DNA methylation-based telomere length is associated with HIV infection, physical frailty, cancer, and all-cause mortality.

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

Association of chronotropic incompetence with reduced cardiorespiratory fitness in older adults with HIV.

OBJECTIVE: Understanding the physiological drivers of reduced cardiorespiratory fitness in people with HIV (PWH) will inform strategies to optimize healthspan. Chronotropic incompetence is common in heart failure and associated with low cardiorespiratory fitness yet is understudied in PWH. The objective was to determine the prevalence of chronotropic incompetence and its relationship with cardiorespiratory fitness. DESIGN: Participants were PWH at least 50 years of age with no prior history of heart failure or coronary heart disease who were enrolled in a randomized exercise trial. Baseline cardiopulmonary exercise testing (CPET) was used to measure cardiorespiratory fitness as peak oxygen consumption (VO2peak) and calculate the chronotropic index from heart rate values. Chronotropic incompetence was defined as an index less than 80%. RESULTS: The 74 participants were on average 61 years old, 80% Black or African American, and 93% men. Chronotropic incompetence was present in 31.1%. VO2peak was significantly lower among participants with chronotropic incompetence compared with participants without chronotropic incompetence [mean (SD) ml/min/kg: 20.9 (5.1) vs. 25.0 (4.5), P = 0.001]. Linear regression showed that chronotropic incompetence and age were independent predictors of VO2peak, but smoking and comorbidity were not. The chronotropic index correlated with VO2peak (r = 0.48, P < 0.001). CONCLUSION: Among older PWH without heart failure or coronary heart disease, chronotropic incompetence was present in approximately one-third of individuals and was associated with clinically relevant impaired cardiorespiratory fitness. Investigation of chronotropic incompetence in large cohorts which includes PWH and heart failure may contribute to strategies that promote healthy aging with HIV infection and offer a preclinical window for intervention.

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.

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.

Associations of inflammation-related proteome with demographic and clinical characteristics of people with HIV in South Africa.

PURPOSE: Elevated levels of inflammation associated with human immunodeficiency virus (HIV) infection are one of the primary causes for the burden of age-related diseases among people with HIV (PWH). Circulating proteins can be used to investigate pathways to inflammation among PWH. EXPERIMENTAL DESIGN: We profiled 73 inflammation-related protein markers and assessed their associations with chronological age, sex, and CD4+ cell count among 87 black South African PWH before antiretroviral therapy (ART). RESULTS: We identified 1, 1, and 14 inflammatory proteins significantly associated with sex, CD4+ cell count, and age respectively. Twelve out of 14 age-associated proteins have been reported to be associated with age in the general population, and 4 have previously shown significant associations with age for PWH. Furthermore, many of the age-associated proteins such as CST5, CCL23, SLAMF1, MMP-1, MCP-1, and CDCP1 have been linked to chronic diseases such as cardiovascular disease and neurocognitive decline in the general population. We also found a synergistic interaction between male and older age accounting for excessive expression of CST5. CONCLUSIONS AND CLINICAL RELEVANCE: We found that advanced age may lead to the elevation of multiple inflammatory proteins among PWH. We also demonstrated the potential utility of proteomics for evaluating and characterizing the inflammatory status of PWH.

Determinants of health-related quality of life in people with Human Immunodeficiency Virus, failing first-line treatment in Africa.

