Virginia A. Triant

Fracture Prevalence among Human Immunodeficiency Virus (HIV)-Infected Versus Non-HIV-Infected Patients in a Large U.S. Healthcare System

CONTEXT Reduced bone mineral density has been demonstrated among HIV-infected patients, but fracture prevalence is unknown. OBJECTIVE The objective of the study was to compare fracture prevalence in HIV-infected and non-HIV-infected patients. DESIGN This was a population-based study. SETTING The study was conducted at a large U.S. health care system. PATIENTS A total of 8525 HIV-infected and 2,208,792 non-HIV-infected patients with at least one inpatient or outpatient encounter between October 1, 1996, and March 21, 2008, was compared. MAIN OUTCOME MEASURE Fracture prevalence using specific International Classification of Diseases, Ninth Revision, Clinical Modification fracture codes was measured. RESULTS The overall fracture prevalence was 2.87 vs. 1.77 patients with fractures per 100 persons in HIV-infected, compared with non-HIV-infected patients (P < 0.0001). Among females, the overall fracture prevalence was 2.49 vs. 1.72 per 100 persons in HIV-infected vs. non-HIV-infected patients (P = 0.002). HIV-infected females had a higher prevalence of vertebral (0.81 vs. 0.45; P = 0.01) and wrist (1.31 vs. 0.83; P = 0.01) fractures per 100 persons, compared with non-HIV-infected females but had a similar prevalence of hip fractures (0.47 vs. 0.56; P = 0.53). Among males, the fracture prevalence per 100 persons was higher in HIV-infected vs. non-HIV-infected patients for any fracture (3.08 vs. 1.83; P < 0.0001), vertebral fractures (1.03 vs. 0.49; P < 0.0001), hip fractures (0.79 vs. 0.45; P = 0.001), and wrist fractures (1.46 vs. 0.99; P = 0.001). Fracture prevalence was higher relative to non-HIV-infected patients among African-American and Caucasian females and Caucasian males. CONCLUSIONS Fracture prevalence is increased in HIV-infected compared with non-HIV-infected patients.

Association of C-Reactive Protein and HIV Infection With Acute Myocardial Infarction

Objective:To investigate whether elevated C-reactive protein (CRP) levels and HIV infection are independently associated with acute myocardial infarction (AMI) among patients receiving care in a large US health care system. Methods:Analyses included patients receiving care in the Partners HealthCare System between January 1997 and December 2006, with a most recent CRP less than 3 years and more than 1 week before AMI. Over this period, 70,357 (487 HIV and 69,870 non-HIV) patients met these criteria, from the background population of 1,648,687 patients followed in the system. We included both CRP and high-sensitivity CRP and defined elevated CRP based on the normal range of the assay used. We used multivariate logistic regression analysis to test the association of elevated CRP and HIV with AMI after adjustment for demographic and other cardiovascular covariates, including hypertension, diabetes, and dyslipidemia. Results:In univariate analyses, elevated CRP and HIV were each significantly associated with AMI [odds ratio (OR) 2.51; 95% confidence interval (CI) 2.27 to 2.78; P < 0.0001 for elevated CRP and OR 2.07; 95% CI 1.31 to 3.10; P = 0.001 for HIV]. In a combined model including CRP category and HIV status, elevated CRP (OR 2.50; 95% CI 2.26 to 2.77; P < 0.0001) and HIV (OR 1.74; 95% CI 1.10 to 2.61; P = 0.01) were both independently associated with AMI. In a fully adjusted model controlling for age, sex, race, hypertension, diabetes, and dyslipidemia, both elevated CRP (OR 2.13; 95% CI 1.92 to 2.37; P < 0.0001) and HIV (OR 1.93; 95% CI 1.21 to 2.93; P = 0.004) remained independently associated with AMI. Compared with patients with normal CRP and without HIV, the OR for AMI was increased more than 4-fold among patients with HIV and elevated CRP. Conclusions:Elevated CRP and HIV are independently associated with increased AMI risk, and patients with HIV with increased CRP have a markedly increased relative risk of AMI. Measurement of CRP may be useful in the cardiovascular risk assessment of patients with HIV.

