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author:("Butt, adee A.")
1.  CD8+ T-Cells Count in Acute Myocardial Infarction in HIV Disease in a Predominantly Male Cohort 
BioMed Research International  2015;2015:246870.
Human Immunodeficiency Virus- (HIV-) infected persons have a higher risk for acute myocardial infarction (AMI) than HIV-uninfected persons. Earlier studies suggest that HIV viral load, CD4+ T-cell count, and antiretroviral therapy are associated with cardiovascular disease (CVD) risk. Whether CD8+ T-cell count is associated with CVD risk is not clear. We investigated the association between CD8+ T-cell count and incident AMI in a cohort of 73,398 people (of which 97.3% were men) enrolled in the U.S. Veterans Aging Cohort Study-Virtual Cohort (VACS-VC). Compared to uninfected people, HIV-infected people with high baseline CD8+ T-cell counts (>1065 cells/mm3) had increased AMI risk (adjusted HR = 1.82, P < 0.001, 95% CI: 1.46 to 2.28). There was evidence that the effect of CD8+ T-cell tertiles on AMI risk differed by CD4+ T-cell level: compared to uninfected people, HIV-infected people with CD4+ T-cell counts ≥200 cells/mm3 had increased AMI risk with high CD8+ T-cell count, while those with CD4+ T-cell counts <200 cells/mm3 had increased AMI risk with low CD8+ T-cell count. CD8+ T-cell counts may add additional AMI risk stratification information beyond that provided by CD4+ T-cell counts alone.
PMCID: PMC4320893
2.  Medical ICU Admission Diagnoses and Outcomes in Human Immunodeficiency Virus–Infected and Virus–Uninfected Veterans in the Combination Antiretroviral Era 
Critical care medicine  2013;41(6):1458-1467.
Human immunodeficiency virus (HIV)–infected (HIV+) patients on combination antiretroviral therapy are living longer but have increased risk for aging-associated disease which may lead to increasing critical care requirements. We compare medical ICU admission characteristics and outcomes among HIV infected and demographically similar uninfected patients (uninfected) and considered whether an index which combines routine clinical biomarkers (the Veterans Aging Cohort Study Index) predicts 30-day medical ICU mortality.
Observational data analyses (Veterans Aging Cohort Study).
Eight Veterans Affairs medical centers nationwide.
HIV infected and uninfected with a medical ICU admission between 2002 and 2010.
Measurements and Main Results
Medical ICU admission was determined using bedsection (Veterans Affairs) and revenue center codes (Medicare). For Veterans Affairs admissions, we used clinical data to calculate Veterans Aging Cohort Study Index scores and multivariable logistic regression to determine factors associated with 30-day mortality. Overall, 539 of 3,620 (15%) HIV infected and 375 of 3,639 (10%) uninfected had a medical ICU admission; 72% and 78%, respectively, were Veterans Affairs based. HIV+ patients were younger at admission (p < 0.0001). Although most HIV+ patients were on antiretroviral therapy (71%) with undetectable HIV-1 RNA (54%), compared with uninfected they were more commonly admitted with respiratory diagnoses or infections (21% vs. 12%), were more likely to require mechanical ventilation (17% vs. 9%; p = 0.001), and had a higher mortality rate (18.6% vs. 11.2%, p = 0.003). Cardiovascular diagnoses were less common among HIV infected (18% vs. 29%; p < 0.0001). In logistic regression (c-statistic 0.87), a 5-point increment in Veterans Aging Cohort Study Index was associated with an odds ratio of death of 1.22 (95% confidence interval 1.14–1.30) among HIV infected and of 1.50 (95% confidence interval 1.29–1.76) among uninfected; infection/sepsis and respiratory diagnoses were also associated with mortality.
Medical ICU admission was frequent, 30-day mortality higher, and mechanical ventilation more common in HIV infected compared with uninfected. The Veterans Aging Cohort Study Index calculated at medical ICU admission predicted 30-day mortality for HIV infected and uninfected. As more individuals age with HIV, their requirements for medical ICU care may be greater than demographically similar uninfected individuals.
