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1.  Combining Epidemiologic and Biostatistical Tools to Enhance Variable Selection in HIV Cohort Analyses 
PLoS ONE  2014;9(1):e87352.
Background
Variable selection is an important step in building a multivariate regression model for which several methods and statistical packages are available. A comprehensive approach for variable selection in complex multivariate regression analyses within HIV cohorts is explored by utilizing both epidemiological and biostatistical procedures.
Methods
Three different methods for variable selection were illustrated in a study comparing survival time between subjects in the Department of Defense’s National History Study and the Atlanta Veterans Affairs Medical Center’s HIV Atlanta VA Cohort Study. The first two methods were stepwise selection procedures, based either on significance tests (Score test), or on information theory (Akaike Information Criterion), while the third method employed a Bayesian argument (Bayesian Model Averaging).
Results
All three methods resulted in a similar parsimonious survival model. Three of the covariates previously used in the multivariate model were not included in the final model suggested by the three approaches. When comparing the parsimonious model to the previously published model, there was evidence of less variance in the main survival estimates.
Conclusions
The variable selection approaches considered in this study allowed building a model based on significance tests, on an information criterion, and on averaging models using their posterior probabilities. A parsimonious model that balanced these three approaches was found to provide a better fit than the previously reported model.
doi:10.1371/journal.pone.0087352
PMCID: PMC3906149  PMID: 24489902
2.  Unhealthy Alcohol and Illicit Drug Use are Associated with Decreased Quality of HIV Care 
Background
HIV-infected patients with substance use experience suboptimal health outcomes, possibly to due to 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 3,410 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 vs. not (59.3% vs. 70.0%, p<.001) and those using illicit drugs vs. not (57.8% vs. 70.7%, p<.001). In multivariable models, unhealthy alcohol use (adjusted β −2.74; 95% CI −4.23, −1.25) and illicit drug use (adjusted β −3.51 95% CI −4.99, −2.02) remained inversely associated with the percentage of QIs received.
Conclusions
Though 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.
doi:10.1097/QAI.0b013e31826741aa
PMCID: PMC3460799  PMID: 22820808
Alcohol; Quality of Health Care; HIV; Quality Indicators; Health Care; Opioid-Related Disorders
3.  Comorbid diabetes and the risk of progressive chronic kidney disease in HIV-infected adults: Data from the Veterans Aging Cohort Study 
Introduction
Approximately 15% of HIV-infected individuals have comorbid diabetes. Studies suggest that HIV and diabetes have an additive effect on chronic kidney (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 four groups based on baseline HIV and diabetes status, and the rate of progression to an estimated glomerular filtration rate (eGFR) < 45ml/min/1.73m2 was compared using Cox-proportional hazards modeling to adjust for CKD risk factors.
Results
31,072 veterans with baseline eGFR ≥ 45ml/min/1.73m2 (10,626 with HIV only, 5,088 with diabetes only, and 1,796 with both) were followed for a median of 5 years. Mean baseline eGFR was 94ml/min/1.73m2, and 7% progressed to an eGFR < 45ml/min/1.73m2. Compared to 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) 2.19–2.80], HIV only [HR 2.80, 95% CI 2.50–3.15], and both HIV and diabetes [HR 4.47, 95% CI 3.87–5.17].
Discussion
Compared to 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.
doi:10.1097/QAI.0b013e31825b70d9
PMCID: PMC3392432  PMID: 22592587
non-AIDS complications; HIV; chronic kidney disease; diabetes; risk factors
4.  HIV Status, Burden of Comorbid Disease, and Biomarkers of Inflammation, Altered Coagulation, and Monocyte Activation 
We investigated the association between human immunodeficiency virus (HIV) and prevalence of elevated biomarkers of inflammation, altered coagulation, and monocyte activation in a cohort of HIV-infected and uninfected veterans who had a comparable burden of comorbid conditions.
Background. Biomarkers of inflammation, altered coagulation, and monocyte activation are associated with mortality and cardiovascular disease (CVD) in the general population and among human immunodeficiency virus (HIV)–infected people. We compared biomarkers for inflammation, altered coagulation, and monocyte activation between HIV-infected and uninfected people in the Veterans Aging Cohort Study (VACS).
Methods. Biomarkers of inflammation (interleukin-6 [IL-6]), altered coagulation (d-dimer), and monocyte activation (soluble CD14 [sCD14]) were measured in blood samples from 1525 HIV-infected and 843 uninfected VACS participants. Logistic regression was used to determine the association between HIV infection and prevalence of elevated (>75th percentile) biomarkers, adjusting for confounding comorbidities.
