ( p = .02), but not TSC22D3 ( p = .32), after DEX stimulation., Conclusions: Collectively, these data suggest that HIV serostatus and age may modify the influence of the GCR, such that the receptor is likely engaged to a similar extent, but the downstream influence of the receptor is altered, potentially through epigenetic modification of target genes., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Psychosomatic Society.)

Neuropsychiatric complications are common among women with HIV (WWH). The pathophysiological mechanisms underlying these complications are not fully known but likely driven in part by immune modulation. We examined associations between T-cell activation states which are required to mount an effective immune response (activation, co-stimulation/normal function, exhaustion, senescence) and neuropsychiatric complications in WWH. 369 WWH (78% HIV RNA undetectable/<20cp/mL) enrolled in the Women's Interagency HIV Study completed neuropsychological testing and measures of depression (Center for Epidemiological Studies Depression Scale-CES-D), self-reported stress levels (Perceived Stress Scale-10), and post-traumatic stress (PTSD Checklist-Civilian Scale). Multiparametric flow cytometry evaluated T-cell activation state. Partial least squares regressions were used to examine T-cell phenotypes and neuropsychiatric outcome associations after confounder adjustment. In the total sample and among virally suppressed (VS)-WWH, CD4 + T-cell exhaustion was associated with poorer learning and attention/working memory ( P 's < 0.05). In the total sample, CD4 + T-cell activation was associated with better attention/working memory and CD8 + T-cell co-stimulation and senescence was associated with poorer executive function ( P 's < 0.05). For mental health outcomes, in the total sample, CD4 + T-cell activation was associated with more perceived stress and CD4 + T-cell exhaustion was associated with less depressive symptoms ( P 's < 0.05). Among VS-WWH, CD4 + senescence was associated with less perceive stress and CD8 + T-cell co-stimulation and senescence was associated with higher depression ( P's  < 0.05). Together, results suggest the contribution of peripheral CD4 + and CD8 + T-cell activation status to neuropsychiatric complications in WWH., Competing Interests: LHR is a consultant for Digital Artefacts, Inc. All coauthors have nothing to disclose., (© 2022 The Authors. Published by Elsevier Inc.)

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., Competing Interests: Potential conflicts of interest. K. N. A. reports receiving fees as a consultant from the All of Us Research Program (NIH) and received fees as a scientific advisory board member from Trio Health. M. K. reports grants or contracts from Gilead Sciences and ViiV Healthcare outside the submitted work; payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from ViiV Healthcare for Medscape, APLA Health for DKBMed, and SAGE; and a leadership or fiduciary role for Being Alive San Diego. H. M. C. reports grants or contracts from AHRQ and ViiV paid to her institution outside the submitted work, and participation on the NIH Office of AIDS Research Advisory Board. M. J. S. reports a past grant paid to his institution from Gilead Sciences outside the submitted work. V. D. L. has received a grant from the CIHR, unrelated to this work. 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 for the Infectious Diseases Society of America 2021.)

Atherosclerosis is accompanied by a CD4 T cell response to apolipoprotein B (APOB). Major Histocompatibility Complex (MHC)-II tetramers can be used to isolate antigen-specific CD4 T cells by flow sorting. Here, we produce, validate and use an MHC-II tetramer, DRB1*07:01 APOB-p18, to sort APOB-p18-specific cells from peripheral blood mononuclear cell samples from 8 DRB1*07:01+ women with and without subclinical cardiovascular disease (sCVD). Single cell RNA sequencing showed that transcriptomes of tetramer+ cells were between regulatory and memory T cells in healthy women and moved closer to memory T cells in women with sCVD. TCR sequencing of tetramer+ cells showed clonal expansion and V and J segment usage similar to those found in regulatory T cells. These findings suggest that APOB-specific regulatory T cells may switch to a more memory-like phenotype in women with atherosclerosis. Mouse studies showed that such switched cells promote atherosclerosis., Competing Interests: DISCLOSURES There are no conflicts of interest.

