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1.  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
2.  A scenario-based, randomized trial of patient values and functional prognosis on intensivist intent to discuss withdrawing life support 
Critical care medicine  2014;42(6):1455-1462.
To evaluate the effect of (1) patient values as expressed by family members, and (2) a requirement to document patients’ functional prognosis on intensivists’ intention to discuss withdrawal of life support in a hypothetical family meeting.
A 3-armed, randomized trial
179 U.S. hospitals with training programs in critical care accredited by the Accreditation Council for Graduate Medical Education
630 intensivists recruited via e-mail invitation from a database of 1,850 eligible academic intensivists
Each intensivist was randomized to review ten, on-line, clinical scenarios with a range of illness severities involving a hypothetical patient (Mrs. X). In control-group scenarios, the patient did not want continued life support without a reasonable chance of independent living. In the first experimental arm, the patient wanted life support regardless of functional outcome. In the second experimental arm, patient values were identical to the control group, but intensivists were required to record the patient’s estimated three-month functional prognosis
Measurements and Main Results
Response to the question: “Would you bring up the possibility of withdrawing life support with Mrs. X’s family?” answered using a five-point Likert scale. There was no effect of patient values on whether intensivists intended to discuss withdrawal of life support (P = 0.81), but intensivists randomized to record functional prognosis were 49% more likely (95% confidence interval: 20%–85%) to discuss withdrawal.
In this national, scenario-based, randomized trial, patient values had no effect on intensivists’ decisions to discuss withdrawal of life support with family. However, requiring intensivists to record patients’ estimated 3-month functional outcome substantially increased their intention to discuss withdrawal.
PMCID: PMC4128685  PMID: 24584065
Decision Making; Intensive Care; Resuscitation Orders; Prognosis; Withholding Treatment; Life Support Care
3.  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
4.  Correlates of elevated interleukin-6 and C-reactive protein in persons with or at high-risk for HCV and HIV infections 
Journal of acquired immune deficiency syndromes (1999)  2013;64(5):10.1097/QAI.0b013e3182a7ee2e.
HIV and HCV infections may increase interleukin-6 (IL-6) and C-reactive protein (CRP). However, relationships between inflammatory biomarkers, chronic viral infections, clinical factors, and behavioral factors remain poorly understood.
Using linear regression, we modeled cross-sectional associations between loge IL-6 or loge CRP levels and HCV, HIV, injection drug use, and comorbidity among 1191 injection drug users.
Mean age was 47 years, 46.0% reported currently injecting drugs, 59.0% were HCV-monoinfected, and 27% were HCV/HIV-coinfected. In multivariable models, higher loge IL-6 was associated with HCV monoinfection (β=0.191, 95%CI: 0.043 to 0.339) and HCV/HIV coinfection (β=0.394, 95% CI: 0.214 to 0.574). In contrast, HCV monoinfection (β=−0.523, 95%CI: −0.275 to −0.789) and HCV/HIV coinfection (β=−0.554 95%CI: −0.260 to −0.847) were associated with lower CRP. Lower CRP with HCV infection was independent of liver fibrosis severity, synthetic function, or liver injury markers; CRP decreased with higher HCV RNA. Increased injection intensity was associated with higher IL-6 (p=0.003) and CRP (p<0.001); increasing comorbidity (p<0.001) and older age (p=0.028) were associated with higher IL-6; older age was associated with higher CRP among HCV-uninfected participants (p=0.021).
HIV and HCV infections contribute to chronic inflammation; however, reduced CRP possibly occurs through HCV-virally-mediated mechanisms. Findings highlight potentially modifiable contributors to inflammation.
PMCID: PMC3848037  PMID: 23978997
inflammation; interleukin-6; C reactive protein; HCV; HIV; injection drug use; comorbidities
5.  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
6.  Age and decisions to limit life support for patients with acute lung injury: a prospective cohort study 
Critical Care  2014;18(3):R107.
The proportion of elderly Americans admitted to the intensive care unit (ICU) in the last month of life is rising. Hence, challenging decisions regarding the appropriate use of life support are increasingly common. The objective of this study was to estimate the association between patient age and the rate of new limitations in the use of life support, independent of daily organ dysfunction status, following acute lung injury (ALI) onset.
This was a prospective cohort study of 490 consecutive patients without any limitations in life support at the onset of ALI. Patients were recruited from 11 ICUs at three teaching hospitals in Baltimore, Maryland, USA, and monitored for the incidence of six pre-defined limitations in life support, with adjustment for baseline comorbidity and functional status, duration of hospitalization before ALI onset, ICU severity of illness, and daily ICU organ dysfunction score.
