Veterans Aging Cohort Study Index Research Articles

Self-injurious unnatural death among Veterans with HIV: a nested case-control study.

People living with HIV (PWH) are at increased risk of suicide and death from unintentional causes compared with people living without HIV. Broadening the categorization of death from suicide to self-injurious unnatural death (SIUD) may better identify a more complete set of modifiable risk factors that could be targeted for prevention efforts among PWH. We conducted a nested case-control study using data from the Veterans Aging Cohort Study (VACS), a longitudinal, observational cohort of Veterans from 2006-2015. A total of 5,036 Veterans with HIV, of whom 461 died by SIUD, were included in the sample. SIUD was defined using the International Classification of Disease 10th revision cause of death codes. Cases (n = 461) included individuals who died by SIUD (intentional, unintentional, and undetermined causes of death). Controls (n = 4,575) were selected using incidence density sampling, matching on date of birth ± one year, race, sex, and HIV status. SIUD and suicide was estimated using conditional logistic regression. A previous suicide attempt, a diagnosis of an affective disorder, recent use of benzodiazepines, psychiatric hospitalization, and living in the western US significantly increased the risk of suicide and SIUD. Risk factors that appear more important for SIUD than for suicide included a drug use disorder, alcohol use disorder, Hepatitis C, VACS Index 2.0, current smoking, and high pain levels (7-10). Limiting studies to known suicides obscures the larger public health burden of excess deaths from self-injurious behavior. Our findings demonstrate the benefit of expanding the focus to SIUD for the identification of modifiable risk factors that could be targeted for treatment.

Veterans Aging Cohort Study Index 2.0 Shows Improved Discrimination of Neurocognitive Impairment and Frailty in People with HIV

Objective: This study examined whether the revised VACS2.0 index (including serum albumin, body mass index (BMI), and white blood cell (WBC) count) had stronger correlations with cognitive function, brain volume, and frailty in PWH ≥ 50 years compared to the VACS1.0. Design and Methods: Neuropsychological performance (NP) Z-scores (learning, retention, executive functioning (EF), psychomotor function/processing speed (PM/PS), language, and global cognition), and neuroimaging measures (brain volumetrics) were analyzed in PWH (n = 162). A subset of the sample (n = 159) was defined as either frail (n = 18) or non-frail (n = 141) according to the Fried phenotype criteria. Brain volumes, NP scores, and frailty subgroups were analyzed with both VACS scores, albumin, BMI, and WBC count using Pearson's significance tests and independent T-tests. Results: Higher VACS scores significantly correlated with lower brain volumes. Higher VACS2.0 scores were associated with lower NP in the EF and PM/PS domains and were primarily driven by albumin. VACS1.0 scores did not correlate with cognition Z-scores. There was no relationship between frailty status and VACS1.0. PWH who were frail had significantly greater VACS2.0 scores than non-frail PWH. Conclusions: The addition of albumin to the VACS index improved its correlations with NP and frailty in PWH. While low albumin levels may contribute to cognitive decline or frailty, the reverse causality should also be considered. These findings suggest that the VACS2.0 index (especially albumin) is a valuable measure for clinicians to improve outcomes in PWH.

Assessment, Prevalence, and Correlates of Frailty among Moroccan People Aged 50 and above Living with HIV.

Persons living with HIV experience many challenges, such as premature aging and geriatric syndromes. Frailty has become an important determinant of a series of adverse health outcomes. This research aimed to evaluate the prevalence and risk factors for frailty in this population. A cross-sectional outpatient investigation was conducted in an urban HIV clinic. Patients aged 50 and older living with HIV were included. Frailty phenotype was evaluated using the original Fried criteria, and we calculated the Veterans Aging Cohort Study (VACS) index, Charlson Comorbidity Index, Fracture Risk Assessment Tool scores, and Mini-mental State Exam scores. One hundred and nine individuals were studied. Ninety-two (84.4%) were men, with a mean age of 57.65.2 years. Fourteen (12.8%) participants were frail. Frail participants were older (P = 0.001) and less likely to be virally suppressed (P = 0.01). Having ≥3 comorbidities, VACS index, polypharmacy, and 5-year mortality risk was significantly greater in the frail group. Frailty was significantly associated with poorer quality of life (P = 0.02). The cognitive impairment, falls, and malnutrition risk were significantly associated with a risk to manifest a frail phenotype. Frailty is common among Moroccans with HIV, and it is associated with greater morbidity and mortality rates. Our findings should serve as a warning sign to standardize frailty and geriatric syndrome screening in this population.

