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Myocardial infarction risk in HIV-infected patients: epidemiology, pathogenesis, and clinical management

Calza, Leonardo; Manfredi, Roberto; Verucchi, Gabriella

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doi: 10.1097/QAD.0b013e328337afdf
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Since the introduction of HAART leading to a notable extension of life expectancy in patients with HIV infection, questions related to comorbidities and long-term adverse effects of antiretroviral drugs have recently emerged.

An increasing concern is mounting, particularly about the increased risk of coronary artery disease in HIV-infected patients, as initially described in two large prospective studies [1,2].

Several of the traditional risk factors for coronary artery disease are frequently reported in HIV-positive individuals, including factors related to the patients' characteristics (such as cigarette smoking, drug addiction, and premature ageing) and factors associated with HIV infection itself and antiretroviral drugs (such as dyslipidaemia, insulin resistance, diabetes mellitus, central adiposity, arterial hypertension, and direct effects of the virus or antiretroviral agents on the vascular system). Moreover, some data suggest that endothelial dysfunction, impaired fibrinolysis, and increased inflammation are more common in HIV-positive patients than in general population and may contribute to an increased cardiovascular risk [3,4].

To the best of our knowledge, HIV and HAART may contribute to an increased risk of cardiovascular diseases in three principal ways: HIV infection can identify a subgroup of the general population with a greater prevalence of traditional risk factors unrelated to HIV or HAART (e.g., male sex, advancing age, higher smoking rate, alcoholism, or drug addict); HIV infection and HAART can indirectly favour the occurrence of traditional risk factors (e.g., hyperlipidaemia, insulin resistance, diabetes mellitus, fat redistribution, or hypertension); and HIV and HAART can directly affect the pathogenesis of atherosclerotic disease (e.g., through inflammation and endothelial dysfunction) [3–5].

The body of our knowledge suggests that all three above-mentioned mechanisms are plausible, contemporaneously affecting the risk of coronary artery disease in HIV-infected patients. However, experimental and clinical data are often still conflicting today, and several questions remain as to epidemiology, pathogenesis, prevention, and treatment of cardiovascular diseases and related risk factors, which will be discussed in this review.

Myocardial infarction in HIV-infected patients

Even though initial case reports suggested an increased frequency of myocardial infarction in protease inhibitor-treated patients [6–8], data from large retrospective and observational studies demonstrate that considerable controversy exists until now about the association of HAART with increased incidence of coronary heart disease.

Protease inhibitors and myocardial infarction

Several retrospective studies have demonstrated a significantly increased incidence of myocardial infarction and cardiovascular complications in HIV-infected patients compared with HIV-uninfected persons. Current exposure to protease inhibitors was often significantly associated with a greater risk of myocardial infarction regardless of traditional cardiovascular risk factors, such as increased age, tobacco smoking, and metabolic disturbances [9–15].

Similarly, large, prospective, cohort studies have documented an increased incidence of myocardial infarction and cerebrovascular diseases in association with a prolonged exposure to combination antiretroviral therapies. Really, the major limitation of some prospective studies is that the information about cardiovascular endpoints has been retrospectively ascertained and their conclusions are sometimes unreliable.

The Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study is a prospective, observational study of 11 previously established cohorts comprising 23 468 HIV-infected patients followed in 21 countries in Europe, United States, and Australia. The authors showed that the incidence of myocardial infarction increased significantly with increasing exposure to combination antiretroviral therapy, and the adjusted risk rate per year of exposure ranged from 0.32 for no HAART use to 2.93 for at least 6 years of HAART use. Other factors that also independently predicted myocardial infarction in the DAD study were increased age, current or past smoking, previous cardiovascular diseases, male sex, hypercholesterolaemia, hypertriglyceridaemia, and diabetes mellitus [2]. Additional data recorded after further 3 years of follow-up showed that the protease inhibitor exposure was associated with an increased risk of myocardial infarction, which is partly explained by dyslipidaemia, though no evidence of such an association for nonnucleoside reverse transcriptase inhibitors (NNRTIs) was found [16].

A significant association between protease inhibitor exposure and increased risk of myocardial infarction was confirmed also in other prospective studies, and independent cardiovascular risk factors were current or past smoking, hypertension, diabetes mellitus, preexisting cardiovascular diseases, increased BMI, and low income level [1,17–19]. Recently, the French Hospital Database assessed a population of 1151 HIV-infected patients enrolled between 2000 and 2006, including 286 patients with myocardial infarction and 865 controls. In this nested case–control study, the risk of myocardial infarction was significantly increased by cumulative exposure to lopinavir and to amprenavir or fosamprenavir [20].

In contrast, in a large retrospective study using the Veterans' Affairs Database (which included 36 766 patients followed up for an average of 40 months, between years 1993 and 2001), Bozzette et al.[21] showed that protease inhibitor therapy was not associated with an increased risk of coronary heart disease. However, the median duration of exposure to protease inhibitors was only 16 months, and the true cardiovascular disease rate may have been underestimated, because many patients with acute myocardial infarction may not have been admitted to Veterans' Affairs hospitals.

Another important concern about the risk of coronary events in HIV-positive patients has emerged from the Strategies for Management of Antiretroviral Therapy (SMART) study, which assessed intermittent antiretroviral therapy versus continuous antiretroviral therapy. A total of 477 participants were evaluated during a mean follow-up of 18 months and the hazard ratio for risk of cardiovascular diseases for patients allocated to discontinuous therapy versus continuous therapy was 1.57 [22].

Finally, Triant et al.[23] compared myocardial infarction rates (based on hospital claims data) among 3851 HIV-infected patients and 1 044 589 HIV-uninfected controls receiving longitudinal care in two tertiary care hospitals between 1996 and 2004. Incidence of myocardial infarction and prevalence of cardiovascular risk factors (hypertension, diabetes, and dyslipidaemia) were found to be higher in HIV-positive compared with HIV-negative persons, particularly among women.

Abacavir and myocardial infarction

Concern has also been raised regarding the potential cardiovascular risk associated with nucleoside reverse transcriptase inhibitors (NRTIs), and particularly with abacavir. In the DAD study group, recent (within 6 months) or current use of abacavir or didanosine was associated with an increased risk of myocardial infarction (relative risk, 1.9 with abacavir and 1.49 with didanosine). The excess risk did not seem to be explained by underlying established cardiovascular risk factors, but the heightened risk of myocardial infarction with recent abacavir or didanosine exposure was accentuated in patients with preexisting risk factors for coronary artery disease [24]. The SMART study showed also that the current use of abacavir was associated with an excess risk of cardiovascular disease compared with other NRTIs, though the highest risk was concentrated in individuals with five or more known cardiovascular risk factors [25].

Recently, current or recent exposure to abacavir was found to be associated with increased risk of myocardial infarction also in the French Hospital Database [20], in a Danish HIV cohort study [26], and in a randomized, open-label, 96-week, simplification trial of current nucleoside analogue therapy with tenofovir–emtricitabine or abacavir–lamivudine [27].

In contrast to these observational studies, data from GlaxoSmithKline-sponsored trials found no increased cardiovascular risk in patients recently exposed to abacavir [28]. Similar results were obtained from the AIDS Clinical Trials Group (ACTG) A5001 study assessing 3205 patients randomized to their first antiretroviral regimen [29]. A retrospective analysis of the US Veterans Administration's Clinical Case registry showed that cumulative exposure to abacavir was associated with a modest, nonstatistically significant increase in myocardial infarction and cerebrovascular event risk. The association of abacavir use with myocardial infarction was much weaker after adjusting for chronic renal disease and traditional risk factors [30]. Finally, a randomized, double-blind, multicentre trial comparing abacavir–lamivudine and tenofovir–emtricitabine associated with lopinavir–ritonavir in 688 antiretroviral-naive patients provides comparable efficacy and safety (including incidence of cardiovascular events) over 96 weeks [31].

To conclude, no consensus has been reached to date on the association between abacavir use and risk of myocardial infarction, because these studies are only observational and several biases (such as chronic renal disease or intravenous drug abuse) may interfere with the causal assessment of cardiovascular events in HIV-infected individuals receiving antiretroviral compounds. However, a potential increased risk among the subset of individuals at high risk of coronary artery disease should not be ignored, and alternatives to abacavir should be considered in persons at higher risk for cardiovascular complications.