Background: Maps are potent tools for describing the spatial distribution of population and disease characteristics and, thereby, for appropriately targeting public health interventions. People with HIV (PWH) tend to live in densely populated and spatially compact areas that may be difficult to visualize on maps using unadjusted geographic or political borders., Setting: To illustrate these challenges, we used geographic data from adult PWH at the Vanderbilt Comprehensive Care Clinic (VCCC) in Nashville, Tennessee, and aggregated data from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) from 1998 to 2015., Methods: We compared choropleth maps that use differential shading of political/geographic boundaries with density-adjusted cartograms that allow for shading and deformed boundaries according to a variable of interest, such as PWH., Results: Cartograms enlarged high-burden areas and shrank low-burden areas of PWH, improving visual interpretation of where to focus HIV prevention and mitigation efforts, when compared with choropleth maps. Cartograms may also demonstrate cohort representativeness of underlying populations (eg, Tennessee for VCCC or the United States for NA-ACCORD), which can guide efforts to assess external validity and improve generalizability., Conclusion: Choropleth maps and cartograms offer powerful visual evidence of the geographic distribution of HIV disease and cohort representation and should be used to guide targeted public health interventions., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Syphilis rates among women in the USA more than doubled between 2014 and 2018. We sought to identify correlates of syphilis among women enrolled in the Women's Interagency HIV Study (WIHS) to inform targeted interventions., Methods: The retrospective cross-sectional analysis of secondary data included women with HIV or at-risk of HIV who enrolled in the multisite US WIHS cohort between 1994 and 2015. Syphilis screening was performed at baseline. Infection was defined serologically by a positive rapid plasma reagin test with confirmatory treponemal antibodies. Sociodemographic and behavioural characteristics stratified by baseline syphilis status were compared for women enrolled during early (1994-2002) and recent (2011-2015) years. Multivariable binomial modelling with backward selection (p>0.2 for removal) was used to model correlates of syphilis., Results: The study included 3692 women in the early cohort and 1182 women in the recent cohort. Syphilis prevalence at enrolment was 7.5% and 3.7% in each cohort, respectively (p<0.01). In adjusted models for the early cohort, factors associated with syphilis included age, black race, low income, hepatitis C seropositivity, drug use, HIV infection and >100 lifetime sex partners (all p<0.05). In the recent cohort, age (adjusted prevalence OR (aPOR) 0.2, 95% CI 0.1 to 0.6 for 30-39 years; aPOR 0.5, 95% CI 0.2 to 1.0 for 40-49 years vs ≥50 years), hepatitis C seropositivity (aPOR 2.1, 95% CI 1.0 to 4.1) and problem alcohol use (aPOR 2.2, 95% CI 1.1 to 4.4) were associated with infection., Conclusions: Syphilis screening is critical for women with HIV and at-risk of HIV. Targeted prevention efforts should focus on women with hepatitis C and problem alcohol use., Competing Interests: Competing interests: Dr. Van Der Pol receives research support, consulting fees and/or honorarium from the following: Abbott Molecular, BD Diagnostics, Binx Health, BioFire Diagnostics, Hologic, Rheonix, Roche and SpeeDx; Dr. Marrazzo receives research support and/or consulting fees from BD Diagnostics, Gilead, and BioFire Diagnostics. Dr. Adimora has received research funding from Gilead and consulting fees from Merck, Viiv, and Gilead. Dr. Sheth has received research grants from Gilead sciences unrelated to the published work. As a group, we have no other conflicts of interest to report., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: People with HIV (PWH) experience greater declines in both muscle function and muscle mass with aging. Whether changes in muscle quality and quantity with aging differ between men and women with HIV and the implications on muscle function are not established., Design: In coordinated substudies of the Multicenter AIDS Cohort Study and Women's Interagency HIV Study, participants completed physical function and falls assessments; total trunk/thigh density, inversely related to fatty infiltration, and area were quantified from computed tomography (CT) scans., Methods: Generalized linear models were used to explore variables affecting density/area, and associations between area/density and physical function and falls., Results: CT scans were available on 387 men (198 PWH) and 184 women (118 PWH). HIV serostatus was associated with greater lateralis, paraspinal, and hamstring area, but lower psoas area and density. Older age and female sex were associated with smaller trunk muscle area and lower density. Both lower muscle area and muscle density were associated with several measures of impaired physical function. The odds of falling were lower with greater hamstring density, but not associated with other measurers of muscle area or density., Conclusions: In summary, older adults with HIV appear to have smaller and less dense (fattier) psoas, a key component in truncal stability and hip flexion that could have implications on physical function. The longitudinal associations of muscle area and density with physical function require careful investigation, with a particular focus on characteristics and interventions that can preserve muscle area, density, and function over time., Competing Interests: KME has received research grant support from Gilead and has served as a consultant to ViiV and Merck,all paid to her institution. PCT has received research grant support from Merck that was paid to her institution. FJP has been a consultant and/or on the speakers’ bureau for Gilead, Janssen, ViiV and Merck. AS has received funding from Gilead Sciences, Inc. TTB has served as a consultant to ViiV Healthcare, Merck, Gilead, Janssen, and Theratechnologies.

Background: Data on the prevalence and correlates of restless legs syndrome (RLS) in people with HIV are limited. This study sought to determine the prevalence of RLS, associated clinical correlates, and characterize sleep-related differences in men with and without HIV., Methods: Sleep-related data were collected in men who have sex with men participating in the Multicenter AIDS Cohort Study (MACS). Demographic, health behaviors, HIV status, comorbidities, and serological data were obtained from the MACS visit coinciding with sleep assessments. Participants completed questionnaires, home polysomnography, and wrist actigraphy. RLS status was determined with the Cambridge-Hopkins RLS questionnaire. RLS prevalence was compared in men with and without HIV. Multinomial logistic regression was used to examine correlates of RLS among all participants and men with HIV alone. Sleep-related differences were examined in men with and without HIV by RLS status., Results: The sample consisted of 942 men (56% HIV+; mean age 57 years; 69% white). The prevalence of definite RLS was comparable in men with and without HIV (9.1% vs 8.7%). In multinomial regression, HIV status was not associated with RLS prevalence. However, white race, anemia, depression, and antidepressant use were each independently associated with RLS. HIV disease duration was also associated with RLS. Men with HIV and RLS reported poorer sleep quality, greater sleepiness, and had worse objective sleep efficiency/fragmentation than men without HIV/RLS., Conclusions: The prevalence of RLS in men with and without HIV was similar. Screening for RLS may be considered among people with HIV with insomnia and with long-standing disease., Competing Interests: The authors have declared that no competing interests exist.