Frailty assessment: An emerging concept in aged People Living with HIV (PLHIV).

As the life expectancy of People Living with HIV (PLHIV) has improved with effective antiretroviral treatment (ART), they now face the challenges of accelerated ageing. Frailty is an emerging concept in the management of PLHIV and up to 28% of PLHIV are identified as frail. Frailty is a determinant of adverse clinical outcomes and is a complex clinical endpoint that has not been studied in India. This exploratory study was done to evaluate frailty and its determinants among PLHIV in India. This was a cross-sectional study in 76 PLHIV aged 50 years or more. All the study subjects underwent a comprehensive clinical assessment. The Fried's criteria and Veterans Aging Cohort Study (VACS) Index were used to evaluate for frailty. Socio-demographic, clinical, immunological, and virological variables were assessed for their association with frailty. The study was registered under Clinical Trials Registry-India (ICMR-NIMS): REF/2019/05/025616. The mean age of the subjects was 56.05 ± 5.8 years (range 50-76), and males constituted 81.57% (62/76) of the subjects and majority (60.53%) were underweight. On frailty assessment, 57.89% of the PLHIV were identified as prefrail/frail. Frailty had a significant association with low CD4 count (P = 0.0001) and number of comorbidities (P = 0.017) especially when comorbidities ≥2 (P = 0.04) and polypharmacy (P = 0.033). VACS index, polypharmacy, and low CD4 count ≤200 cells/mm3 were strong predictors of frailty. On multivariate regression analysis, CD4 count ≤200 emerged as the strongest independent predictor of frailty. The study highlighted the high prevalence of frailty and under nutrition among aged PLHIV. The study emphasizes the need for a shift away from traditional clinical endpoints to other outcome measures for a holistic approach to PLHIV.

The clinical utility of three frailty measures in identifying HIV-associated neurocognitive disorders.

Frailty measures vary widely and the optimal measure for predicting HIV-associated neurocognitive disorders (HAND) is unclear. A study was conducted to examine the clinical utility of three widely used frailty measures in identifying HIV-associated neurocognitive disorders. The study involved 284 people with HIV (PWH) at least 50 years enrolled at UC San Diego's HIV Neurobehavioral Research Program. Frailty measurements included the Fried Phenotype, the Rockwood Frailty Index, and the Veterans Aging Cohort Study (VACS) Index. HAND was diagnosed according to Frascati criteria. ANOVAs examined differences in frailty severity across HAND conditions. ROC analyses evaluated sensitivity and specificity of each measure to detect symptomatic HAND [mild neurocognitive disorder (MND) and HIV-associated dementia (HAD)] from no HAND. Across all frailty measures, frailty was found to be higher in HAD compared with no HAND. For Fried and Rockwood (not VACS), frailty was significantly more severe in MND vs. no HAND and in HAD vs. ANI (asymptomatic neurocognitive impairment). For discriminating symptomatic HAND from no HAND, Fried was 37% sensitive and 92% specific, Rockwood was 85% sensitive and 43% specific, and VACS was 58% sensitive and 65% specific. These findings demonstrate that Fried and Rockwood outperform VACS in predicting HAND. However, ROC analyses suggest none of the indices had adequate predictive validity in detecting HAND. The results indicate that the combined use of the Rockwood and Fried indices may be an appropriate alternative.

