Priscilla Y. Hsue

Criteria for Evaluation of Novel Markers of Cardiovascular Risk A Scientific Statement From the American Heart Association

There is increasing interest in utilizing novel markers of cardiovascular disease risk, and consequently, there is a need to assess the value of their use. This scientific statement reviews current concepts of risk evaluation and proposes standards for the critical appraisal of risk assessment methods. An adequate evaluation of a novel risk marker requires a sound research design, a representative at-risk population, and an adequate number of outcome events. Studies of a novel marker should report the degree to which it adds to the prognostic information provided by standard risk markers. No single statistical measure provides all the information needed to assess a novel marker, so measures of both discrimination and accuracy should be reported. The clinical value of a marker should be assessed by its effect on patient management and outcomes. In general, a novel risk marker should be evaluated in several phases, including initial proof of concept, prospective validation in independent populations, documentation of incremental information when added to standard risk markers, assessment of effects on patient management and outcomes, and ultimately, cost-effectiveness.

Progression of Atherosclerosis as Assessed by Carotid Intima-Media Thickness in Patients With HIV Infection

Background—HIV-infected patients may be at increased risk for coronary events. The purpose of this study was to identify predictors of carotid intima-media thickness (IMT) in HIV patients at baseline and to measure IMT progression over 1 year. Methods and Results—We measured blood lipids, inflammatory markers, and IMT in 148 HIV-infected adults (mean age, 45±8 years) and in 63 age- and sex-matched HIV-uninfected control subjects. The mean duration of HIV infection was 11 years, and the median duration of protease inhibitor treatment was 3.3 years. Mean baseline IMT was 0.91±0.33 mm in HIV patients and 0.74±0.17 mm in control subjects (P =0.0001). Multivariable predictors of baseline IMT in HIV patients were age (P <0.001), LDL cholesterol (P <0.001), cigarette pack-years (P =0.005), Latino race (P =0.062), and hypertension (P =0.074). When the control group was added to the analysis, HIV infection was an independent predictor of IMT (P =0.001). The rate of progression among the 121 HIV patients with a repeated IMT measurement at 1 year was 0.074±0.13 mm, compared with −0.006±0.05 mm in 27 control subjects (P =0.002). Age (P <0.001), Latino race (P =0.02), and nadir CD4 count ≤200 (P =0.082) were multivariable predictors of IMT progression. Conclusions—Carotid IMT is higher in HIV patients than in age-matched control subjects and progresses much more rapidly than previously reported rates in non-HIV cohorts. In HIV patients, carotid IMT is associated with classic coronary risk factors and with nadir CD4 count ≤200, suggesting that immunodeficiency and traditional coronary risk factors may contribute to atherosclerosis.

Relationship between T Cell Activation and CD4+ T Cell Count in HIV-Seropositive Individuals with Undetectable Plasma HIV RNA Levels in the Absence of Therapy

BACKGROUND Although untreated human immunodeficiency virus (HIV)-infected patients maintaining undetectable plasma HIV RNA levels (elite controllers) have high HIV-specific immune responses, it is unclear whether they experience abnormal levels of T cell activation, potentially contributing to immunodeficiency. METHODS We compared percentages of activated (CD38(+)HLA-DR(+)) T cells between 30 elite controllers, 47 HIV-uninfected individuals, 187 HIV-infected individuals with undetectable viremia receiving antiretroviral therapy (antiretroviral therapy suppressed), and 66 untreated HIV-infected individuals with detectable viremia. Because mucosal translocation of bacterial products may contribute to T cell activation in HIV infection, we also measured plasma lipopolysaccharide (LPS) levels. RESULTS Although the median CD4(+) cell count in controllers was 727 cells/mm(3), 3 (10%) had CD4(+) cell counts <350 cells/mm(3) and 2 (7%) had acquired immunodeficiency syndrome. Controllers had higher CD4(+) and CD8(+) cell activation levels (P < .001 for both) than HIV-negative subjects and higher CD8(+) cell activation levels than the antiretroviral therapy suppressed (P = .048). In controllers, higher CD4(+) and CD8(+) T cell activation was associated with lower CD4(+) cell counts (P = .009 and P = .047). Controllers had higher LPS levels than HIV-negative subjects (P < .001), and in controllers higher LPS level was associated with higher CD8(+) T cell activation (P = .039). CONCLUSION HIV controllers have abnormally high T cell activation levels, which may contribute to progressive CD4(+) T cell loss even without measurable viremia.

