Published online before print June 19, 2008, doi: 10.1161/CIRCULATIONAHA.107.189622
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2008;118:198-210.)
© 2008 American Heart Association, Inc.
AHA Conference Proceedings |
State of the Science Conference
Initiative to Decrease Cardiovascular Risk and Increase Quality of Care for Patients Living With HIV/AIDS: Executive Summary
Key Words: AHA Conference Proceedings • AIDS • HIV • cardiovascular diseases • myocardial infarction • antiretroviral therapy, highly active • protease inhibitors
 |
Introduction |
|---|
Top
Introduction
Contribution of Metabolic and...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 Dubé and Steve Lipshultz); (4) the screening and assessment of CHD in HIV-infected patients (chaired by Drs Priscilla Hsue and Kathleen Squires); (5) the development of appropriate CHD risk prediction models in HIV-infected patients (chaired by Drs Morris Schambelan, Kevin Yarasheski, and Peter Wilson); and (6) prevention strategies for CHD in HIV-infected patients (chaired by Drs James Stein and Colleen Hadigan).
For each area of interest, specific topics were covered in plenary lectures and in subsequent discussions with conference participants. Summaries for each working group were reported to the conference participants for discussion (individual working group summaries and a list of writing group members are available online with the present issue of Circulation). The proceedings were sponsored by an unrestricted educational grant from Bristol-Myers Squibb to the American Heart Association and by the American Academy of HIV Medicine. Per American Heart Association guidelines, the sponsor had no role in the planning of the meeting, choice of speakers, speaker content, or formulation of the scientific summary. In this executive summary, we summarize the major points of discussion and conclusions for each area of interest.
|
Contribution of Metabolic and Anthropometric Abnormalities to Cardiovascular Disease Risk Factors (Chairs: Carl Grunfeld, MD, PhD; Donald P. Kotler, MD) |
|---|
HIV-infected patients manifest a number of metabolic and anthropometric abnormalities, including dyslipidemia and insulin resistance, as well as subcutaneous fat loss and relative visceral fat gain, which may contribute to increased cardiovascular disease risk.3 The metabolic abnormalities may be due to HIV or its therapy and may be affected by environmental factors (eg, lifestyle, dietary intake, and weight changes associated with a restoration of health), as well as immunologic factors. In addition, the metabolic abnormalities may be interrelated (eg, dyslipidemia, insulin resistance, and central fat accumulation). The metabolic changes seen in HIV-infected patients are often heterogeneous and may relate to specific antiretroviral drugs within a class, as well as to the antiretroviral drug class, and they may differ by gender, race, ethnicity, and age. These changes may also present uniquely in HIV-infected children.
Lipid abnormalities occur early in HIV infection, with reduction in high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol and increases in triglycerides and very-low-density lipoprotein cholesterol. The net effect may be proatherogenic owing to the significant reduction in HDL cholesterol and increases in triglyceride levels, oxidized LDL, and small dense LDL. The mechanism of these changes is not completely understood, but increases in de novo lipogenesis and reduced very-low-density lipoprotein clearance have been reported4 and may be related to immunologic status and cytokine levels.5 The effects of these changes on plaque formation, macrophage recruitment, and foam cell formation have not been fully characterized. Although insulin resistance is associated with many of these processes, a reduction in insulin action was not uniformly seen among HIV-infected patients before the era of HAART and may be more prevalent with the increases in body mass index and fat distribution seen with restoration to health and improved virological suppression.
Before the widespread use of HAART, HIV infection was characterized by cachexia, increased resting energy expenditure, and sarcopenia.6 Early studies suggest some relative central adiposity even among patients with low body mass index.7 With the introduction of HAART, longitudinal studies of antiretroviral therapy initiation in antiretroviral therapy–naive patients found early increases in subcutaneous and visceral fat, with subsequent loss of subcutaneous fat and relative preservation of visceral fat with nucleoside reverse-transcriptase (NRTI) treatment.8 Cross-sectional studies are in agreement with regard to the near-universal occurrence of peripheral and subcutaneous fat loss, particularly with NRTI treatment9; however, changes in abdominal fat are more heterogeneous. HIV-infected patients with lipoatrophy may actually have less absolute visceral fat than non–HIV-infected patients but relatively more visceral fat for a given body mass index across a range of body mass indexes, because lipoatrophy reduces body mass index.10
Significant gender differences may also be apparent, with accumulation of more gluteofemoral fat in women, but it remains unknown whether this is protective among HIV-infected women.11 Among both women and men, accumulation of fat in the visceral and upper trunk depots is associated with hyperinsulinemia and dyslipidemia, including low HDL cholesterol and increased triglyceride levels, which suggests the potential utility of strategies to selectively reduce this fat compartment.12 In addition, visceral fat accumulation may be associated with increased inflammation, which may link this depot to insulin resistance. Relative preservation or accumulation of dorsocervical fat (eg, the buffalo hump) and fat in the breasts may also occur in association with insulin resistance. Studies to date have shown that loss of peripheral fat is not linked to accumulation of central fat.9 Morphological changes in different fat depots have not been well characterized in terms of adipocyte size and number.
Numerous effects of HAART, both class-specific and non–class-specific, have been reported with respect to lipids, glucose, and body composition. Among the protease inhibitors (PIs), ritonavir most significantly increases triglyceride.13 Increased triglyceride levels may also occur with stavudine and efavirenz. LDL cholesterol increases modestly with initiation of most forms of HAART; this increase is not due to direct effects of specific antiretroviral drugs, but whether it relates to immune effects or restoration of health remains unclear.14 Significant increases in LDL cholesterol among HIV-infected patients are more likely to be due to genetic and dietary causes. Although nonnucleoside reverse-transcriptase inhibitors (NNRTIs) increase HDL cholesterol, most other antiretroviral therapies do not, and low HDL cholesterol levels may contribute to CHD in HIV-infected patients.
Insulin resistance may be caused by specific drugs, including indinavir and other PIs,15,16 but is less likely to occur with newer PIs. Similarly, NRTIs, in particular stavudine, may result in insulin resistance directly through inhibition of mitochondrial function in the muscle17 or indirectly via effects to reduce peripheral fat.18 Insulin resistance is also associated with changes in body composition, including increased visceral and upper trunk fat.
