Cardiovascular disease in HIV-positive patients

Introduction Use of highly active antiretroviral therapy (HAART) is associated with the development of traditional cardiovascular risk factors, including dyslipidemia and insulin resistance. Recent data also suggests that endothelial dysfunction, impaired fibrinolysis, and excess inflammation may contribute to increased cardiovascular risk in the HIV-positive population. Surrogate markers such as C-reactive protein (CRP), tissue plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1) are increased in the HIV-positive population in association with metabolic abnormalities and altered fat distribution. Carotid intimal–medial thickness (IMT) and coronary calcification assessments suggest increased atherosclerotic disease among certain HIV-positive individuals. Finally, recent studies of large numbers of HIV-positive subjects have documented increased cardiovascular risk using hard endpoints such as myocardial infarction rates. This review will consider the pathogenesis, prevalence, and treatment of cardiovascular risk factors in the HIV-positive population. Pharmacologic strategies for dyslipidemia and abnormal glucose homeostasis will be reviewed in conjunction with non-drug strategies for disease prevention. Risk factors Dyslipidemia Altered lipid metabolism is known to occur in association with HIV disease itself. HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), and total cholesterol (TC) levels are reduced, while triglyceride (TG) levels are increased in HIV-positive patients [1]. Early data suggest that circulating TG levels may be elevated from increased hepatic very low-density lipoprotein (VLDL) production and reduced clearance [1,2]. Cytokines, such as interferon alpha, may play a role in the abnormal lipid homeostasis seen in HIV-positive patients [3,4]. Lipid levels are also influenced by female sex, estrogen use, age, and heritable factors, including lipoprotein genotype in HIV-positive patients [5]. Various HIV-related factors such as viral load, CD4 count, proximity/severity of opportunistic infections, and mechanism of HIV acquisition appear to have modest or minimal direct affects on atherosclerotic lesions [6]. Protease inhibitor (PI) use has been linked to further abnormalities in the serum lipid profile in HIV-positive patients [5,7]. Increased TC, TG rich VLDL, and LDL-C are seen in PI-treated patients relative to PI-naive, HIV-positive individuals [5,8,9]. Data from prospective cohort studies report new-onset hypercholesterolemia and hypertriglyceridemia after 5 years of HAART therapy in 24 and 19% of subjects, respectively [10,11]. In contrast, recent longitudinal data from the Multicenter AIDS Cohort Study (MACS) reinforced that HIV infection itself is associated with reduced HDL-C, TC, and LDL-C. Cholesterol and LDL-C increase with use of HAART to pre-infection levels whereas HDL-C remains low [12]. Individual PIs likely have substantially different affects on the lipid profile. For example, data from the Swiss Cohort study suggest that ritonavir, but not indinavir or nelfinavir, is associated with increased TG levels [10]. Purnell et al. [13] demonstrated significant effects of ritonavir on TG levels after 2 weeks in HIV-negative patients. Similarly, low dose ritonavir in combination with lopinavir over 4 weeks also increased TG levels (but not LDL-C) in HIV-negative men [14]. The newer PI atazanavir appears to have a significantly less pronounced effect on serum lipid levels [15,16]. The mechanisms by which PIs (notably ritonavir) influence serum TGs in HIV-infected patients have not been clearly defined. Preliminary data from rat models [17,18] suggest that PIs may prevent proteosomal degradation of nascent apolipoprotein B, a principle protein component of circulating TGs, leading to increased production of VLDL particles. Furthermore, alterations in apolipoprotein B metabolism may be explained in part by ritonavir-induced intra-hepatocyte accumulation of nuclear transcription factors such as sterol regulatory binding proteins [19], resulting in up-regulation of metabolic pathways and excessive production of VLDL. Other antiretroviral (ARV) medications may affect serum lipids. Kumar et al. [20] reported on a 48-week randomized trial of three different ARV regimens in 258 treatment-naive HIV-positive subjects. PI sparing regimens (zidovudine/lamivudine + abacavir) raised fasting TC and TG least in comparison with regimens containing a PI (zidovudine/lamivudine + nelfinavir) or stavudine and a PI. In a 48-week open-label randomized trial of the non-nucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine or efavirenz in 1216 treatment-naive HIV-positive individuals, van Leth et al. [21] found that nevirapine versus efavirenz-containing regimens were associated with significantly higher HDL-C and lower TC to HDL-C ratios. An earlier study by van der Valk et al. [22] demonstrated similar beneficial effects on HDL-C for subjects receiving the nevirapine versus PI-containing regimens. More recently, cross-sectional data from the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study (n = 7483 patients) [23] reinforce the notion that exposure to NNRTIs is associated with