Background: Persistent inflammation in HIV infection is associated with elevated cardiovascular disease (CVD) risk, even with viral suppression. Identification of novel surrogate biomarkers can enhance CVD risk stratification and suggest novel therapies. We investigated the potential of interleukin 32 (IL-32), a proinflammatory multi-isoform cytokine, as a biomarker for subclinical carotid artery atherosclerosis in virologically suppressed women living with HIV (WLWH)., Methods and Results: Nested within the Women's Interagency HIV Study, we conducted a cross-sectional comparison of IL-32 between 399 WLWH and 100 women without HIV, followed by a case-control study of 72 WLWH (36 carotid artery plaque cases vs. 36 age-matched controls without plaque). Plasma IL-32 protein was measured by ELISA, and mRNA of IL-32 isoforms (IL-32α, β, γ, D, ε, and θ) was quantified by reverse transcription polymerase chain reaction from peripheral blood mononuclear cells. Plasma IL-32 protein levels were higher in WLWH compared with women without HIV (P = 0.02). Among WLWH, although plasma IL-32 levels did not differ significantly between plaque cases and controls, expression of IL-32 isoforms α, β, and ε mRNA was significantly higher in peripheral blood mononuclear cells from cases (P = 0.01, P = 0.005, and P = 0.018, respectively). Upregulation of IL-32β and IL-32ε among WLWH with carotid artery plaque persisted after adjustment for age, race/ethnicity, smoking, systolic blood pressure, body mass index, and history of hepatitis C virus (P = 0.04 and P = 0.045); the adjusted association for IL-32α was marginally significant (P = 0.07)., Conclusions: IL-32 isoforms should be studied further as potential CVD biomarkers. This is of particular interest in WLWH by virtue of altered IL-32 levels in this population., Competing Interests: J.R.K. has stock ownership in Bristol-Myers Squibb, Johnson & Johnson, Medtronic, Merck, and Pfizer. The remaining authors have no conflicts of interest to disclose., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Persons living with human immunodeficiency virus (HIV; PLWH) experience a high burden of cancer. It remains unknown which cancer types are reduced in PLWH with earlier initiation of antiretroviral therapy (ART)., Methods: We evaluated AIDS-free, ART-naive PLWH during 1996-2014 from 22 cohorts participating in the North American AIDS Cohort Collaboration on Research and Design. PLWH were followed from first observed CD4 of 350-500 cells/µL (baseline) until incident cancer, death, lost-to-follow-up, or December 2014. Outcomes included 6 cancer groups and 5 individual cancers that were confirmed by chart review or cancer registry linkage. We evaluated the effect of earlier (in the first 6 months after baseline) versus deferred ART initiation on cancer risk. Marginal structural models were used with inverse probability weighting to account for time-dependent confounding and informative right-censoring, with weights informed by subject's age, sex, cohort, baseline year, race/ethnicity, HIV transmission risk, smoking, viral hepatitis, CD4, and AIDS diagnoses., Results: Protective results for earlier ART were found for any cancer (adjusted hazard ratio [HR] 0.57; 95% confidence interval [CI], .37-.86), AIDS-defining cancers (HR 0.23; 95% CI, .11-.49), any virus-related cancer (HR 0.30; 95% CI, .16-.54), Kaposi sarcoma (HR 0.25; 95% CI, .10-.61), and non-Hodgkin lymphoma (HR 0.22; 95% CI, .06-.73). By 15 years, there was also an observed reduced risk with earlier ART for virus-related NADCs (0.6% vs 2.3%; adjusted risk difference -1.6; 95% CI, -2.8, -.5)., Conclusions: Earlier ART initiation has potential to reduce the burden of virus-related cancers in PLWH but not non-AIDS-defining cancers (NADCs) without known or suspected viral etiology., (© 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.)

