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1.  Disparities in the Quality of HIV Care When Using US Department of Health and Human Services Indicators 
Althoff, Keri N. | Rebeiro, Peter | Brooks, John T. | Buchacz, Kate | Gebo, Kelly | Martin, Jeffrey | Hogg, Robert | Thorne, Jennifer E. | Klein, Marina | Gill, M. John | Sterling, Timothy R. | Yehia, Baligh | Silverberg, Michael J. | Crane, Heidi | Justice, Amy C. | Gange, Stephen J. | Moore, Richard | Kitahata, Mari M. | Horberg, Michael A. | Kirk, Gregory D. | Benson, Constance A. | Bosch, Ronald J. | Collier, Ann C. | Boswell, Stephen | Grasso, Chris | Mayer, Kenneth H. | Hogg, Robert S. | Richard Harrigan, P. | Montaner, Julio SG | Cescon, Angela | Samji, Hasina | Brooks, John T. | Buchacz, Kate | Gebo, Kelly A. | Moore, Richard D. | Moore, Richard D. | Carey, John T. | Horberg, Michael A. | Silverberg, Michael J. | Thorne, Jennifer E. | Goedert, James J. | Jacobson, Lisa P. | Klein, Marina B. | Rourke, Sean B. | Burchell, Ann N. | Rachlis, Anita R. | Hunter-Mellado, Robert F. | Mayor, Angel M. | Gill, M.John | Deeks, Steven G. | Martin, Jeffrey N. | 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. | Althoff, Keri N. | 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. | Morton, Liz | McReynolds, Justin | Lober, William B. | 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
We estimated US Department of Health and Human Services (DHHS)–approved human immunodeficiency virus (HIV) indicators. Among patients, 71% were retained in care, 82% were prescribed treatment, and 78% had HIV RNA ≤200 copies/mL; younger adults, women, blacks, and injection drug users had poorer outcomes. Interventions are needed to reduce retention- and treatment-related disparities.
PMCID: PMC3967825  PMID: 24463281
HIV; quality of care; retention in care; antiretroviral therapy; HIV RNA suppression
2.  End-Stage Renal Disease Among HIV-Infected Adults in North America 
Abraham, Alison G. | Althoff, Keri N. | Jing, Yuezhou | Estrella, Michelle M. | Kitahata, Mari M. | Wester, C. William | Bosch, Ronald J. | Crane, Heidi | Eron, Joseph | Gill, M. John | Horberg, Michael A. | Justice, Amy C. | Klein, Marina | Mayor, Angel M. | Moore, Richard D. | Palella, Frank J. | Parikh, Chirag R. | Silverberg, Michael J. | Golub, Elizabeth T. | Jacobson, Lisa P. | Napravnik, Sonia | Lucas, Gregory M. | 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. | Moore, Richard D. | Carey, John T. | Rodriguez, Benigno | Horberg, Michael A. | Silverberg, Michael J. | Thorne, Jennifer E. | Goedert, James J. | Jacobson, Lisa P. | Klein, Marina B. | Rourke, Sean B. | Burchell, Ann | Rachlis, Anita R. | Hunter-Mellado, Robert F. | Mayor, Angel M. | Gill, M. John | Deeks, Steven G. | Martin, Jeffrey N. | 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. | Althoff, Keri N. | 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
Human immunodeficiency virus-infected individuals have benefited from improved viral suppression, but a discrepancy in end-stage renal disease risk between black and nonblack HIV-infected persons remains, in part due to continued disparities in antiretroviral use and viral suppression, and higher rates of comorbidities.
Background. Human immunodeficiency virus (HIV)-infected adults, particularly those of black race, are at high-risk for end-stage renal disease (ESRD), but contributing factors are evolving. We hypothesized that improvements in HIV treatment have led to declines in risk of ESRD, particularly among HIV-infected blacks.
Methods. Using data from the North American AIDS Cohort Collaboration for Research and Design from January 2000 to December 2009, we validated 286 incident ESRD cases using abstracted medical evidence of dialysis (lasting >6 months) or renal transplant. A total of 38 354 HIV-infected adults aged 18–80 years contributed 159 825 person-years (PYs). Age- and sex-standardized incidence ratios (SIRs) were estimated by race. Poisson regression was used to identify predictors of ESRD.
Results. HIV-infected ESRD cases were more likely to be of black race, have diabetes mellitus or hypertension, inject drugs, and/or have a prior AIDS-defining illness. The overall SIR was 3.2 (95% confidence interval [CI], 2.8–3.6) but was significantly higher among black patients (4.5 [95% CI, 3.9–5.2]). ESRD incidence declined from 532 to 303 per 100 000 PYs and 138 to 34 per 100 000 PYs over the time period for blacks and nonblacks, respectively, coincident with notable increases in both the prevalence of viral suppression and the prevalence of ESRD risk factors including diabetes mellitus, hypertension, and hepatitis C virus coinfection.
Conclusions. The risk of ESRD remains high among HIV-infected individuals in care but is declining with improvements in virologic suppression. HIV-infected black persons continue to comprise the majority of cases, as a result of higher viral loads, comorbidities, and genetic susceptibility.
PMCID: PMC4357817  PMID: 25409471
end-stage renal disease (ESRD); chronic kidney disease (CKD); HIV infection/AIDS; HIV/AIDS; glomerular filtration rate (GFR)
3.  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
4.  Trends and Disparities in Antiretroviral Therapy Initiation and Virologic Suppression Among Newly Treatment-Eligible HIV-Infected Individuals in North America, 2001–2009 
Hanna, David B. | Buchacz, Kate | Gebo, Kelly A. | Hessol, Nancy A. | Horberg, Michael A. | Jacobson, Lisa P. | Kirk, Gregory D. | Kitahata, Mari M. | Korthuis, P. Todd | Moore, Richard D. | Napravnik, Sonia | Patel, Pragna | Silverberg, Michael J. | Sterling, Timothy R. | Willig, James H. | Lau, Bryan | Althoff, Keri N. | Crane, Heidi M. | Collier, Ann C. | Samji, Hasina | Thorne, Jennifer E. | Gill, M. John | Klein, Marina B. | Martin, Jeffrey N. | Rodriguez, Benigno | Rourke, Sean B. | Gange, Stephen J. | Benson, 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. | Rodriguez, Benigno | Horberg, Michael A. | Silverberg, Michael J. | Thorne, Jennifer E. | Goedert, James J. | Jacobson, Lisa P. | Klein, Marina B. | Rourke, Sean B. | Burchell, Ann | Rachlis, Anita R. | Hunter-Mellado, Robert F. | Mayor, Angel M. | Gill, M. John | Deeks, Steven G. | Martin, Jeffrey N. | 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 | Platt, Aaron | Kitahata, Mari M. | Van Rompaey, Stephen E. | Crane, Heidi M. | Webster, Eric | Morton, Liz | Simon, Brenda | Gange, Stephen J. | Abraham, Alison G. | Lau, Bryan | Althoff, Keri N. | Zhang, Jinbing | Jing, Jerry | Golub, Elizabeth | Modur, Shari | Hanna, David B. | Rebeiro, Peter | Wong, Cherise | Mendes, Adell
In the last decade, timely initiation of antiretroviral therapy and resulting virologic suppression have greatly improved in North America concurrent with the development of better tolerated and more potent regimens, but significant barriers to treatment uptake remain.