The median patient age was 52 (range: 18 to 96), with 192 (39%) having a new limitation in life support in the ICU. Of patients with a new limitation, 113 (59%) had life support withdrawn and died, 53 (28%) died without resuscitation, and 26 (14%) survived to ICU discharge. Each ten-year increase in patient age was independently associated with a 24% increase in the rate of limitations in life support (Relative Hazard 1.24; 95% CI 1.11 to 1.40) after adjusting for daily ICU organ dysfunction score and all other covariates.
Older critically ill patients are more likely to have new limitations in life support independent of their baseline status, ICU-related severity of illness, and daily organ dysfunction status. Future studies are required to determine whether this association is a result of differences in patient preferences by age, or differences in the treatment options discussed with the families of older versus younger patients.
PMCID: PMC4075260  PMID: 24886945
7.  HIV Viremia and T-Cell Activation Differentially Affect the Performance of Glomerular Filtration Rate Equations Based on Creatinine and Cystatin C 
PLoS ONE  2013;8(12):e82028.
Serum creatinine and cystatin C are used as markers of glomerular filtration rate (GFR). The performance of these GFR markers relative to exogenously measured GFR (mGFR) in HIV-positive individuals is not well established.
We assessed the performance of the chronic kidney disease epidemiology collaboration equations based on serum concentrations of creatinine (eGFRcr), cystatin C (eGFRcys) and both biomarkers combined (eGFRcr-cys) in 187 HIV-positive and 98 HIV-negative participants. Measured GFR was calculated by plasma iohexol clearance. Bias and accuracy were defined as the difference between eGFR and mGFR and the percentage of eGFR observations within 30% of mGFR, respectively. Activated CD4 and CD8 T-cells (CD38+ HLA-DR+) were measured by flow cytometry.
The median mGFR was >100 ml/min/1.73 m2 in both groups. All equations tended to be less accurate in HIV-positive than in HIV-negative subjects, with eGFRcr-cys being the most accurate overall. In the HIV-positive group, eGFRcys was significantly less accurate and more biased than eGFRcr and eGFRcr_cys. Additionally eGFRcys bias and accuracy were strongly associated with use of antiretroviral therapy, HIV RNA suppression, and percentages of activated CD4 or CD8 T-cells. Hepatitis C seropositivity was associated with larger eGFRcys bias in both HIV-positive and HIV-negative groups. In contrast, eGFRcr accuracy and bias were not associated with HIV-related factors, T-cell activation, or hepatitis C.
The performance of eGFRcys relative to mGFR was strongly correlated with HIV treatment factors and markers of T-cell activation, which may limit its usefulness as a GFR marker in this population.
PMCID: PMC3871673  PMID: 24376511
8.  Alcohol Consumption and CD4 T-cell count response among persons initiating antiretroviral therapy 
We evaluated the longitudinal association of alcohol use with immunological response to combination antiretroviral therapy (ART) among HIV infected individuals.
This was a prospective cohort study of individuals initiating ART. Participants underwent an Audio Computer-Assisted Self Interview querying drug and alcohol use within 6 months of treatment. Immunological response to ART was defined by CD4 T-cell count (CD4). Primary independent variables were self-reported number of drinks consumed per drinking day (quantity) and days of alcohol consumption in a typical week (frequency). We used linear mixed effects models to quantify the association between CD4 T-cell count and alcohol quantity and frequency and Cox proportional hazards models to estimate the relative hazard of an increase 100, 150 and 200 CD4 cells/mm3 per additional drink per drinking day. Analyses were stratified by gender. Viral suppression was examined as a time-varying covariate.
Between 2000-2008, 1107 individuals were eligible for inclusion in this study. There was no statistically significant difference in CD4 T-cell count by average drinks per drinking day at any frequency of alcohol use irrespective of gender or viral suppression. Similarly, we found no difference in the hazard ratio for drinks per drinking day within the categories of drinking frequency for time to CD4 T-cell count increase of 100, 150 and 200 cells/mm3, respectively.
Among individuals initiating antiretroviral therapy (ART) the benefits of therapy and viral suppression on the immune system outweigh detrimental effects of alcohol, reinforcing the importance of initiating ART and ensuring adequate adherence to therapy.
PMCID: PMC3541505  PMID: 22955054
HIV; alcohol; Immune Response; CD4 T-CELL COUNT; antiretroviral therapy
10.  Insurance Status, not Race, is Associated with Mortality After an Acute Cardiovascular Event in Maryland 
Journal of General Internal Medicine  2012;27(10):1368-1376.
It is unclear how lack of health insurance or otherwise being underinsured contributes to observed racial disparities in health outcomes related to cardiovascular disease.