Finally, changes in renal function due to HIV may contribute to increased cardiovascular disease. Microalbuminuria is 5 times more common among HIV-infected patients than among non–HIV-infected subjects in the current era of HAART and is associated with black race and other cardiovascular disease risk factors.19
Important questions and priorities for future research were identified, including the need for better identification of HIV-related direct and indirect (eg, medication, body composition) effects on metabolic parameters, assessment of HIV- or antiretrovirus-induced proatherosclerotic changes in lipoprotein structure, determination of the contribution of dyslipidemia and insulin resistance to the development of cardiovascular disease, identification of the mechanisms and consequences of body composition changes for the development of cardiovascular disease, and identification of individual drug versus class effects on metabolic abnormalities in HIV-infected patients.
|
Epidemiological Evidence for Cardiovascular Disease in HIV-Infected Patients and Relationship to HAART (Chairs: Judith S. Currier, MD; Jens D. Lundgren, MD, PhD) |
|---|
The epidemiological evidence for an association between HIV and cardiovascular disease comes from a number of sources, including retrospective cohort studies, administrative and clinical databases, prospective HIV cohort studies, and randomized clinical trials of antiretroviral therapy. Taken together, these data suggest an increased risk of cardiovascular disease in HIV-infected patients (see Circulation online for the summary of Working Group 2). However, these studies also suggest that overall morbidity and mortality dropped steeply with the introduction of HAART.20 Data from studies including non–HIV-infected control subjects, drawn largely from administrative data sets or retrospective cohort studies, suggest an approximate 1.5- to 2.0-fold increase in CHD in HIV-infected versus non–HIV-infected patients, with potentially larger differences seen among female HIV-infected patients relative to non–HIV-infected control subjects in gender-stratified analyses.21–23 The choice of an appropriate control group with similar demographic background to that of an HIV-infected group (eg, young, racially diverse, and with similar lifestyle habits), is difficult, however, and may limit comparisons in such studies.
Although relative CHD rates appear to be increased, absolute rates remain low, which perhaps reflects the age and demographics of the HIV-infected population and the relatively short duration of risk factor exposure. In addition to ascertainment of relative risk, the relationship of traditional and nontraditional risk factors to the development of CHD in the HIV population has been determined in a number of prospective cohort studies. CHD rates have been associated with HAART, specifically with PI use compared with NNRTI use (eg, 1.16 per year of PI use [95% CI 1.1 to 1.23] versus 1.05 per year of NNRTI use [95% CI 0.98 to 1.13] over 5 to 6 years of exposure).24 Furthermore, adjustment for dyslipidemia significantly (50%) attenuates this relationship, which suggests some role for dyslipidemia as a contributing factor to increased CHD rates.25
Importantly, smoking rates are higher in HIV-infected patients and also contribute significantly to increased risk.24,26 Other traditional risk factors such as male sex and age, as well as diabetes mellitus and dyslipidemia, also contribute to CHD to a degree similar to that seen in non–HIV-infected patients (see Circulation online for summary of Working Group 2); however, rates of dyslipidemia and diabetes appear to be higher among HIV-infected patients.23 Because HIV-infected patients live longer owing to the success of HAART, these factors may become even more important. Rates of nontraditional risk factors such as inflammation have not been well evaluated in terms of cardiovascular disease risk in the HIV-infected population.
Studies investigating the epidemiology of cardiovascular disease in HIV-infected patients must be careful to determine whether HIV infection is simply a marker for a population with increased rates of traditional risk factors. These studies must also determine whether HIV infection and antiretroviral therapy contribute independently to increased cardiovascular disease through effects on traditional or nontraditional risk factors. Importantly, randomized, controlled studies will be necessary to determine causality with respect to risk factors and HIV. For example, in a recent study, HIV-infected patients were randomized to continuous antiretroviral therapy for virological suppression or intermittent antiretroviral therapy on the basis of prespecified virological parameters.27 The study was stopped prematurely because of increased deaths, progression to AIDS, and a marginal but unexpected increase in cardiovascular events in the intermittent-dosing arm. These data raise the question of whether there may also be beneficial effects of continuous antiretroviral therapy on certain traditional and nontraditional cardiovascular risk factors, including lipid levels and inflammation, that contribute to increased cardiovascular disease rates. Randomized trials with cardiovascular disease end points may be difficult to achieve and will take many years to complete in HIV-infected patients. Therefore, only limited data from such studies in HIV-infected patients will be available to inform decision making on cardiovascular disease in the near term.
Important questions and priorities for future research were identified, including the clinical significance of relative increases in CHD rates given the low absolute rates, the importance of appropriate control groups for comparison with non–HIV-infected patients, the relative impact of traditional and nontraditional risk factors on increased CHD rates, determination of the role of individual drugs as distinct from antiretroviral drug class effects, the implications of the epidemiological data for those patients beginning antiretroviral therapy in developing countries, and the risk profiles of new drugs being developed for the treatment of HIV disease. Determination of the true risk of CHD and its causes will become increasingly important in the long-term management of HIV-infected patients receiving antiretroviral therapy.
|
Effects of HIV Infection and Antiretroviral Therapy on the Heart and Vasculature (Chairs: Michael P. Dubé, MD; Steven E. Lipshultz, MD) |
|---|
Infection with HIV and its treatment with antiretroviral therapy may significantly affect the heart and vasculature. A number of potential mechanisms may contribute to these effects. HIV may exert direct effects on the myocardium and vascular endothelium, although data on direct cellular infection are limited.28 Macrophages and other reservoir cells infected with HIV may affect vascular and myocardial function through paracrine and systemic release of inflammatory cytokines. In addition, alterations in lipid metabolism can affect plaque formation. Associated metabolic changes (see Circulation online for the summary of Working Group 1), including insulin resistance and fat redistribution, may also affect endothelial and myocardial function.
Clinically, left ventricular dysfunction is common in HIV-infected patients and may go unrecognized or masked by concurrent illness and misdiagnosed as pulmonary or infectious in origin. Diagnosis is best performed by echocardiography, because ECG abnormalities may be seen in almost 60% of asymptomatic HIV-infected patients.29 In patients undergoing ventricular biopsy for cardiomyopathy, myocarditis was seen in more than half of those studied in 1 series in the pre-HAART era.30 HIV-related cardiomyopathy may carry a worse prognosis than other types of nonischemic cardiomyopathy. Nutritional deficiencies should also be considered.
Among children vertically infected with HIV, inadequate or reduced left ventricular wall thickness is a useful independent predictor of morbidity and increased risk of death within 24 months.31 Even small decreases in fractional shortening can be associated with marked increases in 5-year mortality rates,32 which may be associated with a low CD4 count and low weight, among other factors. However, causality is difficult to determine. Among children followed up in the Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection (P2C2) longitudinal study of HIV-infected children, for example, cardiac mortality was high at 35%.33 Studies suggest that immunomodulatory therapy with immunoglobulin may improve left ventricular function in this population.34 Evidence for the effects of HIV on the heart and vasculature has come most often from studies performed before the current era of HAART, in which viremia was less adequately suppressed. The effects of HIV on the heart and vasculature in the current context of successful HAART have not been fully determined.