The most large studies investigating the incidence of cardiovascular events in HIV-positive patients and their association with antiretroviral regimens are summarized in Table 1.

Table 1
Table 1:
Retrospective and prospective studies evaluating the relationship between risk of cardiovascular events and use of combination antiretroviral therapy.

HIV infection, HAART, and premature atherosclerosis

Investigation of subclinical atherosclerosis using evaluation of intima–media thickness (IMT) and endothelial function has led to new insights into the pathogenesis of structural and functional changes in arterial vessels observed in HIV-infected patients. However, contradictory reports have been published concluding that HIV infection and antiretroviral therapy do or do not promote atherogenesis.

Endothelial dysfunction, reduced flow-mediated arterial dilatation, and premature atherosclerotic lesions have been reported among HIV-infected patients receiving HAART. However, whether the increased atherosclerotic risk in HIV-positive patients is due to HIV infection itself, to antiretroviral therapy, or to a synergistic interaction between these factors, remains to be established. Although both HIV disease and HAART are associated with a lipid and glucose profile known to increase the risk of coronary and cerebrovascular complications, these metabolic factors do not fully account for the premature atherosclerotic lesions observed in these patients, suggesting that other mechanisms or mediators might be involved.

The association of HIV infection and cumulative exposure to protease inhibitors with the occurrence of premature subclinical atherosclerosis was shown in several case–control studies by both carotid ultrasonography and assessment of coronary artery calcification [32–45].

Moreover, in a study involving 110 HIV-positive patients and 91 HIV-negative patients, ultrasonographic structure of the epiaortic lesions in HIV-infected patients substantially differed from those of plaques in atherosclerotic individuals, though they shared similar features with patients affected by arteritis. The authors suggested that the pathogenetic mechanism responsible for carotid lesions associated with HIV infection may be more similar to an inflammatory process than the classical atherogenesis [44].

However, in our study assessing 66 HIV-infected patients, a greater prevalence of carotid plaques was associated with longer duration of HIV infection, more severe dyslipidaemia, and presence of lipodystrophy, but carotid lesions were structurally comparable to classic atheromasic plaques observed in the HIV-negative population [46].

In contrast to the above studies, other published investigations have failed to find a direct effect of antiretroviral therapy on the arterial wall [47–56]. A recent systematic review evaluated the evidence for subclinical atherosclerosis among HIV-positive patients from six cross-sectional, seven case–control, and 13 cohort studies including 5456 HIV-infected and 3600 HIV-uninfected patients. Subclinical atherosclerosis was diagnosed by ultrasonographic evaluation of carotid IMT, focal plaque incidence, or coronary artery calcium detection. The weighted mean carotid IMT was 0.04 mm thicker among HIV-positive patients versus HIV-negative ones, and HIV infection was not associated with carotid plaques or presence of coronary calcium. Similarly, protease inhibitor exposure did not significantly affect carotid IMT, carotid plaques, or coronary artery calcium [57].

The contradictory findings in existing research are likely related to different study designs or populations, limitations of observational methods to control confounding factors, limited follow-up periods, different methods of atherosclerosis evaluation, and frequent absence of HIV-seronegative controls.

The most important reports evaluating the association of HIV infection and protease inhibitors with accelerated atherosclerosis are summarized in Table 2.

Table 2
Table 2:
Cross-sectional and prospective studies evaluating the association of premature atherosclerosis with HIV infection, antiretroviral therapy, and traditional risk factors.

Role of HIV infection

Recent data support the hypothesis that both HIV infection and antiretroviral treatment promote atherosclerosis and its clinical manifestations through inflammatory mechanisms involving arterial wall and endothelial cells, either directly or indirectly, also by the metabolic alterations they induce [58–61].

If an inflammation systemic state participates pivotally in all stages of atherosclerosis, from fatty streak formation up to plaque progression and destabilization, soluble biological markers of inflammation should provide independent diagnostic and prognostic value by reflecting and underlying the disease state. Recent studies suggest that several inflammatory biomarkers such as C-reactive protein (CRP), fibrinogen, secretory phospholipase A2, interleukin (IL)-1, IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1), soluble CD40 ligand, E-selectin, P-selectin, matrix metalloproteinases (MMPs), myeloperoxidase (MPO), tumour necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), and vascular adhesion molecule-1 (VCAM-1) may have a potential role for the prediction of risk for developing coronary artery disease and may correlate with severity and mortality of atherosclerotic disease, also in HIV-positive patients [62–65].

Numerous mechanisms exist as to how HIV can directly or indirectly promote inflammation and damage endothelium, including infection of endothelial cells [66,67], secretion of proinflammatory cytokines [68,69], secretion of viral proteins [70–74], and oxidative stress [75,76] (Fig. 1).

Fig. 1
Fig. 1:
Hypothetic pathogenetic mechanisms of HIV-induced endothelial dysfunction that may lead to inflammatory alterations in endothelium and premature atherosclerosis. ICAM-1, intercellular adhesion molecule-1; IL-6, interleukin-6; IL-8, interleukin-8; PAI-1, plasminogen activator inhibitor 1; PAK-1, p21-activated kinase-1; PKC, protein kinase C; ROS, reactive oxygen species; STAT, signal transducers and activators of transcription; tPA, tissue plasminogen activator; VCAM-1, vascular adhesion molecule-1.

The activation of endothelium induced by a leucocyte-mediated inflammatory cascade triggered by the same virus leads to the increased expression of endothelial cellular adhesion molecules, such as ICAM-1, VCAM-1, E-selectin, P-selectin, thrombomodulin, tissue plasminogen activator (tPA), and plasminogen activator inhibitor 1 (PAI-1) [68,69]. HIV-infected antiretroviral-naive patients display markers of endothelial activation. Increased serum levels of ICAM-1, VCAM-1, E-selectin, von Willebrand factor, PAI-1, and thrombomodulin were demonstrated in patients with advanced HIV infection and opportunistic diseases, and higher levels of these markers were found in these patients compared with healthy controls [77–79]. Calmy et al.[80] investigated whether HIV replication modified serum levels of soluble inflammatory molecules in the Swiss Thai Australia Treatment Interruption (STACCATO) trial and showed that plasma concentrations of several inflammatory and endothelial activation markers of cardiovascular disease were associated with viral replication and increased plasma viral load.

Tat protein is the principal transactivator for HIV-1 replication, is actively secreted by infected cells, and is probably involved in HIV-induced endothelial dysfunction. Low concentrations of Tat protein significantly impair endothelium-dependent vasorelaxation in isolated pig coronary arteries [70], and in-vitro and in-vivo studies have shown that endothelial cells of diverse origin (umbilical vein, pulmonary artery, aorta, and brain) release MCP-1 and induce expression of VCAM-1 in response to Tat [71,72].

Similarly to Tat, gp120 glycoprotein in vitro induces the expression of ICAM-1, significantly increases the adhesion of monocytes and lymphocytes to the endothelium, promotes endothelial cell apoptosis, and negatively affects endothelial function through the production of potent vasoconstrictors such as endothelin-1 [73,74,81–83]. Reactive oxygen species (ROS) have also implicated in gp120-induced toxicity of endothelium, and the molecular mechanism by which gp120 exerts its endothelial damage may involve protein kinase C and p38 mitogen-activated protein kinase signalling [74–76].

The HIV-induced endothelial dysfunction is clinically demonstrated by some studies assessing the flow-mediated dilatation (FMD) of the brachial artery, which correlated inversely with HIV viral load and showed a significant impairment of endothelial function [84,85].

Role of antiretroviral therapy

The ability of HAART to accelerate atherosclerosis and increase cardiovascular risk in HIV-positive patients has been controversial in that some studies have found an association and other studies have not found an association. Numerous mechanisms exist as to how antiretroviral treatment can protect or damage the vascular endothelium, as shown by experimental and clinical data, and the global effect is still unknown.