Comparison of ischemic stroke incidence in HIV-infected and non-HIV-infected patients in a US health care system.

Background: Cardiovascular disease is increased among HIV-infected patients, but little is known regarding ischemic stroke rates. We sought to compare stroke rates and determine stroke risk factors in HIV-infected versus non-HIV-infected patients. Methods: An HIV cohort and matched non-HIV comparator cohort seen between 1996 and 2009 were identified from a Boston health care system. The primary endpoint was ischemic stroke, defined using International Classification of Diseases (ICD) codes. Unadjusted stroke incidence rates were calculated. Cox proportional hazards modeling was used to determine adjusted hazard ratios (HRs). Results: The incidence rate of ischemic stroke was 5.27 per 1000 person-years in HIV-infected compared with 3.75 in non-HIV-infected patients, with an unadjusted HR of 1.40 [95% confidence interval (CI): 1.17 to 1.69, P < 0.001]. HIV remained an independent predictor of stroke after controlling for demographics and stroke risk factors (HR: 1.21, 95% CI: 1.01 to 1.46, P = 0.043). The relative increase in stroke rates (HIV vs. non-HIV) was significantly higher in younger HIV patients (incidence rate ratio: 4.42, 95% CI: 1.56 to 11.09, age 18–29; 2.96, 1.69–4.96, age: 30–39; 1.53, 1.06–2.17, age: 40–49), and in women [HR: 2.16 (95% CI: 1.53 to 3.04) for women vs. HR: 1.18 (95% CI: 0.95 to 1.47) for men]. Among HIV patients, increased HIV RNA (HR: 1.10, 95% CI: 1.04 to 1.17, P = 0.001) was associated with an increased risk of stroke. Conclusions: Stroke rates were increased among HIV-infected patients, independent of common stroke risk factors, particularly among young patients and women.

Association of Immunologic and Virologic Factors With Myocardial Infarction Rates in a US Healthcare System

Background:The effects of immunologic and virologic factors on acute myocardial infarction (AMI) rates in patients with HIV are unclear. Methods:HIV-infected patients in a US healthcare system were assessed for AMI. Results:Of 6517 patients with HIV, 273 (4.2%) had an AMI. In a model adjusting for cardiovascular risk factors, antiretroviral medications, and HIV parameters, CD4 count less than 200/mm3 (odds ratio, 1.74; 95% confidence interval, 1.07 to 2.81; P = 0.02) predicted AMI. Increased HIV viral load was associated with AMI accounting for cardiovascular disease risk factors and antiretroviral medications but was not significant when CD4 count was considered. Conclusions:Immunologic control appears to be the most important HIV-related factor associated with AMI.

Increased coronary atherosclerosis and immune activation in HIV-1 elite controllers.

HIV-1 elite controllers spontaneously maintain suppressed levels of viremia, but exhibit significant immune activation. We investigated coronary atherosclerosis by coronary computed tomography angiography (CTA) in elite controllers, nonelite controller, chronically HIV-1 infected, antiretroviral therapy (ART)-treated patients with undetectable viral load (‘chronic HIV’), and HIV-negative controls. Prevalence of atherosclerosis (78 vs. 42%, P < 0.05) and markers of immune activation were increased in elite controllers compared with HIV-negative controls. sCD163, a monocyte activation marker, was increased in elite controllers compared with chronic HIV-1 (P < 0.05) and compared with HIV-negative controls (P < 0.05). These data suggest a significant degree of coronary atherosclerosis and monocyte activation among elite controllers.