Background. Since the mid-1990s, effective antiretroviral therapy (ART) regimens have improved in potency, tolerability, ease of use, and class diversity. We sought to examine trends in treatment initiation and resulting human immunodeficiency virus (HIV) virologic suppression in North America between 2001 and 2009, and demographic and geographic disparities in these outcomes.
Methods. We analyzed data on HIV-infected individuals newly clinically eligible for ART (ie, first reported CD4+ count <350 cells/µL or AIDS-defining illness, based on treatment guidelines during the study period) from 17 North American AIDS Cohort Collaboration on Research and Design cohorts. Outcomes included timely ART initiation (within 6 months of eligibility) and virologic suppression (≤500 copies/mL, within 1 year). We examined time trends and considered differences by geographic location, age, sex, transmission risk, race/ethnicity, CD4+ count, and viral load, and documented psychosocial barriers to ART initiation, including non–injection drug abuse, alcohol abuse, and mental illness.
Results. Among 10 692 HIV-infected individuals, the cumulative incidence of 6-month ART initiation increased from 51% in 2001 to 72% in 2009 (Ptrend < .001). The cumulative incidence of 1-year virologic suppression increased from 55% to 81%, and among ART initiators, from 84% to 93% (both Ptrend < .001). A greater number of psychosocial barriers were associated with decreased ART initiation, but not virologic suppression once ART was initiated. We found significant heterogeneity by state or province of residence (P < .001).
Conclusions. In the last decade, timely ART initiation and virologic suppression have greatly improved in North America concurrent with the development of better-tolerated and more potent regimens, but significant barriers to treatment uptake remain, both at the individual level and systemwide.
PMCID: PMC3657490  PMID: 23315317
antiretroviral therapy; healthcare disparities; HIV; time factors; viral load
5.  Comparison of AUDIT-C Collected via Electronic Medical Record and Self-Administered Research Survey in HIV Infected and Uninfected Patients 
Drug and alcohol dependence  2016;168:196-202.
Using electronic medical record (EMR) data for clinical decisions, quality improvement, and research is common. While unhealthy alcohol use is particularly risky among HIV infected individuals (HIV+), the validity of EMR data for identifying unhealthy alcohol use among HIV+ is unclear. Among HIV+ and uninfected, we: 1) assess agreement of EMR and research AUDIT-C at validated cutoffs for unhealthy alcohol use; 2) explore EMR cutoffs that maximize agreement; and 3) assess subpopulation variation in agreement.
Using data from the Veterans Aging Cohort Study (VACS), EMR AUDIT-C cutoffs of 2+, 3+, and 4+ for men (2+ and 3+ for women) were compared to research AUDIT-C 4+ for men (3+ for women). Agreement was compared by demographics, HIV, hepatitis C infection, and alcohol related diagnosis.
Among 1,082 HIV+ and 1,160 uninfected men, 14% and 22% had an EMR and research AUDIT-C 4+, respectively. Among 32 HIV+ and 115 uninfected women, 9% and 14% had an EMR and research AUDIT-C 3+. For men, EMR agreement with the research AUDIT-C 4+ was highest at a cutoff of 3+ (kappa = 0.49). For women, EMR agreement with AUDIT-C 3+ was highest at a cutoff of 2+ (kappa = 0.60). Moderate agreement was consistent across subgroups.
EMR AUDIT-C underestimates unhealthy alcohol use compared to research AUDIT-C in both HIV+ and uninfected individuals. Methods for improving quality of clinical screening may be in need of investigation. Researchers and clinicians may consider alternative EMR cutoffs that maximize agreement given limitations of clinical screening.
PMCID: PMC5086273  PMID: 27694059
Alcohol consumption; population-based screening; AUDIT-C; electronic health record; veterans; HIV
6.  Increased non‐AIDS mortality among persons with AIDS‐defining events after antiretroviral therapy initiation 
HIV‐1 infection leads to chronic inflammation and to an increased risk of non‐AIDS mortality. Our objective was to determine whether AIDS‐defining events (ADEs) were associated with increased overall and cause‐specific non‐AIDS related mortality after antiretroviral therapy (ART) initiation.
We included HIV treatment‐naïve adults from the Antiretroviral Therapy Cohort Collaboration (ART‐CC) who initiated ART from 1996 to 2014. Causes of death were assigned using the Coding Causes of Death in HIV (CoDe) protocol. The adjusted hazard ratio (aHR) for overall and cause‐specific non‐AIDS mortality among those with an ADE (all ADEs, tuberculosis (TB), Pneumocystis jiroveci pneumonia (PJP), and non‐Hodgkin's lymphoma (NHL)) compared to those without an ADE was estimated using a marginal structural model.
The adjusted hazard of overall non‐AIDS mortality was higher among those with any ADE compared to those without any ADE (aHR 2.21, 95% confidence interval (CI) 2.00 to 2.43). The adjusted hazard of each of the cause‐specific non‐AIDS related deaths were higher among those with any ADE compared to those without, except metabolic deaths (malignancy aHR 2.59 (95% CI 2.13 to 3.14), accident/suicide/overdose aHR 1.37 (95% CI 1.05 to 1.79), cardiovascular aHR 1.95 (95% CI 1.54 to 2.48), infection aHR (95% CI 1.68 to 2.81), hepatic aHR 2.09 (95% CI 1.61 to 2.72), respiratory aHR 4.28 (95% CI 2.67 to 6.88), renal aHR 5.81 (95% CI 2.69 to 12.56) and central nervous aHR 1.53 (95% CI 1.18 to 5.44)). The risk of overall and cause‐specific non‐AIDS mortality differed depending on the specific ADE of interest (TB, PJP, NHL).
In this large multi‐centre cohort collaboration with standardized assignment of causes of death, non‐AIDS mortality was twice as high among patients with an ADE compared to without an ADE. However, non‐AIDS related mortality after an ADE depended on the ADE of interest. Although there may be unmeasured confounders, these findings suggest that a common pathway may be independently driving both ADEs and NADE mortality. While prevention of ADEs may reduce subsequent death due to NADEs following ART initiation, modification of risk factors for NADE mortality remains important after ADE survival.
PMCID: PMC5810321  PMID: 29334197
AIDS‐defining events; non‐AIDS mortality; tuberculosis; Pneumocystis jiroveci pneumonia; non‐Hodgkin's lymphoma; marginal structural model
7.  Weight Gain and Incident Diabetes among HIV Infected-Veterans Initiating Antiretroviral Therapy Compared to Uninfected Individuals 
The health implications of weight gain after antiretroviral therapy (ART) for HIV infection are not well characterized and may differ from weight gain among uninfected individuals. We use data from the Veterans Aging Cohort Study (VACS) to determine whether weight gain after ART has a similar association with incident type-2 diabetes mellitus (DM) as weight gained among HIV-uninfected (uninfected) individuals.
We explored associations of weight gain and incident diabetes (A1c ≥ 6.5 %), in VACS, a national observational study of HIV infected (HIV+) individuals demographically matched 1:2 to uninfected controls. From 2000 to 2011, weight change was assessed in the year following ART initiation for HIV+ individuals and date of first available BMI for uninfected individuals. We estimated hazard ratios (HR) and 95% CI adjusted for baseline BMI using Cox regression.