To determine the relative risk of death associated with insurance and race after hospital admission for an acute cardiovascular event.
Prospective cohort study in three hospitals in Maryland representing different demographics between 1993 and 2007.
Patients with an incident admission who were either white or black, and had either private insurance, state-based insurance or were uninsured. 4,908 patients were diagnosed with acute myocardial infarction, 6,759 with coronary atherosclerosis, and 1,293 with stroke.
Demographic and clinical patient-level data were collected from an administrative billing database and neighborhood household income was collected from the 2000 US Census. The outcome of all-cause mortality was collected from the Social Security Death Master File.
In an analysis adjusted for race, disease severity, location, neighborhood household income among other confounders, being underinsured was associated with an increased risk of death after myocardial infarction (relative hazard, 1.31 [95 % CI: 1.09, 1.59]), coronary atherosclerosis (relative hazard, 1.50 [95 % CI: 1.26, 1.80]) or stroke (relative hazard, 1.25 [95 % CI: 0.91, 1.72]). Black race was not associated with an increased risk of death after myocardial infarction (relative hazard, 1.03 [95 % CI: 0.85, 1.24]), or after stroke (relative hazard, 1.18 [95 % CI: 0.86, 1.61]) and was associated with a decreased risk of death after coronary atherosclerosis (relative hazard, 0.82 [95 % CI: 0.69, 0.98]).
Race was not associated with an increased risk of death, before or after adjustment. Being underinsured was strongly associated with death among those admitted with myocardial infarction, or a coronary atherosclerosis event. Our results support growing evidence implicating insurance status and socioeconomic factors as important drivers of health disparities, and potentially racial disparities.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-012-2147-9) contains supplementary material, which is available to authorized users.
PMCID: PMC3445670  PMID: 22821570
health disparities; insurance coverage; socioeconomic status; race; cardiovascular disease
11.  Changes in sexual and drug-related risk behavior following antiretroviral therapy initiation among HIV-infected injection drug users 
AIDS (London, England)  2012;26(18):2383-2391.
To evaluate whether HAART is associated with subsequent sexual and drug-related risk behavior compensation among injection drug users (IDUs).
A community-based cohort study of 362 HIV-infected IDUs initiating HAART in Baltimore, Maryland.
HAART use and risk behavior was assessed at 8316 biannual study visits (median 23). Using logistic regression with generalized estimating equations (GEE), we examined the effect of HAART initiation on changes in risk behavior while adjusting for sociodemographics, alcohol use, CD4+ cell count, year of initiation and consistency of HAART use.
At HAART initiation, participants were a median of 44.4 years old, 71.3% men and 95.3% African–American. In multivariable analysis, HAART initiation was associated with a 75% reduction in the likelihood of unprotected sex [adjusted odds ratio (aOR) 0.25; 95% confidence interval (CI), 0.19–0.32] despite no change in overall sexual activity (aOR 0.95; 0.80–1.12). Odds of any injecting decreased by 38% (aOR 0.62; 0.51–0.75) after HAART initiation. Among the subset of persistent injectors, needle-sharing increased nearly two-fold (aOR 1.99; 1.57–2.52). Behavioral changes were sustained for more than 5 years after HAART initiation and did not differ by consistency of HAART use. Reporting specific high-risk behaviors in the year prior to initiation was a robust predictor of engaging in those behaviors subsequent to HAART.
Overall, substantial declines in sexual risk-taking and active injecting argue against significant behavioral compensation among IDUs following HAART initiation. These data also provide evidence to support identifying persons with risky pre-HAART behavior for targeted behavioral intervention.
PMCID: PMC3678983  PMID: 23079804
antiretroviral therapy; HIV prevention; injecting; injection drug users; risk compensation; sexual behavior
12.  Risk of Anal Cancer in HIV-Infected and HIV-Uninfected Individuals in North America 
In a large North American cohort study, anal cancer incidence rates were substantially higher for HIV-infected men who have sex with men, other men, and women compared with HIV-uninfected individuals. Rates increased from 1996–1999 to 2000–2003 but plateaued by 2004–2007.
Background. Anal cancer is one of the most common cancers affecting individuals infected with human immunodeficiency virus (HIV), although few have evaluated rates separately for men who have sex with men (MSM), other men, and women. There are also conflicting data regarding calendar trends.
Methods. In a study involving 13 cohorts from North America with follow-up between 1996 and 2007, we compared anal cancer incidence rates among 34 189 HIV-infected (55% MSM, 19% other men, 26% women) and 114 260 HIV-uninfected individuals (90% men).
