Risk of premature atherosclerosis and ischemic heart disease associated with HIV infection and antiretroviral therapy

Journal of Infection (2008) 57, 16e32

www.elsevierhealth.com/journals/jinf

REVIEW

Risk of premature atherosclerosis and ischemic heart disease associated with HIV infection and antiretroviral therapy Leonardo Calza*, Roberto Manfredi, Daria Pocaterra, Francesco Chiodo Department of Clinical and Experimental Medicine, Section of Infectious Diseases, ‘‘Alma Mater Studiorum’’ University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy Accepted 10 February 2008 Available online 21 March 2008

KEYWORDS HIV infection; Antiretroviral therapy; Cardiovascular diseases; Dyslipidaemia; Insulin resistance

Summary The use of new potent protease inhibitor-based antiretroviral therapies in patients with human immunodeficiency virus (HIV) infection has been increasingly associated with cardiovascular risk factors, including hyperlipidaemia, fat redistribution syndrome, insulin resistance, and diabetes mellitus. The introduction of highly active antiretroviral therapy (HAART) in clinical practice has remarkably changed the natural history of HIV disease, leading to a notable extension of life expectancy, and prolonged lipid and glucose metabolism abnormalities are expected to lead to significant effects on the long-term prognosis and outcome of HIV-infected patients. Prediction modeling, surrogate markers and hard cardiovascular endpoints suggest an increased incidence of cardiovascular diseases in HIV-infected subjects receiving HAART, even though the absolute risk of cardiovascular complications remains still low, and must be balanced against the evident virological, immunological, and clinical benefits descending from combination antiretroviral therapy. Nevertheless, the assessment of cardiovascular risk should be performed on regular basis in HIV-positive individuals, especially after initiation or change of antiretroviral treatment. Appropriate lifestyle measures (including smoking cessation, dietary changes, and aerobic physical activity) are critical points, and switching HAART may be considered, although maintaining viremic control should be the main goal of therapy. Pharmacological treatment of dyslipidaemia (usually with statins and fibrates), and hyperglycaemia (with insulin-sensitizing agents and thiazolidinediones), becomes suitable when lifestyle modifications and switching therapy are ineffective or not applicable. ª 2008 The British Infection Society. Published by Elsevier Ltd. All rights reserved.

* Corresponding author. Department of Clinical and Experimental Medicine, Section of Infectious Diseases, ‘‘Alma Mater Studiorum’’ University of Bologna, S. Orsola-Malpighi Hospital, via G. Massarenti 11, I-40138 Bologna, Italy. Tel.: þ39 051 636 3355; fax: þ39 051 343 500. E-mail address: [email protected] (L. Calza). 0163-4453/$34 ª 2008 The British Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2008.02.006

HIV infection and cardiovascular diseases

17

Introduction

Lipodystrophy syndrome

The introduction in clinical practice of protease inhibitors (PIs) as a component of highly active antiretroviral therapy (HAART) has dramatically reduced morbidity and mortality associated with the human immunodeficiency virus (HIV) infection.1 However, long-term toxicity of antiretroviral drugs is becoming recognized and widely assessed, therefore detecting a wide range of side effects including fat redistribution syndrome (or lipodystrophy) and metabolic alterations (such as dyslipidaemia and insulin resistance).2 Since new PI-containing antiretroviral regimens have led to a notable extension of life expectancy in HIV-positive patients, prolonged lipid and glucose metabolism abnormalities could significantly act on the long-term prognosis and outcome of HIV-infected persons. An increasing concern is mounting particularly about the increased risk of cardiovascular complications, as recently described in two large prospective studies.3,4 Besides, some data suggest that endothelial dysfunction, impaired fibrinolysis, and excess inflammation are more common in HIV-positive patients than in general population, and may contribute to an increased cardiovascular risk.5 At the same time, carotid intimal-media thickness and coronary calcification assessments suggest increased incidence of atherosclerotic disease and premature occurrence of arterial atherosclerotic lesions among HIV-infected individuals.6 Finally, recent reports raise the suspicion that combination antiretroviral therapy may also induce arterial hypertension,7e9 even though a few comparative studies on blood pressure in HIV-positive subjects have been reported still today. Although hypolipidaemic diet and physical exercise may certainly improve dyslipidaemia and insulin resistance, the use of non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, or the nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) abacavir and tenofovir, or the PI atazanavir is usually associated with a more favourable metabolic profile and may be helpful in this setting. However pharmacological treatment (with lipid-lowering or anti-diabetic drugs) become mandatory when plasma lipid or glucose levels excessively increase or persist for a long time, but the choice of drugs is often influenced by adjunctive problems, including expected drugedrug interactions with antiretroviral compounds, toxicity, and decreased patient adherence to multiple pharmacological regimens.10 Current guidelines recommend that the risk of cardiovascular disease be assessed from a conventional riskprediction model, such as the Framingham score, but few studies have explored whether such models accurately predict the risk of coronary heart disease in HIV-positive patients.11 The present review take into consideration of the most recent literature data on cardiovascular side effects and cardiovascular risk associated with antiretroviral therapy. Moreover, the prevalence and pathogenesis of lipid and glucose metabolism alterations will be discussed, in conjunction with pharmacological and non-pharmacological strategies for cardiovascular disease prevention.

Lipodystrophy syndrome is a common term in the literature traditionally used to describe several morphologic (fat loss and fat accumulation) and/or metabolic (dyslipidaemia, insulin resistance and hyperglycaemia) disturbances extensively reported in HIV-infected patients receiving antiretroviral therapy, especially in PI-treated adults and children.2,12,13 However, it remains uncertain if the occurrence of abnormal body fat distribution, hyperlipidaemia and glucose metabolism alteration are interrelated and associated with PI clinical use only. Even though morphologic and metabolic alterations appear to be a prevalent condition among patients receiving a PI-based treatment, these abnormalities have been sometimes associated with the administration of NRTIs and NNRTIs. Moreover, increasing evidence suggest these disorders, though commonly clustering in a syndromal pattern, have distinct pathologic pathways and may occur independently of each other.14,15 A classification of morphological and metabolic abnormalities included in the lipodystrophy syndrome is summarized in Table 1. Abnormalities of body composition have been very commonly reported in HIV-infected patients receiving combination antiretroviral therapy, but prevalence rates vary widely (from 11 to 83%), when comparing the available cross-sectional studies.16e18 The fat redistribution syndrome includes lipoatrophy, lipohypertrophy and a mixed form (including both abnormalities at a different extent). Lipoatrophy indicates a localized subcutaneous fat loss in the face, arms, legs, and buttocks. Lipohypertrophy usually represents a central visceral fat accumulation in the abdomen, but can also be found in breasts, dorsocervical region (‘‘buffalo hump’’), lipomata, and within the muscle and liver. Lipoatrophy and lipohypertrophy are frequently associated (mixed form), but they may also be occur independently of each other.16 A clear-cut definition of clinically significant peripheral fat loss and central fat accumulation have not yet been Table 1 Classification of morphological and metabolic disorders included in the lipodystrophy syndrome, as proposed by the Antiretroviral-Associated Lipodystrophy European Comparative Study (ALECS) Group Type

Main morphological and metabolic features

Subclassification

I

Fat loss (lipoatrophy)

a) Without Bichat fat pad reduction b) With Bichat fat pad reduction

II

Fat accumulation (lipohypertrophy)

c) Involvement of 1 site (excluding lipoma) d) Involvement of >1 site e) Lipomatosis

III

Combined form

(a/b) þ (c/d/e)