Endothelial dysfunction is present in antiretroviral therapy–naive HIV-infected patients but improves only somewhat with introduction of antiretroviral therapy. This may be because of the negative effects of specific individual antiretroviral drugs, viral protein–mediated endothelial activation,35 or chemokine dysregulation, with activation of macrophages, smooth muscle cells, and enhanced atheroma formation. Data on direct infection of the vasculature are limited.36
Pulmonary hypertension is seen in 1 of 200 HIV-infected adults, with similar pathophysiology to that seen in non–HIV-infected patients.37 Pulmonary hypertension carries a poor prognosis among HIV-infected adults.38 In addition to ischemic cardiovascular disease, autonomic dysfunction and vasculitis are common among HIV-infected patients. The incidence of pericardial effusion has been reported to be up to 11% per year in HIV-infected adults.39
An increasing body of evidence suggests adverse effects of specific antiretroviral agents on the heart and vasculature, but these effects may not be class-specific. Toxicities may vary among drugs in a similar class and with respect both to cause and to whether exposure occurs in utero, in childhood, or during adult life. For example, zidovudine and stavudine may contribute to adverse effects on the myocardium through effects on myocardial function and depletion of mitochondrial DNA.40
Other potential mechanisms include disruption of normal glucose uptake into the myocardial cells with the use of specific PIs, including indinavir. Exposure to HAART in utero is associated with reductions in left ventricular wall mass and septal wall thickness in the first year after birth,41 and these effects may resemble anthracycline cardiotoxicity. However, the overwhelming benefits of preventing mother-to-child transmission outweigh the potential negative long-term effects on cardiac function. Long-term follow-up of these children is important.
In general, antiretroviral therapy improves endothelial function in HIV-infected patients, although data suggest that use of older PI regimens containing indinavir but not other PIs may worsen endothelial function. The potential mechanisms by which specific PI-based regimens can adversely affect endothelial function include reduction in nitric oxide production or release,42 increases in reactive oxygen species,43,44 impairment of cholesterol efflux from foam cells, and increased macrophage cholesterol ester accumulation through upregulation of the CD36 scavenger receptor.45,46 Specific NRTIs, including stavudine and zidovudine, may also increase superoxide production in experimental models.47
Significant progress has been made in determining the mechanism and prevalence of HIV and antiretrovirus-related myocardial and vascular dysfunction, but important questions and priorities for future research were identified. These included the need to establish the specific effects of individual antiretroviral agents and identify the direct effects of HIV, as well as related indirect effects, establish biomarkers for vascular and myocardial dysfunction, and develop effective treatment strategies for these cardiovascular complications.
|
Screening and Assessment of CHD in HIV-Infected Patients (Chairs: Priscilla Y. Hsue, MD; Kathleen Squires, MD) |
|---|
With an increase in CHD rates and aging of the HIV-infected population, screening for CHD assumes increasing importance. Insufficient data currently exist to recommend a screening strategy different from that for non–HIV-infected patients. However, specific cardiovascular risk factors that result from the complex metabolic effects of HIV infection and its therapy (eg, dyslipidemia, insulin resistance, and fat redistribution) suggest a number of useful approaches to screen for cardiovascular disease in HIV-infected patients.48 As for the non–HIV-infected population, it is important to establish the pretest likelihood for CHD and then formulate a screening strategy to detect established disease based on the pretest likelihood of risk.
A number of tools exist to calculate the pretest probability of CHD, but these have not been fully validated in HIV-infected patients. The Framingham risk equation incorporates age, sex, blood pressure, total cholesterol, HDL cholesterol, diabetes mellitus, and smoking to calculate a 10-year CHD risk. This equation has been investigated in the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study and has been shown to perform reasonably well, although it somewhat underestimates CHD risk, particularly in smokers.49 Further validation is required, and development of optimal risk stratification models, perhaps including antiretroviral use and other specific HIV factors, is important (see also Circulation online for the summary of Working Group 5 on the development of cardiac risk prediction models in HIV-infected patients). Low, intermediate, and high risk are defined on the basis of 10-year risk of CHD <10%, 10% to 20%, and >20%, respectively.50,51 According to the US Preventive Services Task Force,52 patients with a low pretest probability and a low global CHD risk score (eg, <10%) should not be referred for further testing, whereas those with a high pretest probability (>20%) have a high false-positive rate on noninvasive tests, such as exercise ECG, and should be considered for invasive arteriography. Patients at intermediate risk are most suitable for noninvasive testing. These conclusions, however, are not derived from specific data on HIV-infected patients, in whom further research is needed. Furthermore, screening recommendations may be individualized to account for severity of individual risk factors, such as a significant family history of early cardiac disease.
The use of graded levels of stress is most commonly employed to detect myocardial ischemia. Stress may be physiological (eg, exercise) or pharmacological (eg, dipyridamole) and may be assessed with ECG, echocardiography, or nuclear imaging. The treadmill ECG has a sensitivity of 68% and specificity of 77% for detecting angiographically significant CHD, but these data have not been determined specifically for HIV-infected patients. In general, women have a higher false-positive rate of ST depression on exercise ECG, which makes it more difficult to formulate screening recommendations. It remains unknown whether higher false-positive rates are seen with ECG screening among HIV-infected women.
Newer inflammatory biomarkers, such as high-sensitivity C-reactive protein and adiponectin, may prove useful for identifying HIV-infected patients at risk for CHD; however, the specificity of such markers for the detection of CHD remains unclear in HIV-infected patients. Although the Centers for Disease Control and Prevention/American Heart Association guidelines recommend measuring high-sensitivity C-reactive protein in non–HIV-infected patients at intermediate risk for cardiovascular disease,53 this strategy requires validation in HIV-infected patients, in whom high-sensitivity C-reactive protein levels are increased and have been shown to predict mortality in at least 1 cohort.54 Adiponectin levels are decreased with increasing abdominal adiposity and lipoatrophy among HIV-infected patients and are increased with use of PIs among HIV-infected patients.55 Long-term data on the clinical significance of reduced adiponectin in HIV-infected patients with fat redistribution are not available. In addition, apolipoprotein B100 may prove useful as a biomarker for CHD, especially in patients in whom LDL cholesterol levels are normal and triglyceride levels increased.56
Surrogate markers for CHD, including carotid intimal-medial thickness and computed tomographic angiography, have been investigated but not validated as independent predictors of CHD outcomes in HIV-infected patients. Among HIV-infected patients, some studies have reported increased carotid intimal-medial thickness in association with traditional risk factors and PI use. In a longitudinal study, traditional risk factors were also associated with more rapid progression of carotid intimal-medial thickness in HIV-infected versus non–HIV-infected subjects.57 Similarly, coronary artery calcium scores have been reported in several studies of HIV-infected patients and have been associated with the presence of traditional risk factors58 and PI use59 in some studies. A limitation in this regard is that the coronary artery calcium score may not detect early plaque lesions, especially in young adults, women, and ethnic minorities. In contrast, endothelial dysfunction, as assessed by flow-mediated dilation or other techniques, may be an early manifestation of atherosclerosis. Studies have demonstrated endothelial dysfunction in association with the PI indinavir,60 but this effect may not occur with other PIs. The long-term clinical significance of these effects on endothelial function is not known.