modest yet significantly increased TG (> 200 mg/dl) levels (odds ratio, 1.90; 95% confidence interval, 1.06–3.39), but not with low HDL-C (< 40 mg/dl) or increased LDL-C (> 160 mg/dl). Taken together, the data indicate that PI-sparing regimens with nevirapine and without stavudine may have the least adverse influence on serum lipids in HIV-positive individuals. Insulin resistance, impaired glucose tolerance and diabetes mellitus Abnormalities in glucose homeostasis are common among HIV-positive individuals treated with HAART. HIV-positive individuals may be diabetic, or more commonly, demonstrate impaired glucose tolerance and insulin resistance. Use of the WHO definitions (fasting glucose > 126 mg/dl defines diabetes, and fasting glucose > 110 mg/dl impaired fasting glycemia) is recommended to characterize glucose abnormalities in the HIV-positive population [24]. The glucose response to a standard 75 g glucose challenge may also be useful to identify individuals with impaired glucose tolerance. Insulin resistance is common during HAART therapy, and may manifest as fasting hyperinsulinemia [25] or reduced glucose disposal after an oral or IV glucose challenge [26]; fasting glucose need not be elevated. The prevalence of diabetes is increased among HIV-infected patients treated with HAART. Recent data [27] from the MACS cohort using the WHO criteria found diabetes in 14% of men, with an odds ratio of 4.4 after adjustment for age and body mass index (BMI). The hazard ratio for developing diabetes over 3 years of follow-up was 3.1 versus the control HIV-negative population. Exposure to a PI-containing HAART regimen, stavudine or efavirenz, were each independently associated with the development of diabetes. The prevalence of insulin resistance among those treated with HAART is not known, but data suggest that up to 60% of those treated may be affected [5,28], depending on the criteria and techniques used. Mechanisms of insulin resistance in the HIV-positive population are not known, but may relate to altered nutrient metabolism, changes in body composition, and/or direct effects of antiviral agents. Preliminary data include the demonstration of altered lipolysis and increased serum free fatty acids in HIV-positive individuals [29,30]. Excess free fatty acids in the circulation may reduce insulin sensitivity through inappropriate lipid storage in muscle [31] and liver [32], resulting in impaired glucose utilization [33] and insulin-mediated inhibition of glycogenolysis and gluconeogenesis [34]. PI therapy is associated with higher rates of diabetes mellitus, impaired glucose tolerance, and hyperinsulinemia among HIV-positive individuals [35]. This effect is not class specific, and newer PI drugs such as atazanavir appear less likely to affect glucose homoestastis [36]. A direct link between ARV medication and abnormal glucose homeostasis is substantiated by physiologically rigorous evaluation of indinavir [37], and more recently, lopinavir/ritonavir [14] in HIV-negative individuals. The mechanisms behind PI-induced insulin resistance are complex and multi-factorial. Initial studies suggested an effect on Glut-4-mediated glucose transport [38,39]. Islet cell dysfunction [40] and dysregulated hepatic glucose production [41] may complicate glucose homeostasis further in HIV-positive individuals receiving HAART. Preliminary data suggest that PIs may inhibit the processing of insulin from pro-insulin [5]. Mitochondrial toxicity could contribute to the detrimental effect of NRTIs on tissue insulin sensitivity either through impaired oxidative phosphorylation and excess lipid accumulation in liver or muscle or via a reduction in the absolute or relative amounts of subcutaneous fat. NRTIs use can be linked to abnormal glucose homeostasis as well. These effects may be indirect through chronic changes in fat distribution [25,42]. Furthermore, stavudine administration may lead to changes in lipolysis, resulting in increased serum free fatty acids and decreased insulin sensitivity [30]. A similar independent effect of stavudine on insulin sensitivity was also noted in the MACS cohort [27]. Abnormal body fat partitioning among HIV-positive individuals strongly predicts insulin resistance and/or glucose intolerance. In a study comparing serum glucose and insulin responses to a standard oral glucose challenge in HIV-positive subjects (n = 71) with evidence of fat redistribution by clinical exam [26], the prevalence of DM was 7% compared to 0.5% (P = 0.01 for difference) in age and BMI-matched Framingham subjects (n = 213). The prevalence of impaired glucose tolerance (2 h serum glucose > 140 mg/dl) was markedly higher at 35% in the lipodystrophic group compared to 5% (P = 0.001) in the matched Framingham subjects [26]. As in the general population, excess trunk or visceral fat is a risk factor for insulin resistance among those with HIV infection, independent of PI use [26,43]. In addition, insulin resistance is itself independently associated with fat loss in HIV-positive individuals [44,45]. Additional factors can influence the development of insulin resistance in HIV-infected patients, including increasing age and hepatitis C co-infection [28,35,46]. In sum, the particular