PMCID: PMC4283206  PMID: 23507717
30-day mortality; comorbidity; human immunodeficiency virus; medical ICU; Veterans Aging Cohort Study Index
3.  Hepatic Decompensation in Antiretroviral-Treated HIV/Hepatitis C-Coinfected Compared to Hepatitis C-Monoinfected Patients: A Cohort Study 
Annals of internal medicine  2014;160(6):369-379.
The incidence and determinants of hepatic decompensation have been incompletely examined among HIV/hepatitis C virus (HCV)-coinfected patients in the antiretroviral therapy (ART) era, and few studies have compared rates of outcomes to those of patients with chronic HCV alone.
To compare the incidence of hepatic decompensation between antiretroviral-treated HIV/HCV-coinfected and HCV-monoinfected patients, and evaluate factors associated with decompensation among coinfected patients on ART.
Retrospective cohort study.
Veterans Health Administration.
4,280 HIV/HCV-coinfected patients who initiated ART and 6,079 HCV-monoinfected patients receiving care between 1997 and 2010. All patients had detectable HCV RNA and were HCV treatment-naïve.
Incident hepatic decompensation, determined by diagnoses of ascites, spontaneous bacterial peritonitis, or esophageal variceal hemorrhage.
The incidence of hepatic decompensation was greater among coinfected than monoinfected patients (at 10 years: 7.4% versus 4.8%; p<0.001). Compared to HCV-monoinfected patients, antiretroviral-treated HIV/HCV-coinfected patients had a higher rate of hepatic decompensation (hazard ratio [HR] accounting for competing risks, 1.56 [95% confidence interval (CI), 1.31–1.86]). Coinfected patients who maintained HIV RNA levels <1,000 copies/mL still had higher rates of decompensation than HCV-monoinfected patients (HR, 1.44 [95% CI, 1.05–1.99]). Baseline advanced hepatic fibrosis (FIB-4 >3.25; HR, 5.45 [95% CI, 3.79–7.84]), baseline hemoglobin <10 g/dL (HR, 2.24 [CI, 1.20–4.20]), diabetes mellitus (HR, 1.88[95% CI, 1.38–2.56]), and non-black race (HR, 2.12 [95% CI, 1.65–2.72]) were each associated with higher rates of decompensation among coinfected patients on ART.
Observational study of predominantly male patients.
Despite ART, HIV/HCV-coinfected patients had higher rates of hepatic decompensation than HCV-monoinfected individuals. Rates of decompensation were higher for coinfected patients with advanced liver fibrosis, severe anemia, diabetes, and non-black race.
PMCID: PMC4254786  PMID: 24723077
hepatic decompensation; end-stage liver disease; HIV/HCV coinfection; HIV; hepatitis C
4.  Hepatitis C Viremia and the Risk of Chronic Kidney Disease in HIV-Infected Individuals 
Lucas, Gregory M. | Jing, Yuezhou | Sulkowski, Mark | Abraham, Alison G. | Estrella, Michelle M. | Atta, Mohamed G. | Fine, Derek M. | Klein, Marina B. | Silverberg, Michael J. | Gill, M. John | Moore, Richard D. | Gebo, Kelly A. | Sterling, Timothy R. | Butt, Adeel A. | Kirk, Gregory D. | Benson, Constance A. | Bosch, Ronald J. | Collier, Ann C. | Boswell, Stephen | Grasso, Chris | Mayer, Ken | Hogg, Robert S. | Harrigan, Richard | Montaner, Julio | Cescon, Angela | Brooks, John T. | Buchacz, Kate | Gebo, Kelly A. | Moore, Richard D. | Carey, John T. | Rodriguez, Benigno | Horberg, Michael A. | Silverberg, Michael J. | Horberg, Michael A. | Thorne, Jennifer E. | Goedert, James J. | Jacobson, Lisa P. | Klein, Marina B. | Rourke, Sean B. | Burchell, Ann | Rachlis, Anita