Management of Cocaine-Associated Chest Pain and Myocardial Infarction A Scientific Statement From the American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology

The goals of the present article are to provide a critical review of the literature on cocaine-associated chest pain and myocardial infarction (MI) and to give guidance for diagnostic and therapeutic interventions. Classification of recommendations and levels of evidence are expressed in the American College of Cardiology/American Heart Association (ACC/AHA) format as follows: The Writing Committee conducted a comprehensive search of the medical literature concerning cocaine-associated chest pain and MI. The literature search included English-language publications on humans and animals from 1960 to 2007. In addition to broad-based searching concerning cocaine, specific targeted searches were performed on cocaine and the following topics: MI, chest pain, emergency department (ED), aspirin, nitroglycerin, calcium channel blocker, benzodiazepine, thrombolytics, phentolamine, heparin, primary angioplasty, ECG, and stress testing. Literature citations were generally limited to published articles listed in Index Medicus. The article was reviewed by 4 outside reviewers nominated by the AHA. Cocaine is the second most commonly used illicit drug in the United States, with only marijuana …

Role of viral replication, antiretroviral therapy, and immunodeficiency in HIV-associated atherosclerosis

Objective:HIV-seropositive patients are at higher risk for atherosclerosis than HIV-seronegative persons. This has been variably attributed to antiretroviral drug toxicity, immunodeficiency, and/or HIV-associated inflammation. To evaluate the contributions of these factors to HIV-associated atherosclerosis, we assessed carotid artery intima-media thickness in a diverse cohort of HIV-seronegative and seropositive adults, including a unique group of HIV-infected patients who were untreated, had undetectable viral loads, and had preserved CD4+ T-cell counts (HIV controllers). Methods and results:Carotid intima-media thickness was measured in 494 participants, including 33 HIV controllers and 93 HIV-seronegative controls. HIV controllers had higher intima-media thickness than seronegative controls even after adjustment for traditional risk factors (P = 0.003). Intima-media thickness in controllers was similar to antiretroviral-untreated patients with detectable viremia. Across all participants, intima-media thickness was strongly associated with the presence of HIV disease rather than viral load or CD4+ T-cell count. C-reactive protein was higher in HIV controllers than HIV-seronegative persons. Antiretroviral drug exposure was also associated with higher intima-media thickness. Conclusions:Increased atherosclerosis with HIV infection can occur in the absence of antiretroviral therapy, detectable viremia, or overt immunodeficiency. Chronic inflammation – which is higher in controllers than in HIV-uninfected persons – may account for early atherosclerosis in these patients.

Increased carotid intima-media thickness in HIV patients is associated with increased cytomegalovirus-specific T-cell responses.

