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Cardiovascular Research 2003 60(1):87-95; doi:10.1016/S0008-6363(02)00828-3
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Copyright © 2003, European Society of Cardiology

HIV infection, highly active antiretroviral therapy and the cardiovascular system

Giuseppe Barbaro*

Department of Medical Pathophysiology, University ‘La Sapienza’, Rome, Italy

*Viale Anicio Gallo 63, 00174. Tel./fax: +39-6-7102-889. Email address: g.barbaro{at}tin.it

Received 26 September 2002; accepted 27 November 2002


   Abstract
Top
 Abstract
1. Introduction
 2. HIV infection and...
 3. Antiretroviral therapy and...
 4. Antiretroviral therapy and...
 5. Conclusions
 References
 
Cardiovascular complications in the course of human immunodeficiency virus (HIV) infection are multifactorial and may be caused by the virus itself or by the related opportunistic infections and neoplasms. Highly active antiretroviral therapy (HAART) has prolonged many patients’ lives, but many cardiac sequelae of HIV are not affected by HAART and continue to develop even with treatment. In addition, HAART itself causes in a high proportion of patients a metabolic syndrome, characterized by lipodystrophy/lipoatrophy, dyslipidemia and insulin resistance that may be associated with an increase in peripheral artery and coronary artery diseases. Careful cardiovascular evaluation in the course of HIV disease can identify cardiac complications early enough to treat. All HIV-infected patients candidate to antiretroviral therapy and patients already under treatment should undergo an assessment that includes the evaluation of the cardiovascular risk with the available guidelines.

KEYWORDS Cardiomyopathy; Coronary disease; Infection/inflammation


   1. Introduction
Top
 Abstract
 1. Introduction
2. HIV infection and...
 3. Antiretroviral therapy and...
 4. Antiretroviral therapy and...
 5. Conclusions
 References
 
Studies published before the introduction of highly active antiretroviral therapy (HAART) have tracked the incidence and course of HIV infection in relation to both pediatric and adult cardiac disease [1].These studies showed that subclinical echocardiographic abnormalities independently predict adverse outcomes and identify high risk groups to target for early intervention and therapy [1]. The introduction of HAART has significantly modified the course of HIV disease, with longer survival and improved quality of life. Although there is no evidence from prospective studies to suggest that HAART has a beneficial effect on HIV-associated cardiomyopathy [1], some retrospective studies suggest that by preventing opportunistic infections and reducing the incidence of myocarditis HAART might reduce the incidence of HIV-associated cardiomyopathy and improve its course [2,3]. On the contrary, the prevalence of infective endocarditis did not vary in HIV-infected patients who use intravenous drugs after the introduction of HAART, being similar to that observed in HIV-uninfected intravenous drug addicts [1].

Though inconclusive at this time, early data have raised concern that HAART regimens, especially those including protease inhibitors (PIs), are associated with an increased incidence of metabolic and somatic changes that in the general population are associated with an increased risk for both peripheral and coronary artery disease, producing an intriguing clinical scenario [1].


   2. HIV infection and vascular disease
Top
 Abstract
 1. Introduction
 2. HIV infection and...
3. Antiretroviral therapy and...
 4. Antiretroviral therapy and...
 5. Conclusions
 References
 
A wide range of inflammatory vascular diseases including polyarteritis nodosa, Henoch–Schonlein purpura, and drug-induced hypersensitivity vasculitis may develop in HIV-infected individuals [1]. Kawasaki-like syndrome [4] and Takayasu's arteritis [5] have also been described. The course of vascular disease may be accelerated in HIV-infected patients because of atherogenesis stimulated by HIV-infected monocyte-macrophages, possibly via altered leukocyte adhesion or arteritis [6].

Some patients with AIDS have a clinical presentation resembling systemic lupus erythematosus (SLE) including vasculitis, arthralgias, myalgias, and autoimmune phenomena with a low titer positive antinuclear antibody, coagulopathy with lupus anticoagulant, hemolytic anemia, and thrombocytopenic purpura. Hypergammaglobulinemia from polyclonal B-cell activation may be present, but often diminishes in the late stages of AIDS. Specific autoantibodies to double-stranded DNA, Sm antigen, RNP antigen, SSA, SSB and other histones may be found in a majority of HIV-infected persons, but their significance is unclear [6].