Preadmission Veterans Aging Cohort Study Index Is Associated with AKI in Hospitalized People with HIV

Preadmission Veterans Aging Cohort Study Index Is Associated with AKI in Hospitalized People with HIV

Contingency management with stepped care for unhealthy alcohol use among individuals with HIV: Protocol for a randomized controlled trial

BackgroundAlthough unhealthy alcohol use is associated with increased morbidity and mortality among people with HIV (PWH), many are ambivalent about engaging in treatment and experience variable responses to treatment. We describe the rationale, aims, and study design for the Financial Incentives, Randomization, with Stepped Treatment (FIRST) Trial, a multi-site randomized controlled efficacy trial. MethodsPWH in care recruited from clinics across the United States who reported unhealthy alcohol use, had a phosphatidylethanol (PEth) >20 ng/mL, and were not engaged in formal alcohol treatment were randomized to integrated contingency management with stepped care versus treatment as usual. The intervention involved two steps; Step 1: Contingency management (n = 5 sessions) with potential rewards based on 1) short-term abstinence; 2) longer-term abstinence; and 3) completion of healthy activities to promote progress in addressing alcohol consumption or conditions potentially impacted by alcohol; Step 2: Addiction physician management (n = 6 sessions) plus motivational enhancement therapy (n = 4 sessions). Participants' treatment was stepped up at week 12 if they lacked evidence of longer-term abstinence. Primary outcome was abstinence at week 24. Secondary outcomes included alcohol consumption (assessed by TLFB and PEth) and the Veterans Aging Cohort Study (VACS) Index 2.0 scores; exploratory outcomes included progress in addressing medical conditions potentially impacted by alcohol. Protocol adaptations due to the COVID-19 pandemic are described. ConclusionsThe FIRST Trial is anticipated to yield insights on the feasibility and preliminary efficacy of integrated contingency management with stepped care to address unhealthy alcohol use among PWH.ClinicalTrials.gov identifier: NCT03089320.

Accelerated epigenetic aging in older adults with HIV disease: associations with serostatus, HIV clinical factors, and health literacy.

The prevalence of older persons with HIV (PWH) disease has increased considerably in the last 20 years, but our understanding of biological factors of aging and their clinical correlates among PWH remains limited. Study participants were 149 persons aged 50 and older, including 107 PWH and 42 seronegatives. All participants completed a blood draw, research medical evaluation, structured psychiatric interview, neurocognitive assessment, questionnaires, and measures of health literacy. Four epigenetic clocks were generated from stored blood samples using standardized laboratory methods. In regression models adjusting for sex and smoking status, PWH had significantly higher epigenetic aging acceleration values than seronegatives on all four indicators. Within the PWH sample, higher levels of epigenetic aging acceleration were moderately associated with lower current CD4 count, AIDS diagnoses, higher scores on the Veterans Aging Cohort Study Index, and lower telomere values. Higher epigenetic aging acceleration indices were also associated with lower health literacy among PWH. PWH experience accelerated aging as measured by a series of epigenetic clocks, which may be linked to immune compromise and risk of all-cause mortality. Health literacy may be a modifiable target for mitigating the risk of accelerated aging among older PWH.

Rationale and design of the Anal HPV, HIV and Aging (AHHA) study: Protocol for a prospective study of anal HPV infection and HSIL among men who have sex (MSM) or trans women living with and without HIV, ages 50 and older.