Results. HIV-infected veterans had less prevalent CVD, hypertension, diabetes, obesity, hazardous drinking, and renal disease, but more dyslipidemia, hepatitis C, and current smoking than uninfected veterans. Compared to uninfected veterans, HIV-infected veterans with HIV-1 RNA ≥500 copies/mL or CD4 count <200 cells/µL had a significantly higher prevalence of elevated IL-6 (odds ratio [OR], 1.54; 95% confidence interval [CI],1.14–2.09; OR, 2.25; 95% CI, 1.60–3.16, respectively) and d-dimer (OR, 1.97; 95% CI, 1.44–2.71, OR, 1.68; 95% CI, 1.22–2.32, respectively) after adjusting for comorbidities. HIV-infected veterans with a CD4 cell count <200 cells/µL had significantly higher prevalence of elevated sCD14 compared to uninfected veterans (OR, 2.60; 95% CI, 1.64–4.14). These associations still persisted after restricting the analysis to veterans without known confounding comorbid conditions.
Conclusions. These data suggest that ongoing HIV replication and immune depletion significantly contribute to increased prevalence of elevated biomarkers of inflammation, altered coagulation, and monocyte activation. This contribution is independent of and in addition to the substantial contribution from comorbid conditions.
doi:10.1093/cid/cis406
PMCID: PMC3493182  PMID: 22534147
5.  Sex Disparities in Overall Burden of Disease Among HIV-Infected Individuals in the Veterans Affairs Healthcare System 
Journal of General Internal Medicine  2013;28(Suppl 2):577-582.
ABSTRACT
BACKGROUND
Whether sex disparities exist in overall burden of disease among human immunodeficiency virus (HIV)-infected individuals in the Veterans Affairs healthcare system (VA) is unknown.
OBJECTIVE
To determine whether sex differences exist in overall burden of disease after 1 year of combined antiretroviral therapy (ART) among HIV-infected individuals in VA.
DESIGN
Retrospective cohort study.
PARTICIPANTS
Among patients in the Veterans Aging Cohort Study Virtual Cohort (VACS-VC), all ART-naïve HIV-infected Veterans who received VA-based HIV care between 1996 and 2009.
MAIN MEASURES
Overall burden of disease was measured using the VACS Index, an index that incorporates HIV (e.g. CD4 cell count) and non-HIV biomarkers (e.g. hemoglobin) and is highly predictive of all-cause mortality. Possible scores range from 0 to 164, although scores typically range from 0 to 50 for 80 % of patients in VACS-VC. A higher score indicates greater burden of disease (each additional five points indicates approximately 20 % increased 5-year mortality risk). ART adherence was measured using pharmacy data.
KEY RESULTS
Complete data were available for 227 women and 8,073 men. At ART initiation, compared with men, women were younger and more likely to be Black, less likely to have liver dysfunction, but more likely to have lower hemoglobin levels. Median VACS Index scores changed from ART initiation to 1 year after ART initiation: women’s scores went from 41 to 28 for women (13 point improvement) and men’s from 42 to 27 for men (15 point improvement). In multivariable regression, women had 3.6 point worse scores than men after 1 year on ART (p = 0.002); this difference decreased to 3.2 points after adjusting for adherence (p = 0.004).
CONCLUSIONS
In VA, compared to men, women experienced less improvement in overall burden of disease after 1 year of HIV treatment. Further study is needed to elucidate the modifiable factors that may explain this disparity.
doi:10.1007/s11606-013-2346-z
PMCID: PMC3695278  PMID: 23807068
women; Veterans; HIV; health care disparities; burden of illness
6.  Risk of Heart Failure With Human Immunodeficiency Virus in the Absence of Prior Diagnosis of Coronary Heart Disease 
Archives of internal medicine  2011;171(8):737-743.
Background
Whether human immunodeficiency virus (HIV) infection is a risk factor for heart failure (HF) is not clear. The presence of coronary heart disease and alcohol consumption in this population may confound this association.
Methods
To determine whether HIV infection is a risk factor for incident HF, we conducted a population-based, retrospective cohort study of HIV-infected and HIV-uninfected veterans enrolled in the Veterans Aging Cohort Study Virtual Cohort (VACS-VC) and the 1999 Large Health Study of Veteran Enrollees (LHS) from January 1, 2000, to July 31, 2007.
Results
There were 8486 participants (28.2% HIV-infected) enrolled in the VACS-VC who also participated in the 1999 LHS. During the median 7.3 years of follow-up, 286 incident HF events occurred. Age- and race/ethnicity–adjusted HF rates among HIV-infected and HIV-uninfected veterans were 7.12 (95% confidence interval [CI],6.90-7.34) and 4.82 (95% CI, 4.72-4.91) per 1000 person-years, respectively. Compared with HIV-uninfected veterans, those who were HIV infected had an increased risk ofHF (adjusted hazard ratio [HR], 1.81; 95% CI, 1.39-2.36). This association persisted among veterans who did not have a coronary heart disease event or a diagnosis related to alcohol abuse or dependence before the incident HF event (adjusted HR, 1.96; 95% CI, 1.29-2.98). Compared with HIV-uninfected veterans, those who were HIV infected with a baseline Human immunodeficiency virus 1 (HIV-1) RNA level of 500 or more copies/mL had a higher risk of HF (adjusted HR, 2.28; 95% CI, 1.57-3.32), while those with baseline and a recent HIV-1 RNA level less than 500 copies/mL did not (adjusted HR, 1.10; 95% CI, 0.64-1.89; P< .001 for comparison between high and low HIV-1 RNA groups).
