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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., Competing Interests: V.C.M. has received investigator-initiated research grants (to the institution) and consultation fees (both unrelated to the current work) from Eli Lilly, Bayer, Gilead Sciences, and ViiV. K.J.V. received support from NICHD 1U19HD089881. V.C.M. received support from Emory CFAR P30 AI050409. The remaining authors have no funding or conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: HIV, hepatitis C virus (HCV), and alcohol-related diagnoses (ARD) independently contribute increased risk of all-cause hospitalization. We sought to determine annual medical intensive care unit (MICU) admission rates and relative risk of MICU admission between 1997 and 2014 among people with and without HIV, HCV, and ARD, using data from the largest HIV and HCV care provider in the United States., Setting: Veterans Health Administration., Methods: Annual MICU admission rates were calculated among 155,550 patients in the Veterans Aging Cohort Study by HIV, HCV, and ARD status. Adjusted rate ratios and 95% confidence intervals (CIs) were estimated with Poisson regression. Significance of trends in age-adjusted admission rates were tested with generalized linear regression. Models were stratified by calendar period to identify shifts in MICU admission risk over time., Results: Compared to HIV-/HCV-/ARD- patients, relative risk of MICU admission decreased among HIV-mono-infected patients from 61% (95% CI: 1.56 to 1.65) in 1997-2009% to 21% (95% CI: 1.16 to 1.27) in 2010-2014, increased among HCV-mono-infected patients from 22% (95% CI: 1.16 to 1.29) in 1997-2009% to 54% (95% CI: 1.43 to 1.67) in 2010-2014, and remained consistent among patients with ARD only at 46% (95% CI: 1.42 to 1.50). MICU admission rates decreased by 48% among HCV-uninfected patients (P-trend <0.0001) but did not change among HCV+ patients (P-trend = 0.34)., Conclusion: HCV infection and ARD remain key contributors to MICU admission risk. The impact of each of these conditions could be mitigated with combination of treatment of HIV, HCV, and interventions targeting unhealthy alcohol use.

Background: Despite historically high rates of herpes zoster among people living with HIV (PLWH), comparative studies of herpes zoster by HIV serostatus are lacking since the advent of combination antiretroviral therapy and availability of zoster vaccine., Methods: Annual rates (2002-2015) of first-episode herpes zoster and zoster vaccination were calculated for PLWH and uninfected adults in the Veterans Aging Cohort Study and stratified by HIV serostatus and age. Herpes zoster was captured using ICD9 codes and vaccine receipt with procedural codes and pharmacy data., Results: Of 45,177 PLWH and 103,040 uninfected veterans, rates of herpes zoster decreased among PLWH (17.6-8.1/1000) over the study period but remained higher than uninfected adults (4.1/1000) at the end of study period. Rates were higher in PLWH with lower CD4 (<200 vs >500 cells/µL: 18.0 vs 6.8/1000) and unsuppressed vs suppressed HIV-1 RNA (21.8 vs 7.1/1000). Restricted to virologically suppressed participants with CD4 >350 cells per microliter, herpes zoster rates were similar among PLWH aged younger than 60 years and aged 60 years and older in 2015 (6.6 vs 6.7/1000) but higher than all uninfected age groups. At study end, cumulative receipt of zoster vaccine for PLWH aged 60 years and older was less than half that of uninfected veterans: 98.7 vs 215.2/1000., Conclusions: Herpes zoster rates among PLWH have markedly decreased, but, even in cART-treated individuals, remain 50% higher than uninfected adults. Lower rates of zoster vaccine receipt combined with high rates of herpes zoster support the need for a safe and effective vaccine against herpes zoster for PLWH, formal zoster vaccine guidelines for PLWH, and consideration for expanded use at younger ages.

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

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

Background: The health implications of weight gain after antiretroviral therapy (ART) for HIV infection are not well characterized and may differ from weight gain among uninfected individuals. We use data from the Veterans Aging Cohort Study to determine whether weight gain after ART has a similar association with incident type 2 diabetes mellitus (DM) as weight gained among HIV-uninfected (uninfected) individuals., Methods: We explored associations of weight gain and incident diabetes (A1c ≥ 6.5%), in the Veterans Aging Cohort Study, a national observational study of HIV-infected (HIV+) individuals demographically matched 1:2 to uninfected controls. From 2000 to 2011, weight change was assessed in the year following ART initiation for HIV+ individuals and date of first available body mass index for uninfected individuals. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for baseline body mass index using Cox regression., Results: HIV+ individuals had lower prevalence of DM at baseline (12% HIV+, 23% uninfected) and lower incident diabetes (5% HIV+, 11% uninfected). The association of weight gain with risk of DM was linear for HIV+ and uninfected but the slope of the association was steeper for HIV+. For each 5 pounds of weight gained, HIV+ had 14% increased risk of DM (HR, 1.14; 95% CI: 1.10 to 1.17) and uninfected individuals had 8% increased risk (HR, 1.08; 95% CI: 1.07 to 1.10) (P < 0.01 for interaction)., Conclusions: Weight gained in the first year after ART initiation is associated with greater risk of DM than that among uninfected individuals. HIV+ individuals initiating ART who are not underweight should avoid substantial weight gain., Competing Interests: No potential conflicts of interest relevant to this article were reported.