HIV+ individuals had lower prevalence of DM at baseline (12%, HIV+, 23% uninfected) and lower incident diabetes (5% HIV+, 11% uninfected). The association of weight gain with risk of DM was linear for HIV+ and uninfected but the slope of the association was steeper for HIV+. For each 5 pounds of weight gained, HIV+ had 14% increased risk of DM (HR, 1.14; 95% CI, 1.10–1.17) and uninfected individuals had 8% increased risk (HR: 1.08; 95% CI, 1.07–1.10) (p<0.01 for interaction).
Weight gained in the first year after ART initiation is associated with greater risk of DM than that among uninfected individuals. HIV+ individuals initiating ART who are not underweight should avoid substantial weight gain.
PMCID: PMC5023454  PMID: 27171741
Diabetes; HIV; weight gain; obesity; Veterans; Inflammation
8.  The Starting Treatment for Ethanol in Primary care Trials (STEP Trials): Protocol for Three Parallel Multi-Site Stepped Care Effectiveness Studies for Unhealthy Alcohol Use in HIV-Positive Patients 
Unhealthy alcohol use is common among HIV-positive patients, yet effective evidence-based treatments are rarely provided in clinical settings providing HIV care. Further, given patient variability in response to initial treatments, stepped care approaches may be beneficial. We describe the rationale, aims and study design for the current Starting Treatment for Ethanol in Primary care Trials (STEP Trials); three parallel randomized controlled effectiveness trials being conducted in five Infectious Disease Clinics. Participants meeting criteria for: 1) at-risk drinking, 2) moderate alcohol use with liver disease (MALD), or 3) alcohol use disorder (AUD) are randomized to integrated stepped care versus treatment as usual. For those with at-risk drinking or MALD, integrated stepped care starts with a one session brief intervention and follow-up 2-week telephone booster. Based on pre-specified nonresponse criteria, participants may be “stepped up” at week 4 to receive four sessions of motivational enhancement therapy (MET) and “stepped up” again at week 12 for addiction physician management (APM) and consideration of alcohol pharmacotherapy. For those with AUD, integrated stepped care begins with APM. Non-responders may be “stepped up” at week 4 to receive MET and again at week 12 for a higher level of care (e.g. intensive outpatient program). The primary outcome is alcohol consumption assessed at 24 weeks, and secondary outcome is the VACS Index, a validated measure of HIV morbidity and mortality risk. Results from the STEP Trials should inform future research and the implementation of interventions to address unhealthy alcohol use among HIV-positive individuals.
PMCID: PMC5253227  PMID: 27876616
Multicenter study; Randomized controlled trial; Algorithms; HIV; Alcohol
9.  DNA methylation signatures of illicit drug injection and hepatitis C are associated with HIV frailty 
Nature Communications  2017;8:2243.
Intravenous illicit drug use (IDU) and hepatitis C infection (HCV) commonly co-occur among HIV-infected individuals. These co-occurring conditions may produce interacting epigenetic effects in white blood cells that influence immune function and health outcomes. Here, we report an epigenome-wide association analysis comparing IDU+/ HCV+ and IDU−/HCV− in 386 HIV-infected individuals as a discovery sample and in 412 individuals as a replication sample. We observe 6 significant CpGs in the promoters of 4 genes, NLRC5, TRIM69, CX3CR1, and BCL9, in the discovery sample and in meta-analysis. We identify 19 differentially methylated regions on chromosome 6 harboring MHC gene clusters. Importantly, a panel of IDU+/HCV+-associated CpGs discriminated HIV frailty based upon a validated index with an area under the curve of 79.3% for high frailty and 82.3% for low frailty. These findings suggest that IDU and HCV involve epigenetic programming and that their associated methylation signatures discriminate HIV pathophysiologic frailty.
Intravenous illicit drug use (IDU) and hepatitis C infection (HCV) often occur among HIV-infected individuals. Here, the authors report an epigenome-wide association analysis of IDU and HCV in HIV-infected individuals, finding that their associated methylation signatures inform HIV frailty.
PMCID: PMC5740109  PMID: 29269866
10.  Baseline, Time-Updated, and Cumulative HIV Care Metrics for Predicting Acute Myocardial Infarction and All-Cause Mortality 
Six human immunodeficiency virus (HIV) care metrics predicted acute myocardial infarction (AMI) and mortality among HIV-infected individuals. Time-updated Veterans Aging Cohort Study Index provided the best prediction for both AMI and mortality.
Background. After adjustment for cardiovascular risk factors and despite higher mortality, those with human immunodeficiency virus (HIV+) have a greater risk of acute myocardial infarction (AMI) than uninfected individuals.
Methods. We included HIV+ individuals who started combination antiretroviral therapy (cART) in the Veterans Aging Cohort Study (VACS) from 1996 to 2012. We fit multivariable proportional hazards models for baseline, time-updated and cumulative measures of HIV-1 RNA, CD4 counts, and the VACS Index. We used the trapezoidal rule to build the following cumulative measures: viremia copy-years, CD4-years, and VACS Index score-years, captured 180 days after cART initiation until AMI, death, last clinic visit, or 30 September 2012. The primary outcomes were incident AMI (Medicaid, Medicare, and Veterans Affairs International Classification of Diseases-9 codes) and death.
Results. A total of 8168 HIV+ individuals (53 861 person-years) were analyzed with 196 incident AMIs and 1710 deaths. Controlling for known cardiovascular risk factors, 6 of the 9 metrics predicted AMI and all metrics predicted mortality. Time-updated VACS Index had the lowest Akaike information criterion among all models for both outcomes. A time-updated VACS Index score of 55+ was associated with a hazard ratio (HR) of 3.31 (95% confidence interval [CI], 2.11–5.20) for AMI and a HR of 31.77 (95% CI, 26.17–38.57) for mortality.
Conclusions. Time-updated VACS Index provided better AMI and mortality prediction than CD4 count and HIV-1 RNA, suggesting that current health determines risk more accurately than prior history and that risk assessment can be improved by biomarkers of organ injury.
PMCID: PMC5106607  PMID: 27539575
acute myocardial infarction; HIV; mortality; VACS Index
11.  Incarceration History and Uncontrolled Blood Pressure in a Multi-Site Cohort 
Journal of General Internal Medicine  2016;31(12):1496-1502.
Incarceration is associated with increased risk of hypertension and cardiovascular disease mortality. We used data from the Veterans Aging Cohort Study (VACS) to explore the impact of incarceration on blood pressure (BP) control.
Among hypertensive VACS participants, we measured the association between self-reported recent incarceration or past (not recent) history of incarceration and BP control in the year following the survey. To analyze the association between incarceration and BP control, we used logistic regression models adjusted for sociodemographic characteristics, clinical factors (HIV status and body mass index), and behavioral factors (history of smoking, unhealthy alcohol use, illicit drug use). We explored potential mediators including post-traumatic stress disorder (PTSD), depression, primary care engagement, and adherence to antihypertensive medications.