cause(s) of insulin resistance in any one patient will vary depending on many of the factors noted. Assessment of glucose homeostasis in HIV-infected patients should include measurement of periodic fasting glucose in all subjects, particularly in those with risk factors for the development of diabetes or in whom ARV regimens have changed or are about to change. Performance of glucose tolerance testing may also be useful in patients with significant risk factors for diabetes mellitus. Body composition changes HIV-positive individuals receiving HAART commonly manifest evidence of fat redistribution, characterized by loss of subcutaneous extremity fat, relative preservation of fat in the trunk, and an increased waist-to-hip ratio (WHR) [28,43,47]. It is well established that increased truncal adiposity confers heightened risk of cardiovascular complications in the general population [48]. Intra-abdominal fat delivers excess free fatty acids directly into the portal blood system [49] and secretes cytokines and other factors that contribute to insulin resistance, impaired fibrinolysis [50,51], and endothelial dysfunction [52]. Excess truncal adiposity is an established risk factor for insulin resistance in HIV-negative individuals. In the HIV-positive population, increased WHR is often a function of increased waist and reduced hip circumference, and is associated with increased metabolic risk indices including hyperlipidemia [53]. In the general population, advancing age [54], male gender [54], and ethnicity [55,56] also predict excess abdominal adiposity, and are likely to contribute to body composition changes in HIV-positive patients. While it is unclear if changes in trunk and subcutaneous fat are linked as part of a single syndrome [57], evidence from prospective studies in treatment-naive subjects suggest such changes may occur simultaneously. Mallon et al. [58] prospectively studied 40 HIV-positive, therapy naïve men for 96 weeks and demonstrated decreased extremity fat and increased relative central fat accumulation. Similarly, Dube et al. [59] demonstrated increased trunk fat and reduced extremity fat in response to NNRTI and NRTI regimens, respectively, with reduced extremity fat most clearly linked to the PI nelfinavir and an NRTI regimen containing stavudine. The relative risk of extremity subcutaneous fat with to cardiovascular disease is not known, but et al. a higher risk of myocardial infarction in subjects with Other factors and appear to as risk factors for comparing HIV-negative and HIV-positive individuals [6]. studies report that rates among HIV-positive individuals are as as a cardiovascular risk factor in population markers of cardiovascular risk and altered metabolism evidence suggests that markers of impaired fibrinolysis are increased in HIV in association with insulin resistance and altered metabolic The factor is increased in association with and with risk of myocardial infarction Similarly, increased is associated with myocardial infarction and in HIV-negative individuals Increased also with excess cardiovascular risk HIV-positive subjects treated with are treatment decreased serum and in patients with HIV in association with in insulin sensitivity The of chronic As C-reactive protein has a clinical to predict complications from atherosclerotic disease studies have in HIV-infected patients. In a recent increased cardiovascular in HIV-positive in the HIV Study et al. demonstrated increased as a function of increased central fat accumulation in HIV-positive for ARV use and function an in tissue has and may affect the insulin protein insulin muscle and hepatic glucose production levels have been in many such as diabetes and also has It cell of the in and cell models of and of endothelial Preliminary data suggest that reduced may increase the risk of myocardial but has not been studied in HIV studies have significant independent between low and traditional and risk such as insulin resistance excess visceral adiposity subcutaneous fat lipid higher liver fat and higher circulating levels of and strategies may include treatment for low if reduced predict excess cardiovascular The of increase levels of in HIV-infected patients with and may be useful in treatment markers and hard endpoints cardiovascular disease in the HIV-positive population into three risk to predict in HIV-infected of markers known to be associated with increased cardiovascular disease in the general population increased or markers of endothelial and evaluation of hard cardiovascular endpoints including and myocardial infarction rates. models The Framingham is a of cardiovascular disease risk in the general population The Framingham into age, sex, TC, HDL-C, blood diabetes, and and has been to predict myocardial infarction rates in longitudinal of Framingham Study et al. the Framingham to risk of cardiovascular disease among individuals receiving HAART. While age, sex, and were the of complications For a male receiving HAART with and without metabolic complications a risk of and for were and et al. also the Framingham to predict risk in patients for evidence of fat redistribution [53]. of HIV-positive subjects with fat redistribution versus of an and BMI-matched HIV-negative