Important questions and priorities for future research were identified, including the need to determine the optimal screening strategy and risk stratification algorithm, define the sensitivity and specificity of diagnostic tests for CHD, and determine the clinical utility of inflammatory and surrogate markers of CHD in HIV-infected patients.
|
Development of Appropriate CHD Risk Prediction Models in HIV-Infected Patients (Chairs: Morris Schambelan, MD; Peter W.F. Wilson, MD; Kevin E. Yarasheski, PhD) |
|---|
Validation of CHD risk prediction models is important for the development of prevention strategies in HIV-infected patients (see also Circulation online for the summary of Working Group 6 on prevention strategies for CHD in HIV-infected patients). An important question in the development of risk prediction models is whether existing risk stratification equations, such as the Framingham equation, are valid in HIV-infected patients and whether HIV-specific equations need to be developed. In this regard, it is important to determine whether traditional risk factors captured in existing equations relate similarly to risk among HIV-infected patients and whether HIV-specific variables, such as antiretroviral use and duration of HIV, should be included to improve the accuracy of risk stratification models.
Current risk stratification equations were generally developed on the basis of long-term (>10 years) prospective observations of homogeneous populations of middle-aged patients with chronic exposure to risk. In contrast, HIV-infected patients are diverse in terms of both demographics (eg, younger and more racially diverse) and intensity and duration of risk exposures. In addition, existing equations do not take into account important factors relating to substance abuse, immune function, lifestyle choices, and the unique risks of specific antiretroviral drugs. An important related question is the degree to which CHD risk is increased with newer antiretroviral agents.
Although estimates of risk are generally similar in HIV-infected and non–HIV-infected patients,24,61 potential differences with respect to both traditional and nontraditional risk factors suggest the need to determine the value of HIV-specific equations. Indeed, preliminary data using existing models may overpredict49 or underpredict62 cardiovascular risk depending on whether the end point is myocardial infarction or a broader composite end point and whether patients are smokers or nonsmokers. New models will need to account for the dynamic and changing nature of antiretroviral therapy and will likely need to be developed and validated separately for diverse geographic regions and for subpopulations such as adolescents. Longitudinal studies of sufficient duration that capture critical end points (eg, myocardial infarction versus composite end points that include stroke or cardiac procedure) and risk factors are necessary to develop accurate CHD risk stratification models for HIV-infected patients.
Several key indices are utilized in the development of CHD-prediction models. It is important to know the relative risk associated with a given risk factor and to determine discrimination, the probability that a model assigns a higher risk to those who develop the factor (eg, diabetes mellitus) than those who do not. Calibration of a model determines how closely the predicted outcomes agree with actual outcome. Risk-stratification models can be recalibrated if relative risk is ranked appropriately but is consistently overestimated or underestimated.
HIV-specific models for CHD risk prediction have been proposed. For example, the DAD study assessed a model that incorporated PI exposure along with traditional risk factors to predict myocardial infarction. The HIV-specific equation predicted 153 events over 33 594 person-years compared with 157 actual events and 183 events predicted by the Framingham study.49 The receiver operating characteristic discrimination statistic was good at 0.78. However, the Framingham risk prediction equation has yet to be validated among a general population of patients living with HIV. Other risk prediction models such as PROCAM (Prospective Cardiovascular Munster Study) have not been tested in HIV-infected patients. Moreover, it is not known whether surrogate end points, such as carotid intimal-medial thickness, will perform as well as or better than clinical end points in these models. It is important to recognize that equations such as the Framingham equation were developed for risk stratification and that individual patients may have a myocardial infarction even if characterized as being at low risk. Prevention may be undertaken in patients at lower risk, but strategies for such patients must balance risk and benefit.
Important questions and priorities for future research were identified, including the design of appropriate prospective studies, choice of end points and risk factors resulting in optimal sensitivity and specificity, and rigorous validation of newly derived models. In this regard, a multicenter, multinational prospective study will be necessary to develop an accurate risk prediction model for use in HIV-infected patients, but this will take many years and require careful planning for the capture of relevant risk factors and end points. In the interim, the use of preliminary HIV-specific and existing non–HIV-specific equations, such as Framingham, may help clinicians identify patients who are most appropriate for risk factor reduction. Finally, it will be useful to recalibrate existing models that appear to predict events reasonably well but systematically overestimate or underestimate risk.
|
Prevention Strategies for Cardiovascular Disease in HIV-Infected Patients (Chairs: James H. Stein, MD; Colleen M. Hadigan, MD, MPH) |
|---|
As with non–HIV-infected patients, an important principle for HIV-infected patients is that risk-reducing interventions should be based on the level of CHD risk and whether the presence of cardiovascular disease has been established. In this regard, the focus of the Chicago conference was on the prevention of cardiovascular disease among patients without established disease and strategies to reduce modifiable risks in this large population of HIV-infected patients. Unique considerations among the HIV-infected patients include other comorbid conditions and potential drug interactions with antiretroviral medications. Cigarette smoking is highly prevalent in patients with HIV, with estimates of >50% prevalence in some studies,26 and smoking is a significant risk factor for CHD in HIV-infected patients. Smoking prevention and cessation strategies are important but have not been fully evaluated or implemented among HIV-infected patients. Evaluation of efficacy and the potential for drug interactions with smoking cessation pharmacotherapies is also critical.
Traditional risk factors for cardiovascular disease, including diabetes mellitus and dyslipidemia, are more prevalent among HIV-infected patients than among the general population.23 Evidence to date also shows a modest increase in the prevalence of hypertension, and this risk may further increase with aging of the HIV-infected population. Preliminary studies suggest a relatively modest relationship of hypertension to CHD among patients with HIV compared with non–HIV-infected patients61 and a beneficial effect of lifestyle intervention on blood pressure in this population.63 Until further data are available on the mechanisms of hypertension and the potential for drug interaction with antiretroviral agents, existing guidelines for the prevention and treatment of hypertension in non–HIV-infected patients should be used.
Dyslipidemia, with decreased total and HDL cholesterol and increased triglyceride, is seen in untreated HIV infection. Additional atherogenic changes, including increases in total and small dense LDL, triglycerides, and apolipoprotein B100, occur in patients receiving antiretroviral therapy, but these effects vary by drug within class and between classes.60 Furthermore, these effects can be influenced by concomitant insulin resistance, changes in fat distribution (including subcutaneous fat loss and accumulation of visceral or upper trunk fat12), and increased saturated fat intake among HIV-infected patients.64
Few data are available on the effects of lipid-lowering therapy for primary or secondary prevention of CHD outcomes, although small studies have shown improvement in lipid levels and endothelial function in HIV-infected patients.65 In addition, strategies to improve visceral adiposity may improve dyslipidemia,66 although lifestyle modification programs have had only limited effects on serum lipids in HIV-infected patients.63 Specific guidelines for the approach to lipid management in HIV-infected patients have been published that outline the potential interactions with antiretroviral therapy and unique considerations for therapy in this population.67 These guidelines focus on the importance of reducing LDL and non-HDL cholesterol levels given the proven cardiovascular disease risk reduction that is observed when these lipid markers are reduced in patients without HIV.67
Diabetes mellitus occurs in 6% to 18% of patients with HIV68 and may be related to antiretroviral therapy, HIV infection, or changes in body composition. Furthermore, insulin resistance and impaired glucose tolerance are seen in almost 50% of HIV-infected patients with body composition changes69 and are also associated with antiretroviral exposure. No data are available as to the optimal regimens for the treatment of diabetes mellitus in HIV-infected patients, nor is it known whether the use of lifestyle modification or insulin-sensitizing agents prevents the development of diabetes mellitus in HIV-infected patients with impaired glucose tolerance. The clinical significance of impaired glucose tolerance remains unknown in this population, but preliminary studies of lifestyle modification in HIV-infected patients modeled after the Diabetes Prevention Program do suggest reductions in hemoglobin A1c over 6 months.63 Insulin-sensitizing agents may be useful to reduce insulin resistance and may also help to reduce central fat accumulation70 or induce small increases in subcutaneous fat in some lipoatrophic insulin-resistant patients,71 but they should not be used for the sole purpose of improving body composition. Moreover, the risk profile of these drugs may be great, with the potential for interaction with antiretroviral therapy. Measurement of fasting glucose and lipids at least yearly in HIV-infected patients and with changes in antiretroviral therapy is critical.