Conclusions
Our data suggest that HIV infection is a risk factor for HF. Ongoing viral replication is associated with a higher risk of developing HF.
doi:10.1001/archinternmed.2011.151
PMCID: PMC3687533  PMID: 21518940
7.  Do Patterns of Comorbidity Vary by HIV Status, Age, and HIV Severity? 
Patterns of comorbidity among persons with human immunodeficiency virus (HIV) are not well described. We compared comorbidity among veterans with and without HIV infection. The sample consisted of 33,420 HIV-infected veterans and 66,840 HIV-uninfected veterans. We identified and clustered 11 comorbid conditions using validated International Classification of Diseases, 9th Revision, Clinical Modification codes. We defined multimorbidity as the presence of conditions in all clusters. Models restricted to HIV-infected veterans were adjusted for CD4 cell count and viral load. Comorbidity was common (prevalence, 60%–63%), and prevalence varied by HIV status. Differences remained when the veterans were stratified by age. In multivariable analyses, older HIV-infected veterans were more likely to have substance use disorder and multimorbidity. Renal, vascular, and pulmonary diseases were associated with CD4 cell count <200 cells/mm3; hypertension was associated with CD4 cell count >200 cells/mm3. Comorbidity is the rule, and multimorbidity is common among veterans with HIV infection. Patterns of comorbidity differ substantially by HIV status, age, and HIV severity. Primary care guidelines require adaptation for persons with HIV infection.
doi:10.1086/523577
PMCID: PMC3687553  PMID: 18190322
8.  MRSA nasal colonization burden and risk of MRSA infection 
Background
Staphylococcus aureus nasal colonization burden has been identified as a risk factor for infection. This study evaluates methicillin-resistant S aureus (MRSA) nasal burden, as defined by the cycle threshold (Ct) and risk of subsequent infection.
Methods
In a retrospective cohort study, United States veterans were classified into 3 MRSA nasal colonization groups: noncarriers, low burden (Ct > 24 cycles), and high burden (Ct ≤ 24 cycles). MRSA infections were identified prospectively, and clinical information was obtained by chart review. Multivariate logistic regression assessed the association of MRSA nasal burden and risk of MRSA infection.
Results
During 4-years of follow-up, 4.3% of noncarriers, 18.5% of low burden, and 17.2% of high burden developed a MRSA infection. In multivariate analysis, MRSA nasal colonization was a risk factor for MRSA infection (P = .008) with low burden (risk ratio [RR], 3.62; 95% confidence interval [CI]: 1.47–8.93) and high burden (RR, 2.71; 95% CI: 0.95–7.72) associated with subsequent MRSA infection when compared with noncarriers. When compared with low burden, high burden nasal carriers were not at increased risk of infection (RR, 0.75; 95% CI 0.36–1.55).
Conclusion
MRSA nasal colonization was a risk factor for MRSA infection. High nasal burden of MRSA did not increase the risk of infection.
doi:10.1016/j.ajic.2012.07.017
PMCID: PMC3685139  PMID: 23261345
Staphylococcus aureus; Carriage quantification; Cycle threshold
9.  Reduction of Methicillin-Resistant Staphylococcus aureus Infection among Veterans in Atlanta 
OBJECTIVE
Describe local changes in the incidence of community-onset and hospital-onset methicillin-resistant Staphylococcus aureus (MRSA) infection and evaluate the impact of MRSA active surveillance on hospital-onset infection.
DESIGN
Observational study using prospectively collected data.
SETTING
Atlanta Veterans Affairs Medical Center (AVAMC).
PATIENTS
All patients seen at the AVAMC over an 8-year period with clinically and microbiologically proven MRSA infection.
METHODS
All clinical cultures positive for MRSA were prospectively identified, and corresponding clinical data were reviewed. MRSA infections were classified into standard clinical and epidemiologic categories. The Veterans Health Administration implemented the MRSA directive in October 2007, which required active surveillance cultures in acute care settings.
RESULTS
The incidence of community-onset MRSA infection peaked in 2007 at 5.45 MRSA infections per 1,000 veterans and decreased to 3.14 infections per 1,000 veterans in 2011 (P ≤ .001 for trend). Clinical and epidemiologic categories of MRSA infections did not change throughout the study period. The prevalence of nasal MRSA colonization among veterans admitted to AVAMC decreased from 15.8% in 2007 to 11.2% in 2011 (P < .001 for trend). The rate of intensive care unit (ICU)–related hospital-onset MRSA infection decreased from October 2005 through March 2007, before the MRSA directive. Rates of ICU-related hospital-onset MRSA infection remained stable after the implementation of active surveillance cultures. No change was observed in rates of non-ICU-related hospital-onset MRSA infection.