BACKGROUND: Antiretroviral treatment improves health related quality of life (HRQoL) of people with human immunodeficiency virus (PWH). However, one third initiating first-line treatment experience virological failure and the determinants of HRQoL in this key population are unknown. Our study aims to identify determinants of among PWH failing antiretroviral treatment in sub-Saharan Africa. METHODS: We analysed data from a cohort of PWH having virological failure (> 1,000 copies/mL) on first-line ART in South Africa and Uganda. We measured HRQoL using the EuroQOL EQ-5D-3L and used a two-part regression model to obtain by-country analyses for South Africa and Uganda. The first part identifies risk factors that were associated with the likelihood of participants reporting perfect health (utility = 1) versus non-perfect health (utility < 1). The second part identifies risk factors that were associated with the EQ-5 L-3L utility scores for participants reporting non-perfect health. We performed sensitivity analyses to compare the results between the two-part model using tobit models and ordinary least squares regression. RESULTS: In both countries, males were more likely to report perfect health and participants with at least one comorbidity were less likely to report perfect health. In South Africa, participants with side effects and in Uganda those with opportunistic infections were also less likely to report perfect health. In Uganda, participants with 100% ART adherence were more likely to report perfect health. In South Africa, high HIV viral load, experiencing ART side effects, and the presence of opportunistic infections were each associated with lower HRQoL, whereas participants with 100% ART adherence reported higher HRQoL. In Uganda participants with lower CD4 count had lower HRQoL. CONCLUSION: Markers of advanced disease (opportunistic infection, high viral load, low CD4), side effects, comorbidities and lack of ART adherence negatively impacted HRQoL for PWH experiencing virological failure. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02787499.

Evaluating Clinic-Based Interventions to Reduce Racial Differences in Mortality Among People With Human Immunodeficiency Virus in the United States.

BACKGROUND: Mortality remains elevated among Black versus White adults receiving human immunodeficiency virus (HIV) care in the United States. We evaluated the effects of hypothetical clinic-based interventions on this mortality gap. METHODS: We computed 3-year mortality under observed treatment patterns among >40 000 Black and >30 000 White adults entering HIV care in the United States from 1996 to 2019. We then used inverse probability weights to impose hypothetical interventions, including immediate treatment and guideline-based follow-up. We considered 2 scenarios: "universal" delivery of interventions to all patients and "focused" delivery of interventions to Black patients while White patients continued to follow observed treatment patterns. RESULTS: Under observed treatment patterns, 3-year mortality was 8% among White patients and 9% among Black patients, for a difference of 1 percentage point (95% confidence interval [CI], .5-1.4). The difference was reduced to 0.5% under universal immediate treatment (95% CI, -.4% to 1.3%) and to 0.2% under universal immediate treatment combined with guideline-based follow-up (95% CI, -1.0% to 1.4%). Under the focused delivery of both interventions to Black patients, the Black-White difference in 3-year mortality was -1.4% (95% CI, -2.3% to -.4%). CONCLUSIONS: Clinical interventions, particularly those focused on enhancing the care of Black patients, could have significantly reduced the mortality gap between Black and White patients entering HIV care from 1996 to 2019.

Mapping digital health ecosystems in Africa in the context of endemic infectious and non-communicable diseases.

Investments in digital health technologies such as artificial intelligence, wearable devices, and telemedicine may support Africa achieve United Nations (UN) Sustainable Development Goal for Health by 2030. We aimed to characterize and map digital health ecosystems of all 54 countries in Africa in the context of endemic infectious and non-communicable diseases (ID and NCD). We performed a cross-national ecological analysis of digital health ecosystems using 20-year data from the World Bank, UN Economic Commission for Africa, World Health Organization, and Joint UN Programme on HIV/AIDS. Spearman's rank correlation coefficients were used to characterize ecological correlations between exposure (technology characteristics) and outcome (IDs and NCDs incidence/mortality) variables. Weighted linear combination model was used as the decision rule, combining disease burden, technology access, and economy, to explain, rank, and map digital health ecosystems of a given country. The perspective of our analysis was to support government decision-making. The 20-year trend showed that technology characteristics have been steadily growing in Africa, including internet access, mobile cellular and fixed broadband subscriptions, high-technology manufacturing, GDP per capita, and adult literacy, while many countries have been overwhelmed by a double burden of IDs and NCDs. Inverse correlations exist between technology characteristics and ID burdens, such as fixed broadband subscription and incidence of tuberculosis and malaria, or GDP per capita and incidence of tuberculosis and malaria. Based on our models, countries that should prioritize digital health investments were South Africa, Nigeria, and Tanzania for HIV; Nigeria, South Africa, and Democratic Republic of the Congo (DROC) for tuberculosis; DROC, Nigeria, and Uganda for malaria; and Egypt, Nigeria, and Ethiopia for endemic NCDs including diabetes, cardiovascular disease, respiratory diseases, and malignancies. Countries such as Kenya, Ethiopia, Zambia, Zimbabwe, Angola, and Mozambique were also highly affected by endemic IDs. By mapping digital health ecosystems in Africa, this study provides strategic guidance about where governments should prioritize digital health technology investments that require preliminary analysis of country-specific contexts to bring about sustainable health and economic returns. Building digital infrastructure should be a key part of economic development programs in countries with high disease burdens to ensure more equitable health outcomes. Though infrastructure developments alongside digital health technologies are the responsibility of governments, global health initiatives can cultivate digital health interventions substantially by bridging knowledge and investment gaps, both through technology transfer for local production and negotiation of prices for large-scale deployment of the most impactful digital health technologies.