Despite the success of antiretroviral therapy (ART), people living with HIV (PLWH) are still at higher risk for cardiovascular diseases (CVDs) that are mediated by chronic inflammation. Identification of novel inflammatory mediators with the inherent potential to be used as CVD biomarkers and also as therapeutic targets is critically needed for better risk stratification and disease management in PLWH. Here, we investigated the expression and potential role of the multi-isoform proinflammatory cytokine IL-32 in subclinical atherosclerosis in PLWH (n=49 with subclinical atherosclerosis and n=30 without) and HIV- controls (n=25 with subclinical atherosclerosis and n=24 without). While expression of all tested IL-32 isoforms (α, β, γ, D, ϵ, and θ) was significantly higher in peripheral blood from PLWH compared to HIV- controls, IL-32D and IL-32θ isoforms were further upregulated in HIV+ individuals with coronary artery atherosclerosis compared to their counterparts without. Upregulation of these two isoforms was associated with increased plasma levels of IL-18 and IL-1β and downregulation of the atheroprotective protein TRAIL, which together composed a unique atherosclerotic inflammatory signature specific for PLWH compared to HIV- controls. Logistic regression analysis demonstrated that modulation of these inflammatory variables was independent of age, smoking, and statin treatment. Furthermore, our in vitro functional data linked IL-32 to macrophage activation and production of IL-18 and downregulation of TRAIL, a mechanism previously shown to be associated with impaired cholesterol metabolism and atherosclerosis. Finally, increased expression of IL-32 isoforms in PLWH with subclinical atherosclerosis was associated with altered gut microbiome (increased pathogenic bacteria; Rothia and Eggerthella species) and lower abundance of the gut metabolite short-chain fatty acid (SCFA) caproic acid, measured in fecal samples from the study participants. Importantly, caproic acid diminished the production of IL-32, IL-18, and IL-1β in human PBMCs in response to bacterial LPS stimulation. In conclusion, our studies identified an HIV-specific atherosclerotic inflammatory signature including specific IL-32 isoforms, which is regulated by the SCFA caproic acid and that may lead to new potential therapies to prevent CVD in ART-treated PLWH., Competing Interests: JK has stock ownership in Bristol-Myers Squibb, Johnson & Johnson, Medtronic, Merck and Pfizer. J-PG was employed by the company Caprion Inc. (now CellCarta). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 El-Far, Durand, Turcotte, Larouche-Anctil, Sylla, Zaidan, Chartrand-Lefebvre, Bunet, Ramani, Sadouni, Boldeanu, Chamberland, Lesage, Baril, Trottier, Thomas, Gonzalez, Filali-Mouhim, Goulet, Martinson, Kassaye, Karim, Kizer, French, Gange, Ancuta, Routy, Hanna, Kaplan, Chomont, Landay and Tremblay.)

HIV coinfection is associated with more rapid liver fibrosis progression in hepatitis C (HCV) infection. Recently, much work has been done to improve outcomes of liver disease and to identify targets for pharmacological intervention in coinfected patients. In this study, we analyzed clinical data of 1,858 participants from the Women's Interagency HIV Study (WIHS) to characterize risk factors associated with changes in the APRI and FIB-4 surrogate measurements for advanced fibrosis. We assessed 887 non-synonymous single nucleotide variants (nsSNV) in a subset of 661 coinfected participants for genetic associations with changes in liver fibrosis risk. The variants utilized produced amino acid substitutions that either altered an N-linked glycosylation (NxS/T) sequon or mapped to a gene related to glycosylation processes. Seven variants were associated with an increased likelihood of liver fibrosis. The most common variant, ALPK2 rs3809973, was associated with liver fibrosis in HIV/HCV coinfected patients; individuals homozygous for the rare C allele displayed elevated APRI (0.61, 95% CI, 0.334 to 0.875) and FIB-4 (0.74, 95% CI, 0.336 to 1.144) relative to those coinfected women without the variant. Although warranting replication, ALPK2 rs3809973 may show utility to detect individuals at increased risk for liver disease progression., Competing Interests: The authors of this manuscript have the following competing interests: National Heart, Lung, and Blood Institute (NHLBI; https://www.nhlbi.nih.gov) provided grant support to the following co-authors: U01- HL146242 (BEA, JCP); U01-HL146205 (SGK); U01-HL146202 (MHA); U01-HL146245 (ALF); U01-HL146193 (SJG); and U01-HL146204 (KMA). This does not alter our adherence to PLOS ONE policies on sharing data and materials. The ethical and legal restrictions to the sharing of the data utilized in this manuscript, as well as the steps necessary to obtain the data are detailed in Data Availability Section.

Introduction: Weight gain following antiretroviral therapy (ART) initiation is common, potentially predisposing some persons with HIV (PWH) to cardio-metabolic disease. We assessed relationships between ART drug class and weight change among treatment-naïve PWH initiating ART in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD)., Methods: Adult, treatment-naïve PWH in NA-ACCORD initiating integrase strand transfer inhibitor (INSTI), protease inhibitor (PI) or non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based ART on/after 1 January 2007 were followed through 31 December 2016. Multivariate linear mixed effects models estimated weight up to five years after ART initiation, adjusting for age, sex, race, cohort site, HIV acquisition mode, treatment year, and baseline weight, plasma HIV-1 RNA level and CD4 + cell count. Due to shorter follow-up for PWH receiving newer INSTI drugs, weights for specific INSTIs were estimated at two years. Secondary analyses using logistic regression and all covariates from primary analyses assessed factors associated with >10% weight gain at two and five years., Results: Among 22,972 participants, 87% were male, and 41% were white. 49% started NNRTI-, 31% started PI- and 20% started INSTI-based regimens (1624 raltegravir (RAL), 2085 elvitegravir (EVG) and 929 dolutegravir (DTG)). PWH starting INSTI-based regimens had mean estimated five-year weight change of +5.9kg, compared to +3.7kg for NNRTI and +5.5kg for PI. Among PWH starting INSTI drugs, mean estimated two-year weight change was +7.2kg for DTG, +5.8kg for RAL and +4.1kg for EVG. Women, persons with lower baseline CD4 + cell counts, and those initiating INSTI-based regimens had higher odds of >10% body weight increase at two years (adjusted odds ratio = 1.37, 95% confidence interval: 1.20 to 1.56 vs. NNRTI)., Conclusions: PWH initiating INSTI-based regimens gained, on average, more weight compared to NNRTI-based regimens. This phenomenon may reflect heterogeneous effects of ART agents on body weight regulation that require further exploration., (© 2020 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