CONCLUSIONS
Our study of the AVAMC population over an 8-year period shows a consistent trend of reduction in the incidence of MRSA infection in both the community and healthcare settings. The etiology of this reduction is most likely multifactorial.
doi:10.1086/668776
PMCID: PMC3677855  PMID: 23221194
10.  Methicillin-Resistant Staphylococcus aureus Colonization of the Groin and Risk for Clinical Infection among HIV-infected Adults 
Emerging Infectious Diseases  2013;19(4):623-629.
Data on the interaction between methicillin-resistant Staphylococcus aureus (MRSA) colonization and clinical infection are limited. During 2007–2008, we enrolled HIV-infected adults in Atlanta, Georgia, USA, in a prospective cohort study. Nares and groin swab specimens were cultured for S. aureus at enrollment and after 6 and 12 months. MRSA colonization was detected in 13%–15% of HIV-infected participants (n = 600, 98% male) at baseline, 6 months, and 12 months. MRSA colonization was detected in the nares only (41%), groin only (21%), and at both sites (38%). Over a median of 2.1 years of follow-up, 29 MRSA clinical infections occurred in 25 participants. In multivariate analysis, MRSA clinical infection was significantly associated with MRSA colonization of the groin (adjusted risk ratio 4.8) and a history of MRSA infection (adjusted risk ratio 3.1). MRSA prevention strategies that can effectively prevent or eliminate groin colonization are likely necessary to reduce clinical infections in this population.
doi:10.3201/eid1904.121353
PMCID: PMC3647417  PMID: 23631854
HIV; methicillin-resistant Staphylococcus aureus; colonization; viruses; bacteria; Georgia; MRSA; staphylococci
11.  HIV as an Independent Risk Factor for Incident Lung Cancer 
AIDS (London, England)  2012;26(8):1017-1025.
doi:10.1097/QAD.0b013e328352d1ad
PMCID: PMC3580210  PMID: 22382152
Human Immunodeficiency Virus (HIV); lung cancer; incidence; smoking; immunosuppression; non-AIDS defining malignancy
12.  Replication-Independent Expression of Anti-Apoptosis Marker Genes in Human Peripheral Blood Mononuclear Cells Infected with the Wild-Type HIV-1 and Reverse Transcriptase Variants 
Viral Immunology  2012;25(1):12-20.
Abstract
Clinical trials with highly-active antiretroviral therapy (HAART) have shown that a substantial number of patients continue to show a decrease in viral load and/or increase or stable CD4+ T-cell numbers even in the presence of multidrug resistant (MDR) viruses. We compared replication capacity (RC) and expression of anti-apoptosis marker genes (AAMGs) in human peripheral blood mononuclear (PBM) cells infected with NL4-3 (wild-type; WT) and mutant viruses. Replication kinetics assays showed a significant decrease in RC of all mutant viruses in comparison to the WT virus. The viruses containing patient-derived MDR RT without the K65R mutation (PSD5.2) replicated efficiently in comparison to the viruses with MDR RT containing the K65R mutation (PSD5.1), or the single mutations K65R and M184V. Compared with WT, a significant decrease in RCs of viruses: K65R (RC=0.39±0.02; p≤0.0001), M184V (RC=0.72±0.04; p≤0.0001), PSD5.1 (RC=0.32±0.04; p≤0.0001), and PSD5.2 (RC=0.90±0.04; p=0.002) was observed on day 10. RT-PCR-based apoptosis array was performed on total cellular RNA. Recombinant virus PSD5.2 showed a 1.5- to 6-fold upregulation in 8 AAMGs (AKT1, BAG3, BCL2A1, BFAR, BIRC2, BNIP1, BNIP3, and CFLAR) on day 1 and day 7 post-infection with respect to WT virus. PSD5.1 showed upregulation of only one gene (BAG1) on day 1 (1.75-fold) and day 7 (1.97-fold). Point mutant K65R showed a 1.5- to 4-fold upregulation of six AAMGs on day 7. Viruses with the M184V mutation showed upregulation of only one gene (BAG1). These observations indicate that the upregulation of specific AAMGs may not be dependent on the RCs of HIV-I variants, and that the possible interaction among mutated RT residues and viral and/or host proteins may induce CD4+ T-cell-protective anti-apoptosis proteins.
doi:10.1089/vim.2011.0057
PMCID: PMC3271366  PMID: 22239233
13.  HIV-Associated Lung Cancer in the Era of Highly Active Antiretroviral Therapy (HAART) 
Cancer  2011;118(1):164-172.
Background
Lung cancer is the leading cause of death among non-acquired immunodeficiency syndrome (AIDS) defining malignancies. Since highly active anti-retroviral therapy (HAART) has improved survival for human immunodeficiency virus (HIV) patients, we evaluated lung cancer outcomes in the HAART era.
Methods
HIV-positive patients diagnosed with lung cancer in our institution during the HAART era (1995-2008) were analyzed. Patient charts were reviewed for clinical and laboratory data. CD4 count at diagnosis was treated as a continuous variable and subcategorized into distinct variables with 3 cut-off points (50, 200, & 500 μl). Pearson’s correlation coefficients were estimated for each covariate studied. Survival was determined by the Kaplan-Meier method.