IV

Isolated metabolic alterations

18 established. A preliminary case definition based on data obtained by dual-energy X-ray absorptiometry and computed tomography (CT) was recently validated in a prospective study by the HIV Lipodystrophy Case Definition Study Group.19 Based on a case-control study of patients with or without features of fat redistribution, this case definition includes ten different variables: gender, age, duration of HIV infection, stage of disease, waist/hip circumference ratio, anion gap, high-density lipoprotein (HDL) cholesterol, leg fat percentage, trunk/limb fat ratio, and intra-abdominal/superficial abdominal fat ratio. This case definition has 79% sensitivity and 80% specificity for the diagnosis of fat redistribution, and may be used to obtain a more precise evaluation of the incidence and prevalence of the morphological alterations in HIV-infected subjects. Prospective studies investigating body composition in patients starting antiretroviral therapy for the first time have shown initial increases in limb fat during the first few months of therapy, followed by a progressive decline during the ensuing three years. In contrast, truncal fat increases initially and then remains stable during the ensuing two to three years, resulting in relative central adiposity. Abnormalities in peripheral and central fat masses are clinically evident in 20e35% of patients after approximately 12e 24 months of combination antiretroviral treatment.16,20e22 Risk factors and pathogenetic pathways leading to the occurrence of lipodystrophy associated with HAART are not fully understood still today. The most common statistically significant risk factors associated with lipoatrophy are exposure to and duration of nucleoside thymidine analogues (most commonly stavudine), age, presence of markers of disease severity (CD4 lymphocyte count and plasma HIV viral load), duration of therapy, and the white (Caucasian) race. On the other hand, the most common statistically significant risk factors for lipohypertophy are duration of therapy, PI administration, markers of disease severity, and age. However, rigorous multivariate analyses controlled for numerous variables detect multiple risk factors, suggesting that the pathogenetic mechanisms for fat redistribution syndrome are likely the result of complex interactions between host, infection, and drugs.15 PI may induce lipoatrophy by inhibiting sterol regulatory enhancer-binding protein 1 (SREBP1)-mediated activation of the heterodimer consisting of adipocyte retinoid X receptor and peroxisome proliferator-activated receptor g (PPARg) or related transcription factors such as coactivator PPARg 1.23,24 Furthermore, in vitro studies have demonstrated that PIs can inhibit lipogenesis and adypocyte differentiation, stimulate lipolysis, and impair SREBP1 nuclear localization, leading to adipocyte apoptosis and peripheral fat loss.25e27 Lipoatrophy associated with nucleoside analogues may be due in part to mitochondrial damage resulting from inhibition of DNA polymerase g within adipocytes and depletion of mitochondrial DNA induced by NRTIs (mostly stavudine, zidovudine, and didanosine). Nucleoside analogues may inhibit adipogenesis and adipocyte differentiation, promote lipolysis, and exert synergistic toxic effects with those of PIs.28e31 Moreover, lipoatrophic tissue from HIV-positive patients showed increased expression of tumor necrosis factor-a (a cytokine known to induce apoptosis of adipocytes) and dysregulation of 11-b-hydroxysteroid dehydrogenase (an enzyme implicated in the conversion of the hormonally

L. Calza et al. inactive cortisone to cortisol, which is required for adipocyte differentiation).15 Recent data suggest that HIV-1 Vpr (an accessory viral protein) expressed at low levels in adipose tissue and liver can circulate in the blood, regulate lipid and fatty acid metabolism, and alter fuel selection for oxidation in the fasted state.32 It is well established that increased truncal adiposity is associated with a greater risk of cardiovascular complications in the general population. Intra-abdominal visceral fat delivers excess free fatty acids directly into the portal blood system and secretes cytokines and other factors that contribute to insulin resistance, impaired fibrinolysis, and endothelial dysfunction.33e35 Moreover, excess central adiposity is an established risk factor for insulin resistance in HIV-negative individuals, and in HIV-positive patients increased waist-to-hip ratio is often a function of increased waist and reduced hip circumference, and is associated with increased metabolic risk indices, such as hyperlipidaemia.36

Dyslipidaemia A wide range of lipid metabolism abnormalities has been increasingly recognized among HIV-infected subjects since the introduction of HAART. Even though therapy with stavudine, zidovudine, didanosine or efavirenz has been sometimes associated with the occurrence of dyslipidaemia, disorders of plasma lipid levels appear to be more frequent among patients receiving PIs.10,14 The scenario of plasma lipid profile alterations associated with antiretroviral treatment includes hypertriglyceridaemia, increased total and low density lipoprotein (LDL) cholesterol, decreased high density lipoprotein (HDL) cholesterol, and mixed forms. In patients receiving HAART the prevalence of hyperlipidaemia ranges from 28 to 80% in different studies, and it includes hypertriglyceridaemia in the majority of cases (40e80%), followed by hypercholesterolaemia (10e50%) and mixed forms (10e40%).14 In a recent, large cross-sectional study, the prevalence of hypertriglyceridaemia was 40% in subjects receiving antiretroviral therapy that included a PI, 32% in those treated with antiretroviral therapy that included an NNRTI, and 23% in those receiving only NRTIs, while the prevalence of hypercholesterolaemia was 27%, 23%, and 10%, respectively.37 Data from prospective cohort studies describe new-onset hypertriglyceridaemia and hypercholesterolaemia after 5 years of HAART in 19% and 24% of subjects, respectively.38 On the contrary, recent longitudinal data reinforced that HIV infection itself is associated with reduced serum levels of total, LDL and HDL cholesterol. In this study, after the initiation of HAART total and LDL cholesterol concentrations increase to pre-infection values, whereas HDL cholesterol remains low.39 Dyslipidaemia is frequently, but not always associated with fat redistribution syndrome: although lipid and glucose metabolism alterations are more common in patients with body-fat abnormalities, they are also observed in those without these morphological changes. It has been reported that metabolic alterations usually precede the body fat

HIV infection and cardiovascular diseases redistribution. Particularly, a lipoatrophy picture is more commonly related to the hypertriglyceridaemia, while lipohypertrophy is more frequently accompanied by mixed hyperlipidaemia and insulin resistance.14 Epidemiological, clinical, and laboratory risk factors for the HAART-related hyperlipidaemia are still controversial when comparing the different available published reports. Lipid levels are influenced by gender, age, estrogen use, and heritable factors, including lipoprotein genotype in HIVpositive patients. However, various HIV-related variables, such as plasma viral load, CD4 lymphocyte count, stage of HIV infection, opportunistic diseases, and mechanism of HIV acquisition appear to have controversial or modest direct affects on hyperlipidaemia and atherosclerotic disease.6 Even though elevations in serum lipid levels have been associated with all the available PIs, hypertriglyceridaemia seems more common in patients receiving a ritonavir, ritonaviresaquinavir, or ritonavirelopinavir combination therapy, compared with indinavir-, nelfinavir-, or amprenavir-based ones, and may sometimes be extreme, reaching a triglyceride plasma concentration >1000 mg/dL in patients on ritonavir therapy. At the same time, a mild to moderate increase in total and LDL cholesterol levels seems more frequent among patients treated with ritonavir and probably nelfinavir, as opposed to indinavir. On the other hand, the newer PI atazanavir seems to have a significantly less pronounced effect on plasma lipid levels,39e43 and the full-dose ritonavir is practically out of use nowadays. Several pathogenetic mechanisms have been proposed to explain the HAART-associated hyperlipidaemia, which seems the result of a complex and multifactorial pathologic process. The common elements in these proposed mechanisms are an increased intra-hepatic production and an impaired clearance of lipids from the bloodstream. The first hypothesized mechanism is based upon the structural similarity between the catalytic region of HIV-1 protease and two human proteins involved in the lipid metabolism: the cytoplasmic retinoic acid-binding protein type 1 (CRABP-1) and the low-density lipoprotein-receptorrelated protein (LRP). PIs probably bind to CRABP-1 and erroneously inhibit the formation of cis-9-retinoic acid, leading to increased apoptosis of peripheral adipocytes, decreased lipid storage and increased lipid release into the bloodstream. Similarly, PIs may inhibit the normal function of LRP and interfere with fatty acid storage in the adipocytes.44 Furthermore, preliminary data from in vitro and in vivo studies suggest that PIs may prevent proteosomal degradation of nascent apolipoprotein B, a key protein component of circulating triglycerides, leading to increased production of very low-density lipoprotein (VLDL) particles. An up-regulation of metabolic pathways leading to an excessive production of VLDL, can also be caused by the PI-induced intra-hepatocyte accumulation of nuclear transcription factors involved in the metabolism of apolipoprotein B, such as sterol regulatory binding proteins. In addition, the levels of lipoprotein particles containing apolipoprotein C-III and apolipoprotein E increase in PI-treated patients.43e46 The mitochondrial toxicity found in HIV-infected patients and mostly associated with NRTI therapy could also play a role in the occurrence of antiretroviral-induced dyslipidaemia. Nucleoside analogues would cause mitochondrial