Effect of Immune-Modulatory Interventions on Asymptomatic Cytomegalovirus Shedding During Suppressive Antiretroviral Therapy.

Long-term consequences of human immunodeficiency virus (HIV) are likely the result of persistent inflammation and immune dysfunction of which cytomegalovirus (CMV) is a known contributor. We leveraged 2 AIDS Clinical Trials Group clinical trials exploring the effects of immune modulators (ruxolitinib and sirolimus) on inflammation in people with HIV on antiretroviral therapy to determine whether these interventions affected CMV shedding at various mucosal sites. Analyzing 635 mucosal samples collected, we found no significant difference in CMV levels across study arms or time points. Men had more CMV shedding than women. We did confirm an association between higher CMV DNA and immune markers associated with HIV persistence and HIV-associated mortality rates.

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.

Human Immunodeficiency Virus Status, Tenofovir Exposure, and the Risk of Poor Coronavirus Disease 19 Outcomes: Real-World Analysis From 6 United States Cohorts Before Vaccine Rollout.

BACKGROUND: People with human immunodeficiency virus (HIV) (PWH) may be at increased risk for severe coronavirus disease 2019 (COVID-19) outcomes. We examined HIV status and COVID-19 severity, and whether tenofovir, used by PWH for HIV treatment and people without HIV (PWoH) for HIV prevention, was associated with protection. METHODS: Within 6 cohorts of PWH and PWoH in the United States, we compared the 90-day risk of any hospitalization, COVID-19 hospitalization, and mechanical ventilation or death by HIV status and by prior exposure to tenofovir, among those with severe acute respiratory syndrome coronavirus 2 infection between 1 March and 30 November 2020. Adjusted risk ratios (aRRs) were estimated by targeted maximum likelihood estimation, with adjustment for demographics, cohort, smoking, body mass index, Charlson comorbidity index, calendar period of first infection, and CD4 cell counts and HIV RNA levels (in PWH only). RESULTS: Among PWH (n = 1785), 15% were hospitalized for COVID-19 and 5% received mechanical ventilation or died, compared with 6% and 2%, respectively, for PWoH (n = 189 351). Outcome prevalence was lower for PWH and PWoH with prior tenofovir use. In adjusted analyses, PWH were at increased risk compared with PWoH for any hospitalization (aRR, 1.31 [95% confidence interval, 1.20-1.44]), COVID-19 hospitalizations (1.29 [1.15-1.45]), and mechanical ventilation or death (1.51 [1.19-1.92]). Prior tenofovir use was associated with reduced hospitalizations among PWH (aRR, 0.85 [95% confidence interval, .73-.99]) and PWoH (0.71 [.62-.81]). CONCLUSIONS: Before COVID-19 vaccine availability, PWH were at greater risk for severe outcomes than PWoH. Tenofovir was associated with a significant reduction in clinical events for both PWH and PWoH.