Results
Out of 80 patients, 73 had non-small cell lung cancer. Baseline characteristics were: median age-52 yrs; male-80%; African American-84%; injection drug use-25%; smokers-100%; and prior exposure to antiretroviral agents-55%. Mean CD4 count and viral load were 304 μL and 82,420 copies/ml, respectively at cancer diagnosis. The latency between diagnosis of HIV and lung cancer was significantly shorter in women (4.1 yrs vs. 7.7 yrs, P=0.02) and 71% of the patients received anti-cancer therapy. The 1- and 3-year survival rates were 31% and 4% overall. Grade 3/4 toxicities occurred in 60% with chemo-radiation vs. 36% with chemotherapy. Cancer-related survival was better for patients with CD4 count >200 (P=0.0298) and >500 (P=0.0076).
Conclusions
The latency from diagnosis of HIV to lung cancer was significantly shorter for women. Although outcomes for lung cancer patients with HIV remain poor, high CD4 count is associated with an improved lung cancer-related survival.
doi:10.1002/cncr.26242
PMCID: PMC3184336  PMID: 21713759
lung cancer; HIV; survival; anti-retroviral therapy; HAART
14.  Validating Smoking Data From the Veteran’s Affairs Health Factors Dataset, an Electronic Data Source 
Nicotine & Tobacco Research  2011;13(12):1233-1239.
Introduction:
We assessed smoking data from the Veterans Health Administration (VHA) electronic medical record (EMR) Health Factors dataset.
Methods:
To assess the validity of the EMR Health Factors smoking data, we first created an algorithm to convert text entries into a 3-category smoking variable (never, former, and current). We compared this EMR smoking variable to 2 different sources of patient self-reported smoking survey data: (a) 6,816 HIV-infected and -uninfected participants in the 8-site Veterans Aging Cohort Study (VACS-8) and (b) a subset of 13,689 participants from the national VACS Virtual Cohort (VACS-VC), who also completed the 1999 Large Health Study (LHS) survey. Sensitivity, specificity, and kappa statistics were used to evaluate agreement of EMR Health Factors smoking data with self-report smoking data.
Results:
For the EMR Health Factors and VACS-8 comparison of current, former, and never smoking categories, the kappa statistic was .66. For EMR Health Factors and VACS-VC/LHS comparison of smoking, the kappa statistic was .61.
Conclusions:
Based on kappa statistics, agreement between the EMR Health Factors and survey sources is substantial. Identification of current smokers nationally within the VHA can be used in future studies to track smoking status over time, to evaluate smoking interventions, and to adjust for smoking status in research. Our methodology may provide insights for other organizations seeking to use EMR data for accurate determination of smoking status.
doi:10.1093/ntr/ntr206
PMCID: PMC3223583  PMID: 21911825
15.  FIB-4 index is associated with hepatocellular carcinoma risk in HIV-infected patients 
Background
Chronic inflammation caused by hepatitis B virus infection, hepatitis C virus infection, and/or heavy alcohol use can lead to fibrosis, cirrhosis, and eventually hepatocellular carcinoma (HCC). FIB-4 is an index score calculated from platelet count, alanine transaminase, aspartate transaminase, and age that predicts fibrosis and cirrhosis. We hypothesized that high FIB-4 would be associated with development of HCC in HIV-infected persons, who are at high risk due to high prevalence of viral hepatitis and alcohol consumption, and possibly due to HIV infection itself.
Methods
Using proportional hazards models, we tested this hypothesis among 22,980 HIV-infected men from the Veterans Aging Cohort Study. We identified incident HCC cases from the VA Central Cancer Registry.
Results
During follow-up, there were 112 incident HCC diagnoses. The age-and race/ethnic group-adjusted HR was 4.2 (95% CI: 2.4, 7.4)for intermediate FIB-4 and 13.0 (95% CI: 7.2, 23.4) for high FIB-4, compared to low FIB-4. After further adjustment for enrollment year, CD4 count, HIV-1 RNA level, antiretroviral therapy use, hepatitis B and C virus infection, alcohol abuse/dependency, and diabetes, FIB-4 remained a strong, significant, independent risk factor for HCC. The multivariate-adjusted HR was 3.6 (95% CI: 2.1, 6.4) for intermediate FIB-4 and 9.6 (95% CI: 5.2, 17.4) for high FIB-4.
Conclusions
Calculated from routine, non-invasive laboratory tests, FIB-4 is a strong, independent HCC risk factor in HIV-infected patients.
Impact
FIB-4 might prove valuable as an easily measured index to identify those at highest risk for HCC, even prior to development of clinical cirrhosis.
doi:10.1158/1055-9965.EPI-11-0582
PMCID: PMC3237927  PMID: 22028407
hepatocellular carcinoma; FIB-4; HIV; liver neoplasms; hepatic fibrosis
16.  Cepheid Xpert MRSA Cycle Threshold in Discordant Colonization Results and as a Quantitative Measure of Nasal Colonization Burden 
Journal of Clinical Microbiology  2012;50(6):2079-2081.