Background: FRAX is a validated, computer-based clinical fracture risk calculator that estimates the 10-year risk of major osteoporotic (clinical spine, forearm, hip, or shoulder) fracture, and hip fracture alone. It is widely used for decision making in fracture prevention, but it may underestimate the risk in HIV-infected individuals. Some experts recommend considering HIV as a cause of secondary osteoporosis when calculating FRAX in HIV-infected individuals., Methods: From the Veterans Aging Cohort Study Virtual Cohort, we included 24,451 HIV-infected and uninfected men aged 50-70 years with complete data in the year 2000 to approximate all but 2 factors (ie, history of secondary osteoporosis and parental hip fracture) for modified-FRAX calculation without bone density and 10-year observational data for incident fragility fracture. The accuracy of the modified-FRAX calculation was compared by the observed/estimated (O/E) ratios of fracture by HIV status., Results: The accuracy of modified-FRAX was less for HIV-infected [O/E = 1.62, 95% confidence interval (CI) 1.45 to 1.81] than uninfected men (O/E = 1.29, 95% CI: 1.19 to 1.40), but improved when HIV was included as a cause of secondary osteoporosis (O/E = 1.20, 95% CI: 1.08 to 1.34). However, only 3%-6% of men with incident fractures were correctly identified by the modified-FRAX using accepted FRAX thresholds for pharmacologic therapy., Conclusions: Modified-FRAX underestimated the fracture rates more in older HIV-infected than in otherwise similar uninfected men. The accuracy improved when HIV was included as a cause of secondary osteoporosis, but it still performed poorly for case finding. Further studies are necessary to determine how to use FRAX or define an HIV-specific index to risk stratify for screening and treatment in older HIV-infected individuals.

Background: HIV infection and biomarkers of inflammation [measured by interleukin-6 (IL-6)], monocyte activation [soluble CD14 (sCD14)], and coagulation (D-dimer) are associated with morbidity and mortality. We hypothesized that these immunologic processes mediate (explain) some of the excess risk of mortality among HIV infected (HIV+) versus uninfected people independently of comorbid diseases., Methods: Among 2350 (1521 HIV+) participants from the Veterans Aging Cohort Study Biomarker Cohort (VACS BC), we investigated whether the association between HIV and mortality was altered by adjustment for IL-6, sCD14, and D-dimer, accounting for confounders. Participants were followed from date of blood draw for biomarker assays (baseline) until death or July 25, 2013. Analyses included ordered logistic regression and Cox Proportional Hazards regression., Results: During 6.9 years (median), 414 deaths occurred. The proportional odds of being in a higher quartile of IL-6, sCD14, or D-dimer were 2-3 fold higher for viremic HIV+ versus uninfected people. Mortality rates were higher among HIV+ compared with uninfected people [incidence rate ratio (95% CI): 1.31 (1.06 to 1.62)]. Mortality risk increased with increasing quartiles of IL-6, sCD14, and D-dimer regardless of HIV status. Adjustment for IL-6, sCD14, and D-dimer partially attenuated mortality risk among HIV+ people with unsuppressed viremia (HIV-1 RNA ≥10,000 copies per milliliter) compared with uninfected people-hazard ratio (95% CI) decreased from 2.18 (1.60 to 2.99) to 2.00 (1.45 to 2.76)., Conclusions: HIV infection is associated with elevated IL-6, sCD14, and D-dimer, which are in turn associated with mortality. Baseline measures of these biomarkers partially mediate excess mortality risk among HIV+ versus uninfected people.

Objective: To examine the cost-effectiveness of the HIV Translating Initiatives for Depression Into Effective Solutions (HITIDES) intervention., Design: Randomized controlled effectiveness and implementation trial comparing depression collaborative care with enhanced usual care., Setting: Three Veterans Health Administration HIV clinics in the Southern United States., Subjects: Two hundred forty-nine HIV-infected patients completed the baseline interview; 123 were randomized to the intervention and 126 to usual care., Intervention: HITIDES consisted of an offsite HIV depression care team that delivered up to 12 months of collaborative care. The intervention used a stepped-care model for depression treatment, and specific recommendations were based on the Texas Medication Algorithm Project and the VA/Department of Defense Depression Treatment Guidelines., Main Outcome Measures: Quality-adjusted life years (QALYs) were calculated using the 12-Item Short Form Health Survey, the Quality of Well Being Scale, and by converting depression-free days to QALYs. The base case analysis used outpatient, pharmacy, patient, and intervention costs. Cost-effectiveness was calculated using incremental cost-effectiveness ratios (ICERs) and net health benefit. ICER distributions were generated using nonparametric bootstrap with replacement sampling., Results: The HITIDES intervention was more effective and cost saving compared with usual care in 78% of bootstrapped samples. The intervention net health benefit was positive and therefore deemed cost-effective using an ICER threshold of $50,000/QALY., Conclusions: In HIV clinic settings, this intervention was more effective and cost saving compared with usual care. Implementation of offsite depression collaborative care programs in specialty care settings may be a strategy that not only improves outcomes for patients but also maximizes the efficient use of limited health care resources.