19 DNA depletion and respiratory chain dysfunction by inhibiting the mitochondrial DNA polymerase, leading to several abnormalities in different cell types, including adipocytes.47 Since the peripheral lipoatrophy is seen most often in the lower extremities and buttocks, the femoral-gluteal adipose depot probably represents the most significant site of dysregulation. The increased net plasma flux of free fatty acids from peripheral fat depots lead to a greater free fatty acids uptake in other tissues, such as skeletal muscle, central fat depots, and liver. In the liver, increased uptake of fatty acids enhances the synthesis of triglycerides and apolipoprotein B, reduces the degradation of apolipoprotein B, and increases the production of VLDL, contributing to the observed hypertriglyceridaemia, as proposed by the ‘‘systemic steatosis’’ model.48 Finally, HAART-associated dyslipidaemia probably involves a genetic predisposition, too. Recent experimental researches document an evident association between increased serum triglyceride levels and several polymorphisms found in the apo C-III gene. Variations at nucleosides 455 and 482 are both associated with increased concentrations of VLDL and decreased levels of HDL cholesterol.49

Insulin resistance, diabetes and metabolic syndrome Glucose metabolism alterations are frequent in HIV-positive individuals treated with antiretroviral agents, and may include insulin resistance, impaired glucose tolerance, and a frank diabetes mellitus. Hyperinsulinaemia, a surrogate measure of insulin resistance, is commonly seen in individuals treated with antiretroviral combinations, mostly in association with central fat accumulation, ‘‘buffalo hump’’, fat loss in the limbs, and increased waist-to-hip ratio. The prevalence of insulin resistance in HAART-treated population is not known, but data from cross-sectional studies suggest that up to 30e40% of these patients may be affected. On the other hand, frank hyperglycaemia is more rarely reported among subjects treated with antiretroviral drugs. In fact, the prevalence of impaired glucose tolerance and diabetes mellitus is usually below 10e15%, with the higher estimates including diabetes diagnosed by oral glucose tolerance testing (up to 40%).17 Recent data from the Multicenter AIDS Cohort Study (MACS) using the World Health Organization criteria (fasting glucose >110 mg/dL defines impaired glucose tolerance and >126 mg/dL defines diabetes) found diabetes mellitus in 14% of men, with an odds ratio of 4.4 after adjustment for age and body mass index. Risk factors associated with the development of diabetes included exposure to PIs, stavudine or efavirenz, which were independently associated with this metabolic disorder.50 The pathogenesis of glucose metabolism disorders is still unclear and, although a direct effect of potent antiretroviral combinations is certainly involved, it is likely that multiple factors play a role, including genetic predisposition, cytokine and hormonal alterations, changes in the immune system, non-antiretroviral drug-induced toxic effects, opportunistic diseases, and perhaps the HIV infection itself. Risk factors for the development of insulin resistance

20 in HIV-positive population include duration of antiretroviral therapy, PI treatment, concurrent fat redistribution syndrome, dyslipidaemia, increasing age, hepatitis C virus coinfection, as well as pharmacological treatment with pentamidine or megestrol acetate.17,50,51 Particularly, PI therapy is associated with higher rates of diabetes mellitus, impaired glucose tolerance, and hyperinsulinaemia. A direct link between antiretroviral therapy and abnormal glucose homeostasis has been recently substantiated for indinavir and lopinavir-ritonavir, while atazanavir and saquinavir appear less likely to induce insulin resistance.41 The pathogenetic mechanism responsible for the HAART-associated insulin resistance may mimic the pathogenesis in type 2 diabetes mellitus, which greatly resembles to the glucose homeostasis disorders observed in the setting of lipodystrophy syndrome. In such a context, reduced binding of insulin to its receptors, alterations in intracellular pathways, and a reduced cellular uptake of glucose may be involved, leading to initial decrease in insulin sensitivity and hyperinsulinaemic state, with normal glucose tolerance. Subsequently, the inability of the pancreatic b-cells to maintain elevated insulin secretion would result a hypoinsulinaemic state, with severe hyperglycaemia and hyperlipidaemia.51 Experimental data have shown that excess free fatty acids in the circulation may reduce insulin sensitivity through inappropriate lipid storage in skeletal muscle and liver, resulting in impaired glucose utilization and insulinmediated inhibition of glycogenolysis and gluconeogenesis.51,52 Moreover, glucose and lipid metabolism alterations in HIV-infected patients with lipodystrophy were simultaneously observed in liver, muscle tissue and pancreatic beta-cells. Compared with patients without lipodystrophy or naı¨ve to antiretroviral agents, subjects with lipodystrophy show reduced hepatic insulin sensitivity, incremental glucose disposal, incremental exogenous glucose storage, and attenuated insulin-mediated suppression of lipid oxidation. These data suggest that normoglycaemic lipodystrophic individuals display impaired glucose and lipid metabolism in multiple pathways, including liver, muscle tissue and betacell function.53 PIs (including indinavir, amprenavir, nelfinavir, and ritonavir) have been shown to induce insulin resistance in vitro by reducing glucose transport mediated by the glucose transporter 4, without affecting postreceptor insulin signalling.50,51 Mitochondrial damage could also contribute to the detrimental effect of NRTIs on tissue insulin sensitivity either through the oxidative phosphorylation dysfunction and excess lipid accumulation in liver and muscle. Further more, administration of stavudine may cause changes in lipolysis, resulting in increased serum free fatty acids and decreased insulin sensitivity.50,53e57 In the general population, hyperinsulinaemia and hyperglycaemia were found to be independent risk factors for atherosclerosis, coronary heart disease and cerebrovascular disease, apart from their effects on lipids and endothelial cell function. In HIV-positive subjects, abnormal body fat distribution strongly predicts insulin resistance and/or glucose intolerance, and fat redistribution syndrome is frequently associated with lipid and glucose metabolism abnormalities. The association of central adiposity, hyperinsulinaemia and

L. Calza et al. dyslipidaemia is close to that reported to be present in the very common metabolic syndrome, and some of the pathophysiological mechanisms are probably the same. The metabolic syndrome (also called syndrome X or insulin resistance syndrome) is affecting the general population in epidemic proportions and is commonly associated with increased cardiovascular risk.58 The National Cholesterol Education Program Adult Treatment Panel (ATP) III has recently reviewed the working definition of this syndrome. The diagnosis requires at least three of the following criteria: waist circumference 102 cm in men and 88 cm in women; fasting triglycerides 150 mg/dL (1.69 mmol/l); HDL cholesterol <40 mg/dL (1.04 mmol/l) in men and <50 mg/dL (1.29 mmol/l) in women; fasting glucose 100 mg/dL (6.1 mmol/l); and blood pressure 130/ 85 mmHg. Patients meet criteria for high blood pressure or high glucose concentration if they are currently on antihypertensive or oral hypoglycaemic drugs, respectively.59 In Southern Europe the prevalence of this syndrome in the general population is lower than 10%, while in the United States it is up to 25% of adults. Diagnosis of metabolic syndrome is also frequently performed among HIV-infected individuals receiving antiretroviral therapy.60 In a recent, cross-sectional study involving 710 ambulatory HIV-positive persons, the prevalence of metabolic syndrome was 17%, and its occurrence was independently associated with increasing age, higher body mass index, past and current exposure to PIs, and diagnosis of lipodystrophy syndrome. When assessing the role of individual antiretroviral drugs in its pathogenesis, only stavudine and lopinavir/ritonavir were independently associated with the occurrence of metabolic syndrome.61 Wand et al. evaluated 881 HIV-positive persons initiating HAART for prevalence and incidence of metabolic syndrome, type 2 diabetes mellitus, and cardiovascular diseases. Substantial progression to metabolic syndrome occurs within 3 years following initiation of antiretroviral treatment and incidence of this syndrome was significantly associated with an increased risk of diabetes mellitus and cardiovascular diseases.62 The metabolic syndrome is usually associated with increased levels of LDL cholesterol, uric acid, and plasminogen activator inhibitor-1 (PAI-1), together with insulin resistance, which appears to play a central role in this hypothesized pathogenetic pathway. Moreover, the metabolic syndrome is commonly accompanied by visceral fat accumulation with central obesity, non-alcoholic steatohepatitis, and development of premature atherosclerotic lesions, with a significantly increased risk of cardiovascular complications.59e61 Mangili et al. examined the association between carotid and coronary atherosclerosis and metabolic syndrome in HIV-infected adults, and demonstrated that HIV-positive persons with metabolic syndrome were more likely to have higher values of carotid intima-media thickness and detectable coronary artery calcium score.63