Results. Among men, the unadjusted anal cancer incidence rates per 100 000 person-years were 131 for HIV-infected MSM, 46 for other HIV-infected men, and 2 for HIV-uninfected men, corresponding to demographically adjusted rate ratios (RRs) of 80.3 (95% confidence interval [CI], 42.7–151.1) for HIV-infected MSM and 26.7 (95% CI, 11.5–61.7) for other HIV-infected men compared with HIV-uninfected men. HIV-infected women had an anal cancer rate of 30/100 000 person-years, and no cases were observed for HIV-uninfected women. In a multivariable Poisson regression model, among HIV-infected individuals, the risk was higher for MSM compared with other men (RR, 3.3; 95% CI, 1.8–6.0), but no difference was observed comparing women with other men (RR, 1.0; 95% CI, 0.5–2.2). In comparison with the period 2000–2003, HIV-infected individuals had an adjusted RR of 0.5 (95% CI, .3–.9) in 1996–1999 and 0.9 (95% CI, .6–1.2) in 2004–2007.
Conclusions. Anal cancer rates were substantially higher for HIV-infected MSM, other men, and women compared with HIV-uninfected individuals, suggesting a need for universal prevention efforts. Rates increased after the early antiretroviral therapy era and then plateaued.
PMCID: PMC3297645  PMID: 22291097
13.  Impact of Bariatric Surgery on Healthcare Utilization and Costs among Patients with Diabetes 
Medical care  2012;50(1):58-65.
The effect of bariatric surgery on health care utilization and costs among individuals with type 2 diabetes remains unclear.
To examine healthcare utilization and costs in an insured cohort of individuals with type 2 diabetes after bariatric surgery.
Research Design
Cohort study derived from administrative data from 2002–2008 from 7 Blue Cross Blue Shield Plans.
7,806 individuals with type 2 diabetes who had bariatric surgery
Cost (inpatient, outpatient, pharmacy, other) and utilization (number of inpatient days, outpatient visits, specialist visits).
Compared to pre-surgical costs, the ratio of hospital costs (excluding the initial surgery), among beneficiaries who had any hospital costs, was higher in years 2 through 6 of the post-surgery period and increased over time [post 1: OR = 0.58 (95% CI: 0.50, 0.67); post 6: OR = 3.43 (95% CI: 2.60, 4.53)]. In comparison to the pre-surgical period, the odds of having any healthcare costs was lower in the post-surgery period and remained relatively flat over time. Among those with hospitalizations, the adjusted ratio of inpatient days was higher after surgery [post 1: OR = 1.05 (95% CI: 0.94, 1.16); post 6: OR = 2.77 (95% CI: 1.57, 4.90)]. Among those with primary care visits, the adjusted odds ratio was lower after surgery [post 1: OR = 0.80 (95% CI: 0.78, 0.82); post 6: OR = 0.66 (95% CI: 0.57, 0.76)].
In the six years following surgery, individuals with type 2 diabetes did not have lower healthcare costs than before surgery.
PMCID: PMC3241012  PMID: 22167064
14.  Risk factors for chronic kidney disease in a large cohort of HIV-1 infected individuals initiating antiretroviral therapy in routine care 
AIDS (London, England)  2012;26(15):1907-1915.
To examine long-term effects of antiretroviral therapy (ART) on kidney function, we evaluated the incidence and risk factors for chronic kidney disease (CKD) among ART-naive, HIV-infected adults and compared changes in estimated glomerular filtration rates (eGFR) before and after starting ART.
Multicenter observational cohort study of patients with at least one serum creatinine measurement before and after initiating ART. Cox proportional hazard models, and marginal structure models examined CKD risk factors; mixed-effects linear models examined eGFR slopes.
Three thousand, three hundred and twenty-nine patients met entry criteria, contributing 10 099 person-years of observation on ART. ART was associated with a significantly slower rate of eGFR decline (from −2.18 to −1.37 ml/min per 1.73 m2 per year; P = 0.02). The incidence of CKD defined by eGFR thresholds of 60, 45 and 30 ml/min per 1.73 m2 was 10.5, 3.4 and 1.6 per 1000 person-years, respectively. In adjusted analyses black race, hepatitis C coinfection, lower time-varying CD4 cell count and higher time-varying viral load on ART were associated with higher CKD risk, and the magnitude of these risks increased with more severe CKD. Tenofovir and a ritonavir-boosted protease inhibitor (rPI) was also associated with higher CKD risk [hazard odds ratio for an eGFR threshold <60 ml/min per 1.73 m2: 3.35 (95% confidence interval (CI) = 1.40–8.02)], which developed in 5.7% of patients after 4 years of exposure to this regimen-type.
ART was associated with reduced CKD risk in association with CD4 cell restoration and plasma viral load suppression, despite an increased CKD risk that was associated with initial regimens that included tenofovir and rPI.