Among the 3515 eligible VACS participants, 2304 participants met the inclusion criteria. Of these, 163 (7 %) reported recent incarceration, and 904 (39 %) reported a past history of incarceration. Participants with recent or past history of incarceration were more likely to have uncontrolled BP than those without a history of incarceration (67 % vs. 56 % vs. 51 %, p < 0.001). In multivariable analysis, recent incarceration (adjusted odds ratio [AOR] = 1.57 95 % confidence interval [CI]: 1.09–2.26), but not a past history of incarceration (AOR = 1.08 95 % CI: 0.90–1.30), was associated with uncontrolled BP compared with those who were never incarcerated.
Among patients with a history of hypertension, recent incarceration is associated with having uncontrolled BP following release. Interventions are needed for recently released individuals to improve hypertension outcomes.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-016-3857-1) contains supplementary material, which is available to authorized users.
PMCID: PMC5130961  PMID: 27619934
hypertension/epidemiology; hypertension/therapy; prisoners; socioeconomic factors; chronic disease/epidemiology; chronic disease/therapy; incarceration
12.  The Impact of Prescribed Opioids on CD4 Cell Count Recovery among HIV-Infected Patients Newly Initiating Antiretroviral Therapy 
HIV medicine  2016;17(10):728-739.
Certain prescribed opioids have immunosuppressive properties, yet their impact on clinically relevant outcomes, including antiretroviral therapy (ART) response among HIV-infected patients, remains understudied.
Using the Veterans Aging Cohort Study data, we conducted a longitudinal analysis of 4,358 HIV-infected patients initiating ART between 2002 and 2010 and then followed them for 24 months. The primary independent variable was prescribed opioid duration, categorized using pharmacy data as none prescribed, short-term (<90 days), and long-term (≥90 days). Outcomes included CD4 cell count over time. Analyses adjusted for demographics, comorbid conditions, ART type and year of initiation, and overall disease severity (ascertained with the VACS index). Sensitivity analyses examined whether effects varied according to baseline CD4 cell count, achievement of viral load suppression, and opioid properties (i.e., dose and known immunosuppressive properties).
Compared to those with none, patients with short-term prescribed opioids had a similar increase in CD4 cell count (rise per year: 74 vs. 68 cells/mm3, p=0.11), as did those with long-term prescribed opioids (rise per year: 74 vs. 75 cells/mm3, p=0.98). In sensitivity analysis, compared to those with none, short-term prescribed opioid effects were statistically significant among those with baseline CD4 cell count ≥500 cells/mm3 (rise per year: 52 vs. 20 cells/mm3, p=0.04); findings were otherwise unchanged.
Despite immunosuppressive properties intrinsic to opioids, prescribed opioids appeared to have no effect on CD4 cell counts over 24 months among HIV-infected patients initiating antiretroviral therapy.
PMCID: PMC5053822  PMID: 27186715
HIV; analgesics; opioid; CD4 lymphocyte count; disease progression; antiretroviral therapy
13.  The Effect of Substance Use Disorders on the Association Between Guideline-Concordant Long-Term Opioid Therapy and All-Cause Mortality 
Journal of addiction medicine  2016;10(6):418-428.
Patients with substance use disorders (SUDs) prescribed long-term opioid therapy (LtOT) are at risk for overdose and mortality. Prior research has shown that receipt of LtOT in accordance with clinical practice guidelines has the potential to mitigate these outcomes. Our objective was to determine whether the presence of a SUD modifies the association between guideline-concordant care and 1-year all-cause mortality among patients receiving LtOT for pain.
Among HIV+ and HIV- patients initiating LtOT (≥ 90d opioids) between 2000 and 2010 as part of the Veterans Aging Cohort Study, we used time-updated Cox regression and propensity-score matching to examine—stratified by SUD status—the association between 1-year all-cause mortality and 3 quality indicators derived from national opioid prescribing guidelines. Specifically, we examined whether patients received: psychotherapeutic co-interventions (≥ 2 outpatient mental health visits), benzodiazepine co-prescriptions (≥ 7d), and SUD treatment (≥ 1 inpatient day or outpatient visit). These indicators were among those found in a previous study to have a strong association with mortality.
Among 17,044 patients initiating LtOT, there were 1,048 (6.1%) deaths during one year of follow-up. Receipt of psychotherapeutic co-interventions was associated with lower mortality in the sample overall and was more protective in patients with SUDs (adjusted hazard ratio [AHR] 0.43, 95% confidence interval [CI] 0.33–0.56 vs. AHR 0.65, 95% CI 0.53–0.81; P for interaction = .002). Benzodiazepine co-prescribing was associated with higher mortality in the sample overall (AHR 1.41; 95% CI 1.22–1.63), but we found no interaction by SUD status (P for interaction = .11). Among patients with SUDs, receipt of SUD treatment was associated with lower mortality (AHR 0.43; 95% CI 0.33–0.57).
For clinicians prescribing LtOT to patients with untreated SUDs, engaging patients with psychotherapeutic and SUD treatment services may reduce mortality. Clinicians should also avoid, when possible, prescribing opioids with benzodiazepines.
PMCID: PMC5083184  PMID: 27610580
Opioid analgesics; practice guideline; quality of healthcare; mortality; substance use disorders
14.  Assessment of geriatric syndromes and physical function in people living with HIV 
Virulence  2016;8(5):586-598.
As the number of older adults living with HIV continues to increase, understanding how to incorporate geriatric assessments within HIV care will be critical. Assessment of geriatric syndromes and physical function can be useful tools for HIV clinicians and researchers to help identify the most vulnerable older adults and to better understand the aging process in people living with HIV (PLWH). This review focuses on the assessment of falls, frailty, and physical function, first in the general population of older adults, and includes a specific focus on use of these assessments in older adults living with HIV.
PMCID: PMC5538333  PMID: 27715455
aging; disability; falls; frailty; geriatric syndrome; HIV
15.  White Blood Count, Albumin, and BMI Enhance VACS Index Prognostic Model, but Nadir CD4 and CD8 Metrics Do Not 
Open Forum Infectious Diseases  2017;4(Suppl 1):S210.
People living with HIV frequently achieve long-term viral suppression necessitating better metrics of disease burden for clinical management and research. The Veterans Aging Cohort Study (VACS) Index predicts hospitalization, mortality, and other outcomes, using routinely available clinical data. We sought to enhance the index by evaluating whether nadir CD4, CD8, CD4/CD8 ratio, white blood count (WBC) or absolute neutrophil count (ANC), albumin, and body mass index (BMI) enhanced prediction. The original index categorized predictors for ease of understanding and calculation of a risk score. We also sought to expand categories and develop a continuous variable model, suitable for use with automated calculation, to provide higher resolution.
VACS, includes all HIV infected patients in VA Care. Among those who initiated ART 1996–2013, (excluding any treated for HCV infection), we obtained laboratory values from a randomly selected visit 2000–2014, at least one year after ART initiation. Patients were followed for 5-year, all cause mortality until September 30, 2016. We fit Cox models starting with currently used predictors (age, CD4, HIV-1 RNA, hemoglobin, FIB4, eGFR and HCV status) and decided to include new variables based on model fit, chi-square, strength and significance of individual levels and c-statistic. Functional form for continuous variables was determined graphically. Adequacy of final models was assessed with Kaplan-Meier plots by deciles of risk.