We analyzed the cycle threshold (CT) of PCR surveillance MRSA swabs obtained from veterans. Lower CT on admission was associated with a positive culture from nasal swabs at discharge. Compared to PCR, direct plating of nasal swabs performed poorly, especially for patients with an elevated CT. The CT is strongly correlated with quantitative nasal cultures. Clinical and infection control applications of the CT have yet to be defined and warrant further evaluation.
doi:10.1128/JCM.06690-11
PMCID: PMC3372118  PMID: 22442322
17.  Association of Increased Upper Trunk and Decreased Leg Fat With 2-h Glucose in Control and HIV-Infected Persons 
Diabetes Care  2011;34(11):2448-2453.
OBJECTIVE
Changes in body fat distribution and abnormal glucose metabolism are common in HIV-infected patients. We hypothesized that HIV-infected participants would have a higher prevalence of impaired glucose tolerance (IGT) compared with control subjects.
RESEARCH DESIGN AND METHODS
A total of 491 HIV-infected and 187 control participants from the second examination of the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) underwent glucose tolerance testing (GTT). Multivariable regression was used to identify factors associated with GTT parameters.
RESULTS
The prevalence of impaired fasting glucose (IFG) (>110 mg/dL) was similar in HIV-infected and control participants (21 vs. 25%, P = 0.23). In those without IFG, the prevalence of IGT was slightly higher in HIV-infected participants compared with control subjects (13.1 vs. 8.2%, P = 0.14) and in HIV+ participants with lipoatrophy versus without (18.1 vs. 11.5%, P = 0.084). Diabetes detected by GTT was rare (HIV subjects 1.3% and control subjects 0%, P = 0.65). Mean 2-h glucose levels were 7.6 mg/dL higher in the HIV-infected participants (P = 0.012). Increased upper trunk subcutaneous adipose tissue (SAT) and decreased leg SAT were associated with 2-h glucose and IGT in both HIV-infected and control participants. Adjusting for adipose tissue reduced the estimated effects of HIV. Exercise, alcohol use, and current tenofovir use were associated with lower 2-h glucose levels in HIV-infected participants.
CONCLUSIONS
In HIV infection, increased upper trunk SAT and decreased leg SAT are associated with higher 2-h glucose. These body fat characteristics may identify HIV-infected patients with normal fasting glucose but nonetheless at increased risk for diabetes.
doi:10.2337/dc11-0616
PMCID: PMC3198295  PMID: 21926283
18.  Validity of Diagnostic Codes and Liver-Related Laboratory Abnormalities to Identify Hepatic Decompensation Events in the Veterans Aging Cohort Study 
SUMMARY
Purpose
The absence of validated methods to identify hepatic decompensation in cohort studies has prevented a full understanding of the natural history of chronic liver diseases and impact of medications on this outcome. We determined the ability of diagnostic codes and liver-related laboratory abnormalities to identify hepatic decompensation events within the Veterans Aging Cohort Study (VACS).
Methods
Medical records of patients with hepatic decompensation codes and/or laboratory abnormalities of liver dysfunction (total bilirubin ≥5.0 gm/dL, albumin ≤2.0 gm/dL, international normalized ratio ≥1.7) recorded one year before through six months after VACS entry were reviewed to identify decompensation events (i.e., ascites, spontaneous bacterial peritonitis, variceal hemorrhage, hepatic encephalopathy, hepatocellular carcinoma) at VACS enrollment. Positive predictive values (PPVs) of diagnostic codes, laboratory abnormalities, and their combinations for confirmed outcomes were determined.
Results
Among 137 patients with a hepatic decompensation code and 197 with a laboratory abnormality, the diagnosis was confirmed in 57 (PPV, 42%; 95% CI, 33% – 50%) and 56 (PPV, 28%; 95% CI, 22% – 35%), respectively. The combination of any code plus laboratory abnormality increased PPV (64%; 95% CI, 47% - 79%). One inpatient or ≥2 outpatient diagnostic codes for ascites, spontaneous bacterial peritonitis, or variceal hemorrhage had high PPV (91%; 95% CI, 77% – 98%) for confirmed hepatic decompensation events.
Conclusion
An algorithm of 1 inpatient or ≥2 outpatient codes for ascites, peritonitis, or variceal hemorrhage has sufficiently high PPV for hepatic decompensation to enable its use for epidemiologic research in VACS. This algorithm may be applicable to other cohorts.
doi:10.1002/pds.2148
PMCID: PMC3131229  PMID: 21626605
hepatic decompensation; end-stage liver disease; epidemiologic methods; outcomes; validation studies
19.  The Risk of Incident Coronary Heart Disease Among Veterans with and without HIV and Hepatitis C 
Background
Whether hepatitis C (HCV) confers additional coronary heart disease (CHD) risk among Human Immunodeficiency Virus (HIV) infected individuals is unclear. Without appropriate adjustment for antiretroviral therapy, CD4 count, and HIV-1 RNA, and substantially different mortality rates among those with and without HIV and HCV infection, the association between HIV, HCV, and CHD may be obscured.