The remarkable decrease in viral replication and plasma HIV viral load induced by combination antiretroviral therapy should improve T-cell function and reduce the HIV-associated endothelial dysfunction. In fact, several authors have reported a significant decrease in serum concentrations of VCAM-1 and ICAM-1 after the first months of HAART, suggesting that the reported reversion of endothelial activation is mediated by control of viral replication obtained by potent antiretroviral treatment [85,86]. Similarly, the SMART study showed that the risks for all-cause mortality (including mortality for cardiovascular diseases) were higher in participants randomized to treatment interruption than in those who received continuous antiretroviral therapy [22]. The effect of different antiretroviral regimens on endothelial function was evaluated by the ACTG 5152 study including 82 HIV-infected patients randomly assigned to receive an antiretroviral association, including NRTIs with efavirenz, NRTIs with lopinavir/ritonavir, or efavirenz with lopinavir/ritonavir. The decrease in plasma HIV RNA observed at 24 weeks was associated with a significant increase in brachial artery FMD in all considered groups, showing that antiretroviral therapy rapidly improved endothelial function [87].

On the contrary, a prospective, observational, cross-sectional study including 73 HIV-infected patients and 21 controls showed that increases in both serum markers of inflammation and carotid artery IMT occurred in HIV-infected patients despite antiretroviral therapy [88].

Effects of protease inhibitors

HAART seems to indirectly or directly induce endothelial dysfunction. It has early been assumed that use of several antiretroviral agents (mostly protease inhibitors, stavudine, efavirenz) favours the occurrence of multiple metabolic and morphologic abnormalities, including dyslipidaemia, insulin resistance, diabetes mellitus, subcutaneous fat loss, visceral fat accumulation, and metabolic syndrome, which are associated with an increased risk of premature atherosclerosis and myocardial infarction [89,90].

Data from Multicenter AIDS Cohort study have shown that HIV infection results in substantial decreases in serum total, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol levels, whereas subsequent HAART initiation is associated with significant increases in triglyceride, total and LDL cholesterol values [91,92]. Particularly, antiretroviral therapy was associated with an ‘atherogenic lipoprotein phenotype’, with higher numbers of very LDL and small LDL particles [93].

Protease inhibitor-related dyslipidaemia has been attributed to inhibition of lipid metabolism and adipocyte regulatory proteins that have partial homology to the catalytic site of HIV-1 protease, to which protease inhibitors bind. These regulatory proteins include the cytoplasmic retinoic acid-binding protein type 1 (CRABP-1), which is critical for maturation and proliferation of adipocytes, and the LDL-receptor-related protein (LRP), an hepatic cell receptor which cleaves fatty acids from circulating triglycerides [94,95]. Moreover, several other pathogenetic mechanisms have been described, such as inhibition of apolipoprotein B degradation, reduced function of lipoprotein lipase, and decreased secretion of adiponectin in the adipose tissue [89,90,94–97].

Data obtained from experimental investigations on animal models have also proved a direct effect of HAART on endothelial cells and function. The molecular mechanism of protease inhibitor damage in endothelium has been described in detail, and many in-vivo and in-vitro experiments suggest an oxidative stress in protease inhibitor-related endothelial dysfunction. In fact, protease inhibitors reduce the excretion of urinary nitrate, a stable degradation product of nitric oxide, and decrease the expression of endothelial nitric oxide synthase. In addition to decrease in nitric oxide production and impairment in endothelium-dependent vasodilatation capacity, protease inhibitors have been reported to increase superoxide production and subsequently oxidative stress [81,97,98] (Fig. 2).

Fig. 2
Fig. 2:
Possible protective and detrimental effects of antiretroviral therapy on endothelial cells. ICAM-1, intercellular adhesion molecule-1; NO, nitric oxide; ROS, reactive oxygen species; VCAM-1, vascular adhesion molecule-1.

Effects of nucleoside reverse transcriptase inhibitors

In-vitro studies showing a direct endothelial toxicity related to NRTIs are not numerous, but some experimental evidence supports a direct role for this class in endothelial dysfunction. In general, mitochondrial toxicity caused by nucleoside analogues is responsible for abnormal oxidative phosphorylation, aberrant cellular respiration, and cellular toxicity also in endothelium [99,100] (Fig. 2). Moreover, in-vitro studies have shown that phosphate and glucose transport in epithelial cells are stimulated by adenosine analogues acting at a receptor coupled to more than one intracellular signal [101].

The recent association of the use of the nucleoside analogue abacavir with an increased risk of myocardial infarction was investigated in several studies, in order to find plausible pathogenetic mechanisms. In the SMART study, serum high-sensitivity CRP (HS-CRP) and IL-6 levels were significantly higher for patients receiving abacavir, and a direct role of this drug in vascular inflammation was suggested [25]. Similar results were found in a cohort study including 61 antiretroviral-treated patients with undetectable HIV RNA, which showed a significant lower FMD of the brachial artery in abacavir-treated patients [102]. Abacavir has been shown to induce cardiomyopathy in mice and rats, and it is metabolized intracellularly to carbovir, which has the potential to be cytotoxic [103].

On the other hand, recent reports have not shown significant increases in serum levels of inflammatory markers after initiation of abacavir treatment, and they do not support a role of recent abacavir use in promoting inflammation and endothelial dysfunction [104,105]. Given that, the biological mechanism of possible endothelial damage associated with abacavir is still unknown, and a possible contribution of cell-mediated immune responses to the pathogenesis of the atherosclerosis associated with HIV infection was also supposed [106,107].

Screening and assessment of cardiovascular risk

With an increase in cardiovascular disease rates and ageing of HIV-infected patients, screening and appropriate assessment of cardiovascular risk in this population assumes great importance. A founding element of preventing cardiovascular diseases is that the intensity of risk-reducing interventions should be based on the level of cardiovascular risk. Patients with established cardiovascular disease or high cardiovascular risk qualify for the most aggressive risk factor management, with special focus on strategies able to prevent myocardial infarction and death.

To date, the estimates of the relative effects of traditional risk factors on cardiovascular outcomes appear similar between HIV-infected and non-HIV-infected individuals. The Framingham risk equation has been applied to HIV-infected people and has been shown to perform reasonably well, though it tended to underestimate coronary events in HIV-positive smokers and overestimate cardiovascular risk in nonsmokers [108–110].

However, specific cardiovascular risk factors were found in HIV-infected patients, and the above-mentioned equations may not provide suitable predictions for young people living with HIV infection [111]. New specific algorithms for prediction of coronary heart disease risk in HIV-infected population have been recently proposed. These HIV-specific prediction models incorporated traditional risk factors associated with exposure to antiretroviral agents and captured cardiovascular events as the dependent variable [112,113,19]. Further external validation of the DAD prediction algorithm is warranted to assess whether it is applicable to people living with HIV infection.

All HIV-infected patients should be carefully evaluated at their first clinical visit for categorical risk factors for coronary events. Laboratory parameters for identifying alterations in lipid and glucose metabolism should include total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, and glycaemia (obtained after a minimum of 8 h of fasting). The lipid and glucose panel should be repeated every 3–4 months if patients are assuming stable antiretroviral treatment, or annually if patients are not being treated and have normal lipid and glucose values. Risk factors more specific to HIV-positive patients should also be collected, including lifestyle (alcoholism, cocaine, and other psychotropic substances), drugs interfering with glucose and lipid metabolism (such as growth hormone, estrogens, corticosteroids, thyroid hormones), BMI, abdominal circumference, lipodystrophy, renal function (estimated glomerular filtration rate and dip stick), duration and type of HAART, HIV viral load, nadir and CD4 lymphocyte count, and chronic hepatitis C [114–119]. In patients with basal glycaemia on an empty stomach above 100 mg/dl, the oral glucose tolerance test (OGTT) should be performed [116–118].

Finally, newer inflammatory biomarkers, such as HS-CRP and adiponectin, may prove useful also for identifying HIV-infected patients at risk for coronary heart disease, but to date the specificity of such markers for the assessment of coronary risk in HIV-positive patients remains unclear [90,119]. Other surrogate markers for coronary heart disease, including IMT, computed tomographic angiography, and coronary artery calcification have been investigated but not validated as independent predictors of coronary heart disease outcomes in HIV-infected population [116,118].