PMCID: PMC3531628  PMID: 22824630
antiretroviral therapy; chronic kidney disease; tenofovir
15.  HIV Infection, Immune Suppression, and Uncontrolled Viremia Are Associated With Increased Multimorbidity Among Aging Injection Drug Users 
Human immunodeficiency virus (HIV)-infected persons, especially those with advanced immune suppression or uncontrolled viremia, experienced increased numbers of multimorbid non-AIDS-defining conditions compared with epidemiologically comparable HIV-uninfected persons. Many of these clinically identified chronic diseases were unrecognized and untreated.
Background. Despite an increasing burden of age-associated non-AIDS outcomes, few studies have investigated the prevalence or correlates of multimorbidity among aging human immunodeficiency virus (HIV)–infected and epidemiologically comparable at-risk populations.
Methods. Among 1262 AIDS Linked to the IntraVenous Experience (ALIVE) study participants followed in a community-based observational cohort, we defined the prevalence of 7 non-AIDS-defining chronic conditions (diabetes, obstructive lung disease, liver disease, anemia, obesity, kidney dysfunction, and hypertension) using clinical and laboratory criteria. Ordinal logistic regression was used to model the odds of increased multimorbidity associated with demographic, behavioral, and clinical factors. Self-reported prevalence was compared with clinically defined prevalence.
Results. Participants were a median of 48.9 years of age; 65.1% were male, 87.5% were African-American, and 28.7% were HIV infected. In multivariable analysis, HIV infection (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.13–1.99) was positively associated with increased multimorbidity. Among HIV-infected participants, multimorbidity was increased with lower nadir CD4 T-cell count (OR, 1.14 per 100-cell decrease; 95% CI, 1.00–1.29) and higher current HIV RNA (OR, 1.32 per log10 increase; 95% CI, 1.08–1.60). Older age, being female, not using cigarettes or drugs, and having depressive symptoms were also associated with increased multimorbidity. A substantial proportion of multimorbid conditions in HIV-infected and HIV-uninfected participants were unrecognized and untreated.
Conclusions. HIV-infected participants experienced increased numbers of multimorbid conditions; risk increased with advanced immunosuppression and higher viremia. These results underscore the heavy burden of multimorbidity associated with HIV and highlight the need for incorporating routine assessment and integrated management of chronic diseases as part of comprehensive healthcare for aging, HIV-infected persons.
PMCID: PMC3214585  PMID: 21976463
16.  Viremia Copy-Years Predicts Mortality Among Treatment-Naive HIV-Infected Patients Initiating Antiretroviral Therapy 
Viremia copy-years predicted all-cause mortality independent of traditional, cross-sectional viral load measures and time-updated CD4+ T-lymphocyte count in antiretroviral therapy-treated patients suggesting cumulative human immunodeficiency virus replication causes harm independent of its effect on the degree of immunodeficiency.
Background. Cross-sectional plasma human immunodeficiency virus (HIV) viral load (VL) measures have proven invaluable for clinical and research purposes. However, cross-sectional VL measures fail to capture cumulative plasma HIV burden longitudinally. We evaluated the cumulative effect of exposure to HIV replication on mortality following initiation of combination antiretroviral therapy (ART).
Methods. We included treatment-naive HIV-infected patients starting ART from 2000 to 2008 at 8 Center for AIDS Research Network of Integrated Clinical Systems sites. Viremia copy-years, a time-varying measure of cumulative plasma HIV exposure, were determined for each patient using the area under the VL curve. Multivariable Cox models were used to evaluate the independent association of viremia copy-years for all-cause mortality.
Results. Among 2027 patients contributing 6579 person-years of follow-up, the median viremia copy-years was 5.3 log10 copy × y/mL (interquartile range: 4.9–6.3 log10 copy × y/mL), and 85 patients (4.2%) died. When evaluated separately, viremia copy-years (hazard ratio [HR] = 1.81 per log10 copy × y/mL; 95% confidence interval [CI], 1.51–2.18 per log10 copy × y/mL), 24-week VL (1.74 per log10 copies/mL; 95% CI, 1.48–2.04 per log10 copies/mL), and most recent VL (HR = 1.89 per log10 copies/mL; 95% CI: 1.63–2.20 per log10 copies/mL) were associated with increased mortality. When simultaneously evaluating VL measures and controlling for other covariates, viremia copy-years increased mortality risk (HR = 1.44 per log10 copy × y/mL; 95% CI, 1.07–1.94 per log10 copy × y/mL), whereas no cross-sectional VL measure was independently associated with mortality.