Improvements in life expectancy among people living with human immunodeficiency virus (PLWH) receiving antiretroviral treatment in the United States and Canada might differ among key populations. Given the difference in substance use among key populations and the current opioid epidemic, drug- and alcohol-related deaths might be contributing to the disparities in life expectancy. We sought to estimate life expectancy at age 20 years in key populations (and their comparison groups) in 3 time periods (2004-2007, 2008-2011, and 2012-2015) and the potential increase in expected life expectancy with a simulated 20% reduction in drug- and alcohol-related deaths using the novel Lives Saved Simulation model. Among 92,289 PLWH, life expectancy increased in all key populations and comparison groups from 2004-2007 to 2012-2015. Disparities in survival of approximately a decade persisted among black versus white men who have sex with men and people with (vs. without) a history of injection drug use. A 20% reduction in drug- and alcohol-related mortality would have the greatest life-expectancy benefit for black men who have sex with men, white women, and people with a history of injection drug use. Our findings suggest that preventing drug- and alcohol-related deaths among PLWH could narrow disparities in life expectancy among some key populations, but other causes of death must be addressed to further narrow the disparities., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

In 1984, a large prospective study of the natural history of human immunodeficiency virus (HIV) infection, the Multicenter AIDS Cohort Study (MACS), was established; 10 years later, the Women's Interagency HIV Study (WIHS) was launched. Motivated by the merger and redesign of these long-standing HIV cohort studies in 2019, we review ways in which HIV epidemiology in the United States has transformed over the lives of these studies and how this evolution has influenced planning for enrollment and follow-up. We highlight changes that have occurred in the 3 major domains that are central to epidemiologic science: changes to key populations at highest risk for HIV, refinements in measurement and shifts in the outcomes of interest, and a new era in the tools and approaches that epidemiologists use to synthesize evidence from measurements made on populations. By embracing foundational principles with modern methods, the epidemiologic approach of analyzing the causes and distributions of diseases in contemporaneous populations will continue to advance HIV science over the next decade., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Objectives: To identify factors associated with incarceration among women and examine the relationship between incarceration and human immunodeficiency virus (HIV)-related outcomes. Materials and Methods: We analyzed longitudinal data from 3324 women (2372 with HIV and 952 uninfected) from 2007 to 2016 in the Women's Interagency HIV Study, a U.S. cohort of women with and without HIV. Lifetime history of incarceration before first study visit was used as the outcome and then as a predictor for HIV outcomes and mortality. Using multivariable models, we assessed associations between socio-demographic, behavioral, and clinical characteristics and incarceration, and between incarceration and HIV outcomes, including mortality. Results: Overall, 1256 (38%) of women reported ever being incarcerated. Women who had a history of drug use had a 44% greater prevalence of incarceration compared with those who did not use drugs. Sexual minority women and women who experienced physical and sexual abuse had a 47% and 28%, respectively, greater prevalence of incarceration than heterosexual women and those not abused. For the 862 women with HIV and a history of incarceration, having an incarceration history was independently associated with less viral suppression (adjusted prevalence ratios = 0.95; confidence intervals [CI]:0.90-1.00 p  = 0.04) and higher likelihood of death (adjusted hazard ratios = 1.39; CI:1.04-1.86 p  = 0.03). Conclusions: Incarceration is common in this cohort and may put women with HIV at increased odds of worse HIV outcomes and mortality than those without a history of incarceration. Addressing the intersecting epidemics of HIV, substance use, and incarceration by providing needed treatment and resources and avoiding criminalization may improve health outcomes in vulnerable women with HIV.

Background: Expression of tissue factor (TF) on the surface of activated monocytes may trigger thrombosis, leading to clotting risk, inflammation, and atherosclerosis. TF-positive microparticles (MP-TF) represent a functionally active form of TF that may be promulgated by long-term HIV infection. We hypothesized that greater MP-TF activity is associated with carotid artery plaque in HIV+ women., Setting: In a case-control study nested within the Women's Interagency HIV Study (WIHS), eligible HIV+ participants underwent B-mode carotid artery ultrasound at 2 study visits occurring 7 years apart. Cases were defined by the presence of at least 1 carotid artery plaque assessed at either visit. Cases were matched 1:2 to controls who were found not to have carotid artery plaques., Methods: Conditional logistic regression estimated the association of MP-TF activity with the presence of carotid artery plaque, adjusting for demographic and behavioral characteristics, HIV-related factors, cardiometabolic risk factors, and serum inflammation biomarkers (high-sensitivity C-reactive protein, IL-6, sCD14, sCD163, Gal-3, and Gal-3BP)., Results: Elevated MP-TF activity (>0.537 pg/mL) was found to be significantly associated with greater odds of plaque (adjusted odds ratio 3.86, 95% confidence interval: 1.06 to 14.07, P = 0.04). The association was attenuated after further adjustment for IL-6 but was unaffected by adjustment for other biomarkers including those denoting monocyte activation., Conclusions: Our findings suggest a link among HIV infection, innate immune system perturbation, coagulation, and atherosclerosis.