Prevention strategies to reduce cardiovascular risk

HIV-infected patients clearly have a significant risk of atherosclerosis given their underlying traditional risk factors. Early intervention to reduce these risks is recommended in all HIV-infected patients and includes lifestyle changes, blood pressure management, and correction of lipid and glucose metabolism abnormalities.

The Infectious Disease Society of America (IDSA), the Adult AIDS Clinical Trials Group (AACTG), and the European AIDS Clinical Society (EACS) have updated specific guidelines for evaluation and management of HAART-related metabolic disturbances [115,118,119]. These recommendations are based on those provided by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines, which adjust the intensity of risk reduction therapy to the patient's risk of developing an acute coronary event [117].

Except for patients with triglycerides more than 500 mg/dl, in whom the primary goal is to reduce triglyceride concentration and prevent pancreatitis, the primary target is reduction in LDL cholesterol levels. Lipid goals and cut-offs for lifestyle modification and drug therapy are summarized in Table 3. Treatment of HAART-associated dyslipidaemia includes three levels of medical intervention: lifestyle changes (diet therapy, exercise, smoking cessation), modification of current antiretroviral regimen, and lipid-lowering drugs.

Table 3
Table 3:
Adult Treatment Panel III low-density lipoprotein cholesterol goals and cut-points for therapeutic lifestyle changes and lipid-lowering therapy in different risk categories.

Nondrug therapies should generally be instituted first and given a thorough trial before starting drug therapies. Apart from stopping smoking, patients with HIV infection and receiving antiretroviral therapy should regularly perform moderate aerobic activity (for a minimum of 30 min five times per week) and restrict calories to achieve their ideal body weight [115,120,121].

In patients with significant dyslipidaemia and taking thymidine analogues or protease inhibitors, modification of antiretroviral regimen should be considered. Significant improvement in serum lipid concentrations was reported after switching from stavudine or zidovudine to abacavir or tenofovir, or after replacing current protease inhibitor with nevirapine or atazanavir, which are usually associated with a more favourable plasma lipid profile [115,118,122–124]. New antiretroviral compounds, such as the integrase inhibitor raltegravir and the CCR5 antagonist maraviroc, seem to produce negligible effects on the lipid metabolism, but their precise metabolic impact is still unknown and needs further clinical assessment [125–127].

Lipid-lowering therapy becomes suitable when lifestyle modifications and switching treatment are ineffective or not applicable, and for patients with urgent need of drug intervention (such as those with coronary heart disease or equivalent and those with extreme elevation in serum lipid levels). Drug therapy for dyslipidaemia in HIV-infected patients receiving HAART is problematic, because of potential drug interactions, toxicity, intolerance, and reduced patient adherence to multiple pharmacologic regimens.

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, are considered the current first-line therapy for primary hypercholesterolaemia. Most of these compounds are metabolized by the cytochrome P450 3A4 and may cause clinically relevant interactions with other agents that are changed by this enzymatic complex, such as protease inhibitors and NNRTIs. Therefore, simvastatin and lovastatin should not be employed for the high risk of drug–drug interactions [126–129]. Statins recommended for the treatment of hypercholesterolaemia in patients taking HAART are listed in Table 4.

Table 4
Table 4:
Recommendations for choice of initial pharmacologic treatment for hyperlipidaemia in HIV-infected patients receiving HAART.

Recent results showed a significant increase in rosuvastatin plasma levels in HIV-negative and HIV-positive patients who are being treated with lopinavir/ritonavir, though the protease inhibitor levels were not affected by the lipid-lowering drug. Therefore, the combination of rosuvastatin and lopinavir–ritonavir should be used with caution (at the lowest dosage of rosuvastatin) until safety and efficacy of this treatment have been confirmed in further studies [130].

Fibrates represent the cornerstone of drug therapy for hypertriglyceridaemia and mixed hyperlipidaemia. However, concomitant use of both fibrates and statins can increase the risk of skeletal muscle toxicity and should be avoided [129–131]. Second-line lipid-lowering agents include fish oils in patients with hypertriglyceridaemia, ezetimibe in those with increased LDL cholesterol levels, and niacin in those with mixed hyperlipidaemia [115,118,132] (Table 4).

Prevalence of impaired fasting glucose (defined as fasting blood glucose > 100 mg/dl) and impaired glucose tolerance (defined as a 2-h glucose >140 mg/dl after a 75-g glucose load) is increased in patients with HIV infection and higher in those exposed to HAART [133,134]. The initial management approach for the HAART-related hyperglycaemia includes increased physical exercise and dietary therapy. If diet and physical activity fail to achieve the desired level of glucose (defined by fasting glucose concentrations <126 mg/dl or random levels <200 mg/dl) after 8 weeks, patient should be sent to a diabetes specialist and pharmacologic therapy should be considered.

There are very few data about efficacy and safety of antidiabetic medications in HIV-positive patients, but the insulin-sensitizing compounds (such as metformin and thiazolidinediones) seem to be preferable because they can ameliorate insulin resistance and visceral fat accumulation [135–141].

The algorithm for clinical management of cardiovascular risk in HIV-positive patients is suggested in Fig. 3.

Fig. 3
Fig. 3:
Suggested screening and treatment algorithm to assess and reduce cardiovascular risk in HIV-infected patients. Categorical risk factors include age (≥45 years for men, ≥55 years for women), family history of premature coronary heart disease, arterial hypertension (≥140/90 mmHg or receipt of antihypertensive therapy), cigarette smoking, HDL cholesterol less than 40 mg/dl. Moderate-to-high-risk patients are those with a 10-year risk of myocardial infarction at least 10% using Framingham equation. HDL, high density lipoprotein; LDL, low density lipoprotein.


Atherosclerosis in HIV-positive patients is clearly multifactorial in origin and ensues from traditional cardiac risk factors, HIV itself, and antiretroviral therapy. However, the absolute risk of cardiovascular events among HIV-infected patients remains low and must be balanced against the remarkable benefits from HAART in terms of improvement in immune function and related morbidity and mortality.

Maintaining virological suppression should be considered still today the main concern in HIV-infected patients treated with HAART, because short-term rates of cardiovascular complications remain quite low and are significantly lower than death rates for AIDS-related conditions in patients with virological failure and immunological impairment. However, HIV and HAART should be routinely considered among the more traditional risk factors in assessing a patient for coronary heart disease, and a more aggressive intervention to reduce cardiac risk factors in persons with HIV infection is mandatory today.

Nonetheless, as HIV-infected patients live longer on new potent antiretroviral combinations, coronary events could become increasingly frequent and cardiovascular risk evaluation should be performed regularly in these patients, especially after initiation or change of antiretroviral regimen.

Preliminary guidelines regarding pharmacological therapy of metabolic alterations associated with HAART can be made from a limited number of studies. Moreover, the benefit of aggressive management of hyperlipidaemia and diabetes must be balanced with the risk of additional medications, potential drug interactions, additional pill burden, compromise in patient adherence, and potential compromise of optimal HIV infection control.

Further, prospective studies with adequate design (including accuracy of collected data, prospective ascertainment of endpoints, and enough length of follow-up) are certainly needed in order to better investigate the association between HIV disease and myocardial infarction and to define specific guidelines for the management of HIV-related cardiovascular risk.


R.M. and G.V. performed a revision of current data available in the literature and collected the most relevant papers regarding cardiovascular risk in HIV-infected patients. L.C. evaluated the collected data and wrote the article.