More than half of people living with HIV in the US are 50+ years old. Despite the benefits of antiretroviral therapy, older individuals with HIV are at higher risk for illnesses than their HIV-negative counterparts. Anal cancer, anal high-grade squamous intraepithelial lesions (HSIL), and anal HPV-16 infection occur most frequently among men who have sex with men living with HIV (MSMLWH). Men aged 60+ are 3-fold more likely to be diagnosed with anal cancer compared with younger men. Despite the increasing risk of anal cancer with age and HIV, little is known about the relationships among aging, HPV infection, HSIL and HIV. The Anal HPV, HIV, and Aging (AHHA) Study is a two-stage project to evaluate the relationships among anal HPV infection, HSIL, HIV infection, and biomarkers of biological aging in MSM or trans women over the age of 50 years. Stage 1 will estimate the cross-sectional prevalence of both anal HPV infection and HSIL, based on outcomes of anal HPV DNA testing, and high-resolution anoscopy with biopsy. We will also study associations with study outcomes and serological biomarkers of inflammation (interleukin-6, C-reactive protein, D-dimer) and with the Veterans Aging Cohort Study Index and the Fried Frailty Phenotype using multivariable models. Participants living with HIV (n = 150) and HIV-negative participants (n = 150) will be enrolled. The 3-year Stage 2 longitudinal sample restricted to HSIL-negative and anal HPV-16 DNA-negative participants will estimate the 3-year incidence of both anal HSIL and anal HPV, stratified by HIV status through Cox proportional hazards regression. The effect of biomarkers of inflammation and markers of aging on study outcomes will be evaluated through multivariable repeated measures models stratified by HIV status. This protocol was approved by the University of California, San Francisco Institutional Review Board (IRB: 16-18966). Results will be disseminated through presentations at national/international scientific conferences and publication in peer-reviewed journals.

Alcohol use, physical activity, and muscle strength moderate the relationship between body composition and frailty risk among people living with HIV.

Antiretroviral therapy has improved life expectancy among people living with HIV (PLWH). Despite increased longevity, PLWH are at increased risk of age-related comorbidities, including frailty. We examined the relationship between body composition and frailty among PLWH, and moderation of this relationship by substance use, physical activity (PA), and physical function. Participants (n= 341; 71% male, 48 ± 10 years, body mass index (BMI)=27.3 ± 7.0 kg/m2 ) enrolled in the New Orleans Alcohol Use in HIV (NOAH) study underwent measures of body composition, muscle strength, and gait speed. Whole blood phosphatidylethanol (PEth) was measured, and substance use and PA were self-reported. Frailty risk measures included the 58-Item Deficit Index (DI58) and the Veterans Aging Cohort Study (VACS) Index 1.0, where higher scores indicate greater frailty risk. Multivariable linear regression adjusted for age, sex, and race showed that higher fat-free mass index (FFMI), body fat (%), waist-to-hip ratio, and body mass index (BMI) ≥ 25.0 kg/m2 vs. < 25.0 kg/m2 were significantly (p< 0.05) associated with decreased frailty risk measured by the VACS Index, whereas adjusted analyses showed no association between body composition variables and the DI58 score. Recent alcohol use, muscle strength, and PA, but not lifetime alcohol use or gait speed, significantly moderated associations between body composition variables and frailty risk with medium-to-large effect sizes. Subgroup analyses revealed a negative relationship between DI58 and FFMI among people with PEth>8 ng/ml and negative relationships of VACS Index with FFMI and WHR in people with lower muscle strength. Overweight or obese BMI categories were positively associated with DI58 in people with lower muscle strength or higher PA level but negatively associated in those with higher muscle strength. Our findings indicate that body composition has significant modulatory effects on frailty risk in PLWH, where obesity increases the risk of frailty and greater muscle mass may be protective, even in individuals who use alcohol. These results highlight the importance of considering body composition, physical activity, and physical function in assessing frailty risk in PLWH, particularly among individuals who use alcohol. Moreover, they support the implementation of physical activity interventions to ameliorate the risk of frailty in aging PLWH.

Predictive Risk Model for Serious Falls Among Older Persons Living With HIV.