Among 28,390 patients there were 7,293 deaths (7.2 per 100 person-years) in median 4.1 years of follow-up. Nadir CD4, CD8, CD4:CD8 did not improve prediction. WBC and ANC performed equally but WBC was more widely available. C-statistics improved from 0.776 for the original VACS Index (in this sample) to 0.805.
Addition of WBC, albumin, and BM enhances utility of the VACS Index as a measure of overall severity of disease both as an outcome for research and for patient monitoring in the clinical setting. Validation in external cohorts is in progress.
All authors: No reported disclosures.
PMCID: PMC5631891
16.  Ten-year trends in antiretroviral therapy persistence among US Medicaid beneficiaries 
AIDS (London, England)  2017;31(12):1697-1707.
Whether the rate of HIV antiretroviral therapy (ART) persistence has improved over time in the United States is unknown. We examined ART persistence trends between 2001 and 2010, using non-HIV medications as a comparator.
We conducted a retrospective cohort study using Medicaid claims. We defined persistence as the duration of treatment from the first to the last fill date before a 90-day permissible gap and used Kaplan–Meier curves and Cox proportional hazard models to assess crude and adjusted nonpersistence. The secular trends of ART persistence in 43 598 HIV patients were compared with the secular trends of persistence with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (ACEI/ARB), statins, and metformin in non-HIV-infected patients and subgroups of HIV patients who started these control medications while using ART.
Median time to ART nonpersistence increased from 23.9 months in 2001– 2003 to 35.4 months in 2004–2006 and was not reached for those starting ART in 2007–2010. In adjusted models, ART initiators in 2007–2010 had 11% decreased hazard of nonpersistence compared with those who initiated in 2001–2003 (P < 0.001). For non-HIV patients initiating angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEI/ARB), statins, and metformin, the hazard ratios for nonpersistence comparing 2007–2010 to 2001–2003 were 1.07, 0.94, and 1.02, respectively (all P < 0.001). For HIV patients initiating the three control medications, the hazard ratios of nonpersistence comparing 2007–2010 to 2001–2003 were 0.71, 0.65, and 0.63, respectively (all P < 0.001).
Persistence with ART improved between 2001 and 2010. Persistence with control medications improved at a higher rate among HIV patients using ART than HIV-negative controls.
PMCID: PMC5625296  PMID: 28700393
antiretroviral therapy; Medicaid; medication adherence; medication persistence; United States
17.  Higher Time-updated Body Mass Index: Association with Improved CD4+ Cell Recovery on HIV Treatment 
Prior studies found overweight or obese HIV-infected individuals had greater early CD4+ cell recovery on antiretroviral therapy (ART), but the results have been inconsistent. We assessed the longitudinal relationship between body mass index (BMI) and CD4+ cell recovery on ART in a large, multi-site cohort to identify potential physiologic links between adiposity and CD4+ cell expansion.
We modeled the relationship of time-updated BMI with CD4+ count in patients starting ART from 17 North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) cohorts. The primary analysis used a linear mixed effects model incorporating up to 13 years of data per patient and adjusted for age, sex, race, ART regimen, baseline CD4+ count and other covariates. Sensitivity analyses limited the cohort to patients with sustained viral suppression or censored at virologic failure.
14,084 HIV-infected individuals initiating ART contributed data between 1998 and 2010. Time-updated BMI was significantly associated with CD4+ cell recovery over time (p<0.001). After 5 years of ART, the mean CD4+ count at a BMI of 30 kg/m2 was 22% higher than at a BMI of 22 kg/m2 (606 vs. 498 cells/µL), and 34% higher at a BMI of 40 kg/m2 (665 vs. 498 cells/µL). Results were similar in the sensitivity analyses.
Higher BMI is associated with long-term advantages in immune recovery on ART. While it is unclear if this impacts health outcomes, including balancing the negative health effects of obesity, elucidating the underlying mechanism could identify therapies for patients with suboptimal immune reconstitution.
PMCID: PMC5023455  PMID: 27116044
HIV; obesity; immune reconstitution; CD4; antiretroviral therapy; nutrition
18.  Association Between Depressive Disorders and Incident Acute Myocardial Infarction in Human Immunodeficiency Virus–Infected Adults 
JAMA cardiology  2016;1(8):929-937.
With the advent of highly effective antiretroviral therapy and improved survival, human immunodeficiency virus (HIV)–infected people are living longer and are now at an increased risk for cardiovascular disease (CVD). There is an urgent need to identify novel risk factors and primary prevention approaches for CVD in HIV. Although depression is prevalent in HIV-infected adults and is associated with future CVD in the general population, its association with CVD events has not been examined in the HIV-infected population.
To examine whether depressive disorders are prospectively associated with incident acute myocardial infarction (AMI) in a large cohort of adults with HIV.
Included in this cohort study were 26 144 HIV-infected veterans without CVD at baseline (1998–2003) participating in the US Department of Veterans Affairs Veterans Aging Cohort Study from April 1, 2003, through December 31, 2009. At baseline, 4853 veterans (19%) with major depressive disorder (MDD; International Classification of Diseases, Ninth Revision [ICD-9] codes 296.2 and 296.3) and 2296 (9%) with dysthymic disorder (ICD-9 code 300.4) were identified. The current analysis was conducted from January 2015 to November 2015.
Incident AMI (defined by discharge summary documentation, enzyme/electrocardiography evidence of AMI, inpatient ICD-9 code for AMI (410), or AMI as underlying cause of death [International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code 121]) between the enrollment date and December 31, 2009.
The mean (SD) age of those with MDD was 47.3 (7.9) years and for those without MDD was 48.2 (9.7) years. During 5.8 years of follow-up, 490 AMI events (1.9%) occurred. Baseline MDD was associated with incident AMI after adjusting for demographics (hazard ratio [HR], 1.31; 95% CI, 1.05–1.62), CVD risk factors (HR, 1.29; 95% CI, 1.04–1.60), and HIV-specific factors (HR, 1.30; 95% CI, 1.05–1.62). Further adjustment for hepatitis C, renal disease, substance abuse, and hemoglobin level (HR, 1.25; 95% CI, 1.00–1.56) and antidepressant use (HR, 1.12; 95% CI, 0.87–1.42) attenuated associations. Baseline dysthymic disorder was not associated with incident AMI.
We report novel evidence that HIV-infected adults with MDD have a 30% increased risk for AMI than HIV-infected adults without MDD after adjustment for many potential confounders. Our findings raise the possibility that MDD may be independently associated with incident atherosclerotic CVD in the HIV-infected population.