Objectives:HIV-infected subjects are at increased risk for myocardial infarction. The mechanism of this increased risk remains unclear. Since cytomegalovirus (CMV) infection has been associated with accelerated atherosclerosis in the transplant population and immune responses against CMV may be altered by HIV disease, we hypothesized that enhanced T-cell responses against CMV would be associated with increased atherosclerosis in subjects with HIV. Methods:We measured high-sensitivity C-reactive protein (hs-CRP), T-cell activation, CMV-specific T-cell responses, and carotid artery intima-media thickness (IMT) in 93 HIV-infected subjects and in 37 uninfected controls. Results:The mean age of the HIV-infected subjects was 48 years and 85 (91%) were male. The median carotid IMT was higher in the HIV-infected group compared to the uninfected group (0.95 mm versus 0.68 mm, P < 0.001). This difference remained significant after controlling for all traditional risk factors. Compared to HIV-negative controls, HIV-infected subjects had higher median levels of hs-CRP (P = 0.05), higher levels of CD4 and CD8 T-cell activation (P < 0.0001) and higher CMV-specific interferon-γ CD8 T-cell responses (P < 0.0001). CMV-specific T-cell responses, but not hs-CRP and T-cell activation, were independently associated with higher carotid IMT (P = 0.001). Conclusions:HIV-infected subjects had thicker carotid IMT compared to controls. While HIV patients also had higher T-cell activation, hs-CRP levels, and CMV-specific T-cell responses, only CMV-specific T-cell responses were independently associated with IMT. Accelerated atherosclerosis in HIV patients may be mediated by heightened CMV-induced immune responses.

Phenotypic, Functional, and Kinetic Parameters Associated with Apparent T-Cell Control of Human Immunodeficiency Virus Replication in Individuals with and without Antiretroviral Treatment

ABSTRACT The human immunodeficiency virus (HIV)-mediated immune response may be beneficial or harmful, depending on the balance between expansion of HIV-specific T cells and the level of generalized immune activation. The current study utilizes multicolor cytokine flow cytometry to study HIV-specific T cells and T-cell activation in 179 chronically infected individuals at various stages of HIV disease, including those with low-level viremia in the absence of therapy (“controllers”), low-level drug-resistant viremia in the presence of therapy (partial controllers on antiretroviral therapy [PCAT]), and high-level viremia (“noncontrollers”). Compared to noncontrollers, controllers exhibited higher frequencies of HIV-specific interleukin-2-positive gamma interferon-positive (IL-2+ IFN-γ+) CD4+ T cells. The presence of HIV-specific CD4+ IL-2+ T cells was associated with low levels of proliferating T cells within the less-differentiated T-cell subpopulations (defined by CD45RA, CCR7, CD27, and CD28). Despite prior history of progressive disease, PCAT patients exhibited many immunologic characteristics seen in controllers, including high frequencies of IL-2+ IFN-γ+ CD4+ T cells. Measures of immune activation were lower in all CD8+ T-cell subsets in controllers and PCAT compared to noncontrollers. Thus, control of HIV replication is associated with high levels of HIV-specific IL-2+ and IFN-γ+ CD4+ T cells and low levels of T-cell activation. This immunologic state is one where the host responds to HIV by expanding but not exhausting HIV-specific T cells while maintaining a relatively quiescent immune system. Despite a history of advanced HIV disease, a subset of individuals with multidrug-resistant HIV exhibit an immunologic profile comparable to that of controllers, suggesting that functional immunity can be reconstituted with partially suppressive highly active antiretroviral therapy.

HIV-Infected Individuals with Low CD4/CD8 Ratio despite Effective Antiretroviral Therapy Exhibit Altered T Cell Subsets, Heightened CD8+ T Cell Activation, and Increased Risk of Non-AIDS Morbidity and Mortality

A low CD4/CD8 ratio in elderly HIV-uninfected adults is associated with increased morbidity and mortality. A subset of HIV-infected adults receiving effective antiretroviral therapy (ART) fails to normalize this ratio, even after they achieve normal CD4+ T cell counts. The immunologic and clinical characteristics of this clinical phenotype remain undefined. Using data from four distinct clinical cohorts and three clinical trials, we show that a low CD4/CD8 ratio in HIV-infected adults during otherwise effective ART (after CD4 count recovery above 500 cells/mm3) is associated with a number of immunological abnormalities, including a skewed T cell phenotype from naïve toward terminally differentiated CD8+ T cells, higher levels of CD8+ T cell activation (HLADR+CD38+) and senescence (CD28− and CD57+CD28−), and higher kynurenine/tryptophan ratio. Changes in the peripheral CD4/CD8 ratio are also reflective of changes in gut mucosa, but not in lymph nodes. In a longitudinal study, individuals who initiated ART within six months of infection had greater CD4/CD8 ratio increase compared to later initiators (>2 years). After controlling for age, gender, ART duration, nadir and CD4 count, the CD4/CD8 ratio predicted increased risk of morbidity and mortality. Hence, a persistently low CD4/CD8 ratio during otherwise effective ART is associated with increased innate and adaptive immune activation, an immunosenescent phenotype, and higher risk of morbidity/mortality. This ratio may prove useful in monitoring response to ART and could identify a unique subset of individuals needed of novel therapeutic interventions.