Background: Pulmonary infections remain more common in HIV-infected (HIV+) compared with uninfected individuals. The increase in chronic lung diseases among aging HIV+ individuals may contribute to this persistent risk. We sought to determine whether chronic obstructive pulmonary disease (COPD) is an independent risk factor for different pulmonary infections requiring hospitalization among HIV+ patients., Methods: We analyzed data from 41,993 HIV+ Veterans in the nationwide Veterans Aging Cohort Study Virtual Cohort from 1996 to 2009. Using International Classification of Diseases, Ninth Revision codes, we identified baseline comorbid conditions, including COPD, and incident community-acquired pneumonia (CAP), pulmonary tuberculosis (TB), and Pneumocystis jirovecii pneumonia (PCP) requiring hospitalization within 2 years after baseline. We used multivariable Poisson regression to determine incidence rate ratios (IRRs) associated with COPD for each type of pulmonary infection, adjusting for comorbidities, CD4 cell count, HIV viral load, smoking status, substance use, vaccinations, and calendar year at baseline., Results: Unadjusted incidence rates of CAP, TB, and PCP requiring hospitalization were significantly higher among persons with COPD compared to those without COPD (CAP: 53.9 vs. 19.4 per 1000 person-years; TB: 8.7 vs. 2.8; PCP: 15.5 vs. 9.2; P ≤ 0.001). In multivariable Poisson regression models, COPD was independently associated with increased risk of CAP, TB, and PCP (IRR: 1.94, 95% confidence interval [CI]: 1.64 to 2.30; IRR: 2.60, 95% CI: 1.70 to 3.97; and IRR: 1.48, 95% CI: 1.10 to 2.01, respectively)., Conclusions: COPD is an independent risk factor for CAP, TB, and PCP requiring hospitalization among HIV+ individuals. As the HIV+ population ages, the growing burden of COPD may confer substantial risk for pulmonary infections.

Objective: To determine predictors and variations in the rate of newly diagnosed HIV infection among persons who underwent routine (ie, non-risk based) rather than risk-based HIV testing in Veterans Health Administration (VHA) facilities., Methods: Retrospective observational study of the HIV infection new rates during the period when VHA policy called for routine (2009-2012) versus risk-based (2006-2009) HIV testing. Source data for testing results at 18 VHA facilities were obtained from the VHA National Corporate Data Warehouse., Results: New HIV diagnoses were established in 0.14% (95% confidence interval (CI): 0.12 to 0.46) of the 210,957 patients tested in the routine testing period versus 0.46% (95% CI: 0.42 to 1.29) of the 89,652 patients tested in the risk-based testing period. Among persons aged 65-74 years and 75 years or older, the new diagnosis rates were 0.07% (95% CI: 0.04 to 0.09) and 0.02% (95% CI: 0.00 to 0.03), respectively, and thus less than the generally accepted cost-effective threshold of 0.10%. Among African Americans, the upper bound of the 95% CI of the crude rate of new diagnoses during the routine-testing period was greater than 0.1% across all age strata. When assessed by year of testing, the adjusted rates of new diagnoses fell from 0.20% in 2010 to 0.10% in 2012., Conclusions: Routine HIV testing is cost-effective among persons younger than 65 years. Among older patients, risk-based testing may be a more efficient and cost-effective approach. This will be increasingly relevant if rates of new HIV diagnoses in persons undergoing routine testing continue to decrease.