2.1. Endothelial dysfunction
Endothelial dysfunction and injury have been described in HIV infection [7]. Circulating markers of endothelial activation, such as soluble adhesion molecules and procoagulant proteins, are elaborated in HIV infection. HIV may enter endothelium via CD4 or galactosyl-ceramide receptors [7]. Other possible mechanisms of entry include chemokine receptors [8] (CCR3 and CXCR4 HIV-1 coreceptors are strongly expressed on the endothelium isolated from the brain of HIV-infected subjects, whereas coronary endothelium strongly expresses CXCR4 and CCCR2A coreceptors and CCR5 is expressed at a lower level in both types of endothelium) [8]. Endothelial activation in HIV infection may also be caused by cytokines secreted in response to mononuclear or adventitial cell activation by the virus, or may be a direct effect of the secreted HIV-associated proteins gp 120 (envelope glycoprotein) and tat (transactivator of viral replication) on endothelium [7]. Opportunistic agents, such as cytomegalovirus, frequently co-infect HIV-infected patients and may contribute to the development of endothelial damage. It has been also hypothesized that human herpes virus-8 (a virus that is found in all forms of Kaposi's sarcoma) may trigger or accelerate the development of atheroma in the presence of hyperlipidemia [9]. In spite of all these observations, the clinical consequences of HIV-1 and opportunistic agents on endothelial function has not been elucidated.

2.2. HIV infection and coronary arteries
The association between viral infection (cytomegalovirus or HIV-1 itself) and coronary artery lesions is not clear. HIV-1 sequences have recently been detected by in situ hybridization in the coronary vessels of an HIV-infected patient who died from acute myocardial infarction [10]. Potential mechanisms through which HIV-1 may damage coronary arteries include activation of cytokines and cell-adhesion molecules and alteration of major histocompatibility complex class I molecules on the surface of smooth-muscle cells [10].


   3. Antiretroviral therapy and metabolic disorders
Top
 Abstract
 1. Introduction
 2. HIV infection and...
 3. Antiretroviral therapy and...
4. Antiretroviral therapy and...
 5. Conclusions
 References
 
3.1. PIs-associated metabolic and somatic alterations
PIs are designed to target the catalytic region of HIV-1 protease. This region is homologous with regions of two human proteins that regulate lipid metabolism: cytoplasmic retinoic acid binding protein 1 (CRABP-1) and low density lipoprotein receptor-related protein (LRP) [11,12]. It has been hypothesized, although without strong experimental support, that this homology may allow PIs to interfere with these proteins, which may be the cause of the metabolic and somatic alterations that develop in PIs-treated patients (i.e., dyslipidemia, insulin resistance, increased C-peptide levels and lipodystrophy) [11,12]. The hypothesis is that PIs inhibit CRABP-1-modified and cytochrome P450-3A-mediated synthesis of cis-9-retinoic acid and peroxisome proliferator-activated receptor type-{gamma} (PPAR-{gamma}) heterodimer. The inhibition increases the rate of apoptosis of adipocytes and reduces the rate at which pre-adipocytes differentiate into adipocytes, with the final effect of reducing triglyceride storage and increasing lipid release. PIs-binding to LRP would impair hepatic chylomicron uptake and endothelial triglyceride clearance, resulting in hyperlipidemia and insulin resistance [11,12].

Recent data indicate that dyslipidemia may be, at least in part, caused either by PIs-mediated inhibition of proteasome activity and accumulation of the active portion of sterol regulatory element-binding protein-1c in liver cells and adipocytes [13] or to apo C-III polymorphisms in HIV-infected patients [14].

Fauvel et al. described a 2–3-fold increase in apo E and apo C-III, essentially recovered as associated to apo B-containing lipoparticles [15]. In this study multivariate analysis revealed that, among the investigated parameters, apo C-III was the only one found strongly associated with the occurrence of lipodystrophy (odds ratio, 5.5) [15]. Of note is that also an increase of lipoprotein (a) was reported PIs-recipient patients [16]. In non-HIV patients the increase of lipoprotein (a) has been associated with premature atherosclerosis, independent of the levels of cholesterol [17].

There is also evidence that PIs directly inhibit the uptake of glucose in insulin-sensitive tissues, such as fat and skeletal muscle, by selectively inhibiting the glucose transporter Glut4 [18]. The relationship between the degree of insulin resistance and levels of soluble type-2-tumor necrosis factor-{alpha} receptor suggests that an inflammatory stimulus may contribute to the development of HIV-associated lipodystrophy [19]. Endothelial dysfunction has been recently described in PIs recipients, further supporting the increased risk of cardiovascular disease in these patients [20].

3.2. Mitochondrial damage and metabolic disorders
Similarities between HAART-associated fat redistribution and metabolic abnormalities with both inherited lipodystrophies and benign symmetric lipomatosis could suggest the pathophysiological involvement of nuclear factors like lamin A/C and nucleosides-induced mitochondrial dysfunction [21], although no mutations or polymorphisms in the gene encoding lamin A/C associated with aberrant adipocyte tissue distribution or metabolic abnormalities have been detected in HIV-infected patients with lipodystrophy. It has been suggested that lipodystrophy might also be related to an imbalance in the immune system that remains after triple-drug therapy is started; even though triple-drug therapy prevents HIV from attacking immune system cells, it may not halt the negative effects of HIV on other cells in the body [22,23]. However, the temporal and causal relationship between the three major components of the HAART-related metabolic syndrome, i.e., dyslipidemia, visceral adiposity and insulin-resistance remains to be elucidated [24].