PMCID: PMC5621480  PMID: 27557332
19.  Proceedings of the 14th annual conference of INEBRIA 
Holloway, Aisha S. | Ferguson, Jennifer | Landale, Sarah | Cariola, Laura | Newbury-Birch, Dorothy | Flynn, Amy | Knight, John R. | Sherritt, Lon | Harris, Sion K. | O’Donnell, Amy J. | Kaner, Eileen | Hanratty, Barbara | Loree, Amy M. | Yonkers, Kimberly A. | Ondersma, Steven J. | Gilstead-Hayden, Kate | Martino, Steve | Adam, Angeline | Schwartz, Robert P. | Wu, Li-Tzy | Subramaniam, Geetha | Sharma, Gaurav | McNeely, Jennifer | Berman, Anne H. | Kolaas, Karoline | Petersén, Elisabeth | Bendtsen, Preben | Hedman, Erik | Linderoth, Catharina | Müssener, Ulrika | Sinadinovic, Kristina | Spak, Fredrik | Gremyr, Ida | Thurang, Anna | Mitchell, Ann M. | Finnell, Deborah | Savage, Christine L. | Mahmoud, Khadejah F. | Riordan, Benjamin C. | Conner, Tamlin S. | Flett, Jayde A. M. | Scarf, Damian | McRee, Bonnie | Vendetti, Janice | Gallucci, Karen Steinberg | Robaina, Kate | Clark, Brendan J. | Jones, Jacqueline | Reed, Kathryne D. | Hodapp, Rachel M. | Douglas, Ivor | Burnham, Ellen L. | Aagaard, Laura | Cook, Paul F. | Harris, Brett R. | Yu, Jiang | Wolff, Margaret | Rogers, Meighan | Barbosa, Carolina | Wedehase, Brendan J. | Dunlap, Laura J. | Mitchell, Shannon G. | Dusek, Kristi A. | Gryczynski, Jan | Kirk, Arethusa S. | Oros, Marla T. | Hosler, Colleen | O’Grady, Kevin E. | Brown, Barry S. | Angus, Colin | Sherborne, Sidney | Gillespie, Duncan | Meier, Petra | Brennan, Alan | de Vargas, Divane | Soares, Janaina | Castelblanco, Donna | Doran, Kelly M. | Wittman, Ian | Shelley, Donna | Rotrosen, John | Gelberg, Lillian | Edelman, E. Jennifer | Maisto, Stephen A. | Hansen, Nathan B. | Cutter, Christopher J. | Deng, Yanhong | Dziura, James | Fiellin, Lynn E. | O’Connor, Patrick G. | Bedimo, Roger | Gibert, Cynthia | Marconi, Vincent C. | Rimland, David | Rodriguez-Barradas, Maria C. | Simberkoff, Michael S. | Justice, Amy C. | Bryant, Kendall J. | Fiellin, David A. | Giles, Emma L. | Coulton, Simon | Deluca, Paolo | Drummond, Colin | Howel, Denise | McColl, Elaine | McGovern, Ruth | Scott, Stephanie | Stamp, Elaine | Sumnall, Harry | Vale, Luke | Alabani, Viviana | Atkinson, Amanda | Boniface, Sadie | Frankham, Jo | Gilvarry, Eilish | Hendrie, Nadine | Howe, Nicola | McGeechan, Grant J. | Ramsey, Amy | Stanley, Grant | Clephane, Justine | Gardiner, David | Holmes, John | Martin, Neil | Shevills, Colin | Soutar, Melanie | Chi, Felicia W. | Weisner, Constance | Ross, Thekla B. | Mertens, Jennifer | Sterling, Stacy A. | Shorter, Gillian W. | Heather, Nick | Bray, Jeremy | Cohen, Hildie A. | McPherson, Tracy L. | Adam, Cyrille | López-Pelayo, Hugo | Gual, Antoni | Segura-Garcia, Lidia | Colom, Joan | Ornelas, India J. | Doyle, Suzanne | Donovan, Dennis | Duran, Bonnie | Torres, Vanessa | Gaume, Jacques | Grazioli, Véronique | Fortini, Cristiana | Paroz, Sophie | Bertholet, Nicolas | Daeppen, Jean-Bernard | Satterfield, Jason M. | Gregorich, Steven | Alvarado, Nicholas J. | Muñoz, Ricardo | Kulieva, Gozel | Vijayaraghavan, Maya | Adam, Angéline | Cunningham, John A. | Díaz, Estela | Palacio-Vieira, Jorge | Godinho, Alexandra | Kushir, Vladyslav | O’Brien, Kimberly H. M. | Aguinaldo, Laika D. | Sellers, Christina M. | Spirito, Anthony | Chang, Grace | Blake-Lamb, Tiffany | LaFave, Lea R. Ayers | Thies, Kathleen M. | Pepin, Amy L. | Sprangers, Kara E. | Bradley, Martha | Jorgensen, Shasta | Catano, Nico A. | Murray, Adelaide R. | Schachter, Deborah | Andersen, Ronald M. | Rey, Guillermina Natera | Vahidi, Mani | Rico, Melvin W. | Baumeister, Sebastian E. | Johansson, Magnus | Sinadinovic, Christina | Hermansson, Ulric | Andreasson, Sven | O’Grady, Megan A. | Kapoor, Sandeep | Akkari, Cherine | Bernal, Camila | Pappacena, Kristen | Morley, Jeanne | Auerbach, Mark | Neighbors, Charles J. | Kwon, Nancy | Conigliaro, Joseph | Morgenstern, Jon | Magill, Molly | Apodaca, Timothy R. | Borsari, Brian | Hoadley, Ariel | Scott Tonigan, J. | Moyers, Theresa | Fitzgerald, Niamh M. | Schölin, Lisa | Barticevic, Nicolas | Zuzulich, Soledad | Poblete, Fernando | Norambuena, Pablo | Sacco, Paul | Ting, Laura | Beaulieu, Michele | Wallace, Paul George | Andrews, Matthew | Daley, Kate | Shenker, Don | Gallagher, Louise | Watson, Rod | Weaver, Tim | Bruguera, Pol | Oliveras, Clara | Gavotti, Carolina | Barrio, Pablo | Braddick, Fleur | Miquel, Laia | Suárez, Montse | Bruguera, Carla | Brown, Richard L. | Capell, Julie Whelan | Paul Moberg, D. | Maslowsky, Julie | Saunders, Laura A. | McCormack, Ryan P. | Scheidell, Joy | Gonzalez, Mirelis | Bauroth, Sabrina | Liu, Weiwei | Lindsay, Dawn L. | Lincoln, Piper | Hagle, Holly | Wallhed Finn, Sara | Hammarberg, Anders | Andréasson, Sven | King, Sarah E. | Vargo, Rachael | Kameg, Brayden N. | Acquavita, Shauna P. | Van Loon, Ruth Anne | Smith, Rachel | Brehm, Bonnie J. | Diers, Tiffiny | Kim, Karissa | Barker, Andrea | Jones, Ashley L. | Skinner, Asheley C. | Hinman, Agatha | Svikis, Dace S. | Thacker, Casey L. | Resnicow, Ken | Beatty, Jessica R. | Janisse, James | Puder, Karoline | Bakshi, Ann-Sofie | Milward, Joanna M. | Kimergard, Andreas | Garnett, Claire V. | Crane, David | Brown, Jamie | West, Robert | Michie, Susan | Rosendahl, Ingvar | Andersson, Claes | Gajecki, Mikael | Blankers, Matthijs | Donoghue, Kim | Lynch, Ellen | Maconochie, Ian | Phillips, Ceri | Pockett, Rhys | Phillips, Tom | Patton, R. | Russell, Ian | Strang, John | Stewart, Maureen T. | Quinn, Amity E. | Brolin, Mary | Evans, Brooke | Horgan, Constance M. | Liu, Junqing | McCree, Fern | Kanovsky, Doug | Oberlander, Tyler | Zhang, Huan | Hamlin, Ben | Saunders, Robert | Barton, Mary B. | Scholle, Sarah H. | Santora, Patricia | Bhatt, Chirag | Ahmed, Kazi | Hodgkin, Dominic | Gao, Wenwu | Merrick, Elizabeth L. | Drebing, Charles E. | Larson, Mary Jo | Sharma, Monica | Petry, Nancy M. | Saitz, Richard | Weisner, Constance M. | Young-Wolff, Kelly C. | Lu, Wendy Y. | Blosnich, John R. | Lehavot, Keren | Glass, Joseph E. | Williams, Emily C. | Bensley, Kara M. | Chan, Gary | Dombrowski, Julie | Fortney, John | Rubinsky, Anna D. | Lapham, Gwen T. | Forray, Ariadna | Olmstead, Todd A. | Gilstad-Hayden, Kathryn | Kershaw, Trace | Dillon, Pamela | Weaver, Michael F. | Grekin, Emily R. | Ellis, Jennifer D. | McGoron, Lucy | McGoron, Lucy
PMCID: PMC5606215
20.  Hepatic safety of buprenorphine in HIV-infected and uninfected patients with opioid use disorder: The role of HCV-infection 
Individuals with HIV and hepatitis C (HCV) infection, alcohol use disorder, or who are prescribed potentially hepatotoxic medications may be at increased risk for buprenorphine (BUP) associated hepatotoxicity.