1. Holmberg SD, Moorman AC, Williamson JM, Tong TC, Ward DJ, Wood KC, et al. Protease inhibitors and cardiovascular outcomes in patients with HIV-1. Lancet 2002; 360:1747–1748.
2. Friis-Møller N, Sabin CA, Weber R, d'Arminio Monforte A, El Sadr WM, Reiss P, et al, for the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 2003; 349:1993–2003.
3. Stein JH, Klein MA, Bellehumeur JL, McBride PE, Wiebe DA, Otvos JD, et al. Use of human immunodeficiency virus-1 protease inhibitors is associated with atherogenic lipoprotein changes and endothelial dysfunction. Circulation 2001; 104:257–262.
4. De Gaetano Donati K, Rabagliati R, Tumbarello M, Tacconelli E, Amore C, Cauda R, et al. Increased soluble markers of endothelial dysfunction in HIV-positive patients under highly active antiretroviral therapy. AIDS 2003; 17:765–768.
5. Currier JS, Lundgren JD, Carr A, Klein D, Sabin CA, Sax PE, et al. Epidemiological evidence for cardiovascular disease in HIV-infected patients and relationship to highly active antiretroviral therapy. Circulation 2008; 118:e29–e35.
6. Henry K, Melroe H, Huebsch J, Hermundson J, Levine C, Swensen L, et al. Severe premature coronary artery disease with protease inhibitors. Lancet 1998; 351:1328.
7. Vittecoq D, Escaut L, Monsuez JJ. Vascular complications associated with use of HIV protease inhibitors. Lancet 1998; 351:1959.
8. Friedl AC, Attenhofer Jost CH, Schalcher C, Amann FW, Flepp M, Jenni R, et al. Acceleration of confirmed coronary artery disease among HIV-infected patients on potent antiretroviral therapy. AIDS 2000; 14:2790–2792.
9. Stein JH. Managing cardiovascular risk in patients with HIV infection. J Acquir Immune Defic Syndr 2005; 38:115–123.
10. Jütte A, Schwenk A, Franzen C, Römer K, Diet F, Diehl V, et al. Increasing morbidity from myocardial infarction during HIV protease inhibitor treatment? AIDS 1999; 13:1796–1797.
11. Rickerts V, Brodt H, Staszewski S, Stille W. Incidence of myocardial infarctions in HIV-infected patients between 1983 and 1998: the Frankfurt HIV-cohort study. Eur J Med Res 2000; 5:329–333.
12. Klein D, Hurley LB, Quesenberry CP Jr, Sidney S. Do protease inhibitors increase the risk for coronary heart disease in patients with HIV-1 infection? J Acquir Immune Defic Syndr 2002; 30:471–477.
13. Currier JS, Taylor A, Boyd F, Dezii CM, Kawabata H, Burtcel B, et al. Coronary heart disease in HIV-infected individuals. J Acquir Immune Defic Syndr 2003; 33:506–512.
14. Mary-Krause M, Cotte L, Simon A, Partisani M, Costagliola D. Increased risk of myocardial infarction with duration of protease inhibitor therapy in HIV-infected men. AIDS 2003; 17:2479–2486.
15. Escaut L, Monsuez JJ, Chironi G, Merad M, Teicher E, Smadja D, et al. Coronary artery disease in HIV infected patients. Intensive Care Med 2003; 29:969–973.
16. DAD Study Group. Class of antiretroviral drugs and the risk of myocardial infarction.N Engl J Med 2007; 356:1723–1735.
17. Obel N, Thomsen F, Kronborg G, Larsen CS, Hildebrandt PR, Sørensen HT, et al. Ischemic heart disease in HIV-infected and HIV-uninfected individuals: a population-based cohort study. Clin Infect Dis 2007; 44:1625–1631.
18. Iloeje UH, Yuan Y, L'Italien G, Mauskopf J, Holmberg SD, Moorman AC, et al. Protease inhibitor exposure and increased risk of cardiovascular disease in HIV-infected patients. HIV Med 2005; 6:37–44.
19. Kaplan RC, Kingsley LA, Sharrett R, Li X, Lazar J, Tien PC, et al. Ten-year predicted coronary heart disease risk in HIV-infected men and women. Clin Infect Dis 2007; 45:1074–1081.
20. Lang S, Mary-Krause M, Cotte L, Gilquin J, Partisani M, Simon A, et al.Impact of specific NRTI and PI exposure on the risk of myocardial infarction: a case-control study nested within FHDH ANRS CO4 [abstract 43LB]. 16th Conference on Retroviruses and Opportunistic Infections; Montréal, Canada; 8–11 February 2009.
21. Bozzette SA, Ake CF, Tam HK, Chang SW, Louis TA. Cardiovascular and cerebrovascular events in patients treated for human immunodeficiency virus infection. N Engl J Med 2003; 348:702–710.
22. Strategies for Management of Antiretroviral Therapy (SMART) Study Group. Major clinical outcomes in antiretroviral therapy (ART)-naïve participants and in those not receiving ART at baseline in the SMART study.J Infect Dis 2008; 197:1133–1144.
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. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multicohort collaboration.Lancet 2008; 371:1417–1426.
25. Strategies for Management of Antiretroviral Therapy/INSIGHT; DAD Study Groups. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients.AIDS 2008; 22:F17–F24.
26. Obel N, Farkas D, Kronborg G, Larsen C, Pedersen G, Riis A, et al.Abacavir and risk of myocardial infarction in HIV-infected patients on highly active antiretroviral therapy: a population-based nationwide cohort study.HIV Med 2010; 11:130–136.
27. Martin A, Bloch M, Amin J, Baker D, Cooper DA, Emery S, et al. Simplification of antiretroviral therapy with tenofovir-emtricitabine or abacavir-lamivudine: a randomized, 96-week trial. Clin Infect Dis 2009; 49:1591–1601.
28. Brothers CH, Hernandez JE, Cutrell AG, Curtis L, Ait-Khaled M, Bowlin SJ, et al. Risk of myocardial infarction and abacavir therapy: no increased risk across 52 GlaxoSmithKline-sponsored clinical trials in adult subjects. J Acquir Immune Defic Syndr 2009; 51:20–28.
29. Benson C, Ribaudo H, Zheng E, Koletar S, Smurzynski M, Bosch R, et al.No association of abacavir use with risk of myocardial infarction or severe cardiovascular disease events: results from ACTG A5001 [abstract 721.]. 16th Conference on Retroviruses and Opportunistic Infections; Montréal, Canada; 8–11 February 2009.
30. Bedimo R, Westfall A, Drechsler H, Tebas P. Abacavir use and risk of acute myocardial infarction and cerebrovascular disease in the HAART era [abstract MOAB202.]. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Capetown, South Africa; 19–22 July 2009.
31. Smith KY, Patel P, Fine D, Bellos N, Sloan L, Lackey P, et al. Randomized, double-blind, placebo-matched, multicenter trial of abacavir/lamivudine or tenofovir/emtricitabine with lopinavir/ritonavir for initial HIV treatment. AIDS 2009; 23:1547–1556.
32. Maggi P, Lillo A, Perilli F, Maserati R, Chirianni A. Colour-Doppler ultrasonography of carotid vessels in patients treated with antiretroviral therapy: a comparative study. AIDS 2004; 18:1023–1028.
33. Jericò C, Knobel H, Calvo N, Sorli ML, Guelar A, Gimeno-Bayòn JL, et al. Subclinical carotid atherosclerosis in HIV-infected patients: role of combination antiretroviral therapy. Stroke 2006; 37:812–817.
34. Lai S, Lai H, Celentano DD, Vlahov D, Ren S, Margolick J, et al. Factors associated with accelerated atherosclerosis in HIV-1-infected persons treated with protease inhibitors. AIDS Patient Care STDS 2003; 17:211–219.
35. Maggi P, Perilli F, Lillo A, Gargiulo M, Ferraro S, Grisorio B, et al. Rapid progression of carotid lesions in HAART-treated HIV-1 patients. Atherosclerosis 2007; 192:407–412.
36. De Saint Martin L, Vandhuick O, Guillo P, Bellein V, Bressollette L, Roudaut N, et al. Premature atherosclerosis in HIV-positive patients and cumulated time of exposure to antiretroviral therapy (SHIVA study). Atherosclerosis 2006; 185:361–367.