HIV Infection and Coronary Heart Disease: An Intersection of Epidemics

Patients with human immunodeficiency virus (HIV) infection are at increased risk of developing coronary heart disease (CHD). Although factors potentially contributing to this elevated risk include traditional CHD risk factors and antiretroviral medications, more recent data support a role for inflammatory and immunologic factors as central to a complex mechanism. Decreasing CHD risk among HIV-infected patients is likely to involve modification of inflammatory and immunologic factors through antiretroviral therapy or other novel strategies as well as targeted treatment of traditional CHD risk factors. This review will highlight epidemiologic data investigating the association between HIV and CHD outcomes. An overview of potential mechanistic factors associated with CHD in HIV infection and of strategies for managing CHD risk in HIV-infected patients is also included. Specific cardiovascular and metabolic risk factors, CHD risk prediction, and the immunologic basis for CHD in HIV-infected patients will be discussed in separate reviews.

Cardiovascular Disease and HIV Infection

The emergence of chronic disease complications in controlled HIV disease has changed the landscape of HIV clinical care. HIV infection confers an increased cardiovascular disease risk, which is thought to be due to a complex interplay of mechanistic factors. While traditional cardiovascular risk factors likely play a role, recent evidence suggests that HIV-associated inflammation and immune activation are important mediators of cardiovascular risk. It is unclear whether established preventative interventions for the general population are applicable to HIV-infected patients, and the need to translate mechanistic knowledge into HIV-specific clinical interventions represents an important priority. Developing strategies to prevent cardiovascular disease in HIV-infected individuals calls for a multidisciplinary approach and represents an opportunity to exert a major public health impact in an at-risk population.

Persistent Immune Activation and Carotid Atherosclerosis in HIV-Infected Ugandans Receiving Antiretroviral Therapy

BACKGROUND Human immunodeficiency virus (HIV) infection and associated immune activation predict the risk of cardiovascular disease in resource-rich areas. Less is known about these relationships in sub-Saharan Africa. METHODS Beginning in 2005, we enrolled subjects in southwestern Uganda into a cohort at the time of antiretroviral therapy (ART) initiation. Multiple immune activation measures were assessed before and 6 months after ART initiation. Beginning in 2013, participants aged >40 years underwent metabolic profiling, including measurement of hemoglobin A1c and lipid levels and carotid ultrasonography. We fit regression models to identify traditional and HIV-specific correlates of common carotid intima media thickness (CCIMT). RESULTS A total of 105 participants completed carotid ultrasonography, with a median completion time of 7 years following ART initiation. Age, low-density lipoprotein cholesterol level, and pre-ART HIV load were correlated with CCIMT. No association was found between CCIMT and any pre-ART biomarkers of immune activation. However, in multivariable models adjusted for cardiovascular disease risk factors, lower absolute levels of soluble CD14 and interleukin 6 and greater declines in the CD14 level and kynurenine-tryptophan ratio after 6 months of ART predicted a lower CCIMT years later (P < .01). CONCLUSIONS Persistent immune activation despite ART-mediated viral suppression predicts the future atherosclerotic burden among HIV-infected Ugandans. Future work should focus on clinical correlates of these relationships, to elucidate the long-term health priorities for HIV-infected people in the region.

Initiation of antiretroviral therapy at high CD4 cell counts: does it reduce the risk of cardiovascular disease?

Purpose of review Inflammation and immune activation associated with untreated HIV infection may increase the risk for cardiovascular disease (CVD) and are not entirely reversed by antiretroviral therapy (ART). Although older ART regimens were associated with drug-specific risks for CVD, this may not be true for modern ART. Thus, with regard to CVD risk, the net benefit of initiating ART at higher CD4+ T-cell counts remains unclear. Recent findings In addition to the well established risk of coronary heart disease, emerging evidence now suggests that chronic HIV infection is associated with higher risk of ischemic stroke, heart failure, and arrhythmias. These epidemiologic studies have associated immunodeficiency and active viral replication with higher CVD risk. Novel methods of imaging subclinical vascular disease continue to implicate inflammation and immune activation as likely mediators of CVD among patients with HIV. Newer generation protease inhibitors, chemokine receptor 5 antagonists, and integrase inhibitors do not appear to be associated with the adverse cardiometabolic risks of older drugs. Summary Recent evidence suggests that treating HIV infection with ART may reduce the risk of CVD, even at higher CD4 T-cell counts; however, the definitive answer to this question will come from clinical trials and long-term observational studies.