Antiretroviral therapy, particularly the use of PIs, may be associated with CHD, as suggested by the DAD study,24 but limited data on the effects of specific agents are available. However, continuous use of antiretroviral therapy for viral suppression is associated with reduced mortality and less cardiovascular disease than intermittent antiretroviral therapy, which suggests that these agents may also be protective by unknown mechanisms potentially related to reduced inflammation or effects on lipids if used continuously.27 Nonetheless, it is important to consider the known metabolic effects of individual drugs in choosing an antiretroviral regimen, particularly in those patients with preexisting CHD risk factors.
Important questions and priorities for future research were identified, including the reasons for increased smoking rates and the optimal prevention and cessation strategies for smoking, determination of the clinical significance of impaired glucose tolerance and dyslipidemia on CHD outcomes, the optimal treatment strategies and targets for management of dyslipidemia, the role of lifestyle intervention for metabolic abnormalities, and the optimal choice, sequencing, and duration of antiretroviral therapy with respect to primary and secondary prevention of CHD in HIV-infected patients.
|
Conclusions |
|---|
HIV-infected patients are living longer owing to the success of antiretroviral therapy, but a number of recent studies suggest increased cardiovascular disease in this population, and cardiovascular disease now ranks as a major cause of death in this population. Dyslipidemia, insulin resistance, inflammation, and changes in body composition are all likely to contribute to this, and these abnormalities may be interrelated and due to HIV infection, related inflammation, or toxicities associated with specific antiretroviral agents. Development of optimized screening, prediction, and treatment algorithms for cardiovascular disease in HIV-infected patients is of utmost importance. A critical need exists for more research in this area.
|
Acknowledgments |
|---|
Sources of Funding
This work was sponsored by the American Heart Association and the American Academy of HIV Medicine and funded in part by an unrestricted educational grant from Bristol-Myers Squibb to the American Heart Association. The funding sources had no role in the choice of methods, the contents or form of this work, or the decision to submit the results for publication.
Disclosures
|
|
|
|
|
|
Footnotes |
|---|
The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.
The opinions expressed in this manuscript are those of the authors and should not be construed as necessarily representing an official position of the US Department of Health and Human Services, the Centers for Disease Control and Prevention, the Agency for Healthcare Research and Quality, or the US government. These opinions are not necessarily those of the editor or the American Heart Association.
Writing group reports are available online at http://circ.ahajournals.org (Circulation. 2008;118:e20–e28; e29–e35; e36–e40; e41–e47; e48–e53; and e54–e60).
These proceedings were approved by the American Heart Association Science Advisory and Coordinating Committee on February 29, 2008. A copy of these proceedings is available at http://www.americanheart.org/presenter.jhtml?identifier=3003999 by selecting either the "topic list" link or the "chronological list" link (No. 71-0449). To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@wolterskluwer.com.
This article has been copublished in the Journal of Acquired Immune Deficiency Syndromes.
Expert peer review of AHA Scientific Statements is conducted at the AHA National Center. For more on AHA statements and guidelines development, visit http://www.americanheart.org/presenter.jhtml?identifier=3023366.
Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.americanheart.org/presenter.jhtml? identifier=4431. A link to the "Permission Request Form" appears on the right side of the page.
|
References |
|---|
1. Friis-Møller N, Sabin CA, Weber R, d’Arminio Monforte A, El-Sadr WM, Reiss P, Thiébaut R, Morfeldt L, De Wit S, Pradier C, Calvo G, Law MG, Kirk O, Phillips AN, Lundgren JD; Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group. Combination antiretroviral therapy and the risk of myocardial infarction [published correction appears in N Engl J Med. 2004;350:955]. N Engl J Med. 2003; 349: 1993–2003.
2. Lohse N, Hansen AB, Pedersen G, Kronborg G, Gerstoft J, Sørensen HT, Vaeth M, Obel N. Survival of persons with and without HIV infection in Denmark, 1995–2005. Ann Intern Med. 2007; 146: 87–95.
3. Grinspoon S, Carr A. Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med. 2005; 352: 48–62.
4. Hellerstein MK, Grunfeld C, Wu K, Christiansen M, Kaempfer S, Kletke C, Shackleton CH. Increased de novo hepatic lipogenesis in human immunodeficiency virus infection. J Clin Endocrinol Metab. 1993; 76: 559–565.[Abstract]
5. Grunfeld C, Kotler DP, Shigenaga JK, Doerrler W, Tierney A, Wang J, Pierson RN Jr, Feingold KR. Circulating interferon-alpha levels and hypertriglyceridemia in the acquired immunodeficiency syndrome. Am J Med. 1991; 90: 154–162.[Medline] [Order article via Infotrieve]
6. Grunfeld C, Pang M, Shimizu L, Shigenaga JK, Jensen P, Feingold KR. Resting energy expenditure, caloric intake, and short-term weight change in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. Am J Clin Nutr. 1992; 55: 455–460.
7. Kotler DP, Rosenbaum K, Wang J, Pierson RN. Studies of body composition and fat distribution in HIV-infected and control subjects. J Acquir Immune Defic Syndr Hum Retrovirol. 1999; 20: 228–237.[Medline] [Order article via Infotrieve]
8. Dubé MP, Parker RA, Tebas P, Grinspoon SK, Zackin RA, Robbins GK, Roubenoff R, Shafer RW, Wininger DA, Meyer WA III, Snyder SW, Mulligan K. Glucose metabolism, lipid, and body fat changes in antiretroviral-naive subjects randomized to nelfinavir or efavirenz plus dual nucleosides. AIDS. 2005; 19: 1807–1818.[Medline] [Order article via Infotrieve]
9. Bacchetti P, Gripshover B, Grunfeld C, Heymsfield S, McCreath H, Osmond D, Saag M, Scherzer R, Shlipak M, Tien P; Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). Fat distribution in men with HIV infection. J Acquir Immune Defic Syndr. 2005; 40: 121–131.[CrossRef][Medline] [Order article via Infotrieve]
10. Joy T, Keogh HM, Hadigan C, et al. Relationship of body composition to BMI in HIV-infected patients with metabolic abnormalities. J Acquir Immune Defic Syndr. 2008; 42: 174–184.
11. Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). Fat distribution in women with HIV infection. J Acquir Immune Defic Syndr. 2006; 42: 562–571.[CrossRef][Medline] [Order article via Infotrieve]
12. Grunfeld C, Rimland D, Gibert CL, Powderly WG, Sidney S, Shlipak MG, Bacchetti P, Scherzer R, Haffner S, Heymsfield SB. Association of upper trunk and visceral adipose tissue with insulin resistance in control and HIV-infected subjects in the FRAM study. J Acquir Immun Def Syndr. 2007; 46: 283–290.
13. Purnell JQ, Zambon A, Knopp RH, Pizzuti DJ, Achari R, Leonard JM, Locke C, Brunzell JD. Effect of ritonavir on lipids and post-heparin lipase activities in normal subjects. AIDS. 2000; 14: 51–57.[CrossRef][Medline] [Order article via Infotrieve]
14. Riddler SA, Smit E, Cole SR, Li R, Chmiel JS, Dobs A, Palella F, Visscher B, Evans R, Kingsley LA. Impact of HIV infection and HAART on serum lipids in men. JAMA. 2003; 289: 2978–2982.
15. Murata H, Hruz PW, Mueckler M. The mechanism of insulin resistance caused by HIV protease inhibitor therapy. J Biol Chem. 2000; 275: 20251–20254.
16. Noor MA, Lo JC, Mulligan K, Schwarz JM, Halvorsen RA, Schambelan M, Grunfeld C. Metabolic effects of indinavir in healthy HIV-seronegative men. AIDS. 2001; 15: F11–F18.[CrossRef][Medline] [Order article via Infotrieve]
17. Fleischman A, Johnsen S, Systrom DM, Hrovat M, Farrar CT, Frontera W, Fitch K, Thomas BJ, Torriani M, Cote HC, Grinspoon SK. Effects of a nucleoside reverse transcriptase inhibitor, stavudine, on glucose disposal and mitochondrial function in muscle of healthy adults. Am J Physiol Endocrinol Metab. 2007; 292: E1666–E1673
18. van der Valk M, Casula M, Weverlingz GJ, van Kuijk K, van Eck-Smit B, Hulsebosch HJ, Nieuwkerk P, van Eeden A, Brinkman K, Lange J, de Ronde A, Reiss P. Prevalence of lipoatrophy and mitochondrial DNA content of blood and subcutaneous fat in HIV-1-infected patients randomly allocated to zidovudine- or stavudine-based therapy. Antivir Ther. 2004; 9: 385–393.[Medline] [Order article via Infotrieve]
19. Szczech LA, Grunfeld C, Scherzer R, Canchola JA, van der Horst C, Sidney S, Wohl D, Shlipak MG. Microalbuminuria in HIV infection. AIDS. 2007; 21: 1003–1009.[Medline] [Order article via Infotrieve]
20. Bozzette SA, Ake C, Carpenter A, Bommakanty U, Leung V, Tam H, Smith R, Schepps A, Louis T. Cardio- and cerebrovascular outcomes with changing process of anti-HIV therapy in 36,766 US veterans. Presented at: 9th Conference on Retroviruses and Opportunistic Infections; February 24–28, 2002; Seattle, Wash. Abstract No. LB9.
21. Currier JS, Taylor A, Boyd F, Dezii CM, Kawabata H, Burtcel B, Maa JF, Hodder S. Coronary heart disease in HIV-infected individuals. J Acquir Immune Defic Syndr. 2003; 33: 506–512.[Medline] [Order article via Infotrieve]
22. Klein D, Hurley L, Silverberg M, Horberg M, Quesenbery C, Sidney S. Surveillance data for myocardial infarction hospitalizations among HIV+ and HIV– Northern Californians:1994–2006. Presented at: 14th Conference on Retroviruses and Opportunistic Infections; February 25–28, 2007; Los Angeles, Calif. Paper No. 807.
23. Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab. 2007; 92: 2506–2512.
24. DAD Study Group, Friis-Møller N, Reiss P, Sabin CA, Weber R, Monforte A, El-Sadr W, Thiébaut R, De Wit S, Kirk O, Fontas E, Law MG, Phillips A, Lundgren JD. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med. 2007; 356: 1723–1735.
25. El-Sadr W, Reiss P, De Wit S, Monforte AD, Thiébaut R, Morfeldt L, Weber R, Pradier C, Calvo G, Law M, Kirk O, Sabin C, Friis-Møller N, Lundgren J; on behalf of the DAD Study Group. Relationship between prolonged exposure to combination ART and myocardial infarction: effect of sex, age, and lipid changes. Presented at: 12th Conference on Retroviruses and Opportunistic Infections; February 22–25, 2005; Boston, Mass. Page 80. Paper No. 42.
26. Savès M, Chêne G, Ducimetière P, Leport C, Le Moal G, Amouyel P, Arveiler D, Ruidavets JB, Reynes J, Bingham A, Raffi F; French WHO MONICA Project and the APROCO (ANRS EP11) Study Group. Risk factors for coronary heart disease in patients treated for human immunodeficiency virus infection compared with the general population. Clin Infect Dis. 2003; 37: 292–298.[CrossRef][Medline] [Order article via Infotrieve]
27. Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr WM, Lundgren JD, Neaton JD, Gordin F, Abrams D, Arduino RC, Babiker A, Burman W, Clumeck N, Cohen CJ, Cohn D, Cooper D, Darbyshire J, Emery S, Fätkenheuer G, Gazzard B, Grund B, Hoy J, Klingman K, Losso M, Markowitz N, Neuhaus J, Phillips A, Rappoport C. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006; 355: 2283–2296.
28. Lewis W. Cardiomyopathy in AIDS: a pathophysiological perspective. Prog Cardiovasc Dis. 2000; 43: 151–170.[CrossRef][Medline] [Order article via Infotrieve]
29. Barbaro G, Di Lorenzo G, Grisorio B, Barbarini G; Gruppo Italiano per lo Studio Cardiologico dei pazienti affetti da AIDS Investigators. Cardiac involvement in the acquired immunodeficiency syndrome: a multicenter clinical-pathological study. AIDS Res Hum Retroviruses. 1998; 14: 1071–1077.[Medline] [Order article via Infotrieve]
30. Herskowitz A, Wu TC, Willoughby SB, Vlahov D, Ansari AA, Beschorner WE, Baughman KL. Myocarditis and cardiotropic viral infection associated with severe left ventricular dysfunction in late-stage infection with human immunodeficiency virus. J Am Coll Cardiol. 1994; 24: 1025–1032.[Abstract]
31. Lipshultz SE, Easley KA, Orav EJ, Kaplan S, Starc TJ, Bricker JT, Lai WW, Moodie DS, Sopko G, Colan SD; Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection (P2C2 HIV) Study Group. Cardiac dysfunction and mortality in HIV-infected children: the Prospective P2C2 HIV Multicenter Study. Circulation. 2000; 102: 1542–1548.