37. Lorenz MW, Stephan C, Harmjanz A, Staszewski S, Buehler A, Bickel M, et al. Both long-term HIV infection and highly active antiretroviral therapy are independent risk factors for early carotid atherosclerosis. Atherosclerosis 2008; 196:720–726.
38. Grunfeld C, Delaney JA, Wanke C, Currier JS, Scherzer R, Biggs ML, et al.Preclinical atherosclerosis due to HIV infection: carotid intima-media thickness measurements from the FRAM study. AIDS 2009; 23:1841–1849.
39. Kingsley LA, Cuervo-Rojas J, Munoz A, Palella FJ, Post W, Witt MD, et al. Subclinical coronary atherosclerosis, HIV infection and antiretroviral therapy: multicenter AIDS Cohort study. AIDS 2008; 22:1589–1599.
40. Sankatsing RR, Wit FW, Vogel M, de Groot E, Brinkman K, Rockstroh JK, et al. Increased carotid intima-media thickness in HIV patients treated with protease inhibitors as compared to nonnucleoside reverse transcriptase inhibitors. Atherosclerosis 2009; 202:589–595.
41. van Vonderen MG, Smulders YM, Stehouwer CD, Danner SA, Gundy CM, Vos F, et al. Carotid intima-media thickness and arterial stiffness in HIV-infected patients: the role of HIV, antiretroviral therapy, and lipodystrophy. J Acquir Immune Defic Syndr 2009; 50:153–161.
42. McComsey GA, O'Riordan M, Hazen SL, El-Beijani D, Bhatt S, Brennan ML, et al. Increased carotid intima-media thickness and cardiac biomarkers in HIV infected children. AIDS 2007; 21:921–927.
43. Maggi P, Perilli F, Lillo A, Volpe A, Pastore G, Regina G. B-mode ultrasound study of carotid plaques in HIV-positive patients to detect the presence of inflammatory endothelial lesions. Curr HIV Res 2009; 7:541–546.
44. Maggi P, Perilli F, Lillo A, Carito V, Epifani G, Bellacosa C, et al. An ultrasound-based comparative study on carotid plaques in HIV-positive patients vs. atherosclerotic and arteritis patients: atherosclerotic of inflammatory lesions? Coronary Artery Dis 2007; 18:23–29.
45. Coll B, Parra S, Alonso-Villaverde C, Aragonés G, Montero M, Camps J, et al. The role of immunity and inflammation in the progression of atherosclerosis in patients with HIV infection. Stroke 2007; 38:2477–2484.
46. Calza L, Verucchi G, Pocaterra D, Pavoni M, Alfieri A, Cicognani A, et al. Cardiovascular risk factors and ultrasound evaluation of carotid atherosclerosis in patients with HIV-1 infection. Int J STD AIDS 2009; 20:683–689.
47. Depairon M, Chessex S, Sudre P, Rodondi N, Doser N, Chave JP, et al. Premature atherosclerosis in HIV-infected individuals-focus on protease inhibitor therapy. AIDS 2001; 15:329–334.
48. Talwani R, Falusi OM, Mendes de Leon CF, Nerad JL, Rich S, Proia LA, et al. Electron beam computed tomography for assessment of coronary artery disease in HIV-infected men receiving antiretroviral therapy. J Acquir Immune Defic Syndr 2002; 30:191–195.
49. Hsue PY, Lo JC, Franklin A, Bolger AF, Martin JN, Deeks SG, et al. Progression of atherosclerosis as assessed by carotid intima-media thickness in patients with HIV infection. Circulation 2004; 109:1603–1608.
50. Mercié P, Thiébaut R, Aurillac-Lavignolle V, Pellegrin JL, Yvorra-Vives MC, Cipriano C, et al. Carotid intima-media thickness is slightly increased over time in HIV-1-infected patients. HIV Med 2005; 6:380–387.
51. Currier JS, Kendall MA, Zackin R, Henry WK, Alston-Smith B, Torriani FJ, et al. Carotid artery intima-media thickness and HIV infection: traditional risk factors overshadow impact of protease inhibitor exposure. AIDS 2005; 19:927–933.
52. Mangili A, Gerrior J, Tang AM, O'Leary DH, Polak JK, Schaefer EJ, et al. 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.
53. Lebech AM, Wiinberg N, Kristoffersen US, Hesse B, Petersen CL, Gerstolft J, et al. Carotid intima-media thickness in HIV patients treated with antiretroviral therapy. Clin Physiol Funct Imaging 2007; 27:173–179.
54. Bongiovanni M, Casana M, Cicconi P, Pisacreta M, Codemo R, Pelucchi M, et al. Predictive factors of vascular intima media thickness in HIV-positive subjects. J Antimicrob Chemother 2008; 61:195–199.
55. Kaplan RC, Kingsley LA, Gange SJ, Benning L, Jacobson LP, Lazar J, et al. Low CD4+ T-cell count is a major atherosclerosis risk factor in HIV-infected women and men. AIDS 2008; 22:1615–1624.
56. Hsue PY, Hunt PW, Schnell A, Craig Kalapus S, Hoh R, Ganz P, et al. Role of viral replication, antiretroviral therapy, and immunodeficiency in HIV-associated atherosclerosis. AIDS 2009; 23:1059–1067.
57. Hulten E, Mitchell J, Scally J, Gibbs B, Villines TC. HIV positivity, protease inhibitor exposure, and subclinical atherosclerosis: a systematic review and meta-analysis of observational studies.Heart 2009; 95:1826–1835.
58. De Gaetano Donati K, Rabagliati R, Iacoviello L, Cauda R. HIV infection, HAART, and endothelial adhesion molecules: current perspectives. Lancet Infect Dis 2004; 4:213–222.
59. Murphy R, Costagliola D. Increased cardiovascular risk in HIV infection: drugs, virus and immunity. AIDS 2008; 22:1625–1627.
60. Koenig W, Khuseyinova N. Biomarkers of atherosclerotic plaque instability and rupture. Arterioscler Thromb Vasc Biol 2007; 27:15–26.
61. van Leuven SI, Franssen R, Kastelein JJ, Levi M, Stroes ES, Tak PP. Systemic inflammation as a risk factor for atherothrombosis. Rheumatology 2008; 47:3–7.
62. Zakynthinos E, Pappa N. Inflammatory biomarkers in coronary artery disease. J Cardiol 2009; 53:317–333.
63. Melendez MM, McNurlan MA, Mynarcik DC, Khan S, Gelato MC. Endothelial adhesion molecules are associated with inflammation in subjects with HIV disease. Clin Infect Dis 2008; 46:775–780.
64. Triant V, Meigs JB, Grinspoon SK. Association of C-reactive protein and HIV infection with acute myocardial infarction. J Acquir Immune Defic Syndr 2009; 51:268–273.
65. Packard RR, Libby P. Inflammation in atherosclerosis: from vascular biology to biomarker discovery and risk prediction. Clin Chem 2008; 54:24–38.
66. Stefano GB, Salzet M, Bilfinger TV. Long-term exposure of human blood vessels to HIV gp120, morphine, and anandamide increases endothelial adhesion of monocytes: uncoupling of nitric oxide release. J Cardiovasc Pharmacol 1998; 31:862–868.
67. 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.
68. Hwang SJ, Ballantyne CM, Sharrett AR, Smith LC, Davis CE, Gotto AM Jr, et al. Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atherosclerosis Risk in Communities (ARIC) study. Circulation 1997; 96:4219–4225.
69. Jager A, Van Hinsbergh VW, Kostense PJ, Emeis JJ, Nijpels G, Dekker JM, et al. Increased levels of soluble vascular cell adhesion molecule I are associated with risk of cardiovascular mortality in type 2 diabetes: the Hoorn study. Diabetes 2000; 49:485–491.
70. Paladugu R, Fu W, Conklin BS, Lin PH, Lumsden AB, Yao Q, et al. HIV Tat protein causes endothelial dysfunction in porcine coronary arteries. J Vasc Surg 2003; 38:549–555.
71. Dhawan S, Puri RK, Kumar A, Duplan H, Masson JM, Aggarwal BB. Human immunodeficiency virus-1-tat protein induces the cell surface expression of endothelial leukocyte adhesion molecule-1, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 in human endothelial cells. Blood 1997; 90:1535–1544.