State of the Science Conference Initiative to Decrease Cardiovascular Risk and Increase Quality of Care for Patients Living With HIV/AIDS: Executive Summary

With successful antiretroviral therapy, patients infected with the human immunodeficiency virus (HIV) are living longer; however, recent reports suggest increased rates of coronary heart disease (CHD) among HIV-infected patients,1 and cardiovascular disease has become an important cause of morbidity and mortality in this population.2 Increased CHD rates in the HIV population may relate to traditional risk factors, including advancing age, higher smoking rates, dyslipidemia, insulin resistance, and impaired glucose tolerance. Cardiovascular disease may also be due to nontraditional factors, including changes in body composition with loss of subcutaneous fat and/or accumulation of visceral fat in some patients, inflammation, and direct effects of the virus on the vasculature, as well as to direct effects of specific antiretroviral drugs. Important questions remain as to the pathogenesis, detection, and treatment of cardiovascular disease and related risk factors in HIV-infected patients. These questions concern, among other things, the design of adequate trials to determine CHD incidence and the utility of existing CHD guidelines for screening, prevention, treatment, and risk stratification. To ascertain the state of the science with respect to these and related questions, a multidisciplinary conference with interested HIV specialists, cardiologists, endocrinologists, primary care physicians, National Institutes of Health representatives, and patient advocates was convened June 28–30, 2007, in Chicago, Ill, and chaired by Drs Steven Grinspoon and Robert Eckel. The discussions focused on 6 areas of interest, each with its own working group, including the following: (1) the contribution of metabolic and anthropometric abnormalities to cardiovascular disease risk factors (chaired by Drs Carl Grunfeld and Donald Kotler); (2) the epidemiological evidence for cardiovascular disease and its relationship to highly active antiretroviral therapy (HAART; chaired by Drs Judy Currier and Jens Lundgren); (3) the effects of HIV infection and antiretroviral therapy on the heart and vasculature (chaired by Drs Michael Dube …

Clinical Features of Acute Coronary Syndromes in Patients With Human Immunodeficiency Virus Infection

Background—Patients with HIV infection exhibit increased rates of coronary events; however, the clinical features of acute coronary syndromes (ACS) in HIV-infected patients have not been well defined. Methods and Results—Between 1993 and 2003, 68 HIV-infected patients were hospitalized with ACS. We compared the clinical features and outcome of these patients with those of 68 randomly selected control patients with ACS without HIV. HIV patients were on average more than a decade younger than controls and more likely to be male and current smokers and to have low HDL cholesterol. They were less likely than controls to have diabetes or hyperlipidemia, and their TIMI (Thrombolysis In Myocardial Infarction) risk scores on admission were significantly lower. At coronary angiography, the number of vessels with >50% stenosis was 1.3±1.0 in HIV patients and 1.9±1.2 in controls (P =0.007). Restenosis developed in 15 of 29 HIV patients who underwent percutaneous coronary intervention compared with 3 of 21 controls (52% versus 14%, P =0.006). Conclusions—HIV patients with ACS are younger and more likely to be males and current smokers and to have low HDL cholesterol levels compared with other ACS patients. Their TIMI risk scores are lower, and they are more likely to have single-vessel disease; however, their restenosis rates after percutaneous coronary intervention are unexpectedly high.