R. | Rico, Puerto | Hunter-Mellado, Robert F. | Mayor, Angel M. | Gill, M. John | Deeks, Steven G. | Martin, Jeffrey N. | Patel, Pragna | Brooks, John T. | Saag, Michael S. | Mugavero, Michael J. | Willig, James | Eron, Joseph J. | Napravnik, Sonia | Kitahata, Mari M. | Crane, Heidi M. | Justice, Amy C. | Dubrow, Robert | Fiellin, David | Sterling, Timothy R. | Haas, David | Bebawy, Sally | Turner, Megan | Gange, Stephen J. | Anastos, Kathryn | Moore, Richard D. | Saag, Michael S. | Gange, Stephen J. | Kitahata, Mari M. | McKaig, Rosemary G. | Justice, Amy C. | Freeman, Aimee M. | Moore, Richard D. | Freeman, Aimee M. | Lent, Carol | Kitahata, Mari M. | Van Rompaey, Stephen E. | Crane, Heidi M. | Webster, Eric | Morton, Liz | Simon, Brenda | Gange, Stephen J. | Althoff, Keri N. | Abraham, Alison G. | Lau, Bryan | Zhang, Jinbing | Jing, Jerry | Golub, Elizabeth | Modur, Shari | Hanna, David B. | Rebeiro, Peter | Wong, Cherise | Mendes, Adell
The Journal of Infectious Diseases  2013;208(8):1240-1249.
Background. The role of active hepatitis C virus (HCV) replication in chronic kidney disease (CKD) risk has not been clarified.
Methods. We compared CKD incidence in a large cohort of HIV-infected subjects who were HCV seronegative, HCV viremic (detectable HCV RNA), or HCV aviremic (HCV seropositive, undetectable HCV RNA). Stages 3 and 5 CKD were defined according to standard criteria. Progressive CKD was defined as a sustained 25% glomerular filtration rate (GFR) decrease from baseline to a GFR < 60 mL/min/1.73 m2. We used Cox models to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).
Results. A total of 52 602 HCV seronegative, 9508 HCV viremic, and 913 HCV aviremic subjects were included. Compared with HCV seronegative subjects, HCV viremic subjects were at increased risk for stage 3 CKD (adjusted HR 1.36 [95% CI, 1.26, 1.46]), stage 5 CKD (1.95 [1.64, 2.31]), and progressive CKD (1.31 [1.19, 1.44]), while HCV aviremic subjects were also at increased risk for stage 3 CKD (1.19 [0.98, 1.45]), stage 5 CKD (1.69 [1.07, 2.65]), and progressive CKD (1.31 [1.02, 1.68]).
Conclusions. Compared with HIV-infected subjects who were HCV seronegative, both HCV viremic and HCV aviremic individuals were at increased risk for moderate and advanced CKD.
PMCID: PMC3778973  PMID: 23904290
HIV; hepatitis C virus; chronic kidney disease; hepatitis C RNA; cohort study; glomerular filtration rate; injection drug use
5.  Risk factors for hospitalization and medical intensive care unit (MICU) admission among HIV infected Veterans 
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.
We analyzed data from the Veterans Aging Cohort Study (VACS), a prospective study of HIV-infected Veterans receiving care between 2002–2008. 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.
1141/3410 (33.5%) patients were hospitalized within 2 years; 203/1141 (17.8%) included a 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.
The VACS Index predicted hospitalization and MICU admission as did current smoking, hazardous alcohol use, and AIDS and certain non-AIDS diagnoses.
PMCID: PMC4182723  PMID: 23111572
HIV; hospitalization; medical intensive care unit (MICU); aging; VACS Index; comorbidity
6.  Predictors of Mortality among United States Veterans with Human Immunodeficiency Virus and Hepatitis C Virus Coinfection 
ISRN Gastroenterology  2014;2014:764540.