Endothelial dysfunction and atherosclerosis Contradictory reports have been published concluding that HIV infection and antiretroviral therapy do or do not

HIV infection and cardiovascular diseases promote atherogenesis. Endothelial dysfunction, reduced flow-mediated arterial dilatation and premature atherosclerotic lesions have been reported among HIV-infected patients receiving HAART, and new data highlight the incidence of cardiovascular events in this population. However, whether the increased cardiovascular risk in HIV-positive subjects 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. Recent data support the hypothesis that both HIV infection and antiretroviral treatment promote atherosclerosis and its clinical manifestations through inflammatory mechanisms involving endothelial cells, either directly or indirectly, also by the lipid alterations they induce.64,65 Endothelial cells have been shown to be variably permissive for HIV infection. The HIV virus itself is able to penetrate coronary artery and brain microvascular endothelial cell membrane, and to initiate inflammatory and biochemical intracellular reactions. Endothelial activation may also occur either by cytokines secreted in response to mononuclear or adventitial cell activation by the HIV virus, or by the effects of gp120 and Tat, two secretory HIVassociated proteins.66,67 The activation of endothelium induced by either HIV infection itself or by a leukocyte-mediated inflammatory cascade triggered by the same virus leads to the increased expression of endothelial cellular adhesion molecules, such as intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), E-selectin, P-selectin, thrombomodulin, tissue plasminogen activator (tPA), and plasminogen activator inhibitor 1 (PAI-1). A significant association between increasing serum concentrations of adhesion molecules and risk of future myocardial infarction has been shown in apparently healthy men and women, and these molecules are now considered as soluble biomarkers of endothelial inflammation and early atherosclerosis.68,69 Increased serum levels of ICAM-1, VCAM-1, E-selectin, and thrombomodulin were demonstrated in patients with advanced HIV infection and opportunistic diseases, and a correlation between ICAM-1 concentrations and the progression of disease as well as the reduction of CD4 lymphocyte count was also reported. If circulating adhesion molecules indicate vascolar endothelium injury, it seems clear that endothelium injury is associated with the progression and severity of HIV disease.70 On the other hand, the pronounced 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.71 However, HAART may also induce activation of endothelial cells. In a recent study, serum levels of P-selectin, tPA, and

21 PAI-1 were significantly higher in HIV-positive patients treated with PI- or NNRTI-based antiretroviral therapy than in naive HIV-infected subjects, and a positive association between lipid levels and endothelial biomarkers was seen.72 To conclude, HAART should reduce the endothelial damage by controlling HIV infection, but it would also contribute to stimulating endothelial activation by deranging both lipid and glucose metabolism. Furthermore, HAART seems to induce directly endothelial activation. Some authors have recently demonstrated that ritonavir and indinavir are able to directly cause endothelial dysfunction, with mitochondrial DNA damage and cell death, independently of lipid profile.73,74 In a large cohort of HIV-infected individuals, the serum concentrations of PAI-1 were significantly higher both in PI-treated patients and in untreated patients with metabolic syndrome. The PAI-1 concentrations were independently correlated to PI use, triglyceride levels, insulin levels, and body mass index.5 These results show that HAART may promote atherosclerosis both by direct effects on endothelial cells and by indirect effects associated with metabolic disturbances. At the same time, dyslipidaemia and insulin resistance in HAART-treated subjects represent additional risk factors for cardiovascular complications. The pathogenesis of atherosclerosis now includes chronic systemic inflammatory process, and C-reactive protein (CRP) has been employed to predict complications from atherosclerotic disease. In a recent study, increased CRP levels were associated with higher cardiovascular mortality rates in HIV-infected women, and CRP was found to be a marker of increased central fat accumulation in this population.75 Adiponectin is an anti-diabetic and anti-inflammatory protein produced in adipose tissue, and its levels decrease in association with insulin resistance, obesity, and increased expression of endothelial adhesion molecules in the general population. Preliminary data suggest that reduced adiponectin concentrations may increase the risk of coronary heart disease, event though this relationship has not been yet evaluated in HIV-positive subjects.76 Recently, one study including 3T3-F442A cells and mice has found that HIV protease inhibitors decrease adiponectin mRNA levels and secretions.77 Therefore, elevated serum levels of PAI-1, tPA, and CRP, such as reduced serum levels of adiponectin could be considered biochemical markers of endothelial dysfunction, metabolism alterations, and cardiovascular risk in HIV-infected patients.6 The association between antiretroviral therapy and premature atherosclerosis has been shown in some studies. Maggi et al.78 evaluated 293 HIV-positive subjects, receiving (n Z 105) or not receiving (n Z 188) PI therapy, by an epiaortic vessel colour-Doppler ultrasonography. Vascular lesions (including intima media thickness >1 mm and/ or atheromatous plaques) were detected in 52.4% of the PI-treated patients, while only 14.9% of the PI-naive individuals presented acquired lesions of the vascular wall. Antiretroviral therapy, age, cigarette smoking, and CD4 Tcell count were the main predictive risk factors for vascular lesions, but the highest significance value was found to be linked with the administration of PIs.79 Moreover, in a study involving 61 HIV-positive patients and 47 HIV-negative patients, Maggi et al.80 showed that HIV-infected subjects

22 had a significantly higher number of iso-hypoechogenic lesions (not fibrous or calcified) that had homogeneous parietal and endoluminal portions along with a smooth or slightly irregular surface. Ultrasonographic structure of the epiaortic lesions in HIV-infected patients substantially differed from those of plaques in atherosclerotic individuals, although they shared similar features with patients affected by arteritis. These 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.80,81 Jerico ` et al. investigated the relationship between combination antiretroviral therapy and subclinical carotid atherosclerosis according to cardiovascular risk in 132 HIVinfected patients who underwent a carotid high-resolution B-mode ultrasonography. Antiretroviral treatment exposure and 10-year coronary risk 10% were found to be independent variables associated with subclinical carotid atherosclerosis.82 Similarly, de Saint Martin et al.83 assessed 154 HIV-infected individuals and confirmed the occurrence of premature atherosclerosis, which not only correlated with the usual risk factors (such as triglyceride, cholesterol, and glucose levels), but also with the PI exposure, especially that of lopinavir/ritonavir. Moreover, Stein et al.84 demonstrated impaired flow-mediated dilatation of the brachial artery (an early surrogate marker for endothelial dysfunction and subsequent plaque formation) in HIV-positive subjects receiving PIs in comparison with the PI-naive patients. In a case-control survey involving 292 HIV-positive subjects and 1168 age- and sex-matched controls, Lorenz et al. demonstrated that HIV infection and HAART were independent risk factors for early carotid atherosclerosis. In the carotid bifurcation, the intima-media thickness values were 24.4% higher in HIV patients, and premature carotid lesions correlated with the use of combination antiretroviral therapy.85 In a recent report by McComsey et al., a greater prevalence of carotid atherosclerotic lesions was found also in HIV-infected children treated with antiretroviral therapy. Higher levels of carotid intima-media thickness and some markers of cardiovascular risk (such as HOMA-IR, waist-to-hip ratio, cholesterol and triglycerides) were found in 31 HIV-positive children receiving HAART when compared to 31 matched HIV-negative controls.86 These results are certainly worrying, because they suggest that HIVinfected children receiving antiretroviral therapy may be at increased risk of cardiovascular complications. In contrast to the above studies, other works have failed to find a direct effect on the arterial wall of antiretroviral therapy. Depairon et al.87 studied 168 HIV-infected persons, 136 of whom had received PIs. The prevalence of plaque lesions in the carotid or femoral arteries was significantly higher in HIV-positive group in comparison with HIV-negative individuals (55% versus 38%), but PI treatment did not independently predict vascular lesions, whereas traditional risk factors (including age, male gender, cholesterol levels, and smoking) were associated with premature atherosclerosis. Hsue et al.88 reported also a significantly higher rate of intima media thickness progression over one year in 121 HIVpositive subjects versus 27 HIV-negative controls, but in this study PI therapy did not correlate with atheromatous