Conclusions. Viremia copy-years predicted all-cause mortality independent of traditional, cross-sectional VL measures and time-updated CD4+ T-lymphocyte count in ART-treated patients, suggesting cumulative HIV replication causes harm independent of its effect on the degree of immunodeficiency.
PMCID: PMC3189165  PMID: 21890751
17.  Risk Factors for Tuberculosis After Highly Active Antiretroviral Therapy Initiation in the United States and Canada: Implications for Tuberculosis Screening 
The Journal of Infectious Diseases  2011;204(6):893-901.
Background. Screening for tuberculosis prior to highly active antiretroviral therapy (HAART) initiation is not routinely performed in low-incidence settings. Identifying factors associated with developing tuberculosis after HAART initiation could focus screening efforts.
Methods. Sixteen cohorts in the United States and Canada contributed data on persons infected with human immunodeficiency virus (HIV) who initiated HAART December 1995–August 2009. Parametric survival models identified factors associated with tuberculosis occurrence.
Results. Of 37845 persons in the study, 145 were diagnosed with tuberculosis after HAART initiation. Tuberculosis risk was highest in the first 3 months of HAART (20 cases; 215 cases per 100000 person-years; 95% confidence interval [CI]: 131–333 per 100000 person-years). In a multivariate Weibull proportional hazards model, baseline CD4+ lymphocyte count <200, black race, other nonwhite race, Hispanic ethnicity, and history of injection drug use were independently associated with tuberculosis risk. In addition, in a piece-wise Weibull model, increased baseline HIV-1 RNA was associated with increased tuberculosis risk in the first 3 months; male sex tended to be associated with increased risk.
Conclusions. Screening for active tuberculosis prior to HAART initiation should be targeted to persons with baseline CD4 <200 lymphocytes/mm3 or increased HIV-1 RNA, persons of nonwhite race or Hispanic ethnicity, history of injection drug use, and possibly male sex.
PMCID: PMC3156918  PMID: 21849286
18.  Missing Data on the Estimation of the Prevalence of Accumulated Human Immunodeficiency Virus Drug Resistance in Patients Treated With Antiretroviral Drugs in North America 
American Journal of Epidemiology  2011;174(6):727-735.
Determination of the prevalence of accumulated antiretroviral drug resistance among persons infected with human immunodeficiency virus (HIV) is complicated by the lack of routine measurement in clinical care. By using data from 8 clinic-based cohorts from the North American AIDS Cohort Collaboration on Research and Design, drug-resistance mutations from those with genotype tests were determined and scored using the Genotypic Resistance Interpretation Algorithm developed at Stanford University. For each year from 2000 through 2005, the prevalence was calculated using data from the tested subset, assumptions that incorporated clinical knowledge, and multiple imputation methods to yield a complete data set. A total of 9,289 patients contributed data to the analysis; 3,959 had at least 1 viral load above 1,000 copies/mL, of whom 2,962 (75%) had undergone at least 1 genotype test. Using these methods, the authors estimated that the prevalence of accumulated resistance to 2 or more antiretroviral drug classes had increased from 14% in 2000 to 17% in 2005 (P < 0.001). In contrast, the prevalence of resistance in the tested subset declined from 57% to 36% for 2 or more classes. The authors’ use of clinical knowledge and multiple imputation methods revealed trends in HIV drug resistance among patients in care that were markedly different from those observed using only data from patients who had undergone genotype tests.
PMCID: PMC3202147  PMID: 21813792
antiretroviral therapy, highly active; drug resistance; genotype; HIV
19.  Parametric mixture models to evaluate and summarize hazard ratios in the presence of competing risks with time-dependent hazards and delayed entry 
Statistics in medicine  2010;30(6):654-665.
In the analysis of survival data, there are often competing events that preclude an event of interest from occurring. Regression analysis with competing risks is typically undertaken using a cause-specific proportional hazards model. However, modern alternative methods exist for the analysis of the subdistribution hazard with a corresponding subdistribution proportional hazards model. In this paper, we introduce a flexible parametric mixture model as a unifying method to obtain estimates of the cause-specific and subdistribution hazards and hazard ratio functions. We describe how these estimates can be summarized over time to give a single number that is comparable to the hazard ratio that is obtained from a corresponding cause-specific or subdistribution proportional hazards model. An application to the Women’s Interagency HIV Study is provided to investigate injection drug use and the time to either the initiation of effective antiretroviral therapy, or clinical disease progression as a competing event.
PMCID: PMC3069508  PMID: 21337360
Cause-specific hazards; Competing risks; Hazard ratio; Mixture Model; Subdistribution; Subdistribution hazards; Survival analysis
20.  Alcohol Consumption Among HIV-Infected Women: Impact on Time to Antiretroviral Therapy and Survival 
Journal of Women's Health  2011;20(2):279-286.