Optimizing Treatment for Human Immunodeficiency Virus to Improve Clinical Outcomes Using Precision Medicine.

In first-line antiretroviral therapy (ART) for human immunodeficiency virus (HIV) treatment, some subgroups of patients may respond better to an efavirenz-based regimen than an integrase strand transfer inhibitor (InSTI)-based regimen, or vice versa, due to patient characteristics modifying treatment effects. Using data based on nearly 16,000 patients from the North American AIDS Cohort Collaboration on Research and Design from 2009-2016, statistical methods for precision medicine were employed to estimate an optimal treatment rule that minimizes the 5-year risk of the composite outcome of acquired immune deficiency syndrome (AIDS)-defining illnesses, serious non-AIDS events, and all-cause mortality. The treatment rules considered were functions that recommend either an efavirenz- or InSTI-based regimen conditional on baseline patient characteristics such as demographic information, laboratory results, and health history. The estimated 5-year risk under the estimated optimal treatment rule was 10.0% (95% confidence interval (CI): 8.6, 11.3), corresponding to an absolute risk reduction of 2.3% (95% CI: 0.9, 3.8) when compared with recommending an efavirenz-based regimen for all patients and 2.6% (95% CI: 1.0, 4.2) when compared with recommending an InSTI-based regimen for all. Tailoring ART to individual patient characteristics may reduce 5-year risk of the composite outcome compared with assigning all patients the same drug regimen.

Cell-type specific EWAS identifies genes involved in HIV pathogenesis and oncogenesis among people with HIV infection.

Epigenome-wide association studies (EWAS) of heterogenous blood cells have identified CpG sites associated with chronic HIV infection, which offer limited knowledge of cell-type specific methylation patterns associated with HIV infection. Applying a computational deconvolution method validated by capture bisulfite DNA methylation sequencing, we conducted a cell type-based EWAS and identified differentially methylated CpG sites specific for chronic HIV infection among five immune cell types in blood: CD4+ T-cells, CD8+ T-cells, B cells, Natural Killer (NK) cells, and monocytes in two independent cohorts (N total =1,134). Differentially methylated CpG sites for HIV-infection were highly concordant between the two cohorts. Cell-type level meta-EWAS revealed distinct patterns of HIV-associated differential CpG methylation, where 67% of CpG sites were unique to individual cell types (false discovery rate, FDR <0.05). CD4+ T-cells had the largest number of HIV-associated CpG sites (N=1,472) compared to any other cell type. Genes harboring statistically significant CpG sites are involved in immunity and HIV pathogenesis (e.g. CX3CR1 in CD4+ T-cells, CCR7 in B cells, IL12R in NK cells, LCK in monocytes). More importantly, HIV-associated CpG sites were overrepresented for hallmark genes involved in cancer pathology ( FDR <0.05) (e.g. BCL family, PRDM16, PDCD1LGD, ESR1, DNMT3A, NOTCH2 ). HIV-associated CpG sites were enriched among genes involved in HIV pathogenesis and oncogenesis such as Kras-signaling, interferon-α and -γ, TNF-α, inflammatory, and apoptotic pathways. Our findings are novel, uncovering cell-type specific modifications in the host epigenome for people with HIV that contribute to the growing body of evidence regarding pathogen-induced epigenetic oncogenicity, specifically on HIV and its comorbidity with cancers.

A Cost-Effective Analysis of Motivational Interviewing with Palliative Care Versus Usual Care: Results from the Living Well Project.