L. Calza et al. plaques. These findings were corroborate by Currier et al.89 in a prospective matched cohort study involving 134 HIV-infected and uninfected individuals who underwent an ultrasonographic evaluation of the intima media thickness of the carotid artery. No association was found between PI exposure or HIV infection and carotid lesions, while significant predictors of higher carotid intima media thickness in a multivariate model included HDL cholesterol, triglycerides, age, and body mass index. Mangili et al. performed a cross-sectional analysis of 242 men and 85 women with HIV infection and found a more elevated prevalence of abnormal surrogate markers of cardiovascular risk (such as waist circumference, blood pressure, high-sensitivity C-reactive protein and body mass index. However, HAART was not associated with abnormal surrogate markers and increased risk of coronary heart disease.90 A recent study by Lebech et al. involving 25 non-smoking HIV-positive persons has found no sign of accelerated atherosclerosis by evaluation of carotid artery intima-media thickness, and premature carotid lesions correlated with HDL cholesterol but not LDL cholesterol.91 A possible contribution of cell-mediated immune responses to the pathogenesis of the atherosclerosis associated with HIV infection was also supposed. Post-ischaemic flow-mediated dilatation of the brachial artery was found to be significantly associated with percentage of ‘‘naı¨ve’’ CD4 þ 45RA þ T cells, while plasma lipid and insulin concentrations did not correlate with endothelial function among 48 patients assessed by Nolan et al.92 At the same time, relative systolodiastolic variations in diameter of the carotid artery in 49 HIV-infected children were significantly lower than in 24 HIV-negative age- and sex-matched controls, but there was no significant difference in intima-media thickness. HIV-positive children had a vascular dysfunction in the absence of cardiovascular risk factors, but no additional detrimental effects were observed after a mean of 5 years of antiretroviral treatment.93 In conclusion, the real impact of HIV infection and antiretroviral therapy on the development of subclinical atherosclerosis is still incompletely understood, even though most studies seem demonstrate in this population premature atherosclerosis and increased intima-media thickness. Similarly, the full clinical implications of surrogate markers of premature vascular lesions (including biochemical factors and vascular imaging findings) have not been completely evaluated. The most important reports evaluating the association of HIV infection and HAART with accelerated atherosclerosis are summarized in Table 2.

Cardiovascular and cerebrovascular events The first cases of acute myocardial infarction in HIVpositive individuals under combination antiretroviral treatment were described in early year 1998. These initial case reports suggested an increased frequency of cardiovascular diseases in HIV-infected patients receiving combination antiretroviral therapy, raising the question of the association between cardiovascular complications and new, potent PI-based therapies.94e97

HIV infection and cardiovascular diseases

23

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

Type of study

N. of HIVpositive patients

N. of HIVnegative patients

Association with HIV infection

Association with PI therapy

Traditional risk factors associated with premature atherosclerosis

Maggi, 200478 Jerico `, 200682 De Saint Martin, 200683 Lorenz, 200785 Depairon 200187 Hsue, 200488

CS CS CS

293 132 154

e e e

e e e

Yes Yes Yes

Age, smoking, CD4 cell count Age, hypertension, hyperlipidaemia Age, hypertension, hypertriglyceridaemia

CS CS CS

292 168 148

1168 68 63

Yes Yes Yes

Yes No No

Currier, 200589

P

88

44

No

No

Mangili, 200690

CS

327

e

No

Lebech, 200791

CS

25

No

No

Age, body mass index, smoking, hypertension Smoking, hyperlipidaemia Age, smoking, hypertension, race, high LDL cholesterol, CD4 cell count Age, body mass index, hypertriglyceridaemia, low HDL cholesterol Age, body mass index, hypertension, C-reactive protein Low HDL cholesterol

e 14

CS, cross-sectional; P, prospective; PIs, protease inhibitors; LDL, low-density lipoprotein; HDL, high-density lipoprotein.

Subsequently, some retrospective and prospective studies have shown that the incidence of myocardial infarction in HIV-positive subjects treated with antiretroviral therapy tends to be higher than in the general population, particularly in those receiving a PI-based treatment.98 However, reports from large observational studies demonstrate that considerable controversy exists until now over the association of HAART, particularly PI-based combinations, with increased incidence of coronary heart disease risk. The most large studies investigating the association of cardiovascular events with HIV infection and HAART are summarized in Table 3. Rickerts et al. performed a retrospective analysis of a cohort of 4993 HIV-positive patients treated with different antiretroviral treatment strategies between the years 1983 and 1998. The incidence of coronary heart disease increased significantly in this cohort after the introduction of HAART. Particularly, the incidence of myocardial infarction increased from 0.86 (in the period 1983e86) to 3.41 per 1000 patient-years (in the period 1995e98)

(p Z 0.002). Increased age (higher than 40 years), homoor bisexual mode of HIV transmission, previous AIDS diagnosis, and previous HAART were significantly associated with myocardial infarction in univariate analysis, and increased age and previous HAART remained significantly associated with coronary heart disease also in a multiple regression model.99 Klein et al. examined data from the Kaiser Permanente Medical Care Program of Northern California to compare hospitalization rates for coronary heart disease among HIVinfected and HIV-uninfected subjects, before and after PI introduction. This data set identified 4159 HIV-positive patients aged 35e64 years, followed from 1996 up to 2003, with a median total follow-up of 4.1 years. The ageadjusted coronary heart disease hospitalization rate was significantly higher in HIV-positive members than in HIVnegative ones (6.5 vs 3.8; p Z 0.003), and the difference in the myocardial infarction rate also was higher (4.3 vs 2.9; p Z 0.07). However, the age-adjusted rate of myocardial infarction in patients receiving PIs was not statistically

Table 3 Retrospective and prospective studies evaluating the relationship between risk of cardiovascular events and use of combination antiretroviral therapy Authors, years

Type of study

N. of patients

Years of study

Mean age (years)

N. of MI

Incidence of MI per 1000 person/years

Increased risk of CVD associated with HAART

Holmberg, 20023 Friis-Moller, 2003e20074,104 Rickerts, 200099 Klein, 2002100 Currier, 2003101 Mary-Krause, 2003102 Iloeje, 2005106 Bozzette, 2003108

P P

5672 23,468

1993e2002 1999e2002

47 39

21 126

1.42 3.5

Yes (PIs) Yes

R R R R P R

4993 4159 28,513 34,976 7542 36,766

1983e1998 1996e2001 1994e2000 1996e1999 1996e2003 1993e2001

44 42 46 41 39 44

29 47 294 49 112 410

3.41 6.7 5.55 4.9 11.5 5

Yes No Yes Yes (PIs) Yes (PIs) No

MI, myocardial infarction; CVD, cardiovascular diseases; HAART, highly active antiretroviral therapy; R, retrospective; P, prospective; PIs, protease inhibitors.