72. Liu K, Chi DS, Li C, Hall HK, Milhorn DM, Krishnaswamy G. HIV-1 Tat protein-induced VCAM-1 expression in human pulmonary artery endothelial cells and its signaling. Am J Physiol Lung Cell Mol Physiol 2005; 289:L252–L260.
73. Khan NA, Di Cello F, Stins M, Kim KS. Gp120-mediated cytotoxicity of human brain microvascular endothelial cells is dependent on p38 mitogen-activated protein kinase activation. J Neurovirol 2007; 13:242–251.
74. Huang MB, Bond VC. Involvement of protein kinase C in HIV-1 gp120-induced apoptosis in primary endothelium. J Acquir Immune Defic Syndr 2000; 25:375–389.
75. Pace GW, Leaf CD. The role of oxidative stress in HIV disease. Free Radic Biol Med 1995; 19:523–528.
76. Baruchel S, Wainberg WA. The role of oxidative stress in disease progression in individuals infected by the human immunodeficiency virus. J Leukoc Biol 1992; 52:111–114.
77. Galea P, Vermot-Desroches C, Le Contel C, Wijdenes J, Chermann JC. Circulating cell adhesion molecules in HIV-1-infected patients as indicator markers for AIDS progression. Res Immunol 1999; 148:109–117.
78. Farrugia PM, Lucariello R, Coppola JT. Human immunodeficiency virus and atherosclerosis. Cardiol Rev 2009; 17:211–215.
79. Calza L, Pocaterra D, Pavoni M, Colangeli V, Manfredi R, Verucchi G, et al. Plasma levels of VCAM-1, ICAM-1, E-selectin, and P-selectin in 99 HIV-positive patients versus 51 HIV-negative healthy controls. J Acquir Immune Defic Syndr 2009; 50:430–432.
80. Calmy A, Gayet-Ageron A, Montecucco F, Nguyen A, Mach F, Burger F, et al. HIV increases markers of cardiovascular risk: results from a randomized, treatment interruption trial. AIDS 2009; 23:929–939.
81. Kline ER, Sutliff RL. The roles of HIV-1 proteins and antiretroviral drug therapy in HIV-1-associated endothelial dysfunction. J Investig Med 2008; 56:752–769.
82. Vasiliver-Shamis G, Tuen M, Wu TW, Starr T, Cameron TO, Thomson R, et al. Human immunodeficiency virus type 1 envelope gp120 induces a stop signal and virological synapse formation in noninfected CD4+ T cells. J Virol 2008; 82:9445–9457.
83. Takano Y, Shimokado K, Hata Y, Yoshida M. HIV envelope protein gp120-triggered CD4+ T-cell adhesion to vascular endothelium is regulated via CD4 and CXCR4 receptors. Biochim Biophys Acta 2007; 1772:549–555.
84. Blum A, Hadas V, Burke M, Yust I, Kessler A. Viral load of the human immunodeficiency virus could be an independent risk factor for endothelial dysfunction. Clin Cardiol 2005; 28:149–153.
85. Solages A, Vita JA, Thornton DJ, Murray J, Heeren T, Craven DE, et al. Endothelial function in HIV-infected persons. Clin Infect Dis 2006; 42:1325–1332.
86. Monsuez JJ, Charniot JC, Escaut L, Teicher E, Wyplosz B, Couzigou C, et al. HIV-associated vascular diseases: structural and functional changes, clinical implications. Int J Cardiol 2009; 133:293–306.
87. Torriani FJ, Komarow L, Parker RA, Cotter BR, Currier JS, Dubé MP, et al. Endothelial function in human immunodeficiency virus-infected antiretroviral-naïve subjects before and after starting potent antiretroviral therapy: the ACTG (AIDS Clinical Trials Group) study 5152s. J Am Coll Cardiol 2008; 52:569–576.
88. Ross AC, Rizk N, O'Riordan MA, Dogra V, El-Bejjani D, Storer N, et al. Relationship between inflammatory markers, endothelial activation markers, and carotid intima-media thickness in HIV-infected patients receiving antiretroviral therapy. Clin Infect Dis 2009; 49:1119–1127.
89. Calza L, Manfredi R, Chiodo F. Dyslipidaemia associated with antiretroviral therapy in HIV-infected patients. J Antimicrob Chemother 2004; 53:10–14.
90. Grinspoon SK, Grunfeld C, Kotler DP, Currier JS, Lundgren JD, Dubè MP, et al, State of the science conference. Initiative to decrease cardiovascular risk and increase quality of care for patients living with HIV/AIDS. Executive summary. Circulation 2008; 118:198–210.
91. Riddler SA, Smit E, Cole SR, Li R, Chmiel JS, Dobs A, et al. Impact of HIV infection and HAART on serum lipids in men. JAMA 2003; 289:2978–2982.
92. Riddler SA, Li X, Chu H, Kingsley LA, Dobs A, Evans R, et al. Longitudinal changes in serum lipids among HIV-infected men on highly active antiretroviral therapy. HIV Med 2007; 8:280–287.
93. Riddler SA, Li X, Otvos W, Post W, Palella F, Kingsley L, et al. Antiretroviral therapy is associated with an atherogenic lipoprotein phenotype among HIV-1-infected men in the Multicenter AIDS Cohort study. J Acquir Immune Defic Syndr 2008; 48:281–288.
94. Carr A, Samaras K, Cooper CD. Pathogenesis of HIV-1 protease inhibitor-associated peripheral lipodystrophy, hyperlipidemia, and insulin resistance. Lancet 1998; 351:1881–1883.
95. Carr A. HIV lipodystrophy: risk factors, pathogenesis, diagnostic and management. AIDS 2003; 17(Suppl 1):S161–S168.
96. Huy DY. Effects of HIV protease inhibitor therapy on lipid metabolism. Prog Lipid Res 2003; 42:81–92.
97. Thomas CM, Smart EJ. How HIV protease inhibitors promote atherosclerotic lesion formation. Curr Opin Lipidol 2007; 18:561–565.
98. Fisher SD, Miller TL, Lipshultz SE. Impact of HIV and highly active antiretroviral therapy on leukocyte adhesion molecules, arterial inflammation, dyslipidemia, and atherosclerosis. Atherosclerosis 2006; 185:1–11.
99. Sutliff RL, Dikalov S, Weiss D, Parker J, Raidel S, Racine AK, et al. Nucleoside reverse transcriptase inhibitors impair endothelium-dependent relaxation by increasing superoxide. Am J Physiol Heart Circ Physiol 2002; 283:H2363–H2370.
100. Jiang B, Hebert VY, Zavecz JH, Dugas TR. Antiretrovirals induce direct endothelial dysfunction in vivo. J Acquir Immune Defic Syndr 2006; 42:391–395.
101. Coulson R, Johnson RA, Olsson RA, Cooper DR, Scheinman SJ. Adenosine stimulates phosphate and glucose transport in opossum kidney epithelial cells. Am J Physiol 1991; 260:F921–F928.
102. Hsue PY, Hunt PW, Wu Y, Schnell A, Ho JE, Hatano H, et al.Association of abacavir and impaired endothelial function in treated and suppressed HIV-infected patients. AIDS 2009; 23:2021–2027.
103. Parker WB, Shaddix SC, Bowdon BJ, Rose LM, Vince R, Shannon WM, et al. Metabolism of carbovir: a potent inhibitor of human immunodeficiency virus type 1, and its effect on cellular metabolism. Antimicrob Agents Chemother 1993; 37:1004–1009.
104. Hammond E, McKinnon E, Mallal S, Nolan D. Longitudinal evaluation of cardiovascular disease-associated biomarkers in relation to abacavir therapy. AIDS 2008; 22:2540–2543.
105. Martinez E, Larrousse M, Perez I, Lonca' M, Podzamczer D, Gutierrez F, et al.No evidence for recent abacavir/lamivudine use in promoting inflammation, endothelial dysfunction, hypercoagulability, or insulin resistance in virologically suppressed HIV-infected patients: a substudy of the BICOMBO randomized clinical trial [abstract MOAB203]. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Cape Town, South Africa; 19–22 July 2009.
106. Nolan D, Watts GF, Herrmann SE, French MA, John M, Mallal S. Endothelial function in HIV-infected patients receiving protease inhibitor therapy: does immune competence affect cardiovascular risk? QJM 2003; 96:825–832.