Background: We examined trends in adherence to highly active antiretroviral therapy (HAART) and HIV RNA suppression and estimated the minimum cutoff of adherence to newer HAART formulations needed for HIV RNA suppression by regimen type., Methods: We used Veterans Affairs pharmacy dispensing data from the Veterans Aging Cohort Study Virtual Cohort between October 2000 and September 2010 and defined adherence as the duration of time the patient had the medications available, relative to the total number of days between refills for all antiretrovirals in a year. Temporal trends in adherence and viral load suppression were examined by the patient's most frequently used HAART regimen in the year. The minimum needed adherence was defined as the level at which the odds of suppression was not significantly different than that observed with ≥ 95% adherence using repeated-measures logistic regression., Results: A total of 21,865 HAART users contributed 82,217 person-years of follow-up. There was a significant increase (P(trend) < 0.001) in the proportion virally suppressed even among those with <95% adherence (2001: 38% to 2010: 84%), and the trend was similar when restricting to their first HAART regimen. For nonnucleoside reverse transcriptase inhibitor multi-pill users, the odds of suppression did not differ for 85%-89% adherence compared to those with ≥ 95% adherence [odds ratios: 0.82 (0.64-1.04)], but for protease inhibitor users, the odds of suppression significantly differed if adherence levels were <95% compared to ≥ 95% adherence., Conclusions: Although all HIV-infected persons should be instructed to achieve perfect adherence, concerns of slightly lower adherence should not hinder prescribing new HAART regimens early in HIV infection.

Background: Traditional cardiovascular disease risk factors (CVDRFs) increase the risk of acute myocardial infarction (AMI) among HIV-infected (HIV+) participants. We assessed the association between HIV and incident AMI within CVDRF strata., Methods: Cohort-81,322 participants (33% HIV+) without prevalent CVD from the Veterans Aging Cohort Study Virtual Cohort (prospective study of HIV+ and matched HIV- veterans) participated in this study. Veterans were followed from first clinical encounter on/after April 1, 2003, until AMI/death/last follow-up date (December 31, 2009). Predictors-HIV, CVDRFs (total cholesterol, cholesterol-lowering agents, blood pressure, blood pressure medication, smoking, diabetes) used to create 6 mutually exclusive profiles: all CVDRFs optimal, 1+ nonoptimal CVDRFs, 1+ elevated CVDRFs, and 1, 2, 3+ major CVDRFs. Outcome-Incident AMI [defined using enzyme, electrocardiogram (EKG) clinical data, 410 inpatient ICD-9 (Medicare), and/or death certificates]. Statistics-Cox models adjusted for demographics, comorbidity, and substance use., Results: Of note, 858 AMIs (42% HIV+) occurred over 5.9 years (median). Prevalence of optimal cardiac health was <2%. Optimal CVDRF profile was associated with the lowest adjusted AMI rates. Compared with HIV- veterans, AMI rates among HIV+ veterans with similar CVDRF profiles were higher. Compared with HIV- veterans without major CVDRFs, HIV+ veterans without major CVDRFs had a 2-fold increased risk of AMI (HR: 2.0; 95% confidence interval: 1.0 to 3.9; P = 0.044)., Conclusions: The prevalence of optimal cardiac health is low in this cohort. Among those without major CVDRFs, HIV+ veterans have twice the AMI risk. Compared with HIV- veterans with high CVDRF burden, AMI rates were still higher in HIV+ veterans. Preventing/reducing CVDRF burden may reduce excess AMI risk among HIV+ people.

Globally, the HIV epidemic is evolving. Life expectancy for HIV-infected individuals has been extended because of more effective and more widely available antiretroviral therapy. As a result, chronic noncommunicable diseases (NCDs) have become important comorbid conditions. In particular, HIV-infected persons are increasingly at risk of developing metabolic (diabetes, dyslipidemias), body composition (lipodystrophy, overweight/obesity) and bone mineral density abnormalities. We have summarized the published epidemiological and clinical literature regarding these HIV-NCD comorbidities in low- and middle-income countries (LMICs). We found important gaps in knowledge. Specifically, there are few studies that use standardized methods and metrics; consequently, prevalence or incidence data are not comparable. There are very little or no data regarding the effectiveness or cost-effectiveness of clinical monitoring or therapeutic interventions for metabolic disorders in HIV-infected individuals. Also, although NCDs continue to grow in the HIV-negative population of most LMICs, there are few data comparing the incidence of NCD comorbidities between HIV-infected and HIV-negative populations. To address these gaps, we describe potential research and capacity development priorities for the future.

Objective: Chronic lung disease has been associated with greater impairment in self-reported physical function in HIV-infected patients. We sought to study this association using objective measures of physical function and pulmonary function., Design: Baseline data from the Examinations of HIV Associated Lung Emphysema study, a multicenter observational cohort of HIV-infected and uninfected veterans., Methods: We assessed the association between clinical, laboratory, and pulmonary function measures with 6-minute walk test (6-MWT). Multivariable linear regression models were generated to identify factors associated with 6-MWT performance., Results: Three hundred forty participants completed 6-MWT (mean age 55 years), with 68% blacks, 94% men, and 62% current smokers. Overall, 180 (53%) were HIV-infected and 63 (19%) had spirometry-defined chronic obstructive pulmonary disease. In a multivariable model, age, current smoking, and obesity (body mass index > 30) were independently associated with lower 6-MWT performance, but HIV infection was not; there was a significant interaction between HIV and chronic cough, such that distance walked among HIV-infected participants with chronic cough was 51.76 m less (P = 0.04) compared with those without cough or HIV. Among HIV-infected participants, the forced expiratory volume in 1 second (FEV1, percent predicted), to a greater extent than total lung capacity or diffusing capacity, attenuated the association with chronic cough; decreased FEV1 was independently associated with lower 6-MWT performance in those with HIV., Conclusions: Older age, current smoking, and airflow limitation were important determinants of 6-MWT performance in the HIV-infected participants. These findings suggest that potential interventions to improve physical function may include early management of respiratory symptoms and airflow limitation.