Little is known about the impact of early palliative care (EPC) combined with motivational interviewing (MI) for persons living with AIDS (PWA). We compared the cost and quality-adjusted life-years (QALYs) of EPC + MI (n = 61) versus usual care (UC) (n = 60) for patients with AIDS, not on antiretroviral medications, enrolled into the Living Well Project trial. Data on clinic, emergency department, and hospital visits were collected through self-report and billing records. Risk-adjusted average annual health care costs were estimated using a generalized linear model with a gamma log-link function. QALYs were calculated using the SF-12v2. Cost-effectiveness was defined as cost per QALY gained. Estimated intervention costs were $165 per participant. EPC + MI reduced costs by 33% (AOR = 0.67; CI 95%: 0.15, 0.93). QALYs did not differ between groups. Results suggest EPC + MI for PWA is cost-saving and maintains quality of life compared to UC due to reduced hospital and ED costs.

Effect of Adopting the New Race-Free 2021 Chronic Kidney Disease Epidemiology Collaboration Estimated Glomerular Filtration Rate Creatinine Equation on Racial Differences in Kidney Disease Progression Among People With Human Immunodeficiency Virus: An Observational Study.

BACKGROUND: The impact of adopting a race-free estimated glomerular filtration rate (eGFR) creatinine (eGFRcr) equation on racial differences in chronic kidney disease (CKD) progression among people with human immunodeficiency virus (PWH) is unknown. METHODS: We defined eGFR stages using the original race-adjusted Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFRcr equation and the new race-free CKD-EPI eGFRcr equation. We then estimated 5-year probabilities of transitioning from baseline kidney function to more advanced eGFR stages and examined the association of race (black vs white) with rates of CKD progression using Markov models. RESULTS: With the race-adjusted eGFRcr equation, black participants (n = 31 298) had a lower risk of progressing from eGFR stage 1 to 2 (hazard ratio [HR], 0.77; 95% confidence interval [CI], .73-.82), an equal risk of progressing from stage 2 to 3 (1.00; .92-.07) and a 3-fold risk of progressing from stage 3 to 4 or 5 (3.06; 2.60-3.62), compared with white participants (n = 27 542). When we used the race-free eGFRcr equation, 16% of black participants were reclassified into a more severe eGFR stage at baseline. The reclassified black individuals had a higher prevalence of CKD risk factors than black PWH who were not reclassified. With the race-free eGFRcr equation, black participants had a higher risk of disease progression across all eGFR stages than white participants. CONCLUSIONS: The original eGFRcr equation systematically masked a subgroup of black PWH who are at high-risk of CKD progression. The new race-free eGFRcr equation unmasks these individuals and may allow for earlier detection and management of CKD.

Trends in Cause-Specific Mortality Among Veterans With HIV: A 35-Year (1982-2016) Analysis of the HIV Atlanta VA Cohort Study.

BACKGROUND: Causes of death and their trends among veterans with HIV (VWH) are different than those in the general population with HIV, but this has not been fully described. The objective was to understand the trends in, and risk factors for, all-cause and cause-specific mortality across eras of combination antiretroviral therapy (cART) among VWH. SETTING: The HIV Atlanta VA Cohort Study includes all VWH who ever sought care at the Atlanta VA Medical Center. METHODS: Age-adjusted all-cause and cause-specific mortality rates were calculated annually and compared between pre-cART (1982-1996), early-cART (1997-2006), and late-cART (2007-2016) eras. Trends were assessed using Kaplan-Meier curves, cumulative incidence functions, and joinpoint regression models. Risk factors were identified by Cox proportional hazards models. RESULTS: Of the 4674 VWH in the HIV Atlanta VA Cohort Study, 1752 died; of whom, 1399 (79.9%), 301 (17.2%), and 52 (3.0%) were diagnosed with HIV in the pre-cART, early-cART, and late-cART eras, respectively. Significant increases were observed in rates of all-cause, AIDS-related, and non-AIDS-related mortality in the pre-cART era, followed by declines in the early-cART and late-cART eras. All-cause, AIDS-related, and non-AIDS-related mortality rates plummeted by 65%, 81%, and 45%, respectively, from the pre-cART to late-cART eras. However, VWH continue to die at higher rates due to AIDS-related infections, non-AIDS-related malignancies, respiratory disease, cardiovascular disease, and renal failure than those in the general population with HIV. CONCLUSIONS: In older populations with HIV, it is important that providers not only monitor for and treat diseases associated with aging but also intervene and address lifestyle risk factors.