24 greater than in patients not receiving PIs (4.0 vs 3.4 per 1000 patient-years). Similarly, hospitalization rates for cardiovascular diseases were not significantly different before versus after PIs (6.2 vs 6.7 events per 1000 patient-years), or before versus after antiretroviral therapy (5.7 vs 6.8).100 Currier et al. reviewed administrative claims data for the HIV-positive and HIV-negative individuals from the California Medicare population, and investigated the incidence and the relative risk for coronary heart disease using log-linear regression analyses between two groups. The incidence of cardiovascular events among young men (up to age 34) and women (up to age 44) was significantly higher in HIV-positive compared with HIV-negative persons. Moreover, the covariate-adjusted relative risk for the development of coronary heart disease in subjects receiving antiretroviral drugs compared with those not receiving medications was 2.06 (p < 0.001) in HIV-infected patients aged 18e33 years. Notably, there were no statistically significant associations between antiretroviral exposure and cardiovascular complications in other age groups.101 Mary-Krause et al. assessed the incidence of myocardial infarction among 34,976 HIV-infected male patients belonging to the French Hospital Database on HIV, who were followed up for a median of 33 months between 1996 and 1999. Myocardial infarction was diagnosed in 60 men among 88,029 person-years, including 49 cases among men receiving PIs. Exposure to PIs was associated with a higher risk of cardiovascular disease, and the myocardial infarction rates increased in relation to duration of PI therapy (10.8 events per 10,000 person-years in men with <18 months PI use; 33.8 events per 10,000 person-years in those with >30 months PI use). The standardized morbidity ratios relative to the French general male population were 0.8 for men exposed to PI for <18 months, 1.5 for men exposed for 18e29 months, and 2.9 for men exposed for over 30 months. These results have pointed to a duration-related effect relationship between PI and myocardial infarction, with a greater incidence of this cardiac complication among patients exposed to PI for 18 months or more.102 Vittecoq et al. reviewed 16 cases of acute myocardial infarction in two cohorts of HIV-positive individuals in France, comparing the incidence of cardiovascular disease between these cohorts and the general French population. Incidence of acute myocardial infarction appeared to be between 5 and 5.5 per 1000 person-years among HIVpositive subjects, and this accounts for at least a threefold increase in incidence relative to the general population (1.52 per 1000 person-years reported in the Monica Database Registry in France). The association of coronary heart disease with traditional risk factors (such as smoking, hypertension, diabetes mellitus, and low HDL-cholesterol levels) has been confirmed, while the links between cardiac complications and PI exposure is still debated.103 Moreover, recent prospective studies involving large cohorts of HIV-infected patients have documented an increased incidence of myocardial infarction and cerebrovascular diseases in association with a prolonged exposure to combination antiretroviral therapies, even if the absolute risk of cardiovascular events remains low, and should be balanced against the remarkable benefits from HAART in terms of improvement in immune function and related morbidity and mortality.

L. Calza et al. Prospective studies have recently been published which were specifically designed to evaluate the incidence of cardiovascular diseases in HIV-positive population. Prospective observational cohorts with more systematic assessment of cardiovascular disease risk factors and validation of outcomes provide more insight into the epidemiology of cardiac complications in the HAART era, and are certainly more generalizable. In the HIV Outpatient Study (HOPS), Holmberg et al. described 21 cases of myocardial infarction among 5672 patients from nine US HIV clinics during 17,712 patientyears of follow up (performed between years 1993 and 2002). The frequency of myocardial infarction increased after the introduction of PIs in the year 1996; this cardiac complication occurred in 19 patients on PIs (1.42 per 10,000 patient-years) and in two subjects not on PIs (0.46 per 10,000 patient-years; odds ratio Z 7.1). In multivariate Cox proportional hazards models adjusted for smoking, gender, age, diabetes mellitus, hypertension, and dyslipidemia, the hazard ratio was 6.5, suggesting that use of PIs is associated with increased risk of myocardial infarction in subjects with HIV infection.3 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. At baseline, the mean age of participants was 39 years, 74.5% of the study population had been exposed to combination antiretroviral therapy and the median cumulative exposure to combination treatment was 1.9 years, but it ranged from 0 to more than six years. The median individual follow-up time was 1.6 years, and the total number of person-years of prospective follow-up until the first new myocardial infarction or until the censoring date for those who remained free of cardiac events was 36,199. During this study, a total of 126 episodes of myocardial infarction were diagnosed, leading to a crude incidence rate of 3.5 per 1000 patient-years. 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 6 years of HAART use. This suggested that during the first four to six years of combination antiretroviral treatment there was approximately a 26% increase in the relative risk of suffering from a myocardial infarction, but the absolute risk of coronary events was low and must be balanced against the remarkable benefits from antiretroviral therapy. This study, however, had insufficient statistical power to determine whether PIs and non-nucleoside analogues were associated with the same cardiac risk. On the other hand, the incidence rate of myocardial infarction did not exceed that of what should be expected from the background population given the same cluster of cardiovascular risk factors. Moreover, the relative incidence rate of myocardial infarction per year on HAART has been adjusted from 26 to 17% after follow up. 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.4 Particularly,

HIV infection and cardiovascular diseases increased exposure to PIs was associated with an increased risk of myocardial infarction, which is partly explained by dyslipidaemia, while no evidence of such an association for non-nucleoside analogues was found.104 In a case-control survey involving 3953 HIV-infected patients and 373,856 persons in a population-based control group, patients who had not initiated HAART were slightly more likely to be hospitalized for the first time with ischemic heart disease than were control subjects. After initiation of HAART the cardiovascular risk significantly increased, but the relative risk did not further increase and were stable in the initial 8 years of antiretroviral treatment.105 Iloeje et al. estimated the risk of cardiovascular disease events with PI exposure in a prospective observational study involving a cohort of 7542 HIV-infected patients (whose 77% exposed to PIs) followed-up between 1996 and 2003. The study population was derived from the Centers for Disease Control and Prevention HIV Outpatient Study (HOPS) and additional physician offices and clinics funded by the sponsoring agency, Cerner Corporation. The median duration of follow-up was 3.5 years and 2 years for the PI and non-PI groups, respectively, and the median PI exposure in the first group was 1.7 years. The incidence of cardiovascular complications was significantly higher in subjects exposed to PIs: a total of 127 cardiovascular events were observed, with 112 in the PI group for an adjusted event rate of 9.8 per 1000 person-years of follow-up, and 15 in the non-PI group for an adjusted event rate of 6.5 per 1000 person-years of follow-up (p Z 0.0008). In the multivariate analyses, cumulative PI therapy for 60 days was associated with an increased risk of cardiovascular diseases and the cardiovascular event rates were also higher in the PI group among patients in the 35e65-year-old subset. Other independent risk factors were current or past smoking, hypertension, diabetes mellitus, and pre-existing cardiovascular diseases.106 Kaplan et al. estimated the predicted risk of coronary heart disease among 2386 HIV-infected and 1675 HIVuninfected patients on the basis of age, sex, lipid and blood pressure levels, presence of diabetes, and smoking. Among HIV-positive persons, antiretroviral therapy exposure, increased body mass index and low income level were associated with increased predicted risk of coronary disease.107 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. showed that PI therapy was not associated with an increased risk of coronary heart disease. Patient-level regression analyses indicated that there was no relation between the administration of nucleoside analogues, non-nucleoside analogues, or PIs and the hazard of cardiovascular or cerebrovascular events. On the contrary, in this study the use of antiretroviral therapy was associated with a decreased risk of death from any cause. However, the median duration of exposure to PIs 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.108

25 The occurrence of cerebrovascular events, either ischemic or hemorrhagic, was recognized as early as 1983 in patients with HIV infection, before any antiretroviral therapy was available.109 Although studies have often reached conflicting conclusions, there is evidence for an increased general risk of cerebrovascular events during HIV infection, and AIDS diagnosis seems strongly associated with both ischemic stroke and intracerebral hemorrhage.110 The association of HAART with cerebrovascular diseases is still extensively debated. Bozzette et al. did not find any significant association between the use of any class of antiretroviral agents and the incidence of cerebrovascular events.108 These results were comparable with those of Evers et al., who found no difference in the incidence rate of stroke before and after the introduction of HAART, even if the sample was too small to draw firm conclusions.111 In contrast, several results from the DAD study112 confirmed that combination antiretroviral treatment increases the risk of cerebro-vascular events. Among over 36,145 person-years of follow-up, 41 episodes of stroke were diagnosed in 39 patients; of the 38 strokes that occurred as first events, 18.4% were hemorrhagic, and 76.3% were ischemic in nature. From the multivariable Poisson regression analyses, older age, smoking, previous history of cardio- and cerebrovascular diseases, family history of cardio- and cerebrovascular diseases, male gender, hypercholesterolaemia, hypertriglyceridaemia, diabetes mellitus, and hypertension were independently associated with an increased incidence of vascular complications. After controlling for these variables, the incidence rate of cardioand cerebrovascular events was 5.7 per 1000 person-years and increased significantly with longer exposure to combination antiretroviral therapy. Taken together, these data obtained from retrospective and prospective studies suggest that a small but significant and increasing risk exists for cardiovascular diseases (mostly myocardial infarction and stroke) in association with HIV infection and combination antiretroviral therapy. However, additional, larger prospective studies evaluating cardiovascular risks of HIV disease and its various treatments are certainly requested, with appropriate design and statistical consideration of the effects of HAART and other, concomitant risk factors.