Background: The Veterans Aging Cohort Study (VACS) index is a weighted combination of age and 8 clinical variables. It has been well correlated with all-cause mortality among HIV-infected patients. The US Military HIV Natural History Study (NHS) cohort provides a different validation population profile, being younger and healthier. A significant portion of the US HIV population is similarly composed; so, evaluation of the VACS index in this population is of great interest., Methods: NHS subjects have medical history and laboratory data collected at 6-month visits. We performed an external validation of the VACS index in the NHS evaluating correlation, discrimination, and calibration for all-cause mortality after highly active antiretroviral therapy initiation (HI). We then tested whether combining longitudinal VACS index values at different time points improves prediction of mortality., Results: The VACS index at 1 year after HI was well correlated with all-cause mortality (Harrell c statistic 0.78), provided good discrimination (log-rank P < 0.05), and was marginally well calibrated using Brier score. Accounting for VACS index at HI and 6 months after HI significantly improved a standard model, including only the VACS index at 1 year after HI (net reclassification improvement = 25.2%, 95% CI: 10.9% to 48.9%)., Conclusions: The VACS index was well correlated and provided good discrimination with respect to all-cause mortality among highly active antiretroviral therapy initiating subjects in the NHS. Moderate overprediction of mortality in this young, healthy population suggests minor recalibration that could improve fit among similar patients. Considering VACS index at HI and 6 months improved outcome prediction and allowed earlier risk assessment.

Background: Lifetime costs of care and quality-of-life estimates for HIV-infected persons depend on the disease stage at which these persons are diagnosed, enter care, and start antiretroviral therapy. Updated estimates were used to analyze the effects of late versus early diagnosis/entry on US lifetime care costs, quality-of-life estimates, and HIV transmissions., Methods: The Progression and Transmission of HIV/AIDS model was used to estimate discounted (3%) lifetime treatment costs ($US 2011) and quality-of-life variables from time of infection for cohorts of 10,000 HIV-infected index patients in 4 categories of CD4 count at diagnosis: (I) ≤200 cells/μL, (II) 201-350 cells/μL, (III) 351-500 cells/μL, and (IV) 501-900 cells/μL. It is assumed that index patient diagnoses were uniformly distributed across the CD4 count range in each category and that patients entered care at the time of diagnosis, remained in care, and were eligible to initiate antiretroviral therapy at a CD4 count of 500 cells/μL. Lifetime transmissions of the index patients were also estimated., Results: Discounted average lifetime costs varied from $253,000 for category I index patients to $402,000 for category IV patients. Discounted quality-adjusted life years lost decreased from 7.95 to 4.45 across these categories, additional years of life expectancy increased from 30.8 to 38.1, and lifetime transmissions decreased from 1.40 to 0.72., Conclusions: Early diagnosis and treatment of HIV infection increases lifetime costs but improves length and quality of life and reduces the number of new infections transmitted by nearly 50%.

Objective: With improved survival of HIV-infected persons on antiretroviral therapy and growing prevalence of non-AIDS diseases, we asked whether the VACS Index, a composite measure of HIV-associated and general organ dysfunction predictive of all-cause mortality, predicts hospitalization and medical intensive care unit (MICU) admission. We also asked whether AIDS and non-AIDS conditions increased risk after accounting for VACS Index score., Methods: We analyzed data from the Veterans Aging Cohort Study (VACS), a prospective study of HIV-infected Veterans receiving care between 2002 and 2008. Data were obtained from the electronic medical record, VA administrative databases, and patient questionnaires and were used to identify comorbidities and calculate baseline VACS Index scores. The primary outcome was first hospitalization within 2 years of VACS enrollment. We used multivariable Cox regression to determine risk factors associated with hospitalization and logistic regression to determine risk factors for MICU admission, given hospitalization., Results: Of 3410 patients, 1141 were hospitalized within 2 years; 203 (17.8%)/1141 patients included an MICU admission. Median VACS Index scores were 25 (no hospitalization), 34 (hospitalization only), and 51 (MICU). In adjusted analyses, a 5-point increment in VACS Index score was associated with 10% higher risk of hospitalization and MICU admission. In addition to VACS Index score, Hispanic ethnicity, current smoking, hazardous alcohol use, chronic obstructive pulmonary disease, hypertension, diabetes, and prior AIDS-defining event predicted hospitalization. Among those hospitalized, VACS Index score, cardiac disease, and prior cancer predicted MICU admission., Conclusions: The VACS Index predicted hospitalization and MICU admission as did current smoking, hazardous alcohol use, and AIDS and certain non-AIDS diagnoses.