Alcohol use is prevalent among HIV-infected people and is associated with lower antiretroviral adherence and high-risk sexual and injection behaviors. We sought to determine factors associated with alcohol use among HIV-infected women engaged in clinical care and if baseline alcohol use was associated with time to combination antiretroviral therapy (cART) and death in this population.
In an observational clinical cohort, alcohol consumption at the initial medical visit was examined and categorized as heavy, occasional, past, or no use. We used multinomial logistic regression to test preselected covariates and their association with baseline alcohol consumption. We then examined the association between alcohol use and time to cART and time to death using Kaplan-Meier statistics and Cox proportional hazards regression.
Between 1997 and 2006, 1030 HIV-infected women enrolled in the cohort. Assessment of alcohol use revealed occasional and hazardous consumption in 29% and 17% of the cohort, respectively; 13% were past drinkers. In multivariate regression, heavy drinkers were more likely to be infected with hepatitis C than nondrinkers (relative risk ratios [RRR] 2.06, 95% confidence interval [CI] 1.29-3.44) and endorse current drug (RRR 3.51, 95% CI 2.09-5.91) and tobacco use (RRR 3.85 95% CI 1.81-8.19). Multivariable Cox regression adjusting for all clinical covariates demonstrated an increased mortality risk (hazard ratio [HR] 1.40, 95% CI 1.00-1.97, p < 0.05) among heavy drinkers compared to nondrinkers but no delays in cART initiation (1.04 95% CI 0.81-1.34)
Among this cohort of HIV-infected women, heavy alcohol consumption was independently associated with earlier death. Baseline factors associated with heavy alcohol use included tobacco use, hepatitis C, and illicit drug use. Alcohol is a modifiable risk factor for adverse HIV-related outcomes. Providers should consistently screen for alcohol consumption and refer HIV-infected women with heavy alcohol use for treatment.
PMCID: PMC3064875  PMID: 21281111
21.  Virologic and immunologic response to HAART, by age and regimen class 
AIDS (London, England)  2010;24(16):2469-2479.
To determine the impact of age and initial HAART regimen class on virologic and immunologic response within 24 months after initiation.
Pooled analysis of data from 19 prospective cohort studies in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD).
Twelve thousand, one hundred and ninety-six antiretroviral-naive adults who initiated HAART between 1998 and 2008 using a boosted protease inhibitor-based regimen or a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen were included in our study. Discrete time-to-event models estimated adjusted hazard odds ratios (aHOR) and 95% confidence intervals (CIs) for suppressed viral load (≤500 copies/ml) and, separately, at least 100 cells/μl increase in CD4 cell count. Truncated, stabilized inverse probability weights accounted for selection biases from discontinuation of initial regimen class.
Among 12 196 eligible participants (mean age = 42 years), 50% changed regimen classes after initiation (57 and 48% of whom initiated protease inhibitor and NNRTI-based regimens, respectively). Mean CD4 cell count at initiation was similar by age. Virologic response to treatment was less likely in those initiating using a boosted protease inhibitor [aHOR = 0.77 (0.73, 0.82)], regardless of age. Immunologic response decreased with increasing age [18–<30: ref; 30–<40: aHOR 0.92 (0.85, 1.00); 40–<50: aHOR = 0.85 (0.78, 0.92); 50–<60: aHOR = 0.82 (0.74, 0.90); ≥60: aHOR=0.74 (0.65, 0.85)], regardless of initial regimen.
We found no evidence of an interaction between age and initial anti-retroviral regimen on virologic or immunologic response to HAART; however, decreased immunologic response with increasing age may have implications for age-specific when-to-start guidelines.
PMCID: PMC3136814  PMID: 20829678
age; CD4 lymphocyte count; HAART; HIV; viral load
22.  Copy-Years Viremia as a Measure of Cumulative Human Immunodeficiency Virus Viral Burden 
American Journal of Epidemiology  2009;171(2):198-205.
Plasma human immunodeficiency virus type 1 (HIV-1) viral load is a valuable tool for HIV research and clinical care but is often used in a noncumulative manner. The authors developed copy-years viremia as a measure of cumulative plasma HIV-1 viral load exposure among 297 HIV seroconverters from the Multicenter AIDS Cohort Study (1984–1996). Men were followed from seroconversion to incident acquired immunodeficiency syndrome (AIDS), death, or the beginning of the combination antiretroviral therapy era (January 1, 1996); the median duration of follow-up was 4.6 years (interquartile range (IQR), 2.7–6.5). The median viral load and level of copy-years viremia over 2,281 semiannual follow-up assessments were 29,628 copies/mL (IQR, 8,547–80,210) and 63,659 copies × years/mL (IQR, 15,935–180,341). A total of 127 men developed AIDS or died, and 170 survived AIDS-free and were censored on January 1, 1996, or lost to follow-up. Rank correlations between copy-years viremia and other measures of viral load were 0.56–0.87. Each log10 increase in copy-years viremia was associated with a 1.70-fold increased hazard (95% confidence interval: 0.94, 3.07) of AIDS or death, independently of infection duration, age, race, CD4 cell count, set-point, peak viral load, or most recent viral load. Copy-years viremia, a novel measure of cumulative viral burden, may provide prognostic information beyond traditional single measures of viremia.