Effects of Antiretroviral Therapy on Immune Function and Arterial Inflammation in Treatment-Naive Patients With Human Immunodeficiency Virus Infection

IMPORTANCE Individuals with human immunodeficiency virus (HIV) infection receiving combined antiretroviral therapy (ART) have an increased risk of myocardial infarction. Effects of ART on arterial inflammation among treatment-naive individuals with HIV are unknown. OBJECTIVE To determine the effects of newly initiated ART on arterial inflammation and other immune/inflammatory indices in ART-naive patients with HIV infection. DESIGN, SETTING, PARTICIPANTS Twelve treatment-naive HIV-infected individuals underwent fludeoxyglucose F 18 ([18F]-FDG) positron emission tomographic scanning for assessment of arterial inflammation, coronary computed tomographic angiography for assessment of subclinical atherosclerosis, and systemic immune and metabolic phenotyping before and 6 months after the initiation of therapy with elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (combined ART). Systemic immune and metabolic factors were also assessed in 12 prospectively recruited individuals without HIV serving as controls. The study began July 24, 2012, and was completed May 7, 2015. INTERVENTIONS Combined ART in the HIV-infected cohort. MAIN OUTCOMES AND MEASURES The primary outcome was change in aortic target-background ratio (TBR) on [18F]-FDG-PET with combined ART in the HIV-infected group. RESULTS For the 12 participants with HIV infection (mean (SD) age, 35 [11] years), combined ART suppressed viral load (mean [SD] log viral load, from 4.3 [0.6] to 1.3 [0] copies/mL; P < .001), increased the CD4+ T-cell count (median [IQR], from 461 [332-663] to 687 [533-882] cells/mm3; P < .001), and markedly reduced percentages of circulating activated CD4+ T cells (human leukocyte antigen-D related [HLA-DR]+CD38+CD4+) (from 3.7 [1.8-5.0] to 1.3 [0.3-2.0]; P = .008) and CD8+ T cells (HLA-DR+CD38+CD8+) (from 18.3 [8.1-27.0] to 4.0 [1.5-7.8]; P = .008), increased the percentage of circulating classical CD14+CD16- monocytes (from 85.8 [83.7-90.8] to 91.8 [87.5-93.2]; P = .04), and reduced levels of CXCL10 (mean [SD] log CXCL10, from 2.4 [0.4] to 2.2 [0.4] pg/mL; P = .03). With combined ART, uptake of [18F]-FDG in the axillary lymph nodes, as measured by TBR, decreased from a median (IQR) of 3.7 (1.3-7.0) at baseline to 1.4 (0.9-1.9; P = .01) at study end. In contrast, no significant decrease was seen in aortic TBR in response to combined ART (mean [SD], 1.9 [0.2]; median [IQR], 2.0 [1.8-2.1] at baseline to 2.2 [0.4]; 2.1 [1.9-2.6], respectively, at study end; P = .04 by 2-way test, P = .98 for test of decrease by 1-way test). Changes in aortic TBR during combined ART were significantly associated with changes in lipoprotein-associated phospholipase A2 (n = 10; r = 0.67; P = .03). Coronary plaque increased among 3 participants with HIV infection with baseline plaque and developed de novo in 1 participant during combined ART. CONCLUSIONS AND RELEVANCE Newly initiated combined ART in treatment-naive individuals with HIV infection had discordant effects to restore immune function without reducing arterial inflammation. Complementary strategies to reduce arterial inflammation among ART-treated HIV-infected individuals may be needed.