Aims: To test whether human immunodeficiency virus (HIV) infection and subclinical cardiovascular disease (sCVD) are associated with expression of CXCR4 and other surface markers on classical, intermediate, and non-classical monocytes in women., Methods and Results: sCVD was defined as presence of atherosclerotic lesions in the carotid artery in 92 participants of the Women's Interagency HIV Study (WIHS). Participants were stratified into four sets (n = 23 each) by HIV and sCVD status (HIV-/sCVD-, HIV-/sCVD+, HIV+/sCVD-, and HIV+/sCVD+) matched by age, race/ethnicity, and smoking status. Three subsets of monocytes were determined from archived peripheral blood mononuclear cells. Flow cytometry was used to count and phenotype surface markers. We tested for differences by HIV and sCVD status accounting for multiple comparisons. We found no differences in monocyte subset size among the four groups. Expression of seven surface markers differed significantly across the three monocyte subsets. CXCR4 expression [median fluorescence intensity (MFI)] in non-classical monocytes was highest among HIV-/CVD- [628, interquartile range (IQR) (295-1389)], followed by HIV+/CVD- [486, IQR (248-699)], HIV-/CVD+ (398, IQR (89-901)), and lowest in HIV+/CVD+ women [226, IQR (73-519)), P = 0.006 in ANOVA. After accounting for multiple comparison (Tukey) the difference between HIV-/CVD- vs. HIV+/CVD+ remained significant with P = 0.005 (HIV-/CVD- vs. HIV+/CVD- P = 0.04, HIV-/CVD- vs. HIV-/CVD+ P = 0.06, HIV+/CVD+ vs. HIV+/CVD- P = 0.88, HIV+/CVD+ vs. HIV-/CVD+ P = 0.81, HIV+/CVD- vs. HIV-/CVD+, P = 0.99). All pairwise comparisons with HIV-/CVD- were individually significant (P = 0.050 vs. HIV-/CVD+, P = 0.028 vs. HIV+/CVD-, P = 0.009 vs. HIV+/CVD+). CXCR4 expression on non-classical monocytes was significantly higher in CVD- (501.5, IQR (249.5-887.3)) vs. CVD+ (297, IQR (81.75-626.8) individuals (P = 0.028, n = 46 per group). CXCR4 expression on non-classical monocytes significantly correlated with cardiovascular and HIV-related risk factors including systolic blood pressure, platelet and T cell counts along with duration of antiretroviral therapy (P < 0.05). In regression analyses, adjusted for education level, study site, and injection drug use, presence of HIV infection and sCVD remained significantly associated with lower CXCR4 expression on non-classical monocytes (P = 0.003), but did not differ in classical or intermediate monocytes., Conclusion: CXCR4 expression in non-classical monocytes was significantly lower among women with both HIV infection and sCVD, suggesting a potential atheroprotective role of CXCR4 in non-classical monocytes., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