Background. Understanding the predictors of mortality in individuals with human immunodeficiency virus and hepatitis C virus (HIV/HCV) coinfection can be useful in management of these patients. Methods. We used the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) for these analyses. Multivariate Cox-regression models were used to determine predictors of mortality. Results. Among 8,039 HIV infected veterans, 5251 (65.3%) had HCV coinfection. The all-cause mortality rate was 74.1 (70.4–77.9) per 1000 person-years (PY) among veterans with HIV/HCV coinfection and 39.8 (36.3–43.6) per 1000 PY for veterans with HIV monoinfection. The multivariable adjusted hazard ratio (95% confidence interval) of all-cause mortality for HCV infection was 1.58 (1.36–1.84). Positive predictors of mortality included decompensated liver disease (2.33 (1.98–2.74)), coronary artery disease (1.74 (1.32–2.28)), chronic kidney disease (1.62 (1.36–1.92)), and anemia (1.58 (1.31–1.89)). Factors associated with reduced mortality included HCV treatment (0.41 (0.27–0.63)) and higher CD4 count (0.90 (0.87–0.93) per 100 cells/μL higher count). Data were insufficient to make informative analyses of the role of HCV virologic response. Conclusion. HCV coinfection was associated with substantial increased risk of mortality among HIV infected veterans. HCV treatment was associated with significantly lower risk of mortality.
PMCID: PMC4004106  PMID: 25006471
Journal of viral hepatitis  2012;19(11):792-800.
Though health-related quality of life (HRQOL) is diminished in HCV/HIV, the relationship between virologic response or maintenance therapy with HRQOL in this population is unknown. ACTG 5178 was a phase 2, randomized trial, with 3 steps: Step 1: all subjects received PEG-IFN/ribavirin (P/R) for 12 weeks. Step 2: subjects who failed to achieve early viral response (EVR) were randomized to PEG-IFN or observational control for an additional 72 weeks. Step 3: subjects with EVR from Step 1 continued on P/R for a total of 72 weeks with 24 weeks follow-up off therapy. HRQOL, symptom distress and depression levels were measured at multiple time points. In Step 1 (n=329), there was a significant decline in HRQOL in all dimensions. In Step 3 (n=169), the overall HRQOL and 3 of its 8 dimensions (general health, role function and pain score) were increased, and achievement of SVR was associated with increased general health and cognitive function. In the Step 2 group (n=85), there was no significant change in HRQOL and no significant difference between groups (PEG-IFN vs. observational control). There was a significant decline in HRQOL during the initial 12 weeks of therapy. Thereafter the HRQOL profile differed for subjects with EVR vs. without EVR. Maintenance therapy with PEG-IFN had no impact on the HRQOL.
PMCID: PMC3468910  PMID: 23043386
HCV; HIV; confection; treatment; health related quality of life
8.  Impact of Peginterferon Alpha and Ribavirin Treatment on Lipid Profiles and Insulin Resistance in Hepatitis C Virus/HIV–Coinfected Persons: The AIDS Clinical Trials Group A5178 Study 
Peginterferon and ribavirin can significantly affect lipid profile and insulin resistance (IR) in hepatitis C virus/human immunodeficiency virus–coinfected persons. Although the lipid profile returns to near pretreatment levels after completion of treatment, our data suggest persistent modest improvement in IR with treatment.
Background. The effect of peginterferon alpha/ribavirin (PEG-IFN/RBV) and hepatitis C virus (HCV) clearance on lipid and insulin resistance (IR) profiles in HCV/human immunodeficiency virus (HIV) coinfection is unknown.
Methods. We measured fasting total cholesterol (TC), low-density lipoprotein (LDL-C), high-density lipoproteins (HDL-C), triglycerides (TG), glucose, and insulin at defined intervals in the A5178 study (N = 329), a prospective treatment trial in HCV/HIV coinfection. Changes from baseline and the relation between baseline values of these variables to sustained virologic response (SVR) were determined.