   4. Antiretroviral therapy and cardiovascular risk
Top
 Abstract
 1. Introduction
 2. HIV infection and...
 3. Antiretroviral therapy and...
 4. Antiretroviral therapy and...
5. Conclusions
 References
 
4.1. Risk stratification and therapy of metabolic disorders
For HIV-infected patients on HAART, it may be important to evaluate the traditional vascular risk factors according to the Framingham score and to try to intervene on those that can be modified [25].Existing guidelines for the management of dyslipidemias in the general population, such as those of the National Cholesterol Education Program,currently represent the basis for therapeutic recommendations also in HIV-infected individuals [25].

Fibric acid derivatives and statins can lower HIV-associated cholesterol and triglyceride levels, although further data are needed on interactions between statins and PIs. Since most statins are metabolized through the CYP3A4 pathway,the inhibition of CYP3A4 by PIs could potentially increase by several-fold the concentrations of statins, thus increasing the risk of skeletal muscle toxicity or hepatic toxicity. The statin that is least influenced by the CYP3A4 metabolic pathway is pravastatin. Moyle et al. [26] recently reported that dietary advice plus pravastatin significantly reduced total cholesterol in HIV-infected patients taking PIs, without significant adverse effects through week 24. Fibrates are unlikely to have significant interactions with PIs, since their principal metabolic pathway is CYP4A. Hypoglycemic agents may have some role in managing glucose abnormalities, but troglitazone cannot be recommended for fat abnormalities alone and metformin may cause lactic acidosis [27].The principal interactions between antiretrovirals and drugs commonly used to treat cardiovascular disease are reported in Tables 1–3GoGo.


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  		Table 1 Interactions between antiretrovirals and drugs commonly used to treat cardiovascular diseases: interactions among protease inhibitors (PIs) and drugs used to treat cardiovascular diseases

 

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  		Table 2 Interactions among nucleoside reverse transcriptase inhibitors (NRTI) and drugs used to treat cardiovascular diseases

 

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  		Table 3 Interactions among non-nucleoside reverse transcriptase inhibitors (NNRTI) and drugs used to treat cardiovascular diseases

 
4.2. Switching from PIs
An approach to the treatment of dyslipidemia in patients treated with PIs is to switch to PIs-free combination regimens. Although large randomized trials are lacking, some favourable effects have been shown [28–30]. Of interest are preliminary data indicating that patients never treated with HAART, that started a PIs-sparing regimen including some non-nucleoside reverse transcriptase inhibitors, such as nevirapine or efavirenz, showed a significant increase of HDL-cholesterol [31].

4.3. HAART and coronary heart disease
Contrasting opinions exists about the incidence of acute coronary syndromes (unstable angina, myocardial infarction) among HIV-infected patients receiving PIs-including HAART. In fact, studies on the risk of coronary heart disease among HIV-infected individuals receiving PIs therapy have not shown a consistent association.

In the retrospective analysis of the Frankfurt HIV-Cohort Study [32], the incidence of myocardial infarction per 1000 HIV-infected patient-years increased from 0.86 (years 1983–1986), 1.14 (years 1987–1990), 0.59 (years 1991–1994) to 3.41 (years 1995–1998), respectively (P = 0.002). Age >40, previous HAART therapy, homo-, or bisexual mode of HIV transmission and previous AIDS diagnosis were significantly associated with myocardial infarction in univariate analysis. Age >40 and previous HAART therapy remained significantly associated with myocardial infarction in a multiple regression model [32].

A large multinational joint venture with the participation of 11 national HIV-cohorts has been in progress since the beginning of 2000 [33]. Approximately 22 000 subjects are followed at 180 sites across Europe, Australia and USA. The data presently available indicate that HAART-treated subjects with preserved immunity, better viral suppression, lipodystrophy and higher age are at risk for cardiovascular disease (myocardial infarction and stroke) based on lipid profile [33]. In this study lipodystrophy was found among both PIs users and non-nucleoside reverse transcriptase inhibitors (NNRTIs), although it was was most severe among users of four drugs that included both PIs and NNRTIs.To what extent this will lead to accelerated atherosclerosis is presently unknown.

The analysis of HIV Outpatient Study (HOPS) investigators on 5676 outpatients documented a significant increase in the incidence of myocardial infarction after introduction of PIs (P for linear trend =0.01) with an hazard ratio of 5.77 (95% confidence interval: 1.3–25.6; P = 0.009) [34]. In this study the use of PIs was an independent risk factor in the multivariate analysis (hazard ratio:4.92; 95% confidence interval: 1.3–32.3; P = 0.04) [34].