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.

Combining Charlson comorbidity and VACS indices improves prognostic accuracy for all-cause mortality for patients with and without HIV in the Veterans Health Administration.

Introduction: As people age with HIV (PWH), many comorbid diseases are more common than among age matched comparators without HIV (PWoH). While the Veterans Aging Cohort (VACS) Index 2.0 accurately predicts mortality in PWH using age and clinical biomarkers, the only included comorbidity is hepatitis C. We asked whether adding comorbid disease groupings from the Charlson Comorbidity Index (CCI) improves the accuracy of VACS Index. Methods: To maximize our ability to model mortality among older age groups, we began with PWoH in Veterans Health Administration (VA) from 2007-2017, divided into development and validation samples. Baseline predictors included age, and components of CCI and VACS Index (excluding CD4 count and HIV RNA). Patients were followed until December 31, 2021. We used Cox models to develop the VACS-CCI score and estimated mortality using a parametric (gamma) survival model. We compared accuracy using C-statistics and calibration curves in validation overall and within subgroups (gender, age

Analysis of Severe Illness After Postvaccination COVID-19 Breakthrough Among Adults With and Without HIV in the US.

Importance: Understanding the severity of postvaccination SARS-CoV-2 (ie, COVID-19) breakthrough illness among people with HIV (PWH) can inform vaccine guidelines and risk-reduction recommendations. Objective: To estimate the rate and risk of severe breakthrough illness among vaccinated PWH and people without HIV (PWoH) who experience a breakthrough infection. Design, Setting, and Participants: In this cohort study, the Corona-Infectious-Virus Epidemiology Team (CIVET-II) collaboration included adults (aged ≥18 years) with HIV who were receiving care and were fully vaccinated by June 30, 2021, along with PWoH matched according to date fully vaccinated, age group, race, ethnicity, and sex from 4 US integrated health systems and academic centers. Those with postvaccination COVID-19 breakthrough before December 31, 2021, were eligible. Exposures: HIV infection. Main Outcomes and Measures: The main outcome was severe COVID-19 breakthrough illness, defined as hospitalization within 28 days after a breakthrough SARS-CoV-2 infection with a primary or secondary COVID-19 discharge diagnosis. Discrete time proportional hazards models estimated adjusted hazard ratios (aHRs) and 95% CIs of severe breakthrough illness within 28 days of breakthrough COVID-19 by HIV status adjusting for demographic variables, COVID-19 vaccine type, and clinical factors. The proportion of patients who received mechanical ventilation or died was compared by HIV status. Results: Among 3649 patients with breakthrough COVID-19 (1241 PWH and 2408 PWoH), most were aged 55 years or older (2182 patients [59.8%]) and male (3244 patients [88.9%]). The cumulative incidence of severe illness in the first 28 days was low and comparable between PWoH and PWH (7.3% vs 6.7%; risk difference, -0.67%; 95% CI, -2.58% to 1.23%). The risk of severe breakthrough illness was 59% higher in PWH with CD4 cell counts less than 350 cells/µL compared with PWoH (aHR, 1.59; 95% CI, 0.99 to 2.46; P = .049). In multivariable analyses among PWH, being female, older, having a cancer diagnosis, and lower CD4 cell count were associated with increased risk of severe breakthrough illness, whereas previous COVID-19 was associated with reduced risk. Among 249 hospitalized patients, 24 (9.6%) were mechanically ventilated and 20 (8.0%) died, with no difference by HIV status. Conclusions and Relevance: In this cohort study, the risk of severe COVID-19 breakthrough illness within 28 days of a breakthrough infection was low among vaccinated PWH and PWoH. PWH with moderate or severe immune suppression had a higher risk of severe breakthrough infection and should be included in groups prioritized for additional vaccine doses and risk-reduction strategies.