Results. Of 182 subjects with metabolic data, 98 achieved early virologic response (EVR) and continued PEG-IFN/RBV. Among those, median pretreatment HCV RNA was 6.6 log10 IU/mL; 73% had HCV genotype 1. Median pretreatment TC was 176 mg/dL (interquartile range [IQR],150–205]; median LDL-C was 99 mg/dL (IQR, 79–123); median HDL-C was 40 mg/dL (IQR, 31–47); and median TG was 147 mg/dL (IQR, 101–221). Median homeostasis model assessment of IR (HOMA-IR) was 3.3 (IQR, 1.7–5.3). The EVRs demonstrated a decline in TC, LDL-C, and HDL-C, whereas TG increased on treatment but returned to near baseline 24 weeks after end of treatment (EOT). The HOMA-IR decline from entry to 24 weeks after EOT was significant among non–sustained virologic responders and nonsignificant among sustained virologic responders; this difference was offset after adjusting for higher HOMA-IR at baseline among the former. Among all 182 subjects, entry LDL-C was associated with SVR in a joint logistic model adjusted for HCV genotype, race, and prior IFN (odds ratio, 1.17 per 10 mg/dL increase; 95% confidence interval, 1.03–1.32), but TC, HDL, TG, and IR were not.
Conclusions. Peginterferon alpha and RBV can significantly affect lipid profile and IR in HCV/HIV–coinfected persons. Although the lipid profile returns to near pretreatment levels after completion of treatment, our data suggest persistent modest improvement in IR with treatment.
Clinical Trials Registration. NCT00078403.
PMCID: PMC3491848  PMID: 22563020
9.  Comorbid diabetes and the risk of progressive chronic kidney disease in HIV-infected adults: Data from the Veterans Aging Cohort Study 
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.
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.
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].
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.
PMCID: PMC3392432  PMID: 22592587
non-AIDS complications; HIV; chronic kidney disease; diabetes; risk factors
10.  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.
PMCID: PMC3493182  PMID: 22534147
11.  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.
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.
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.
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).
Our data suggest that HIV infection is a risk factor for HF. Ongoing viral replication is associated with a higher risk of developing HF.
PMCID: PMC3687533  PMID: 21518940
12.  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.
PMCID: PMC3687553  PMID: 18190322
13.  Does an Index Composed of Clinical Data Reflect Effects of Inflammation, Coagulation, and Monocyte Activation on Mortality Among Those Aging With HIV? 
The Veterans Aging Cohort Study (VACS) Index, based on age and 8 routine clinical tests, is strongly correlated with 3 biomarkers of inflammation: interleukin 6 (IL-6), D-dimer, and soluble CD14 (sCD14). After adjustment for the VACS Index, D-dimer and sCD14, but not IL-6, remain independently associated with mortality.
Background. When added to age, CD4 count and human immunodeficiency virus type 1 (HIV-1) RNA alone (Restricted Index), hemoglobin, FIB-4 Index, hepatitis C virus (HCV), and estimated glomerular filtration rate improve prediction of mortality. Weighted and combined, these 7 routine clinical variables constitute the Veterans Aging Cohort Study (VACS) Index. Because nonroutine biomarkers of inflammation (interleukin 6 [IL-6]), coagulation (D-dimer), and monocyte activation (sCD14) also predict mortality, we test the association of these indices and biomarkers with each other and with mortality.
Methods. Samples from 1302 HIV-infected veterans on antiretroviral therapy were analyzed. Indices were calculated closest to date of collection. We calculated Spearman correlations stratified by HIV-1 RNA and HCV status and measured association with mortality using C statistics and net reclassification improvement (NRI).