Management of metabolic alterations Since case series, prospective studies, and surrogate markers strongly suggest that HIV infection and antiretroviral therapy may be associated with an increased risk of cardiovascular events and that it may be related in part to concomitant lipid metabolism alterations, the Infectious Disease Society of America (IDSA) and Adult AIDS Clinical Trials Group (AACTG) have updated specific guidelines for evaluation and management of HAART-related hyperlipidaemia.113 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.114

26

L. Calza et al.

The evaluation of dyslipidaemia needs a complete serum lipid profile obtained after a minimum of eight hours of fasting, and including measurement of total serum cholesterol, HDL cholesterol, and triglycerides concentrations, from which serum LDL cholesterol and non-HDL cholesterol levels should be calculated. This lipid panel should be repeated within 3e6 months after initiation of HAART and then yearly unless lipid abnormalities are detected or interventions are initiated. For subjects with serum triglyceride levels >200 mg/dL, the measurement of serum lipid profile should be repeated within 1e2 months after starting antiretroviral therapy. The number of risk factors for coronary heart disease determines the target level of LDL cholesterol and the aggressiveness of lipid-lowering treatment. Categorical risk factors for coronary events that modify the LDL cholesterol goals are summarized in Table 4. The patient’s absolute 10-year risk of myocardial infarction or cardiac death should be calculated using the Framingham risk factor calculator, which can be found at http://www.nhlbi.nih.gov/ guidelines/cholesterol/index.htm.113,114 Predisposing risk factors (such as obesity, physical activity, socioeconomic status, and genetic susceptibility) are not included in Framingham risk calculation, and these algorithms only address short-term (10-year) cardiovascular risk, which may not be an appropriate time frame for young and middleaged HIV-positive patients. Nevertheless, Framingham estimates are a good starting point for patient evaluation and management. High-risk patients are subjects with established coronary heart disease or those with a coronary risk ‘‘equivalent’’, such as cerebrovascular disease, peripheral vascular disease, diabetes mellitus, or two or more risk factors that predict a 10-year risk of myocardial infarction or cardiac death >20%. Moderate-risk patients are those with two or more risk factors but a 10-year risk 20%. Finally, low-risk patients are those with 0 or 1 risk factor for coronary heart disease. Except for subjects with triglycerides >500 mg/dL, in whom the primary goal is to reduce triglyceride

Table 4 Risk factors for coronary heart disease that determine the 10-year risk of myocardial infarction and the target levels of LDL cholesterol Risk factors

Definition

Age

45 years for men 55 years for women Male first-degree relative <55 years old or female first-degree relative <65 years old Blood pressure 140/90 mmHg, or receipt of antihypertensive treatment e <40 mg/dL

Family history of premature CHD Arterial hypertension

Cigarette smoking Low HDL cholesterol*

Adapted from Rickerts et al.99 CHD, coronary heart disease. *An elevated HDL cholesterol concentration (60 mg/dL) is considered a ‘‘negative’’ risk factor and, if present, it subtracts one factor from the above-mentioned risk factor total.

concentration and prevent pancreatitis, the primary target is reduction of LDL cholesterol levels. Lipid goals and cutoffs for lifestyle modification and drug therapy are summarized in Table 5. When patients have triglycerides >200 mg/ dL, the cholesterol content of triglyceride-rich lipoproteins is increased and the estimated LDL-cholesterol underestimates the number of atherogenic particles. In this case, non-HDL cholesterol (calculated as total cholesterol minus HDL cholesterol) becomes the secondary target of medical intervention; the non-HDL cholesterol goals are simply the LDL cholesterol goals plus 30 mg/dL. It is very important to consider the non-HDL cholesterol concentration or its mathematical equivalent (the total cholesterol/HDL cholesterol ratio) when assessing hyperlipidaemia in HIV-infected patients, because such individuals frequently have hypertriglyceridaemia or mixed hyperlipidaemia, and the LDL cholesterol concentrations usually underestimate the overall atherogenic lipoprotein burden.98,113e115 Treatment of HAART-associated dyslipidaemia includes three levels of medical intervention: lifestyle changes and diet therapy, modification of current antiretroviral regimen, and lipid-lowering drugs. Non-drug therapies should generally be instituted first and given a thorough trial before starting drug therapies. Smoking has long been considered a major contributor to overall cardiovascular morbidity and mortality in the general population, and cardiovascular risk drops significantly after cigarette smoking cessation. Cigarette smoking is very common among HIV-infected patients, and prevention and smoking treatment programs may offer substantial benefit to HIV-positive subjects.113 Patients with HIV infection and receiving antiretroviral therapy should regularly perform moderate aerobic activity for a minimum of 30 min five times per week, with a goal of 60 min, to be carried out 5e7 times per week. This routine physical exercise usually improves trunk adiposity and plasma lipid parameters, and might therefore be beneficial to reduce cardiovascular disease risk. At the same time, patients who are overweight should also restrict calories to achieve their ideal body weight. Improvement of cardiovascular outcomes has been associated with substitution of non-hydrogenated unsaturated fats for saturated fats and trans-fats, increased intake of omega-3 fats from fish, fish oil, or plants, and eating a diet that is high in fruits, vegetables, nuts, and whole grains but low in refined grains.

Table 5 The National Cholesterol Education Program treatment decisions based on LDL cholesterol levels Risk category

Goal Lifestyle change Drug (mg/dL) and diet therapy therapy (mg/dL) (mg/dL)

0e1 risk factors

<160

160

2 risk factors and 10-year risk of 20%: 10-year risk of 10% <130 130 10-year risk of 10e20% <130 130 History of CHD or equivalent

<100

100

190 160 130 100

Adapted from Klein et al.100 CHD, coronary heart disease.

HIV infection and cardiovascular diseases Dietary and exercise intervention resulted in a significant 11e25% decrease in total cholesterol and triglyceride levels in HIV-infected patients.116e118 Several studies have showed that an antiretroviral regimen in which a PI is replaced with nevirapine or abacavir in patients with long-lasting viral suppression usually maintains optimal antiviral activity. Furthermore, as compared with PIs, these agents reduce serum lipid abnormalities, offer more convenient dosing regimens, involve fewer pills, and result in fewer potentially serious drugedrug interactions, reduced side effects, and improved adherence to antiretroviral therapy. However, the rate of virological failure might eventually increase among patients who have previously received prolonged non-suppressive antiretroviral treatment, such as single or dual NRTI therapy, as a result of the re-emergence of archived viral resistance.119e121 Significant improvement in serum lipid concentrations was also reported after switching from stavudine or zidovudine to abacavir or tenofovir,122,123 or after replacing current PI with atazanavir, a new azapeptide PI which is usually associated with a more favourable plasma lipid profile.124 Lipid-lowering therapy becomes suitable when lifestyle modifications, dietary changes, physical activity, 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-Co A) 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 cyclosporin, erythromycin, itraconazole, ketoconazole, oral anticoagulants, PIs, and NNRTIs. Simvastatin, lovastatin, and atorvastatin are extensively metabolized by CYP 3A4: these notable drug interactions cause elevated plasma levels of statins, leading to a significantly increased risk of liver and skeletal muscle toxicity (acute hepatitis, myopathy and rhabdomyolysis). On the other hand, fluvastatin is metabolized by CYP 2C9 and pravastatin is not significantly metabolized by the CYP enzyme system, with a very low risk of drug interactions. Consequently, it is reasonable to recommend the use of pravastatin (20e40 mg daily starting dose) or atorvastatin (10 mg daily starting dose) as first-line treatment for hypercholesterolaemia in PI-treated patients, and the use of fluvastatin (20e40 mg starting dose), as second-line regimen. On the other hand, simvastatin and lovastatin should be avoided, because they present a great risk of pharmacological interactions with PIs.125e128 Rosuvastatin is a new HMG-Co A reductase inhibitor that showed the highest dose-to-dose potency in lowering total and LDL cholesterol levels, compared with other currently available statins. Moreover, pharmacokinetic studies have demonstrated that its metabolism is not dependent on the