Purpose: Use of electronic health records (EHRs) in health research may lead to the false assumption of complete event ascertainment. We estimated "observation windows" (OWs), defined as periods within which the assumption of complete ascertainment of events is more likely to hold, as a quality control approach to reducing the likelihood of this false assumption. We demonstrated the impact of OWs on estimating the rates of type II diabetes mellitus (diabetes) from HIV clinical cohorts., Methods: Data contributed by 16 HIV clinical cohorts to the NA-ACCORD were used to identify and evaluate OWs for an operationalized definition of diabetes occurrence as a case study. Procedures included (1) gathering cohort-level data; (2) visualizing and summarizing gaps in observations; (3) systematically establishing start and stop dates during which the assumption of complete ascertainment of diabetes events was reasonable; and (4) visualizing the diabetes OWs relative to the cohort open and close dates to identify immortal person-time. We estimated diabetes occurrence event rates and 95% confidence intervals in the most recent decade that data were available (January 1, 2007, to December 31, 2016)., Results: The number of diabetes events decreased by 17% with the use of the diabetes OWs; immortal person-time was removed decreasing total person-years by 23%. Consequently, the diabetes rate increased from 1.23 (95% confidence interval [1.20, 1.25]) per 100 person-years to 1.32 [1.29, 1.35] per 100 person-years with the use of diabetes OWs., Conclusions: As the use of EHR-curated data for event-driven health research continues to expand, OWs have utility as a quality control approach to complete event ascertainment, helping to improve accuracy of estimates by removing immortal person-time when ascertainment is incomplete., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Adults with HIV have an increased burden of non-AIDS-defining cancers, myocardial infarction, end-stage liver disease, and end-stage renal disease. The objective of this study was to estimate the population attributable fractions (PAFs) of preventable or modifiable HIV-related and traditional risk factors for non-AIDS-defining cancers, myocardial infarction, end-stage liver disease, and end-stage renal disease outcomes., Methods: We included participants receiving care in academic and community-based outpatient HIV clinical cohorts in the USA and Canada from Jan 1, 2000, to Dec 31, 2014, who contributed to the North American AIDS Cohort Collaboration on Research and Design and who had validated non-AIDS-defining cancers, myocardial infarction, end-stage liver disease, or end-stage renal disease outcomes. Traditional risk factors were tobacco smoking, hypertension, elevated total cholesterol, type 2 diabetes, renal impairment (stage 4 chronic kidney disease), and hepatitis C virus and hepatitis B virus infections. HIV-related risk factors were low CD4 count (<200 cells per μL), detectable plasma HIV RNA (>400 copies per mL), and history of a clinical AIDS diagnosis. PAFs and 95% CIs were estimated to quantify the proportion of outcomes that could be avoided if the risk factor was prevented., Findings: In each of the study populations for the four outcomes (1405 of 61 500 had non-AIDS-defining cancer, 347 of 29 515 had myocardial infarctions, 387 of 35 044 had end-stage liver disease events, and 255 of 35 620 had end-stage renal disease events), about 17% were older than 50 years at study entry, about 50% were non-white, and about 80% were men. Preventing smoking would avoid 24% (95% CI 13-35) of these cancers and 37% (7-66) of the myocardial infarctions. Preventing elevated total cholesterol and hypertension would avoid the greatest proportion of myocardial infarctions: 44% (30-58) for cholesterol and 42% (28-56) for hypertension. For liver disease, the PAF was greatest for hepatitis C infection (33%; 95% CI 17-48). For renal disease, the PAF was greatest for hypertension (39%; 26-51) followed by elevated total cholesterol (22%; 13-31), detectable HIV RNA (19; 9-31), and low CD4 cell count (13%; 4-21)., Interpretation: The substantial proportion of non-AIDS-defining cancers, myocardial infarction, end-stage liver disease, and end-stage renal disease outcomes that could be prevented with interventions on traditional risk factors elevates the importance of screening for these risk factors, improving the effectiveness of prevention (or modification) of these risk factors, and creating sustainable care models to implement such interventions during the decades of life of adults living with HIV who are receiving care., Funding: National Institutes of Health, US Centers for Disease Control and Prevention, the US Agency for Healthcare Research and Quality, the US Health Resources and Services Administration, the Canadian Institutes of Health Research, the Ontario Ministry of Health and Long Term Care, and the Government of Alberta., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: Among people with HIV, there are few long-term studies of noninvasive ultrasound-based measurements of the carotid artery predicting major health events. We hypothesized that such measurements are associated with 10-year mortality in the Women's Interagency HIV Study (WIHS) and Multicenter AIDS Cohort Study (MACS), and that associations differ by HIV serostatus., Design: Nested cohort study., Methods: Participants without coronary heart disease underwent B-mode carotid artery ultrasound, with measurement of common carotid artery intima-media thickness (IMT); carotid artery plaque (focal IMT > 1.5 mm) at six locations; and Young's modulus of elasticity, a measure of arterial stiffness. We examined all-cause mortality using Cox models, controlling for demographic, behavioral, cardiometabolic, and HIV-related factors., Results: Among 1722 women (median age 40 years, 90% nonwhite, 71% HIV-positive) and 1304 men (median age 50, 39% nonwhite, 62% HIV-positive), 11% died during follow-up. Mortality was higher among HIV-positive women [19.9 deaths/1000 person-years, 95% confidence interval (CI) 14.7-28.8] than HIV-positive men (15.1/1000, 95% CI 8.3-26.8). In adjusted analyses, plaque was associated with mortality (hazard ratio 1.44, 95% CI 1.10-1.88) regardless of HIV serostatus, and varied by sex (among women, hazard ratio 1.06, 95% CI 0.74-1.52; among men; hazard ratio 2.19, 95% CI 1.41-3.43). The association of plaque with mortality was more pronounced among HIV-negative (hazard ratio 3.87, 95% 1.95-7.66) than HIV-positive participants (hazard ratio 1.35, 95% CI 1.00-1.84). Arterial stiffness was also associated with mortality (hazard ratio 1.43 for highest versus lowest quartile, 95% CI 1.02-2.01). Greater common carotid artery-IMT was not associated with mortality., Conclusion: Carotid artery plaque was predictive of mortality, with differences observed by sex and HIV serostatus.