Older (older than 50 years) persons living with HIV (PWH) are at elevated risk for falls. We explored how well our algorithm for predicting falls in a general population of middle-aged Veterans (age 45-65 years) worked among older PWH who use antiretroviral therapy (ART) and whether model fit improved with inclusion of specific ART classes. This analysis included 304,951 six-month person-intervals over a 15-year period (2001-2015) contributed by 26,373 older PWH from the Veterans Aging Cohort Study who were taking ART. Serious falls (those falls warranting a visit to a health care provider) were identified by external cause of injury codes and a machine-learning algorithm applied to radiology reports. Potential predictors included a fall within the past 12 months, demographics, body mass index, Veterans Aging Cohort Study Index 2.0 score, substance use, and measures of multimorbidity and polypharmacy. We assessed discrimination and calibration from application of the original coefficients (model derived from middle-aged Veterans) to older PWH and then reassessed by refitting the model using multivariable logistic regression with generalized estimating equations. We also explored whether model performance improved with indicators of ART classes. With application of the original coefficients, discrimination was good (C-statistic 0.725; 95% CI: 0.719 to 0.730) but calibration was poor. After refitting the model, both discrimination (C-statistic 0.732; 95% CI: 0.727 to 0.734) and calibration were good. Including ART classes did not improve model performance. After refitting their coefficients, the same variables predicted risk of serious falls among older PWH nearly and they had among middle-aged Veterans.

Veterans Aging Cohort Study Index and Frailty: One Part of the Whole.

In HIV medicine, the Veterans Aging Cohort Study (VACS) index is associated to some geriatric syndromes and has also been recently used as a proxy of frailty. However, using it as a proxy for the frailty phenotype may inadvertently interchange two different concepts. The purpose of this study was to evaluate to what extent the frailty phenotype may be explained by the index. Cross-sectional analysis included 393 participants with HIV aged 50 or older. Somers' delta (d) was calculated, and a multinomial logistic regression model was run to determine to what extent the VACS index scores explained the probability of being prefrail or frail. Mean age was 57.6 (standard deviation 6.5) years and 87.3% men. A weak, but positive association between the VACS 2.0 index score and the frailty phenotype was established (Somers' d = 0.120, p < .001). The multinomial logistic regression showed that prefrail and frail participants had higher probabilities for greater VACS index scores [OR = 1.05, 95% confidence intervals (CI) 1.01-1.09; p = .006 and OR = 1.17, 95% CI 1.09-1.26; p < .001, respectively]; however, VACS index only explained <12% of the variability observed in the frailty phenotype. High VACS index scores were associated with a greater probability of being frail; however, with a weak association. Thus, we should be cautious when using the VACS index as a general proxy of frailty, particularly for the frailty phenotype. However, the VACS index may be used as a means to identify persons who might benefit from further comprehensive geriatric assessment.

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

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. 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. 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. 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.

Association Between VACS Index and Health-Related Quality of Life in Persons with HIV: Moderating Role of Fruit and Vegetable Consumption

BackgroundThe health status of people with HIV (PWH) influences their health-related quality of life (HRQOL). Modifiable lifestyle factors may improve HRQOL. This study (1) explores the association between modifiable lifestyle factors (physical activity and nutrition) and HRQOL and (2) examines if these lifestyle factors moderate the association health status and HRQOL.MethodsParticipants included 91 community dwelling PWH (age 36–65 years) from the university lab. Participants reported mental and physical HRQOL via the Medical Outcome Study 36-Item Short-Form (SF-36). Physical activity was examined via the International Physical Activity Questionnaire and nutrition (i.e., fruit and vegetable consumption) was assessed with the By-Meal Screener. Health status was ascertained via the Veterans Aging Cohort Study (VACS) Index.ResultsAim 1 analyses indicated that neither physical activity nor nutrition was related to mental HRQOL (p’s > .05). However, greater physical activity (β = .33, p < .01) and nutrition (β = .23, p = .03) were each independently related to better physical HRQOL and remained significant after accounting for co-occurring medical conditions. For aim 2, the interaction between health status and nutrition was statistically significant (β = .24, p = .02), such that the association between worse health status and worse physical HRQOL was weaker with better nutrition. There was not a statistically significant interaction between physical activity and health status on physical HRQOL (p > .05).ConclusionPhysical HRQOL is related to self-reported physical activity and nutrition, with nutrition showing a moderating effect on the association between health status and physical HRQOL. Thus, future interventional studies designed to improve physical HRQOL should target both physical activity and nutrition.

Degree of Polypharmacy and Cognitive Function in Older Women with HIV.