control group (P = for difference) demonstrated a significant risk of myocardial infarction [53]. subjects were matched to HIV-negative for the were that increased risk was associated with fat redistribution in population. an increased risk of in subjects with in comparison to subjects with central or [53]. Surrogate endothelial dysfunction and disease studies a of cardiovascular risk in HIV-positive individuals. of is to thickness and of the and has in the general population of the or by with after of is also an for endothelial dysfunction and as is response to The clinical of in HIV-positive subjects is not yet et al. studied HIV-infected men and of whom In comparison with HIV-negative individuals, the HIV-positive group more lesions in the or versus = Protease inhibitor therapy not independently predict whereas traditional factors such as age, male and et al. to while also a significantly higher of thickness over in the HIV-positive subjects versus age and matched HIV-negative versus = for of in the HIV-positive subjects age and In contrast, et al. HIV-infected individuals receiving (n = and (n = to and compared with age and BMI-matched HIV-negative individuals. More of those receiving PIs demonstrated abnormal in comparison with and among and control subjects, et al. reported similar with increased disease in HIV-infected subjects receiving PI et al. demonstrated impaired in HIV-positive subjects receiving PIs in comparison with subjects. The in was explained by abnormal lipoprotein et al. found that of via of with the with whereas traditional risk factors study and complex between risk factors may complicate comparison between Taken together, and clinical studies to evidence for disease and endothelial dysfunction among HIV-positive patients. studies are to abnormal endothelial function and altered in HIV-positive individuals, on the relative of HIV metabolic factors, and endpoints Initial and suggested that increased cardiovascular disease could be by HAART. Data from studies are in of use of ARV medications to increased myocardial infarction rates in the HIV population. et al. data from the of to with years and of the myocardial infarction was higher among HIV-positive men versus HIV-negative matched versus = for among male with PI and ARV medication use not influence myocardial infarction rates. et al. myocardial infarction rates among HIV-positive men from the on HIV were for a of This study found that the myocardial infarction rates among men increased in to of PI use (< PI PI > PI et al. not report data on myocardial infarction rates in HIV-positive, individuals. from the HIV Study cohort demonstrated similar was between of exposure to PI and risk of myocardial et al. coronary disease rates on data for the population. The of among men to age and to age was significantly higher in HIV-positive compared with HIV-negative patients. The relative risk for the development of in individuals receiving ARV medications compared with those not receiving medications was (P 0.001) in HIV-positive individuals increased risk of was not found for HIV-positive patients. In contrast, a large study using a for the years and patients, found that PI use was not associated with increased risk of myocardial infarction the of study subjects a PI was the study not rates to HIV-negative rates and from decreased over between and among the HIV-positive studies have been which were to adverse The prospectively patient data at the between the years and A total of were and 126 individuals myocardial infarction The of increased in association with increasing exposure to combination ARV therapy, with a relative increase in of for age, sex, body mass and cardiovascular male sex, cardiovascular disease and also independently myocardial infarction in the population. or of the study was associated with an increased myocardial infarction of confidence substantially higher the medication for TC and TG reduced the relative of to whereas the of diabetes, and HIV disease not affect the The of myocardial infarction was and many more subjects of traditional HIV-related complications cardiovascular Furthermore, data and such as WHR and of insulin resistance, may have to the rates. Taken together, and other data on hard suggest that a but significant and increasing risk for cardiovascular disease to HIV infection or use studies are to the of infection, direct and metabolic to risk in with The of cardiovascular remains and be in the of the of ARV on the risk may with of the HIV population and of ARV exposure and metabolic between use of highly active antiretroviral therapy HIV infection, and risk of cardiovascular of HIV-positive individuals with established cardiovascular disease should to standard the that ARV medications are to contribute to increased lipid or glucose can be to ARV medications and/or using traditional or depending on the data are on the of and the of treatment should be on including and HIV medications can be and should also be to of metabolic abnormalities with the of ARV The HIV-positive population is in comparison with patients for risk in the general population, but exposure to ARV medications and associated abnormalities further increase risk in population. has