Background: HIV-infected patients with substance use experience suboptimal health outcomes, possibly because of variations in care., Objectives: To assess the association between substance use and the quality of HIV care (QOC) received., Research Design: Retrospective cohort study., Subjects: HIV-infected patients enrolled in the Veterans Aging Cohort Study., Measures: We collected self-report substance use data and abstracted 9 HIV quality indicators (QIs) from medical records. Independent variables were unhealthy alcohol use (AUDIT-C score ≥4) and illicit drug use (self-report of stimulants, opioids, or injection drug use in past year). Main outcome was the percentage of QIs received, if eligible. We estimated associations between substance use and QOC using multivariable linear regression., Results: The majority of the 3410 patients were male (97.4%) and black (67.0%) with a mean age of 49.1 years (SD = 8.8). Overall, 25.8% reported unhealthy alcohol use, 22% illicit drug use, and participants received 81.5% (SD = 18.9) of QIs. The mean percentage of QIs received was lower for those with unhealthy alcohol use versus not (59.3% vs. 70.0%, P < 0.001) and those using illicit drugs vs. not (57.8% vs. 70.7%, P < 0.001). In multivariable models, unhealthy alcohol use (adjusted β -2.74; 95% confidence interval: -4.23 to -1.25) and illicit drug use (adjusted β -3.51; 95% CI: -4.99 to -2.02) remained inversely associated with the percentage of QIs received., Conclusions: Although the overall QOC for these HIV-infected Veteran patients was high, gaps persist for those with unhealthy alcohol and illicit drug use. Interventions that address substance use in HIV-infected patients may improve the QOC received.

Introduction: Approximately, 15% of HIV-infected individuals have comorbid diabetes. Studies suggest that HIV and diabetes have an additive effect on chronic kidney disease (CKD) progression; however, this observation may be confounded by differences in traditional CKD risk factors., Methods: We studied a national cohort of HIV-infected and matched HIV-uninfected individuals who received care through the Veterans Healthcare Administration. Subjects were divided into 4 groups based on baseline HIV and diabetes status, and the rate of progression to an estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m was compared using Cox-proportional hazards modeling to adjust for CKD risk factors., Results: About 31,072 veterans with baseline eGFR ≥45 mL/min/1.73m (10,626 with HIV only, 5088 with diabetes only, and 1796 with both) were followed for a median of 5 years. Mean baseline eGFR was 94 mL/min/1.73m, and 7% progressed to an eGFR < 45 mL/min/1.73m. Compared with those without HIV or diabetes, the relative rate of progression was increased in individuals with diabetes only [adjusted hazard ratio (HR) 2.48; 95% confidence interval (CI): 2.19 to 2.80], HIV only [HR: 2.80, 95% CI: 2.50 to 3.15], and both HIV and diabetes [HR: 4.47, 95% CI: 3.87 to 5.17]., Discussion: Compared with patients with only HIV or diabetes, patients with both diagnoses are at significantly increased risk of progressive CKD even after adjusting for traditional CKD risk factors. Future studies should evaluate the relative contribution of complex comorbidities and accompanying polypharmacy to the risk of CKD in HIV-infected individuals and prospectively investigate the use of cART, glycemic control, and adjunctive therapy to delay CKD progression.

Objectives: To examine the effect of hepatitis C virus (HCV) on the prevalence of chronic kidney disease (CKD) among veterans with HIV and to evaluate independent associations of HCV and CKD with mortality., Methods: We studied a national cohort of HIV-infected patients receiving care through the Veterans Healthcare Administration from 1998 to 2004. CKD was defined as an estimated glomerular filtration rate [eGFR (mL/min/1.73 m2)] < 60. Poisson regression was used to assess relationships between CKD, HCV, and mortality., Results: Among 23,155 HIV-infected veterans, 12% had CKD. Forty percent of the cohort was coinfected with HCV, and a higher proportion of coinfected subjects had CKD compared with monoinfected subjects (14% vs 11%, P < 0.001). During the median follow-up of 7.6 years, 37% of subjects died and a graduated increase in adjusted mortality rates occurred with lower levels of eGFR (P < 0.001). Adjusted mortality rates were consistently higher in HCV-coinfected subjects across all levels of eGFR (P < 0.001). HCV was independently associated with increased mortality (incidence rate ratio 1.23, 95% confidence interval 1.17-1.29)., Conclusions: CKD is prevalent in HIV-infected veterans and associated with substantially higher mortality. Compared with their monoinfected counterparts, veterans coinfected with HCV have significantly higher rates of CKD and mortality.