The number of people with HIV (PWH) experiencing age-associated comorbidities including those treated with medications and cognitive impairment is increasing. We examined associations between polypharmacy and cognition in older women with HIV (WWH) given their vulnerability to this comorbidity. Cross-sectional analysis capitalizing on Women's Interagency HIV Study data collected between 2014 and 2017. WWH meeting the following criteria were analyzed: age ≥50 years; availability of self-reported non-antiretroviral therapy (ART) medications data; and neuropsychological data. The number of non-ART medications used regularly in the prior 6 months was summed. Polypharmacy was categorized as none/low (0-4), moderate (5-9), or severe (≥10). Multivariable linear regression analyses examined polypharmacy-cognition (T-score) associations in the total sample and among virally suppressed (VS; < 20 copies/mL)-WWH after covariate adjustment for enrollment site, income, depressive symptoms, substance use (smoking, heavy alcohol, marijuana, crack, cocaine, and/or heroin), the Veterans Aging Cohort Study index (indicators of HIV disease and organ system function, hepatitis C virus serostatus), ART use, nadir CD4 count, and specific ART drugs (efavirenz, integrase inhibitors). We included 637 women (median age = 55 years; 72% Black). Ninety-four percent reported ART use in the past 6 months and 75% had HIV RNA <20 copies/mL. Comorbidity prevalence was high (61% hypertension; 26% diabetes). Moderate and severe polypharmacy in WWH were 34% and 24%. In WWH, severe polypharmacy was associated with poorer executive function (p = .007) and processing speed (p = .01). The same pattern of findings remained among VS-WWH. Moderate polypharmacy was not associated with cognition. Moderate and severe polypharmacy were common and associated with poorer executive function and processing speed in WWH. Severe polypharmacy may be a major contributor to the persistence of domain-specific cognitive complications in older WWH above and beyond the conditions that these medications are used to treat.

Frailty and sarcopenia among Turkish people aged 40 and above living with HIV.

People living with HIV face a variety of challenges, including accelerated ageing and geriatric syndromes. In this study, we aimed to examine the prevalence of frailty and sarcopenia among Turkish people living with HIV. In total, 100 people living with HIV were recruited in this study. Frailty was determined using Fried's frailty phenotype, and we calculated the Charlson Comorbidity Index, Veterans Aging Cohort Study (VACS) index, fracture risk assessment tool scores, and Mini-Mental State Exam scores. We determined muscle mass using bioelectric impedance analysis, gastrocnemius muscle thickness using ultrasonography, and muscle strength using handgrip strength. The mean±standard deviation age was 50.0±8.3years. In total, 11% of the patients were frail. The risk of comorbidity and mortality, VACS index, and 5-year mortality risk was significantly higher in the frail group, as was sarcopenia. Fat-free muscle mass and handgrip strength were correlated with gastrocnemius muscle thickness. Gastrocnemius muscle thickness suggestive of sarcopenia was defined as 13.05mm. The cognitive impairment rate was 5% and was associated with physical frailty. Frailty is common and associated with higher morbidity and mortality rates among Turkish people living with HIV.

Epigenetic biomarkers of ageing, physiological frailty, and mortality in people with HIV: a longitudinal cohort study