Results. Of 1302 subjects, 915 had HIV-1 RNA <500 copies/mL and 154 died. The VACS Index was more correlated with IL-6, D-dimer, and sCD14 than the Restricted Index (P < .001). It was also more predictive of mortality (C statistic, 0.76; 95% confidence interval [CI], .72–.80) than any biomarker (C statistic, 0.66–0.70) or the Restricted Index (C statistic, 0.71; 95% CI, .67–.75). Compared to the Restricted Index alone, NRI resulted from incremental addition of VACS Index components (10%), D-dimer (7%), and sCD14 (4%), but not from IL-6 (0%).
Conclusions. Among HIV-infected individuals, independent of CD4, HIV-1 RNA, and age, hemoglobin and markers of liver and renal injury are associated with inflammation. Addition of D-dimer and sCD14, but not IL-6, improves the predictive accuracy of the VACS Index for mortality.
PMCID: PMC3297653  PMID: 22337823
14.  HIV as an Independent Risk Factor for Incident Lung Cancer 
AIDS (London, England)  2012;26(8):1017-1025.
PMCID: PMC3580210  PMID: 22382152
Human Immunodeficiency Virus (HIV); lung cancer; incidence; smoking; immunosuppression; non-AIDS defining malignancy
15.  Doxorubicin-loaded cholic acid-polyethyleneimine micelles for targeted delivery of antitumor drugs: synthesis, characterization, and evaluation of their in vitro cytotoxicity 
Nanoscale Research Letters  2012;7(1):687.
Doxorubicin-loaded micelles were prepared from a copolymer comprising cholic acid (CA) and polyethyleneimine (PEI) for the delivery of antitumor drugs. The CA-PEI copolymer was synthesized via pairing mediated by N,N’-dicyclohexylcarbodiimide and N-hydroxysuccinimide using dichloromethane as a solvent. Fourier transform infrared and nuclear magnetic resonance analyses were performed to verify the formation of an amide linkage between CA and PEI and doxorubicin localization into the copolymer. Dynamic light scattering and transmission electron microscopy studies revealed that the copolymer could self-assemble into micelles with a spherical morphology and an average diameter of <200 nm. The CA-PEI copolymer was also characterized by X-ray diffraction and differential scanning calorimetry. Doxorubicin-loaded micelles were prepared by dialysis method. A drug release study showed reduced drug release with escalating drug content. In a cytotoxicity assay using human colorectal adenocarcinoma (DLD-1) cells, the doxorubicin-loaded CA-PEI micelles exhibited better antitumor activity than that shown by doxorubicin. This is the first study on CA-PEI micelles as doxorubicin carriers, and this study demonstrated that they are promising candidates as carriers for sustained targeted antitumor drug delivery system.
PMCID: PMC3552841  PMID: 23270381
Micelles; Nanoparticles; Cholic acid; Polyethyleneimine; Doxorubicin
16.  Validating Smoking Data From the Veteran’s Affairs Health Factors Dataset, an Electronic Data Source 
Nicotine & Tobacco Research  2011;13(12):1233-1239.
We assessed smoking data from the Veterans Health Administration (VHA) electronic medical record (EMR) Health Factors dataset.
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.
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.
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.
PMCID: PMC3223583  PMID: 21911825
17.  FIB-4 index is associated with hepatocellular carcinoma risk in HIV-infected patients 
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.
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.
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.
Calculated from routine, non-invasive laboratory tests, FIB-4 is a strong, independent HCC risk factor in HIV-infected patients.
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.