Objective: To determine the relationship of HIV infection, demographic, and cardiovascular disease (CVD) risk factors with mortality in the recent highly active antiretroviral therapy era., Methods: Vital status was ascertained from 2004 to 2007 in 922 HIV infected and 280 controls in the Study of Fat Redistribution and Metabolic Change in HIV infection; 469 HIV infected were included in analysis comparing HIV with similar age controls. Multivariable exponential survival regression (adjusting for demographic and CVD factors) estimated hazard ratios (HRs) for death., Results: After 5 years of follow-up, the overall adjusted mortality HR was 3.4 [95% confidence interval (CI): 1.35-8.5]; HR was 6.3 among HIV infected with CD4 < 200 (95% CI: 2.2-18.2), 4.3 with CD4 200-350 (95% CI: 1.14-16.0), and 2.3 with CD4 > 350 (95% CI: 0.78-6.9). Among HIV infected, current smoking (HR = 2.73 vs. never smokers, 95% CI: 1.64-4.5) and older age (HR = 1.61 per decade, 95% CI: 1.27-2.1) were independent risk factors for death; higher baseline CD4 count was associated with lower risk (HR = 0.65 per CD4 doubling, 95% CI: 0.58-0.73)., Conclusions: HIV infection was associated with a 3-fold mortality risk compared with controls after adjustment for demographic and CVD risk factors. In addition to low baseline CD4 count, older age and current smoking were strong and independent predictors of mortality in a US cohort of HIV-infected participants in clinical care.

Background: The association of fat distribution with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations is not well-defined in HIV-infected individuals. Obesity is associated with hepatic steatosis, and ALT is a marker of steatosis in the general population., Methods: Cross-sectional analysis of 1119 HIV-infected and 284 control subjects. Hepatitis C virus (HCV) RNA testing determined HCV infection. Magnetic resonance imaging measured regional adipose tissue volume., Results: After adjustment for demographic and lifestyle factors, visceral adipose tissue (VAT) was positively associated with ALT in HIV/HCV-coinfected subjects (+9.8%, 95% confidence interval [CI]: 2.8 to 17.6), HIV-monoinfected subjects (+8.0%, 95% CI: 4.2 to 12.1), and controls (+5.9%, 95% CI: 2.0 to 10.1). In contrast, lower trunk subcutaneous adipose tissue (SAT) was negatively associated with ALT in HIV/HCV-coinfected subjects (-14.3%, 95% CI: -24.7 to -4.2) and HIV-monoinfected subjects (-11.9%, 95% CI: -18.4 to -5.3); there was a trend toward an association in controls (-7.1%, 95% CI: -22.7 to 5.9). Estimated associations between regional adipose tissue and AST were small and did not reach statistical significance., Conclusions: More VAT and less lower trunk SAT are associated with elevated ALT, which likely reflects the presence of steatosis. There was little association with AST. HCV infection and having more VAT or less lower trunk SAT are independently associated with elevated ALT in HIV infection. Study regarding the association between VAT, trunk SAT, HCV, and progression of steatosis and fibrosis is needed in HIV-infected individuals.

Visceral obesity is associated with insulin resistance, but the association of other regional adipose depots with insulin resistance is not understood. In HIV infection, buffalo hump (upper trunk fat) is associated, but the association of upper trunk fat with insulin resistance has not been examined in controls. To determine the independent association of adipose depots other than visceral with insulin resistance, we performed a cross-sectional analysis of controls and HIV-infected subjects in the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) study, who had measurements of glucose, insulin, and adipose tissue volumes by whole-body magnetic resonance imaging. We studied 926 HIV-positive persons from 16 academic medical center clinics and trials units with demographic characteristics representative of US patients with HIV infection and 258 FRAM controls from the population-based Coronary Artery Risk Development in Young Adults study. We measured visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) volume in the legs, arms, lower trunk (back and abdomen), and upper trunk (back and chest) and assessed their association with the homeostasis model of assessment (HOMA) and HOMA >4 by stepwise multivariable analysis. The prevalence of HOMA >4 as a marker of insulin resistance was 28% among controls compared with 37% among HIV-infected subjects (P = 0.005). Among controls, those in the highest tertile of upper trunk SAT volume had an odds ratio (OR) of 9.0 (95% confidence interval [CI]: 2.4 to 34; P = 0.001) for having HOMA >4 compared with the lowest tertile, whereas in HIV-positive subjects, the OR was lower (OR = 2.09, 95% CI: 1.36 to 3.19; P = 0.001). Among controls, the highest tertile of VAT volume had an OR of 12.1 (95% CI: 3.2 to 46; P = 0.0002) of having HOMA >4 compared with the lowest tertile, whereas in HIV-positive subjects, the OR was 3.12 (95% CI: 2.0 to 4.8; P < 0.0001). After adjusting for VAT and upper trunk SAT, the association of other SAT depots with HOMA >4 did not reach statistical significance. Thus, VAT and upper trunk SAT are independently associated with insulin resistance in controls and in HIV-infected persons.