Methods and Results
We analyzed data on 8579 participants (28% HIV+, 9% HIV+HCV+) from the Veterans Aging Cohort Study Virtual Cohort who participated in the 1999 Large Health Study of Veteran Enrollees. We analyzed data collected on HIV and HCV status, risk factors for and the incidence of CHD, and mortality from 1/2000–7/2007. We compared models to assess CHD risk when death was treated as a censoring event and as a competing risk. During the median 7.3 years of follow-up, there were 194 CHD events and 1186 deaths. Compared with HIV−HCV− Veterans, HIV+ HCV+ Veterans had a significantly higher risk of CHD regardless of whether death was adjusted for as a censoring event (adjusted hazard ratio (HR)=2.03, 95% CI=1.28–3.21) or a competing risk (adjusted HR=2.45, 95% CI=1.83–3.27 respectively). Compared with HIV+HCV− Veterans, HIV+ HCV+ Veterans also had a significantly higher adjusted risk of CHD regardless of whether death was treated as a censored event (adjusted HR=1.93, 95% CI=1.02–3.62) or a competing risk (adjusted HR =1.46, 95% CI=1.03–2.07).
Conclusions
HIV+HCV+ Veterans have an increased risk of CHD compared to HIV+HCV−, and HIV−HCV− Veterans.
doi:10.1161/CIRCOUTCOMES.110.957415
PMCID: PMC3159506  PMID: 21712519
viruses; coronary disease; mortality; multi morbidity
20.  HIV Infection and Risk for Incident Pulmonary Diseases in the Combination Antiretroviral Therapy Era 
Rationale: In aging HIV-infected populations comorbid diseases are important determinants of morbidity and mortality. Pulmonary diseases have not been systematically assessed in the combination antiretroviral therapy (ART) era.
Objectives: To determine the incidence of pulmonary diseases in HIV-infected persons compared with HIV-uninfected persons.
Methods: We analyzed data from the Veterans Aging Cohort Study Virtual Cohort, consisting of 33,420 HIV-infected veterans and 66,840 age, sex, race and ethnicity, and site-matched HIV-uninfected veterans. Using Poisson regression, incidence rates and adjusted incidence rate ratios were calculated to determine the association of HIV with pulmonary disease. The Virtual Cohort was merged with the 1999 Veterans Large Health Survey to adjust for self-reported smoking in a nested sample (14%).
Measurements and Main Results: Incident chronic obstructive pulmonary disease, lung cancer, pulmonary hypertension, and pulmonary fibrosis, as well as pulmonary infections, were significantly more likely among HIV-infected patients compared with uninfected patients in adjusted analyses, although rates of asthma did not differ by HIV status. Bacterial pneumonia and chronic obstructive pulmonary disease were the two most common incident pulmonary diseases, whereas opportunistic pneumonias were less common. Absolute rates of most pulmonary diseases increased with age, although the relative differences between those with and without HIV infection were greatest in younger persons. Chronic obstructive pulmonary disease and asthma, as well as pulmonary infections, were less likely in those with lower HIV RNA levels and use of ART at baseline.
Conclusions: Pulmonary diseases among HIV-infected patients receiving care within the Veterans Affairs Healthcare System in the combination ART era reflect a substantial burden of non–AIDS-defining and chronic conditions, many of which are associated with aging.
doi:10.1164/rccm.201006-0836OC
PMCID: PMC3266024  PMID: 20851926
HIV; respiratory tract diseases; lung diseases, obstructive; pneumonia; pneumonia, bacterial
21.  Association of Upper Trunk and Visceral Adipose Tissue Volume With Insulin Resistance in Control and HIV-Infected Subjects in the FRAM Study 
Summary
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.
PMCID: PMC3164883  PMID: 18167644
buffalo hump; fat distribution; insulin resistance; lipodystrophy; visceral obesity
22.  Association Between Hepatitis C Virus Coinfection and Regional Adipose Tissue Volume in HIV-Infected Men and Women 
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.