PMCID: PMC3237927  PMID: 22028407
hepatocellular carcinoma; FIB-4; HIV; liver neoplasms; hepatic fibrosis
18.  A Comparison of Treatment Eligibility for Hepatitis C Virus in HCV-Monoinfected Versus HCV/HIV-Coinfected Persons in Electronically Retrieved Cohort of HCV-Infected Veterans 
Treatment rates for hepatitis C virus (HCV) are low in actual clinical settings. However, the proportion of patients eligible for treatment, especially among those coinfected with HIV, is not well known. Our aim was to determine and compare the rates for HCV treatment eligibility among HCV and HCV-HIV-coinfected persons. We assembled a national cohort of HCV-infected veterans in care from 1998–2003, using the VA National Patient Care Database for demographic/clinical information, the Pharmacy Benefits Management database for pharmacy records, and the Decision Support Systems database for laboratory data. We compared the HCV-monoinfected and HCV-HIV-coinfected subjects for treatment indications and eligibility using current treatment guidelines. Of the 27,452 subjects with HCV and 1225 with HCV-HIV coinfection, 74.0% and 84.6% had indications for therapy and among these, 43.9% of HCV-monoinfected and 28.4% of HCV-HIV-coinfected subjects were eligible for treatment. Anemia, decompensated liver disease (DLD), chronic obstructive pulmonary disease (COPD), recent alcohol abuse, and coronary artery disease were the most common contraindications in the HCV, and anemia, DLD, renal failure, recent drug abuse, and COPD in the HCV-HIV-coinfected group. Among those eligible for treatment, only 23% of the HCV-monoinfected and 15% of the HCV-HIV-coinfected subjects received any treatment for HCV. Most veterans with HCV are not eligible for treatment according to the current guidelines. Even for those who are eligible for treatment, only a minority is prescribed treatment. Several contraindications are modifiable and aggressive management of those may improve treatment prescription rates.
PMCID: PMC3719436  PMID: 21338329
19.  Validity of Diagnostic Codes and Liver-Related Laboratory Abnormalities to Identify Hepatic Decompensation Events in the Veterans Aging Cohort Study 
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).
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.
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.
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.
PMCID: PMC3131229  PMID: 21626605
hepatic decompensation; end-stage liver disease; epidemiologic methods; outcomes; validation studies
20.  The Risk of Incident Coronary Heart Disease Among Veterans with and without HIV and Hepatitis C 
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).
HIV+HCV+ Veterans have an increased risk of CHD compared to HIV+HCV−, and HIV−HCV− Veterans.
PMCID: PMC3159506  PMID: 21712519
viruses; coronary disease; mortality; multi morbidity
21.  Extended Therapy With Pegylated Interferon and Weight-Based Ribavirin for HCV-HIV Coinfected Patients 
HIV Clinical Trials  2012;13(2):70-82.
It is unknown whether extended treatment with pegylated interferon (PEG) and weight-based ribavirin (WBR) results in higher rates of sustained virologic response (SVR) among HCV-HIV coinfected patients compared with standard duration therapy.
The study aimed to measure rates of SVR among coinfected patients who received extended therapy with PEG plus WBR.
HCV-HIV coinfected subjects were treated with PEG and WBR, and those who achieved early virologic response (EVR; ≥2 log decrease in HCV RNA from baseline or HCV RNA<600 IU/mL) at week 12 were eligible to continue treatment for 72 weeks. SVR (HCV RNA<60 IU/mL) was measured 24 weeks after treatment discontinuation. Predictors of SVR were assessed in simple and multivariate logistic regression.
A total of 329 subjects enrolled at 36 sites. Of 184 subjects who achieved EVR, 169 entered Step 3: 89% male, 52% White, 29% Black, and 71% HCV treatment naïve. The overall SVR rate was 27% (95% CI, 22%–32%) among all subjects, and 33% (95% CI, 27%–40%) among the 223 who were HCV treatment naïve. In exploratory analyses, among 120 treatment-naïve subjects who entered Step 3, the SVR rate was 62% (95% CI, 52%–70%). In this subgroup, predictors of SVR were HCV genotype 2 or 3 (P = .03), HCV RNA <800,000 IU/mL at study entry (P = .05), and achievement of complete EVR (HCV RNA<600 IU/mL at week 12; P < .0001).
Among all subjects, we observed a comparable overall SVR rate to prior studies of subjects treated for 48 weeks. Extended treatment with PEG and WBR may be beneficial to subsets of coinfected patients, specifically those who are treatment naïve and achieve complete EVR.