been a to cardiovascular and in the general population, and risk after is particularly common in the HIV the study reported of cohort been or were and treatment may to HIV-positive patients. as is known to reduce risk of myocardial infarction significantly in the general population. Recent found that and muscle trunk adiposity and lipid for HIV-positive individuals. A be beneficial to cardiovascular disease risk in HIV-positive individuals. Dyslipidemia In the general population, on the lipoprotein to therapy the Cholesterol have treatment on the LDL-C and of risk factors to TGs, the established adverse effect of hypertriglyceridemia is most often seen with triglyceride > TG levels may also increase the risk of developing suggest that mg/dl) be treated with medication or more risk factors are those with very mg/dl) TGs should be treated if is a of or a regimen containing a known to Cholesterol treatment on low-density lipoprotein cholesterol of hyperlipidemia ARV medications known to hyperlipidemia and/or using medications and to directly LDL-C and/or studies have found that of NRTI or NNRTI medications for PIs can be beneficial without effects have not been reported treatment to reduce LDL-C and TGs to be the significant between ritonavir and inhibitors and of comparing the and of ARV and medications with to serum TGs and LDL-C. in the HIV-positive population, drugs in the and class of medications LDL-C and TGs, respectively for the of lipid abnormalities in HIV-infected patients have been and insulin resistance mellitus is a risk factor for cardiovascular Similarly, impaired glucose tolerance and insulin resistance are associated with increased risk of cardiovascular disease in the general population of diabetes in the HIV-infected patients should also established with the that may an with insulin resistance into diabetes. In such a of the ARV regimen may be in with and use of agents. A of studies have the use of in patients with HIV and a in a study of HIV-positive individuals with central adiposity after PI-containing HAART Insulin a 75 g oral glucose tolerance visceral fat, and decreased significantly in the group compared with after et al. a in HIV-positive men with and also found insulin sensitivity and decreased trunk levels were the et al. also found that treatment abnormal levels of serum markers and associated with increased cardiovascular disease Taken together, data suggest that may insulin central adiposity, and other risk factors in HIV-infected patients with truncal adiposity and insulin resistance. with liver or associated with NRTI therapy should not Furthermore, use is associated with loss and may be inappropriate for subjects with significant et al. that the combination of and was more in WHR and insulin resistance in HIV-positive patients with fat redistribution class of have to diabetes in individuals. include of and function as well as in muscle glucose is seen in subcutaneous fat from PI-treated subjects studies have been to using et al. a significant increase in abdominal subcutaneous fat in association with insulin sensitivity in a group of highly patients. Similarly, et al. demonstrated a increase in subcutaneous fat by in HIV-infected patients with insulin resistance in a study In insulin resistance significantly as by In addition, modest but significant effects on TC and TG were with the seen in patients. in response to which may also a metabolic In contrast, et al. and et al. found changes in abdominal subcutaneous fat or extremity fat in study patients on insulin resistance. all studies demonstrated in insulin which may by itself et al. also liver fat with and found decreased hepatic fat with therapy in conjunction with decreased serum studies are to the use of can metabolic among HIV-positive individuals. with HIV infection a of the total HIV population. prospective and studies cardiovascular disease risk and HIV therapy have are from cardiovascular in part by the influence of on lipoprotein data from the study indicate that female is the risk of myocardial combination antiretroviral therapy metabolic and body composition changes with the associated with increased with HIV are and HIV-positive may increased risk associated with and et al. prospectively male and female HIV-positive individuals a combination ARV regimen, comparing with matched HIV-negative individuals. The that the HDL-C to LDL-C ratio more in HIV-infected versus men, and that circulating levels of an of inflammation and elevated in versus men, each in comparison with the studies are to risk factors in HIV-positive individuals. risk factors, including insulin resistance and changes in body composition have increased in association with the use of ARV markers and hard cardiovascular endpoints suggest increased in with The relative increase in risk is in an absolute and the effect of ARV is in of in function and and as HIV-positive individuals on ARV cardiovascular disease could risk should occur after and in ARV medication strategies that have been well studied in the general population and increased should be Preliminary treatment of hyperlipidemia and insulin resistance can be from a of will more risk and treatment for of in with HIV in part by and the AIDS and