Background: CD4 + T cells play an important role in atherosclerosis, but their antigen specificity is poorly understood. Immunization with apolipoprotein B (ApoB, core protein of low density lipoprotein) is known to be atheroprotective in animal models. Here, we report on a human APOB peptide, p18, that is sequence-identical in mouse ApoB and binds to both mouse and human major histocompatibility complex class II molecules., Methods: We constructed p18 tetramers to detect human and mouse APOB-specific T cells and assayed their phenotype by flow cytometry including CD4 lineage transcription factors, intracellular cytokines, and T cell receptor activation. Apolipoprotein E-deficient ( Apoe -/- ) mice were vaccinated with p18 peptide or adjuvants alone, and atherosclerotic burden in the aorta was determined., Results: In human peripheral blood mononuclear cells from donors without cardiovascular disease, p18 specific CD4 + T cells detected by a new human leukocyte antigen-antigen D related-p18 tetramers were mostly Foxp3 + regulatory T cells (Tregs). Donors with subclinical cardiovascular disease as detected by carotid artery ultrasound had Tregs coexpressing retinoic acid-related orphan receptor gamma t or T-bet, which were both almost absent in donors without cardiovascular disease. In Apoe -/- mice, immunization with p18 induced Tregs and reduced atherosclerotic lesions. After peptide restimulation, responding CD4 + T cells identified by Nur77-GFP (green fluorescent protein) were highly enriched in Tregs. A new mouse I-A b -p18 tetramer identified the expansion of p18-specific CD4 + T cells on vaccination, which were enriched for interleukin-10-producing Tregs., Conclusions: These findings show that APOB p18-specific CD4 + T cells are mainly Tregs in healthy donors, but coexpress other CD4 lineage transcription factors in donors with subclinical cardiovascular disease. This study identifies ApoB peptide 18 as the first Treg epitope in human and mouse atherosclerosis.

Background: There is persistent confusion as to whether abacavir (ABC) increases the risk of myocardial infarction (MI), and whether such risk differs by type 1 (T1MI) or 2 (T2MI) MI in adults with HIV., Methods: Incident MIs in North American Cohort Collaboration on Research and Design participants were identified from 2001 to 2013. Discrete time marginal structural models addressed channeling biases and time-dependent confounding to estimate crude hazard ratio (HR) and adjusted hazard ratio (aHR) and 95% confidence intervals; analyses were performed for T1MI and T2MI separately. A sensitivity analysis evaluated whether Framingham risk score (FRS) modified the effect of ABC on MI occurrence., Results: Eight thousand two hundred sixty-five adults who initiated antiretroviral therapy contributed 29,077 person-years and 123 MI events (65 T1MI and 58 T2MI). Median follow-up time was 2.9 (interquartile range 1.4-5.1) years. ABC initiators were more likely to have a history of injection drug use, hepatitis C virus infection, hypertension, diabetes, impaired kidney function, hyperlipidemia, low (<200 cells/mm) CD4 counts, and a history of AIDS. The risk of the combined MI outcome was greater for persons who used ABC in the previous 6 months [aHR = 1.84 (1.17-2.91)]; and persisted for T1MI (aHR = 1.62 [1.01]) and T2MI [aHR = 2.11 (1.08-4.29)]. FRS did not modify the effect of ABC on MI (P = 0.14) and inclusion of FRS in the MSM did not diminish the effect of recent ABC use on the combined outcome., Conclusions: Recent ABC use was associated with MI after adjustment for known risk factors and for FRS. However, screening for T1MI risks may not identify all or even most persons at risk of ABC use-associated MIs.

Background: Age-associated conditions are increasingly common among persons living with human immunodeficiency virus (HIV) (PLWH). A longitudinal investigation of their accrual is needed given their implications on clinical care complexity. We examined trends in the co-occurrence of age-associated conditions among PLWH receiving clinical care, and differences in their prevalence by demographic subgroup., Methods: This cohort study was nested within the North American AIDS Cohort Collaboration on Research and Design. Participants from HIV outpatient clinics were antiretroviral therapy-exposed PLWH receiving clinical care (ie, ≥1 CD4 count) in the United States during 2000-2009. Multimorbidity was irreversible, defined as having ≥2: hypertension, diabetes mellitus, chronic kidney disease, hypercholesterolemia, end-stage liver disease, or non-AIDS-related cancer. Adjusted prevalence ratios (aPR) and 95% confidence intervals (CIs) comparing demographic subgroups were obtained by Poisson regression with robust error variance, using generalized estimating equations for repeated measures., Results: Among 22969 adults, 79% were male, 36% were black, and the median baseline age was 40 years (interquartile range, 34-46 years). Between 2000 and 2009, multimorbidity prevalence increased from 8.2% to 22.4% (Ptrend < .001). Adjusting for age, this trend was still significant (P < .001). There was no difference by sex, but blacks were less likely than whites to have multimorbidity (aPR, 0.87; 95% CI, .77-.99). Multimorbidity was the highest among heterosexuals, relative to men who have sex with men (aPR, 1.16; 95% CI, 1.01-1.34). Hypertension and hypercholesterolemia most commonly co-occurred., Conclusions: Multimorbidity prevalence has increased among PLWH. Comorbidity prevention and multisubspecialty management of increasingly complex healthcare needs will be vital to ensuring that they receive needed care.