32. Fisher SD, Easley KA, Orav EJ, Colan SD, Kaplan S, Starc TJ, Bricker JT, Lai WW, Moodie DS, Sopko G, Lipshultz SE; Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection (P2C2 HIV) Study Group. Mild dilated cardiomyopathy and increased left ventricular mass predict mortality: the prospective P2C2 HIV Multicenter Study. Am Heart J. 2005; 150: 439–447.[CrossRef][Medline] [Order article via Infotrieve]
33. Al-Attar I, Orav EJ, Exil V, Vlach SA, Lipshultz SE. Predictors of cardiac morbidity and related mortality in children with acquired immunodeficiency syndrome. J Am Coll Cardiol. 2003; 41: 1598–1605.
34. Lipshultz SE, Orav EJ, Sanders SP, Colan SD. Immunoglobulins and left ventricular structure and function in pediatric HIV infection. Circulation. 1995; 92: 2220–2225.
35. Ren Z, Yao Q, Chen C. HIV-1 envelope glycoprotein 120 increases intercellular adhesion molecule-1 expression by human endothelial cells. Lab Invest. 2002; 82: 245–255.[Medline] [Order article via Infotrieve]
36. Conaldi PG, Serra C, Dolei A, Basolo F, Falcone V, Mariani G, Speziale P, Toniolo A. Productive HIV-1 infection of human vascular endothelial cells requires cell proliferation and is stimulated by combined treatment with interleukin-1 beta plus tumor necrosis factor-alpha. J Med Virol. 1995; 47: 355–363.[Medline] [Order article via Infotrieve]
37. Seoane L, Shellito J, Welsh D, de Boisblanc BP. Pulmonary hypertension associated with HIV infection. South Med J. 2001; 94: 635–639.[Medline] [Order article via Infotrieve]
38. Nunes H, Humbert M, Sitbon O, Morse JH, Deng Z, Knowles JA, Le Gall C, Parent F, Garcia G, Hervé P, Barst RJ, Simonneau G. Prognostic factors for survival in human immunodeficiency virus-associated pulmonary arterial hypertension. Am J Respir Crit Care Med. 2003; 167: 1433–1439.
39. Harmon WG, Dadlani GH, Fisher SD, Lipshultz SE. Myocardial and pericardial disease in HIV. Curr Treat Options Cardiovasc Med. 2002; 4: 497–509.[Medline] [Order article via Infotrieve]
40. Lewis W, Kohler JJ, Hosseini SH, Haase CP, Copeland WC, Bienstock RJ, Ludaway T, McNaught J, Russ R, Stuart T, Santoianni R. Antiretroviral nucleosides, deoxynucleotide carrier and mitochondrial DNA: evidence supporting the DNA pol gamma hypothesis. AIDS. 2006; 20: 675–684.[Medline] [Order article via Infotrieve]
41. Miller TL, Easley KA, Zhang W, Orav EJ, Bier DM, Luder E, Ting A, Shearer WT, Vargas JH, Lipshultz SE; Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection (P2C2 HIV) Study Group. Maternal and infant factors associated with failure to thrive in children with vertically transmitted human immunodeficiency virus-1 infection: the prospective, P2C2 human immunodeficiency virus multicenter study. Pediatrics. 2001; 108: 1287–1296.
42. Shankar SS, Dubé MP, Gorski JC, Klaunig JE, Steinberg HO. Indinavir impairs endothelial function in healthy HIV-negative men. Am Heart J. 2005; 150: 933.[Medline] [Order article via Infotrieve]
43. Fu W, Chai H, Yao Q, Chen C. Effects of HIV protease inhibitor ritonavir on vasomotor function and endothelial nitric oxide synthase expression. J Acquir Immune Defic Syndr. 2005; 39: 152–158.[Medline] [Order article via Infotrieve]
44. Baliga RS, Liu C, Hoyt DG, Chaves AA, Bauer JA. Vascular endothelial toxicity induced by HIV protease inhibitor: evidence of oxidant-related dysfunction and apoptosis. Cardiovasc Toxicol. 2004; 4: 199–206.[CrossRef][Medline] [Order article via Infotrieve]
45. Wang X, Chai H, Yao Q, Chen C. Molecular mechanisms of HIV protease inhibitor-induced endothelial dysfunction. J Acquir Immune Defic Syndr. 2007; 44: 493–499.[CrossRef][Medline] [Order article via Infotrieve]
46. Dressman J, Kincer J, Matveev SV, Guo L, Greenberg RN, Guerin T, Meade D, Li XA, Zhu W, Uittenbogaard A, Wilson ME, Smart EJ. HIV protease inhibitors promote atherosclerotic lesion formation independent of dyslipidemia by increasing CD36-dependent cholesteryl ester accumulation in macrophages. J Clin Invest. 2003; 111: 389–397.[CrossRef][Medline] [Order article via Infotrieve]
47. Sutliff RL, Dikalov S, Weiss D, Parker J, Raidel S, Racine AK, Russ R, Haase CP, Taylor WR, Lewis W. Nucleoside reverse transcriptase inhibitors impair endothelium-dependent relaxation by increasing superoxide. Am J Physiol Heart Circ Physiol. 2002; 283: H2363–H2370.
48. Aberg JA, Gallant JE, Anderson J, Oleske JM, Libman H, Currier JS, Stone VE, Kaplan JE; HIV Medicine Association of the Infectious Diseases Society of America. Primary care guidelines for the management of persons infected with human immunodeficiency virus: recommendations of the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2004; 39: 609–629.[CrossRef][Medline] [Order article via Infotrieve]
49. Friis-Moller N, Thiebaut R, Reiss P, El-Sadr W, Worm S, Kirk O, Phillips A, Sabin C, Lundgren J, Law M; the D:A:D Study Group. Predicting the risk of coronary heart disease in HIV-infected patients: the D:A:D: risk equation. Presented at: 14th Conference on Retroviruses and Opportunistic Infections; February 25–28, 2007; Los Angeles, Calif. Paper No. 808.
50. Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998; 97: 1837–1847.
51. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002; 106: 3143–3421.
52. US Preventive Services Task Force. Screening for coronary heart disease: recommendations statement. Ann Intern Med. 2004; 140: 569–572.
53. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO III, Criqui M, Fadl YY, Fortmann SP, Hong Y, Myers GL, Rifai N, Smith SC Jr, Taubert K, Tracy RP, Vinicor F; Centers for Disease Control and Prevention; American Heart Association. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003; 107: 499–511.
54. Feldman JG, Goldwasser P, Holman S, DeHovitz J, Mikoff H. C-reactive protein is an independent predictor of mortality in women with HIV-1 infection. J Acquir Immune Defic Syndr. 2003; 32: 210–214.[Medline] [Order article via Infotrieve]
55. Tong Q, Sankale JL, Hadigan CM, Tan G, Rosenberg ES, Kanki PJ, Grinspoon SK, Hotamisligil GS. Regulation of adiponectin in human immunodeficiency virus-infected patients: relationship to body composition and metabolic indices. J Clin Endocrinol Metab. 2003; 88: 1559–1564.