Effect of Digital Medication Event Reminder and Monitor-Observed Therapy vs Standard Directly Observed Therapy on Health-Related Quality of Life and Catastrophic Costs in Patients With Tuberculosis: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Little is known about whether digital adherence technologies are economical for patients with tuberculosis (TB) in resource-constrained settings. Objective: To test the hypothesis that for patients with TB, a digital medication event reminder monitor (MERM)-observed therapy provides higher health-related quality of life (HRQoL) and lower catastrophic costs compared with standard directly observed therapy (DOT). Design, Setting, and Participants: This study was a secondary analysis of a randomized, 2-arm, open-label trial conducted in 10 health care facilities in Ethiopia. Eligible participants were adults with new or previously treated, bacteriologically confirmed, drug-sensitive pulmonary TB who were eligible to start first-line anti-TB therapy. Participants were enrolled between June 2, 2020, and June 15, 2021, with the last participant completing follow-up on August 15, 2021. Interventions: Participants were randomly assigned (1:1) to receive a 15-day TB medication supply dispensed with a MERM device to self-administer and return every 15 days (intervention arm) or the standard in-person DOT (control arm). Both groups were observed throughout the standard 2-month intensive treatment phase. Main Outcomes and Measures: Prespecified secondary end points of the original trial were HRQoL using the EuroQoL 5-dimension 5-level (EQ-5D-5L) tool and catastrophic costs, direct (out-of-pocket) and indirect (guardian and coping) costs from the individual patient perspective using the World Health Organization's Tool to Estimate Patient Costs, and common factors associated with lower HRQoL and higher catastrophic costs. Results: Among 337 patients screened for eligibility, 114 were randomly assigned, and 109 were included in the final complete-case intention-to-treat analysis (57 control and 52 intervention participants). The mean (SD) age was 33.1 (11.1) years; 72 participants (66.1%) were men, and 15 (13.9%) had HIV coinfection. EQ-5D-5L overall median (IQR) index value was 0.964 (0.907-1). The median (IQR) value was significantly higher in intervention (1 [0.974-1]) vs control (.908 [0.891-0.964]) (P < .001). EQ-5D-5L minimum and maximum health state utility values in intervention were 0.906 and 1 vs 0.832 and 1 in control. Patients' overall median (IQR) postdiagnosis cost was Ethiopian birr (ETB) 80 (ETB 16-ETB 480) (US $1.53). The median cost was significantly lower in intervention (ETB 24 [ETB 16-ETB 48]) vs control (ETB 432 [ETB 210-ETB 1980]) (P < .001), with median possible cost savings of ETB 336 (ETB 156-ETB 1339) (US $6.44) vs the control arm. Overall, 42 participants (38.5%; 95% CI, 29.4%-48.3%) faced catastrophic costs, and this was significantly lower in the intervention group (11 participants [21.2%]; 95% CI, 11.1%-34.7%) vs control (31 participants [54.4%]; 95% CI, 40.7%-67.6%) (P < .001). Trial arm was the single most important factor in low HRQoL (adjusted risk ratio [ARR], 1.49; 95% CI, 1.35-1.65; P < .001), while trial arm (ARR, 2.55; 95% CI, 1.58-4.13; P < .001), occupation (ARR, 2.58; 95% CI, 1.68-3.97; P < .001), number of cohabitants (ARR, 0.64; 95% CI, 0.43-0.95; P = .03), and smoking (ARR, 2.71; 95% CI, 1.01-7.28; P = .048) were the most important factors in catastrophic cost. Conclusions and Relevance: In patients with TB, MERM-observed therapy was associated with higher HRQoL and lower catastrophic costs compared with standard DOT. Patient-centered digital health technologies could have the potential overcoming structural barriers to anti-TB therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT04216420.