107. Lichtner M, Cuomo MR, Rossi R, Strano S, Massetti AP, Mastroianni CM, et al. Increased carotid intima media thickness is associated with depletion of circulating myeloid dendritic cells in HIV-infected patients on suppressive antiretroviral treatment. Atherosclerosis 2009; 204:e1–e3.
108. 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.
109. Ferrario M, Chiodini P, Chambless LE, Cesana G, Vanuzzo D, Panico S, et al, for the CUORE Project Research Group. Prediction of coronary events in a low incidence population: assessing accuracy of the CUORE Cohort Study prediction equation. Int J Epidemiol 2005; 34:413–421.
110. Law MG, Friis-Moller N, El-Sadr WM, Weber R, Reiss P, D'Arminio-Monforte A, et al. 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.
111. Schambelan M, Wilson PW, Yarasheski KE, Cade WT, Davila-Roman VG, D'Agostino RB, et al. Development of appropriate coronary heart disease risk prediction models in HIV-infected patients. Circulation 2008; 118:e48–e53.
112. Bergersen BM, Sandvik L, Bruun JN, Tonstad S. Elevated Framingham risk score in HIV-positive patients on highly active antiretroviral therapy: results from a Norwegian study of 721 subjects. Eur J Clin Microbiol Infect Dis 2004; 23:625–630.
113. May M, Sterne JA, Shipley M, Brunner E, d'Agostino R, Whincup P, et al. A coronary heart disease risk model for predicting the effect of potent antiretroviral therapy in HIV-1 infected men. Int J Epidemiol 2007; 36:1309–1318.
114. Calza L, Manfredi R, Pocaterra D, Chiodo F. Risk of premature atherosclerosis and ischemic heart disease associated with HIV infection and antiretroviral therapy. J Infect 2008; 57:16–32.
115. Dubé MP, Stein JH, Aberg JA, Fichtenbaum CJ, Gerber JG, Tashima KT, et al. Guidelines for the evaluation and management of dyslipidemia in human immunodeficiency virus (HIV)-infected adults receiving antiretroviral therapy: recommendations of the HIV Medicine Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group. Clin Infect Dis 2003; 37:613–627.
116. Carosi G, Quiros-Roldan E, Torti C, Antinori A, Bevilacqua M, Bonadonna RC, et al. First Italian Consensus Statement on Diagnosis, Prevention and Treatment of Cardiovascular complications in HIV-infected patients in the HAART era (2006). Infection 2007; 35:134–142.
117. Grundy SM, Cleeman JI, Merz NB, Brewer HB Jr, Clark LT, Hunninghake DB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 2004; 110:227–239.
118. Lundgren JD, Battegay M, Behrens G, De Wit S, Guaraldi G, Katlama C, et al. European AIDS Clinical Society (EACS) guidelines on the prevention and management of metabolic diseases in HIV. HIV Med 2008; 9:72–81.
119. European AIDS Clinical Society (EACS). Guidelines. Prevention and management of noninfectious comorbidities in HIV.
120. Gritz ER, Vidrine DJ, Lazev AB, Amick BC III, Arduino RC. Smoking behaviour in a low-income multiethnic HIV/AIDS population. Nicotine Tob Res 2004; 6:71–77.
121. Jones SP, Doran DA, Leatt PB, Maher B, Pirmohamed M. Short-term exercise training improves body composition and hyperlipidaemia in HIV-positive individuals with lipodystrophy. AIDS 2001; 15:2049–2051.
122. Calza L, Manfredi R, Colangeli V, Tampellini L, Sebastiani T, Pocaterra D, et al. Substitution of nevirapine or efavirenz for protease inhibitor versus lipid-lowering therapy for the management of dyslipidaemia. AIDS 2005; 19:1051–1058.
123. Moyle GJ, Sabin CA, Cartledge J, Johnson M, Wilkins E, Churchill D, et al. A randomized comparative trial of tenofovir DF or abacavir as replacement for a thymidine analogue in persons with lipoatrophy. AIDS 2006; 20:2043–2050.
124. Gatell J, Salmon-Ceron D, Lazzarin A, Van Wijngaerden E, Antunes F, Leen C, et al. Efficacy and safety of atazanavir-based highly active antiretroviral therapy in patients with virologic suppression switched from a stable, boosted or unboosted protease inhibitor treatment regimen: the SWAN study (AI424-097) 48-week results. Clin Infect Dis 2007; 44:1484–1492.
125. Cocohoba J. The SWITCHMRK studies: substitution of lopinavir/ritonavir with raltegravir in HIV-positive individuals. Expert Rev Anti Infect Ther 2009; 7:1159–1163.
126. Calza L, Manfredi R, Chiodo F. Statins and fibrates for the treatment of hyperlipidaemia in HIV-infected patients receiving HAART. AIDS 2003; 17:851–859.
127. McGoldrick C, Leen CL. The management of dyslipidaemias in antiretroviral-treated HIV infection: a systematic review. HIV Med 2007; 8:325–334.
128. Calza L. Long-term use of rosuvastatin: a critical risk benefit appraisal and comparison with other antihyperlipidemics. Drug Health Patient Saf 2009; 1:25–33.
129. Calza L, Colangeli V, Manfredi R, Legnani G, Tampellini L, Pocaterra D, et al. Rosuvastatin for the treatment of hyperlipidaemia in HIV-infected patients receiving protease inhibitors: a pilot study. AIDS 2005; 19:1103–1105.
130. van der Lee M, Sankatsing R, Schippers E, Vogel M, Fätkenheuer G, van der Ven A, et al. Pharmacokinetics and pharmacodynamics of combined use of lopinavir-ritonavir and rosuvastatin in HIV-infected patients. Antivir Ther 2007; 12:1127–1132.
131. Calza L, Manfredi R, Chiodo F. Use of fibrates in the management of hyperlipidaemia in HIV-infected patients receiving HAART. Infection 2002; 30:26–31.
132. Manfredi R, Calza L, Chiodo F. Polyunsaturated ethyl esters of n-3 fatty acids in HIV-infected patients with moderate hypertriglyceridemia: comparison with dietary and lifestyle changes, and fibrate therapy. J Acquir Immune Defic Syndr 2004; 36:878–880.
133. Hadigan C. Diabetes, insulin resistance, and HIV. Curr Infect Dis Rep 2006; 8:69–75.
134. Brown TT, Cole SR, Li X, Kingsley LA, Palella FJ, Riddler SA, et al. Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the multicenter AIDS cohort study. Arch Intern Med 2005; 165:1179–1184.
135. 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.
136. Hadigan C, Rabe J, Grinspoon S. Sustained benefits of metformin therapy on markers of cardiovascular risk in human immunodeficiency virus-infected patients with fat redistribution and insulin resistance. J Clin Endocrinol Metab 2002; 87:4611–4615.
137. Van Vijk JP, De Koning EJ, Cabezas MC, Roodt J, Joven J, Rabelink TJ, et al. Comparison of rosiglitazone and metformin for treating HIV lipodystrophy. Ann Intern Med 2005; 143:337–346.
138. Sutinen J, Hakkinen K, Westerbacka J. Rosiglitazone in the treatment of HAART-associated lipodystrophy: a randomized double-blind placebo-controlled study. Antivir Ther 2003; 8:199–207.
139. Carr A, Workman C, Carey D, Rogers G, Martin A, Baker D, et al. No effect of rosiglitazone for treatment of HIV-1 lipoatrophy: randomised, double-blind, placebo-controlled trial. Lancet 2004; 363:429–438.
140. Oette M, Kurowski M, Feldt T, Kroidl A, Sagir A, Vogt C, et al. Impact of rosiglitazone treatment on the bioavailability of antiretroviral compounds in HIV-positive patients. J Antimicrob Chemother 2005; 56:416–419.
141. Aberg JA. Cardiovascular complications in HIV management: past, present, and future. J Acquir Immune Defic Syndr 2009; 50:54–64.

antiretroviral therapy; cardiovascular risk; endothelial dysfunction; HIV infection; myocardial infarction

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