56. Sattar N, Williams K, Sniderman AD, D’Agostino R Jr, Haffner SM. Comparison of the associations of apolipoprotein B and non-high-density lipoprotein cholesterol with other cardiovascular risk factors in patients with the metabolic syndrome in the Insulin Resistance Atherosclerosis Study. Circulation. 2004; 110: 2687–2693.
57. Hsue PY, Lo JC, Franklin A, Bolger AF, Martin JN, Deeks SG, Waters DD. Progression of atherosclerosis as assessed by carotid intima-media thickness in patients with HIV infection. Circulation. 2004; 109: 1603–1608.
58. Mangili A, Gerrior J, Tang AM, O’Leary DH, Polak JK, Schaefer EJ, Gorbach SL, Wanke CA. Risk of cardiovascular disease in a cohort of HIV-infected adults: a study using carotid intima-media thickness and coronary artery calcium score. Clin Infect Dis. 2006; 43: 1482–1489.[CrossRef][Medline] [Order article via Infotrieve]
59. Meng Q, Lima JA, Lai H, Vlahov D, Celentano DD, Strathdee SA, Nelson KE, Wu KC, Chen S, Tong W, Lai S. Coronary artery calcification, atherogenic lipid changes, and increased erythrocyte volume in black injection drug users infected with human immunodeficiency virus-1 treated with protease inhibitors. Am Heart J. 2002; 144: 642–648.[Medline] [Order article via Infotrieve]
60. Stein JH, Klein MA, Bellehumeur JL, McBride PE, Wiebe DA, Otvos JD, Sosman JM. Use of human immunodeficiency virus-1 protease inhibitors is associated with atherogenic lipoprotein changes and endothelial dysfunction. Circulation. 2001; 104: 257–262.
61. Iloeje UH, Yuan Y, L’Italien G, Mauskopf J, Holmberg SD, Moorman AC, Wood KC, Moore RD. Protease inhibitor exposure and increased risk of cardiovascular disease in HIV-infected patients. HIV Med. 2005; 6: 37–44.[CrossRef][Medline] [Order article via Infotrieve]
62. Law MG, Friis-Møller N, El-Sadr WM, Weber R, Reiss P, D’Arminio Monforte A, Thiébaut R, Morfeldt L, De Wit S, Pradier C, Calvo G, Kirk O, Sabin CA, Phillips AN, Lundgren JD; D:A:D Study Group. The use of the Framingham equation to predict myocardial infarctions in HIV-infected patients: comparison with observed events in the D:A:D Study. HIV Med. 2006; 7: 218–230.[CrossRef][Medline] [Order article via Infotrieve]
63. Fitch KV, Anderson EJ, Hubbard JL, Carpenter SJ, Waddell WR, Caliendo AM, Grinspoon SK. Effects of a lifestyle modification program in HIV-infected patients with the metabolic syndrome. AIDS. 2006; 20: 1843–1850.[Medline] [Order article via Infotrieve]
64. Joy T, Keogh HM, Hadigan C, Lee H, Dolan SE, Fitch K, Liebau J, Lo J, Johnsen S, Hubbard J, Anderson EJ, Grinspoon S. Dietary fat intake and relationship to serum lipid levels among HIV-infected subjects with metabolic abnormalities in the HAART era. AIDS. 2007; 21: 1591–1600.[CrossRef][Medline] [Order article via Infotrieve]
65. Stein JH, Merwood MA, Bellehumeur JL, Aeschlimann SE, Korcarz CE, Underbakke GL, Mays ME, Sosman JM. Effects of pravastatin on lipoproteins and endothelial function in patients receiving human immunodeficiency virus protease inhibitors. Am Heart J. 2004; 147: E18.[Medline] [Order article via Infotrieve]
66. Falutz J, Allas S, Blot K, Potvin D, Kotler D, Somero M, Berger D, Brown S, Richmond G, Fessel J, Turner R, Grinspoon S. Metabolic effects of a growth hormone-releasing factor in patients with HIV. N Engl J Med. 2007; 357: 2359–2370.
67. Dubé MP, Stein JH, Aberg JA, Fichtenbaum CJ, Gerber JG, Tashima KT, Henry WK, Currier JS, Sprecher D, Glesby MJ; Adult AIDS Clinical Trials Group Cardiovascular Subcommittee; HIV Medical Association of the Infectious Disease Society of America. Guidelines for the evaluation and management of dyslipidemia in human immunodeficiency virus (HIV)-infected adults receiving antiretroviral therapy: recommendations of the HIV Medical Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group. Clin Infect Dis. 2003; 37: 613–627.[CrossRef][Medline] [Order article via Infotrieve]
68. Brown TT, Cole SR, Li X, Kingsley LA, Palella FJ, Riddler SA, Visscher BR, Margolick JB, Dobs AS. Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the multicenter AIDS cohort study [published correction appears in Arch Intern Med. 2005;165:2541]. Arch Intern Med. 2005; 165: 1179–1184.
69. Hadigan C, Meigs JB, Corcoran C, Rietschel P, Piecuch S, Basgoz N, Davis B, Sax P, Stanley T, Wilson PW, D’Agostino RB, Grinspoon S. Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy. Clin Infect Dis. 2001; 32: 130–139.[CrossRef][Medline] [Order article via Infotrieve]
70. Hadigan C, Corcoran C, Basgoz N, Davis B, Sax P, Grinspoon S. Metformin in the treatment of HIV lipodystrophy syndrome: a randomized controlled trial. JAMA. 2000; 284: 472–477.
71. Hadigan C, Yawetz S, Thomas A, Havers F, Sax PE, Grinspoon S. Metabolic effects of rosiglitazone in HIV lipodystrophy: a randomized, controlled trial. Ann Intern Med. 2004; 140: 786–794.
This article has been cited by other articles:
 |
|
 |
|
  C. L. McDonald and J. R. Kaltman Cardiovascular disease in adult and pediatric HIV/AIDS. J. Am. Coll. Cardiol., September 22, 2009; 54(13): 1185 - 1188. [Full Text] [PDF]
|
|
|
|
 |
|
 J. E Ho and P. Y Hsue Cardiovascular manifestations of HIV infection Heart, July 15, 2009; 95(14): 1193 - 1202. [Full Text] [PDF]
|
|
|
|
 |
|
 S. W. Worm, S. De Wit, R. Weber, C. A. Sabin, P. Reiss, W. El-Sadr, A. D. Monforte, O. Kirk, E. Fontas, F. Dabis, et al. Diabetes Mellitus, Preexisting Coronary Heart Disease, and the Risk of Subsequent Coronary Heart Disease Events in Patients Infected With Human Immunodeficiency Virus: The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D Study) Circulation, February 17, 2009; 119(6): 805 - 811. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||