PMCID: PMC2878100  PMID: 20007202
acquired immunodeficiency syndrome; HIV; HIV infections; viral load; viremia
23.  Clinic-based Treatment for Opioid-dependent HIV-infected Patients versus Referral to an Opioid Treatment Program: A Randomized Controlled Trial 
Annals of internal medicine  2010;152(11):704-711.
Opioid dependence is common in HIV clinics. Buprenorphine/naloxone (BUP) is an effective treatment for opioid dependence that may be used in routine medical settings.
To compare clinic-based treatment with BUP (clinic-based BUP) with case-management and referral to an opioid treatment program (referred-treatment).
Single-center, 12-month randomized trial. Participants and investigators were aware of treatment assignments.
HIV clinic in Baltimore, Maryland.
93 HIV-infected, opioid-dependent subjects who were not receiving opioid agonist therapy and were not dependent on alcohol or benzodiazepines.
The clinic-based BUP strategy included BUP induction and dose titration, urine drug test monitoring, and individual counseling; the referred-treatment arm included case management and referral to an opioid treatment program.
Initiation and long-term receipt of opioid agonist therapy, urine drug test results, visit attendance with primary HIV providers, use of antiretroviral therapy, and changes in HIV RNA levels and CD4 cell counts.
The average estimated participation in opioid agonist therapy was 74% (95% CI 61%–84%) in clinic-based BUP and 41% (29%–53%) in referred-treatment (p<0.001). Opioid and cocaine positive urine drug tests were significantly less frequent in clinic-based BUP than in referred-treatment, and study subjects in clinic-based BUP attended significantly more HIV primary care visits than study subjects in referred-treatment. Use of antiretroviral therapy and changes in HIV RNA levels and CD4 cell counts did not differ in the 2 arms of the study.
This was a small single-center study, follow-up was only fair, and there was an imbalance in recent drug injection in the study arms at baseline.
This study suggests that management of HIV-infected, opioid-dependent patients with a clinic-based BUP strategy facilitates access to opioid agonist therapy and improves substance abuse treatment outcomes.
Primary Funding Source
Health Resources Services Administration, Special Projects of National Significance.
PMCID: PMC2886293  PMID: 20513828
HIV; opioid dependence; buprenorphine; opioid agonist treatment; methadone; opioid treatment program
25.  Identifying individuals with virologic failure after initiating effective antiretroviral therapy: The surprising value of mean corpuscular hemoglobin in a cross-sectional study 
Recent studies have shown that the current guidelines suggesting immunologic monitoring to determine response to highly active antiretroviral therapy (HAART) are inadequate. We assessed whether routinely collected clinical markers could improve prediction of concurrent HIV RNA levels.
We included individuals followed within the Johns Hopkins HIV Clinical Cohort who initiated antiretroviral therapy and had concurrent HIV RNA and biomarker measurements ≥4 months after HAART. A two tiered approach to determine whether clinical markers could improve prediction included: 1) identification of predictors of HIV RNA levels >500 copies/ml and 2) construction and validation of a prediction model.
Three markers (mean corpuscular hemoglobin [MCH], CD4, and change in percent CD4 from pre-HAART levels) in addition to the change in MCH from pre-HAART levels contained the most predictive information for identifying an HIV RNA >500 copies/ml. However, MCH and change in MCH were the two most predictive followed by CD4 and change in percent CD4. The logistic prediction model in the validation data had an area under the receiver operating characteristic curve of 0.85, and a sensitivity and specificity of 0.74 (95% CI: 0.69-0.79) and 0.89 (95% CI: 0.86-0.91), respectively.
Immunologic criteria have been shown to be a poor guideline for identifying individuals with high HIV RNA levels. MCH and change in MCH were the strongest predictors of HIV RNA levels >500. When combined with CD4 and percent CD4 as covariates in a model, a high level of discrimination between those with and without HIV RNA levels >500 was obtained. These data suggest an unexplored relationship between HIV RNA and MCH.
PMCID: PMC2922076  PMID: 20653950

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