Objective: Coinfection with hepatitis C virus (HCV) is reported to be associated with a higher prevalence of lipodystrophy than HIV infection alone. We examine the association between HCV and adipose tissue volume in HIV-infected men and women., Methods: Cross-sectional analysis of HIV-infected subjects from the study of Fat Redistribution and Metabolic Change in HIV Infection. MRI measured regional adipose tissue volume. Detectable HCV RNA defined HCV infection., Results: Twenty percent of 792 men and 26% of 329 women were HIV/HCV-coinfected. HIV/HCV-coinfected and HIV-monoinfected women had similar amounts of subcutaneous adipose tissue (SAT) in the leg, lower trunk, upper trunk, and arm and similar amounts of visceral adipose tissue (VAT). Similar findings were seen in men, except in the leg and VAT. After adjustment, HCV infection remained associated with more leg fat in men (12.2%, 95% confidence interval [CI]: 0.3 to 25.3; P = 0.043). Among those on stavudine, HIV-monoinfected men had less leg fat (-7% effect per year of stavudine use, 95% CI: -9 to -5; P < 0.001); a weaker association was seen in HIV/HCV-coinfected men (-2% effect, 95% CI: -7 to 3; P = 0.45). Indinavir was associated with less leg fat (-4% in HIV-monoinfected men, 95% CI: -6 to -1; P = 0.002; -5% in HIV/HCV-coinfected men, 95% CI: -11 to 2; P = 0.14)., Conclusions: Our findings suggest that HIV/HCV coinfection is not associated with less SAT in men and women. HCV infection seems to mitigate the loss of leg fat seen in HIV-infected men on stavudine.

Objectives: Dyslipidemia has become a common problem in HIV disease, especially in patients on combination antiretroviral (ARV) therapy. However, little data are available to evaluate lipid abnormalities in women on ARV therapy., Methods: Using a cross-sectional design, the prevalence of abnormal plasma lipid and lipoprotein concentrations as well as other biomarkers for vascular disease was determined in 184 HIV-positive women from 2 HIV clinics in Atlanta during 2002., Results: Most of the women were African American (89%), with median age of 41 years (range 21-72); 6% were diabetic, 44% smoked, and 67% were overweight. ARV therapy defined the comparison groups that included treatment with a protease inhibitor (PI)-based regimen for more than 3 months in 76 (41%), treatment with a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen for more than 3 months in 38 (20%), and no ARV therapy for the past 3 months in 70 (38%). Women being treated with a PI or NNRTI had higher total cholesterol and triglyceride levels than patients on no therapy (P < 0.05 for each). Women treated with either PIs or NNRTIs had significantly higher apolipoprotein B and apolipoprotein C-III levels than patients on no therapy (P < 0.01 for each)., Conclusions: In this cross-sectional study of HIV-infected women, either PI or NNRTI therapy elevated levels of total cholesterol and specific apolipoproteins. These findings, on a background of an older population with additional risk factors of smoking, obesity, and diabetes, may lead to future atherosclerotic events in these patients.

Objective: To measure CCR5 and CXCR4 chemokine receptor expression on CD4 and CD8 T cells in HIV-1 infection and to relate levels to the distribution of CD45RO memory and CD45RA-naive subsets, measures of disease activity, and response to highly active antiretroviral therapy (HAART)., Design: Fourteen untreated HIV-1-infected patients, 18 patients at 3-to 4-weeks after beginning HAART, and 35 uninfected control subjects were studied., Methods: Four-color cytofluorometry with appropriate conjugated monoclonal antibodies (mAbs) was performed to define CD45RA and CD45RO subsets of CD4 and CD8 T cells and measure their expression of CCR5, CXCR4, and CD38., Results: HIV-1-infected patients had higher CCR5 levels and lower CXCR4 levels on CD4 and CD8 T cells and their CD45RO/CD45RA subsets than control subjects did. However, CCR5 elevation was statistically significant only for CD4 T cells and their subsets, and CXCR4 depression was significant for CD8 T cells and their subsets (and for CD4:CD45RO cells). The elevation of CCR5 and depression of CXCR4 were not due to shifts in CD45RO/CD45RA subset proportions but to upregulation or downregulation within the subsets. CCR5 elevation on CD4 T cells was significantly restored toward normal by HAART, but the CXCR4 depression was not. CCR5 expression but not CXCR4 expression correlated with other measures of immunodeficiency (CD4 T-cell levels), active infection (viral load), and cellular activation (CD38)., Conclusions: CCR5 elevation is a concomitant of immune activation and viral replication that occurs in HIV-1 infection, but the relation of CXCR4 depression to severity of infection, disease progression, and response to therapy remains undefined.