BackgroundApproaches that provide insight into ageing mechanisms for people with HIV are needed. Epigenetic modifications such as DNA methylation have been operationalised as epigenetic clocks, providing an estimate of age acceleration in years (DNA methylation age acceleration; DNAmAA). Our objective was to determine if measures of DNAmAA predict physiological frailty, as measured by the Veterans Aging Cohort Study (VACS) Index and all-cause mortality, in people with HIV. MethodsAs part of the observational VACS, we profiled epigenome-wide DNA methylation on peripheral blood samples collected from people with HIV as part of a biomarker cohort. We generated six established measures of DNAmAA in samples from 531 participants with VACS Index data at the time of sample collection. All-cause mortality was assessed over 10 years. For each DNAmAA measure, the hazard ratio (HR) per increased unit (1 year) was determined using Cox regression. To test the association of DNAmAA measures with the VACS Index 2.0, linear regression was performed. All regression models were performed with and without adjustment for chronological age. FindingsParticipants were mostly men (98·5% [n=523]; 1·5% [n=8] women); 83·4% (n=448) were Black, 10·5% (n=56) were White, and 5·1% (n=27) were Hispanic; and their mean age was 52·4 years (SD 7·8). There were 136 deaths during a median follow-up of 8·7 years (IQR 7·7–9·4). Hannum's DNAm age acceleration (Hannum AA), extrinsic epigenetic age acceleration (EEAA), Grim age acceleration (Grim AA), and Pheno age acceleration (Pheno AA) were significantly associated with all-cause mortality, but Horvath's DNAm age acceleration (Horvath AA) and intrinsic epigenetic age acceleration (IEAA) were not in unadjusted and age-adjusted models. GrimAA was the strongest predictor (adjusted HR 1·10, 95% CI 1·06–1·14; p<0·0001). Similarly, four of the six DNAmAA measures were significantly associated with the VACS Index in unadjusted and age-adjusted models. Each year increase in GrimAA was associated with a point increase in VACS Index (adjusted β 1·16, 95% CI 0·905–1·42; p<0·0001). InterpretationAmong people with HIV, several DNAmAA measures predicted all-cause mortality and physiological frailty. Each 1-year increase in GrimAA was associated with a 10% increased risk of death. A 5-year increase in GrimAA was associated with a clinically meaningful 5·8-point increase in VACS Index. GrimAA might provide key insights into the molecular mechanisms mediating biological ageing and physiological frailty, while informing the design of novel strategies to reduce mortality and morbidity for people with HIV. FundingKKO received funding from the US Department of Veterans Affairs (grant number I01 RX002790). VCM received funding from Emory (grant number CFAR P30 AI050409). ZW received funding from NIDDK (grant number R01DK125187). KX received funding from NIDA (grant number R01DA042691). MM received funding from NIA (grant numbers P30 AG031679 and P30AI060354). ACJ received funding from NIAAA (grant numbers U24-AA020794, U01-AA020790, U24-AA022001, U10 AA013566 [completed], in kind by US Department of Veterans Affairs). YVS received funding from NIDDK (grant number R01-DK125187) and Emory (grant number CFAR P30 AI050409).

The clinical utility of three frailty measures in identifying HIV-associated neurocognitive disorders: a cross-sectional comparison of the Fried Phenotype, Rockwood Frailty Index, and Veterans Aging Cohort Study Index