Materials and methods
We examined a cohort of HIV-infected and uninfected patients receiving an initial BUP prescription between 2003 and 2012. We compared changes in alanine and aspartate aminotransferases (ALT and AST) and total bilirubin (TB) stratified by HIV status. We identified cases of liver enzyme elevation (LEE), TB elevation (TBE), and conducted chart review to assess for cases of drug induced liver injury (DILI) and death. We examined associations between age, sex, race, HIV-infection, HCV-infection, alcohol use disorder, and prescription of other potentially heptatotoxic medications with the composite endpoint of LEE, TBE, and DILI.
Of 666 patients prescribed BUP, 36% were HIV-infected, 98% were male, 60% had RNA-confirmed HCV infection, 50% had a recent diagnosis of alcohol use disorder, and 64% were prescribed other potentially hepatotoxic medications. No clinically significant changes were observed in median ALT, AST and TB and these changes did not differ between HIV-infected and uninfected patients. Compared with uninfected patients, HIV-infected (OR 7.3, 95% CI 2.1-26.1, p=0.002), HCV-infected (OR 4.9 95% CI 1.6-15.2, p=0.007) or HIV/HCV co-infected patients (OR 6.9, 95%CI 2.1-22.2, p=0.001) were more likely to have the composite endpoint of LEE, TB elevation or DILI, in analyses that excluded 60 patients with evidence of pre-existing liver injury. 31 patients had LEE, 14/187 HIV-infected and 17/340 uninfected (p = 0.25); 11 had TBE, including 9/186 HIV-infected and 2/329 uninfected (p = 0.002); 8 experienced DILI, 4/202 HIV-infected and 2/404 uninfected (p = 0.45). There were no significant associations with alcohol use disorder or prescription of other potentially hepatotoxic medications after adjustment for HIV/HCV status.
Liver enzymes and TB are rarely elevated in HIV-infected and uninfected patients receiving BUP. Risk of hepatotoxicity was greater in individuals infected with HIV, HCV, or HIV/HCV co-infection, who may benefit from increased monitoring.
PMCID: PMC4976086  PMID: 27431048
buprenorphine; HIV; Hepatitis C; drug induced liver injury
21.  Fracture prediction with modified-FRAX in older HIV-infected and uninfected men 
FRAX® is a validated, computer-based clinical fracture risk calculator that estimates 10-year risk of major osteoporotic (clinical spine, forearm, hip or shoulder) fracture, and hip fracture alone. It is widely used for decision-making in fracture prevention, but may underestimate risk in HIV-infected individuals. Some experts recommend considering HIV a cause of secondary osteoporosis when calculating FRAX in HIV-infected individuals.
From the Veterans Aging Study Virtual Cohort (VACS-VC), we included 24451 HIV-infected and uninfected 50-70 year old men with complete data in year 2000 to approximate all but two factors (i.e. history of secondary osteoporosis and parental hip fracture) for modified-FRAX calculation without bone density and 10-year observational data for incident fragility fracture. Accuracy of the modified-FRAX calculation was compared by observed/estimated (O/E) ratios of fracture by HIV status.
Accuracy of modified-FRAX was less for HIV-infected (O/E=1.62, 95%CI: 1.45, 1.81) than uninfected men (O/E=1.29, 95%CI: 1.19, 1.40), but improved when HIV was included as a cause of secondary osteoporosis (O/E=1.20, 95%CI: 1.08, 1.34). However, only 3-6% of men with incident fractures were correctly identified by the modified-FRAX using accepted FRAX thresholds for pharmacologic therapy.
Modified-FRAX underestimated fracture rates more in older HIV-infected than otherwise similar uninfected men. Accuracy improved when HIV was included as a cause of secondary osteoporosis, but it still performed poorly for case-finding. Further studies are necessary to determine how to use FRAX or define an HIV-specific index to risk stratify for screening and treatment in older HIV-infected individuals.
PMCID: PMC4942335  PMID: 27003493
fracture incidence; HIV; men; FRAX
22.  Association Between HIV Infection and the Risk of Heart Failure With Reduced Ejection Fraction and Preserved Ejection Fraction in the Antiretroviral Therapy Era 
JAMA cardiology  2017;2(5):536-546.
With improved survival, heart failure (HF) has become a major complication for individuals with human immunodeficiency virus (HIV) infection. It is unclear if this risk extends to different types of HF in the antiretroviral therapy (ART) era. Determining whether HIV infection is associated with HF with reduced ejection fraction (HFrEF), HF with preserved ejection fraction (HFpEF), or both is critical because HF types differ with respect to underlying mechanism, treatment, and prognosis.
To investigate whether HIV infection increases the risk of future HFrEF and HFpEF and to assess if this risk varies by sociodemographic and HIV-specific factors.
This study evaluated 98 015 participants without baseline cardiovascular disease from the Veterans Aging Cohort Study, an observational cohort of HIV-infected veterans and uninfected veterans matched by age, sex, race/ethnicity, and clinical site, enrolled on or after April 1, 2003, and followed up through September 30, 2012. The dates of the analysis were October 2015 to November 2016.
Human immunodeficiency virus infection.
Outcomes included HFpEF (EF≥50%), borderline HFpEF (EF 40%–49%), HFrEF (EF<40%), and HF of unknown type (EF missing).