PMCID: PMC3367320  PMID: 22510354
extended therapy; HCV; HIV; weight-based ribavirin
22.  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.
PMCID: PMC3266024  PMID: 20851926
HIV; respiratory tract diseases; lung diseases, obstructive; pneumonia; pneumonia, bacterial
23.  Association of Age and Comorbidity with Physical Function in HIV-Infected and Uninfected Patients: Results from the Veterans Aging Cohort Study 
AIDS Patient Care and STDs  2011;25(1):13-20.
HIV clinical care now involves prevention and treatment of age-associated comorbidity. Although physical function is an established correlate to comorbidity in older adults without HIV infection, its role in aging of HIV-infected adults is not well understood. To investigate this question we conducted cross-sectional analyses including linear regression models of physical function in 3227 HIV-infected and 3240 uninfected patients enrolled 2002–2006 in the Veterans Aging Cohort Study-8-site (VACS-8). Baseline self-reported physical function correlated with the Short Form-12 physical subscale (ρ = 0.74, p < 0.001), and predicted survival. Across the age groups decline in physical function per year was greater in HIV-infected patients (βcoef −0.25, p < 0.001) compared to uninfected patients (βcoef −0.08, p = 0.03). This difference, although statistically significant (p < 0.01), was small. Function in the average 50-year old HIV-infected subject was equivalent to the average 51.5-year-old uninfected subject. History of cardiovascular disease was a significant predictor of poor function, but the effect was similar across groups. Chronic pulmonary disease had a differential effect on function by HIV status (Δβcoef −3.5, p = 0.03). A 50-year-old HIV-infected subject with chronic pulmonary disease had the equivalent level of function as a 68.1-year-old uninfected subject with chronic pulmonary disease. We conclude that age-associated comorbidity affects physical function in HIV-infected patients, and may modify the effect of aging. Longitudinal research with markers of disease severity is needed to investigate loss of physical function with aging, and to develop age-specific HIV care guidelines.
PMCID: PMC3030913  PMID: 21214375
24.  Sustained Long-term Antiviral Maintenance Therapy in HCV/HIV Coinfected Patients (SLAM-C) 
HCV/HIV coinfection treatment is suboptimal with low SVR rates to standard therapies. A multicenter randomized clinical trial designed to assess the efficacy/safety of pegylated-interferon maintenance therapy was performed by the NIH-funded ACTG network.
HCV treatment naïve and non-responding interferon-experienced subjects with confirmed HCV and HIV, CD4>200 cells/mm3, and at least Stage 1 fibrosis were enrolled, and treated for 12 weeks with pegylated interferon alfa 2a 180 mcg/week (PEG) + weight-based ribavirin to determine response status. Non-responder subjects (failure to clear HCV RNA or achieve 2-log drop) underwent liver biopsy and were randomized to receive full dose PEG or observation only for 72 weeks. Paired biopsies were evaluated by a central pathologist.
330 subjects were enrolled; median age was 48 years; 43% White, 37% Black, non-Hispanic; 83% male; CD4+ 498 cells/mm3; 32% were interferon experienced; 74% had entry HIV RNA<50 cp/ml. EVR was observed in 55.9% and 42.5% achieved cEVR. A planned interim analysis of occurred when 84 subjects were randomized. With data on 40 paired biopsies available, a safety monitoring board stopped the trial due to lack of fibrosis progression (median = 0 Metavir units/year) in the observation arm.
Lack of fibrotic progression in the control arm was unexpected, and may represent a short-term PEG/ribavirin therapy effect, high levels of HIV viral suppression and use of antiretroviral regimens that may be less toxic than prior generations of therapy.
PMCID: PMC3017670  PMID: 20921898
HCV; HIV; Maintenance; Racial Disparity; Fibrosis
25.  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.
PMCID: PMC3067379  PMID: 21191078

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