BackgroundFrailty is associated with poorer cognitive functioning among people with HIV. Frailty measures vary widely and the optimal measure for predicting HIV-associated neurocognitive disorders (HAND) is unclear. MethodsParticipants were 289 people with HIV, aged 50 years or older (mean age 59·6 years, SD 7·3; 87% male, 13% female), enrolled in University of California San Diego's HIV Neurobehavioral Research Program from 2014 to 2020. Frailty measurements included the Fried Phenotype criteria (0–5 symptoms: weight loss, exhaustion, low physical activity, slowness, weakness), the Rockwood Frailty Index (proportion of general and HIV-specific health deficits ranging from 0 [no deficits] to 1 [all 34 deficits]), and the Veterans Aging Cohort Study (VACS) Index 1.0. HIV-associated Neurocognitive Disorders (HAND) was diagnosed according to the Frascati criteria using a seven-domain neuropsychological test. Separate ANOVAs (ie, one for each frailty measure) were used to examine differences in frailty severity between HAND subgroups, and receiver operating characteristic (ROC) analyses evaluated sensitivity and specificity of each frailty measure to detect symptomatic HAND (mild neurocognitive disorder and HIV-associated dementia) from cognitively normal cases. FindingsParticipants diagnosed with HIV-associated dementia had higher rates of frailty than participants without HAND among all three frailty measures (p<0·05; ds>0·41). Significant differences in frailty severity were observed between no HAND and mild neurocognitive disorder (p<0·05; ds>0·48) as well as asymptomatic HIV-associated neurocognitive impairment and HIV-associated dementia (p<0·05; ds>0·53) when using the Fried Phenotype or the Rockwood Frailty Index, but not with the VACS Index. To detect people who were symptomatic from individuals who were cognitively normal, an optimal cutoff of at least 3 was identified for the Fried Frailty index (area under the curve [AUC] 0·71), with sensitivity of 37% and specificity of 92%; an optimal cutoff of at least 0·206 was identified for the Rockwood Frailty index (AUC 0·66), with sensitivity of 85% and specificity of 43%; and an optimal cutoff of at least 29 was identified for the VACS index (AUC 0·59), with sensitivity of 58% and specificity of 65%. InterpretationFried and Rockwood outperformed VACS in predicting HAND; however, ROC analyses suggest none of the indices had adequate predictive validity in detecting HAND. Given the Rockwood Index's overly inclusiveness (high sensitivity), we proposed it be used as a screening tool. When combined with the Frailty Index, which has demonstrated to be a good exclusionary tool (high specificity), the two measure can be clinically useful together in detecting HAND. FundingNational Institute of Mental Health (R01 MH099987, P30 MH062512), the National Institute on Drug Abuse (T32 DA031098 and F31AG064989), and the National Institute on Alcohol Abuse and Alcoholism (F31 AA027198).

Periods of Homelessness Linked to Higher VACS Index Among HIV-Positive People Who Use Drugs.

We sought to evaluate the impact of homelessness on HIV disease progression among people who use unregulated drugs (PWUD) living with HIV and test if this association was mediated by adherence to antiretroviral therapy (ART). We applied general linear mixed-effects modeling to estimate the longitudinal relationship between homelessness and the Veterans Aging Cohort Study (VACS) Index, a validated measure of HIV disease progression that predicts all-cause mortality, among a prospective cohort of PWUD. In a longitudinal model adjusted for ART adherence, homelessness was significantly associated with increased VACS Index scores and 16% of the association was mediated by ART adherence. These findings indicate that homelessness was a significant risk factor for HIV disease progression and this association was marginally mediated by ART adherence. Future studies are needed to quantify the other mechanisms (e.g., food insecurity, mental health) by which homelessness increases mortality risk among PWUD living with HIV.

Association of the VACS Index With Hospitalization Among People With HIV in the NA-ACCORD.

People with HIV (PWH) have a higher hospitalization rate than the general population. The Veterans Aging Cohort Study (VACS) Index at study entry well predicts hospitalization in PWH, but it is unknown if the time-updated parameter improves hospitalization prediction. We assessed the association of parameterizations of the VACS Index 2.0 with the 5-year risk of hospitalization. PWH ≥30 years old with at least 12 months of antiretroviral therapy (ART) use and contributing hospitalization data from 2000 to 2016 in North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) were included. Three parameterizations of the VACS Index 2.0 were assessed and categorized by quartile: (1) "baseline" measurement at study entry; (2) time-updated measurements; and (3) cumulative scores calculated using the trapezoidal rule. Discrete-time proportional hazard models estimated the crude and adjusted associations (and 95% confidence intervals [CIs]) of the VACS Index parameterizations and all-cause hospitalizations. The Akaike information criterion (AIC) assessed the model fit with each of the VACS Index parameters. Among 7289 patients, 1537 were hospitalized. Time-updated VACS Index fitted hospitalization best with a more distinct dose-response relationship [score <43: reference; score 43-55: aHR = 1.93 (95% CI: 1.66 to 2.23); score 55-68: aHR = 3.63 (95% CI: 3.12 to 4.23); score ≥68: aHR = 9.98 (95% CI: 8.52 to 11.69)] than study entry and cumulative VACS Index after adjusting for known risk factors. Time-updated VACS Index 2.0 had the strongest association with hospitalization and best fit to the data. Health care providers should consider using it when assessing hospitalization risk among PWH.