doi:10.1097/QAI.0b013e3180423a95
PMCID: PMC3164885  PMID: 17356466
adipose tissue volume; fat distribution; hepatitis C virus; HIV; lipodystrophy
23.  Decreased Serum Antibody Responses to Recombinant Pneumocystis Antigens in HIV-Infected and Uninfected Current Smokers▿  
Serologic studies can provide important insights into the epidemiology and transmission of Pneumocystis jirovecii. Exposure to P. jirovecii can be assessed by serum antibody responses to recombinant antigens from the major surface glycoprotein (MsgC), although factors that influence the magnitude of the antibody response are incompletely understood. We determined the magnitudes of antibody responses to P. jirovecii in comparison to adenovirus and respiratory syncytial virus (RSV) in HIV-infected and uninfected patients and identified predictors associated with the magnitude of the response. We performed a cross-sectional analysis using serum samples and data from 153 HIV-positive and 92 HIV-negative subjects enrolled in a feasibility study of the Veterans Aging Cohort 5 Site Study (VACS 5). Antibodies were measured using an enzyme-linked immunosorbent assay (ELISA). Independent predictors of antibody responses were determined using multivariate Tobit regression models. The results showed that serum antibody responses to P. jirovecii MsgC fragments were significantly and independently decreased in current smokers. Antibodies to P. jirovecii also tended to be lower with chronic obstructive pulmonary disease (COPD), hazardous alcohol use, injection drug use, and HIV infection, although these results were not statistically significant. These results were specific to P. jirovecii and did not correlate with adenovirus. Antibody responses to RSV were in the inverse direction. Thus, current smoking was independently associated with decreased P. jirovecii antibody responses. Whether smoking exerts an immunosuppressive effect that affects the P. jirovecii antibody response, colonization, or subsequent risk for disease is unclear; prospective, longitudinal studies are needed to evaluate these findings further.
doi:10.1128/CVI.00421-10
PMCID: PMC3067379  PMID: 21191078
24.  Time to Depression Treatment in Primary Care Among HIV-infected and Uninfected Veterans 
BACKGROUND
Multiple factors, including patient characteristics, competing demands, and clinic type, impact delivery of depression treatment in primary care.
OBJECTIVE
Assess whether depression severity and HIV serostatus have a differential effect on time to depression treatment among depressed patients receiving primary care at Infectious Disease or General Medicine clinics.
DESIGN
Multicenter prospective cohort, (Veterans Aging Cohort Study), comparing HIV-infected to uninfected patients.
PARTICIPANTS AND MEASURES
The total cohort consisted of 3,239 HIV-infected and 3,227 uninfected patients. Study inclusion criteria were untreated depressive symptoms, based on a Patient Health Questionnaire (PHQ-9) score of greater than 9, and no antidepressants or mental health visits in the 90 days prior to PHQ-9 assessment. Treatment was defined as antidepressant receipt or mental health visit within 90 days following PHQ-9 assessment. Depression severity based on PHQ-9 scores was defined as mild-moderate (greater than 9 to 19) and severe (20 or greater). Kaplan-Meier curves were used to estimate time to treatment by depression severity and HIV serostatus. Cox proportional hazards methods adjusted for covariates were used.
KEY RESULTS
Overall, 718 (11%) of the cohort met inclusion criteria, 258 (36%) of whom received treatment. Median time to treatment was 7 days [95% confidence interval (CI) = 4, 13] and was shortest for severely depressed HIV-infected patients (0.5 days; 95% CI = 0.5, 6, p = 0.04). Compared to mildly-moderately depressed uninfected patients, severely depressed HIV-infected patients were significantly more likely to receive treatment [adjusted hazard ratio (HR) 1.67, 95% CI = 1.07, 2.60), whereas mildly-moderately depressed HIV-infected patients (adjusted HR 1.10, 95% CI = 0.79, 1.52) and severely depressed uninfected patients (adjusted HR 0.93, 95% CI = 0.60, 1.44) were not.
CONCLUSIONS
In this large cohort, time to primary care treatment of depression was shortest among severely depressed HIV-infected patients. Regardless of HIV serostatus, if depression was not treated on the assessment day, then it was unlikely to be treated within a 90-day period, leading to the majority of depression being untreated.
doi:10.1007/s11606-010-1323-z
PMCID: PMC2881956  PMID: 20405335
AIDS; antidepressant drugs; HIV; major depression; psychotherapy
25.  Depression Symptoms and Treatment Among HIV Infected and Uninfected Veterans 
AIDS and behavior  2008;14(2):272-279.
Depression is one of the most common comorbid conditions affecting persons with HIV. We compared depressive symptoms and depression treatment using data from the Veterans Aging Cohort Study (VACS), a prospective cohort of HIV-infected and uninfected subjects. We identified subjects with a Patient Health Questionnaire score of 10 or greater. Treatment was defined as prescription of a selective serotonin reuptake inhibitor (SSRI) or mental health counseling. Overall, 16% of 4,480 subjects had depressive symptoms, and HIV-infected patients were more likely to have had depressive symptoms (OR = 1.38, 95% CI = 1.18, 1.62). Geographic site of care and having a mental health provider at the clinic was associated with treatment. In multivariable models restricted to 732 patients with depressive symptoms, receipt of depression treatment did not differ by HIV status (Adjusted OR = 1.11, 95% CI = 0.80, 1.54). Non-Hispanic whites were more likely to receive treatment (Adjusted OR = 2.09, 95% CI 1.04, 4.24). Primary care and HIV providers were equally unlikely to treat active depressive symptoms. Treatment variation by race, site, and availability of a mental health provider, suggests targets for intervention.
doi:10.1007/s10461-008-9428-7
PMCID: PMC3125603  PMID: 18648927
HIV-infection; Depression; Psychiatric status rating scales; Anti-depressive agents

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