Among 98 015 participants, the mean (SD) age at enrollment in the study was 48.3 (9.8) years, 97.0% were male, and 32.2% had HIV infection. During a median follow-up of 7.1 years, there were 2636 total HF events (34.6% were HFpEF, 15.5% were borderline HFpEF, 37.1% were HFrEF, and 12.8% were HF of unknown type). Compared with uninfected veterans, HIV-infected veterans had an increased risk of HFpEF (hazard ratio [HR], 1.21; 95% CI, 1.03–1.41), borderline HFpEF (HR, 1.37; 95% CI, 1.09–1.72), and HFrEF (HR, 1.61; 95% CI, 1.40–1.86). The risk of HFrEF was pronounced in veterans younger than 40 years at baseline (HR, 3.59; 95% CI, 1.95–6.58). Among HIV-infected veterans, time-updated HIV-1 RNA viral load of at least 500 copies/mL compared with less than 500 copies/mL was associated with an increased risk of HFrEF, and time-updated CD4 cell count less than 200 cells/mm3 compared with at least 500 cells/mm3 was associated with an increased risk of HFrEF and HFpEF.
Individuals who are infected with HIV have an increased risk of HFpEF, borderline HFpEF, and HFrEF compared with uninfected individuals. The increased risk of HFrEF can manifest decades earlier than would be expected in a typical uninfected population. Future research should focus on prevention, risk stratification, and identification of the mechanisms for HFrEF and HFpEF in the HIV-infected population.
PMCID: PMC5541383  PMID: 28384660
23.  Time trends in cancer incidence in persons living with HIV/AIDS in the antiretroviral therapy era: 1997–2012 
AIDS (London, England)  2016;30(11):1795-1806.
Utilizing the Veterans Aging Cohort Study, the largest HIV cohort in North America, we conducted one of the few comprehensive comparisons of cancer incidence time trends in HIV-infected (HIV+) versus uninfected persons during the antiretroviral therapy (ART) era.
Prospective cohort study.
We followed 44,787 HIV+ and 96,852 demographically-matched uninfected persons during 1997–2012. We calculated age-, sex-, and race/ethnicity-standardized incidence rates (IR) and incidence rate ratios (IRR, HIV+ versus uninfected) over four calendar periods with IR and IRR period trend p-values for cancer groupings and specific cancer types.
We observed 3,714 incident cancer diagnoses in HIV+ and 5,760 in uninfected persons. The HIV+ all cancer crude IR increased between 1997–2000 and 2009–2012 (p-trend=0.0019). However, after standardization, we observed highly significant HIV+ IR declines for all cancer (25% decline; p-trend<0.0001), AIDS-defining cancers (ADC; 55% decline; p-trend<0.0001), non-AIDS-defining cancers (NADC; 15% decline; p-trend=0.0003), and non-virus-related NADC (20% decline; p-trend<0.0001); significant IRR declines for all cancer (from 2.0 to 1.6; p-trend<0.0001), ADC (from 19 to 5.5; p-trend<0.0001), and non-virus-related NADC (from 1.4 to 1.2; p-trend=0.049); and borderline significant IRR declines for NADC (from 1.6 to 1.4; p-trend=0.078) and virus-related NADC (from 4.9 to 3.5; p-trend=0.071).
Improved HIV care resulting in improved immune function most likely contributed to the HIV+ IR and the IRR declines. Further promotion of early and sustained ART, improved ART regimens, reduction of traditional cancer risk factor (e.g., smoking) prevalence, and evidence-based screening could contribute to future cancer incidence declines among HIV+ persons.
PMCID: PMC4925286  PMID: 27064994
acquired immunodeficiency syndrome; HIV infections; neoplasms; cancer; Veterans
24.  Do Biomarkers Of Inflammation, Monocyte Activation And Altered Coagulation Explain Excess Mortality Between HIV Infected and Uninfected People? 
HIV infection and biomarkers of inflammation (measured by interleukin-6 [IL-6]), monocyte activation (soluble CD14 [sCD14]), and coagulation (D-dimer) are associated with morbidity and mortality. We hypothesized that these immunologic processes mediate (explain) some of the excess risk of mortality among HIV infected (HIV+) versus uninfected people independently of co-morbid diseases.
Among 2350 (1521 HIV+) participants from the Veterans Aging Cohort Study Biomarker Cohort (VACS BC) we investigated whether the association between HIV and mortality was altered by adjustment for IL-6, sCD14 and D-dimer, accounting for confounders. Participants were followed from date of blood draw for biomarker assays (baseline) until death or 7/25/2013. Analyses included ordered logistic regression and Cox Proportional Hazards regression.
During 6·9 years (median), 414 deaths occurred. The proportional odds of being in a higher quartile of IL-6, sCD14 or D-dimer was 2-3 fold higher for viremic HIV+ versus uninfected people. Mortality rates were higher among HIV+ compared to uninfected people (incidence rate ratio (95% CI): 1·31 (1·06-1·62). Mortality risk increased with increasing quartiles of IL-6, sCD14 and D-dimer regardless of HIV status. Adjustment for IL-6, sCD14 and D-dimer partially attenuated mortality risk among HIV+ people with unsuppressed viremia (HIV-1 RNA≥10000 copies/mL) compared to uninfected people – hazard ratio (95% CI) decreased from 2·18 (1·60-2·99) to 2·00 (1·45-2·76).
HIV infection is associated with elevated IL-6, sCD14 and D-dimer, which are in turn associated with mortality. Baseline measures of these biomarkers partially mediate excess mortality risk among HIV+ versus uninfected people.
PMCID: PMC4867134  PMID: 26885807
HIV; mortality; inflammation; monocyte activation; coagulation
25.  The Association Between Receipt of Guideline-Concordant Long-Term Opioid Therapy and All-Cause Mortality 
For patients receiving long-term opioid therapy (LtOT), the impact of guideline-concordant care on important clinical outcomes—notably mortality—is largely unknown, even among patients with a high comorbidity and mortality burden (e.g., HIV-infected patients). Our objective was to determine the association between receipt of guideline-concordant LtOT and 1-year all-cause mortality.
Among HIV-infected and uninfected patients initiating LtOT between 2000 and 2010 through the Department of Veterans Affairs, we used Cox regression with time-updated covariates and propensity-score matched analyses to examine the association between receipt of guideline-concordant care and 1-year all-cause mortality.
Of 17,044 patients initiating LtOT between 2000 and 2010, 1048 patients (6%) died during 1 year of follow-up. Patients receiving psychotherapeutic co-interventions (hazard ratio [HR] 0.62; 95% confidence interval [CI] 0.51–0.75; P < 0.001) or physical rehabilitative therapies (HR 0.81; 95% CI 0.67–0.98; P = 0.03) had a decreased risk of all-cause mortality compared to patients not receiving these services, whereas patients prescribed benzodiazepines concurrent with opioids had a higher risk of mortality (HR 1.39; 95% CI 1.12–1.66; P < 0.001). Among patients with a current substance use disorder (SUD), those receiving SUD treatment had a lower risk of mortality than untreated patients (HR 0.47; 95% CI 0.32–0.68; P = < 0.001). No association was found between all-cause mortality and primary care visits (HR 1.12; 95% CI 0.90–1.26; P = 0.32) or urine drug testing (HR 0.96; 95% CI 0.78–1.17; P = 0.67).
Providers should use caution in initiating LtOT in conjunction with benzodiazepines and untreated SUDs. Patients receiving LtOT may benefit from multi-modal treatment that addresses chronic pain and its associated comorbidities across multiple disciplines.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-015-3571-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4835362  PMID: 26847447
Opioid analgesics; practice guideline; quality of health care; mortality; pain

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