27 cytochrome P450 3A4 isoenzyme, and its use could be considered in PI-treated individuals as a result of the low risk of drugedrug interactions.129 In a small, observational, pilot study involving 16 HAART-treated patients with hypercholesterolaemia, a 24-week treatment with 10 mg daily of rosuvastatin reduced significantly total cholesterol and triglyceride levels and was associated with a favourable tolerability profile.130 However, a recent study by van der Lee et al. involving 22 patients on lopinavir-ritonavir and treated with rosuvastatin for 12 weeks showed a significant increase (1.6-fold) in the statin plasma levels, while the PI 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 larger studies.131 Fibrates represent the cornerstone of drug therapy for hypertriglyceridaemia and mixed hyperlipidaemia. These compounds are also metabolized by hepatic cytochrome P450 enzymes, but they appear to primarily affect only CYP 4A, and do not show clinically relevant interactions with PIs. However, concomitant use of both fibrates and statins can increase the risk of skeletal muscle toxicity and should be avoided. Treatment with gemfibrozil (600 mg twice daily), bezafibrate (400 mg daily) or fenofibrate (200 mg daily) generally results in a significant reduction in triglyceride and cholesterol levels in HIV-infected patients receiving a PI-containing therapy, with a more evident improvement of hypertriglyceridaemia.132,133 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. However, these compounds have not yet been studied in detail in HIV infected patients. Moreover, niacin and ezetimibe require monitoring of hepatic transaminases, and niacin may be associated with hyperglycaemia, hyperuraemia, and skin rash.113 Recommendations for choice of initial drug therapy for dyslipidaemia are listed in Table 6. The initial management approach for the HAART-related hyperglycaemia or diabetes mellitus 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 eight weeks, hypoglycaemic pharmacologic therapy should be offered. Since alterations in glucose metabolism associated with HAART resemble those seen in type 2 diabetes mellitus, drug therapy in HIV-positive patients with hyperglycaemia should be that recommended for type 2 diabetes and started with an oral hypoglycaemic agent, which may reduce glycaemia and improve insulin sensitivity. The two major classes of oral antidiabetic agents are the insulin secretogogues and the insulin-sensitizing agents. The first one includes sulfonylureas (such as gliclazide), while the second one includes biguanides (such as metformin), and thiazolidinediones (such as pioglitazone and rosiglitazone). However, there are very few data about efficacy and safety of these medications in HIV-positive patients, but the insulin-sensitizing compounds seem to be preferable

28

L. Calza et al.

Table 6 Recommendations for choice of initial pharmacologic treatment for hyperlipidaemia in HIV-infected patients receiving HAART Lipid alterations

First choice therapy (rating)

Alternatives (rating)

Elevated LDL cholesterol or elevated non-HDL cholesterol with triglyceride level of 200e500 mg/dL

Statin (B1): e pravastatin, 20e40 mg daily e atorvastatin, 10 mg daily e fluvastatin, 20e40 mg daily

Fibrate (C1) or niacin (C3)

Triglyceride level >500 mg/dL

Fibrate (B1): e gemfibrozil, 1200 mg daily e fenofibrate, 200 mg daily e bezafibrate, 400 mg daily

Niacin (C3) or fish oils (C3)

Ratings: strength of recommendation: B, moderate evidence to support a recommendation; C, poor evidence to support a recommendation; quality of evidence: 1, evidence from 1 properly randomized controlled trials; 2, evidence from 1 well-designed clinical trials without randomization, case-controlled analytic studies, or multiple case-series; 3, evidence from opinion of respected authorities.113

because they can ameliorate insulin resistance and visceral fat accumulation. Metformin was generally well tolerated and only mild gastrointestinal adverse effects were rarely observed. Since this biguanide is not metabolized by the liver, there are no risks of drug interactions with PIs, but it should be employed with caution in patients receiving NRTIs, because of the increased risk of mitochondrial toxicity and lactic acidosis. However, at least over three months, metformin did not result in any increase of transaminase or lactic acid levels in recent trials,134,135 even though metformin may seriously enhance the risk of lipoatrophy in such patients.136 The insulin-sensitizing compounds thiazolidinediones have been shown to improve insulin sensitivity and hyperglycaemia in patients with type 2 diabetes, and also promote adipocyte differentiation in vitro. They have obtained promising results because of their potential to ameliorate insulin resistance, decrease visceral adiposity, and increase subcutaneous adipose tissue. On the other hand, in a recent randomized, placebo-controlled trial, rosiglitazone did not produce significant changes in body fat composition, although seemed to ameliorate insulin resistance and decrease live fat content.137,138 However, rosiglitazone appeared to have some detrimental effects on lipid profiles.128 The major cytochrome P450 3A4 isoenzymes are involved in the hepatic metabolism of pioglitazone, which is associated with the risk of potential drug interactions with other drugs metabolized by CYP 3A4 (such as PIs). Rosiglitazone, in contrast, is mostly metabolized by CYP 2C8 and presents lower risks of drugedrug interactions. However, little is known about its pharmacological interactions with antiretroviral drugs, and treatment with 4 mg daily of rosiglitazone has been associated with a reduced bioavailability of nevirapine.139 If fasting plasma glucose level of <126 mg/dL are not achieved with oral antidiabetic monotherapy, oral combination treatment consisting of a sulfonylurea with metformin or rosiglitazone should be considered. Finally, in subjects who are severely hyperglycaemic at baseline (fasting glycaemia >300 mg/dL), or who are symptomatic, insulin therapy alone or in combination with an oral hypoglycaemic

agent (such as metformin or rosiglitazone) should be prescribed.140

Conclusions Recent retrospective and prospective studies involving large cohorts of HIV-infected patients have documented an increased incidence of myocardial infarction in association with a prolonged exposure to combination antiretroviral therapies, even if the absolute risk of cardiovascular events remains low and must be balanced against the remarkable benefits from HAART in terms of improvement in immune function and related morbidity and mortality. Nonetheless, as HIV-infected patients live longer on new potent antiretroviral combinations, cardiovascular events could become increasingly frequent and cardiovascular risk evaluation should be performed regularly in these subjects, especially after initiation or change of antiretroviral regimen. Lifestyle modification strategies (including cigarette smoking cessation, dietary changes, and regular exercise) should be rigorously encouraged, obtaining frequently a significant improvement in lipid and glucose metabolism abnormalities and reducing cardiovascular disease risk. Moreover, the use of abacavir, tenofovir, or atazanavir should be considered because of their more favourable effect on the lipid profile. Pharmacological treatment of dyslipidaemia (usually with statins and fibrates) and diabetes (with biguanides and thiazolidinediones) becomes mandatory when lifestyle changes and switching therapy are ineffective or not applicable, and when increases in lipid and glucose concentrations are severe or persist for a long time. However, 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.

HIV infection and cardiovascular diseases 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 subjects with virological failure and immunological impairment. However, owing to the notable extension of life expectancy in HIV-positive subjects on antiretroviral therapy, cardiovascular complications may become significantly more frequent and require a routine and appropriate evaluation and management of the cardiovascular disease risk. Further, enlarged, prospective studies are certainly needed in order to better evaluate the cardiovascular disease risk in HIV-positive individuals receiving HAART, and to define specific guidelines for the management of HAART-related metabolic abnormalities.

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