A similar trend has been reported also by the Gruppo Italiano per lo Studio Cardiologico dei pazienti affetti da AIDS (GISCA) [35]. According to the GISCA experience, the incidence of coronary heart disease (in terms of recently developed angina, unstable angina and fatal and non-fatal myocardial infarction) in HIV-infected male smokers, aged <50 years, receiving PIs, who developed metabolic disorders (mainly dyslipidemia) and lipodystrophy was about 3-fold greater than that observed in the general age- and gender-matched italian population, with a mean annual incidence of myocardial infarction of 5.1 per 1000 patients [35].

Other studies that evaluated the relationship between HAART and coronary heart disease found no increase in the risk of coronary heart disease associated with HAART. The largest of these, the US Veterans Administration Study, was reported as late breaker at the 2002 Conference on Retroviruses and Opportunistic Infections [36]. This study among 36 000 HIV-positive individuals insured by the Veterans Administration found a decrease in cardiovascular morbidity and mortality among HIV-positive individuals after the introduction of HAART as compared to before HAART was available in spite of 30–40% of HIV-infected individuals using PIs [36].

Klein et al. performed an observational study among HIV-positive members of the Kaiser Permanente Medical Care Program of Northern California, before and after PIs use, and before and after any antiretroviral therapy [37] With 4.1 years’ median total follow-up, age-adjusted coronary heart disease and myocardial infarction hospitalization rates were not significantly different before versus after PIs (6.2 vs. 6.7 events per 1000 person-years); or before versus after any antiretroviral therapy (5.7 vs. 6.8). However, comparing HIV-positive and -negative members, the coronary heart disease hospitalization rate was significantly higher (6.5 vs. 3.8, P = 0.003), and the difference in the myocardial infarction rate also was higher (4.3 vs. 2.9, P = 0.07). The data reported by Klein et al. suggest that PIs may be not specifically involved in the increase of coronary heart disease or myocardial infarction hospitalization in HIV-infected persons receiving HAART and that other HIV-related factors,even in combination, may be responsible for an increase of coronary heart disease risk among all HIV-infected persons [37].

A meta-analysis of Phase III studies of PIs conducted by the first four companies that developed PIs among 8700 HIV-positive subjects who were randomized to HAART that contained PIs or two nucleoside analogues found no increase in the risk of myocardial infarction among PIs users after an average of 1 year on drug [38]. Similarly, an analysis of Phase III of the protease inhibitor, indinavir, found no increase in risk of coronary heart disease among patients randomized to indinavir-containing therapy as compared to patients randomized to two nucleoside analogues [39].

4.4. HAART and peripheral vascular disease
Also the issue of surrogate markers of subclinical atherosclerosis has been addressed. A study was performed on a cohort of 168 HIV-infected patients to measure the intima-media thickness and assess indirectly the cardiovascular risk. In this population a high prevalence of atherosclerotic plaques within the femoral or carotid arteries was observed, but their presence was not associated with the use of PIs [40]. Different results were reported in another study, in which a higher than expected prevalence of premature carotid lesions in PIs-treated patients when compared to PIs-naive patients was observed [41].

4.5. HAART, hypertension and coagulative disorders
Recent reports indicate that elevated blood pressure in HIV-infected patients may be related to PIs-induced lipodystrophy and metabolic disorders, especially to fasting triglyceride with a prevalence of hypertension in up to 74% of patients with HAART-related metabolic syndrome [42].The prevalence of hypertension associated with erythropoietin therapy is 47%; the effect may be related to the increase in hematocrit and blood viscosity [43]. A syndrome of acquired glucocorticoid resistance has been described in HIV-infected patients with hypercortisolism and a lower affinity of the glucocorticoid receptors [44]. The syndrome is characterized clinically by weakness, hypertension or hypotension, and skin pigmentation changes.

Moreover, HIV-infected patients, especially those with fat redistribution, may develop coagulation abnormalities (e.g., increased levels of fibrinogen, D-dimer, plasminogen activator inhibitor-1, and tissue-type plasminogen activator antigen, or deficiency of protein S) [45,46]. These abnormalities have been associated with documented thromboses involving both veins and arteries and seem to be related to PIs-containing HAART [45,47,48]. The routine evaluation of coagulation parameters is probably not advisable until the benefit of widespread screening is assessed in prospective studies. However, clinicians should be aware of the increased risk of coagulative disorders in HIV-infected patients receiving HAART.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. HIV infection and...
 3. Antiretroviral therapy and...
 4. Antiretroviral therapy and...
 5. Conclusions
References
 
It is hoped that HAART, by improving the clinical course of HIV disease, will reduce the incidence of pericardial effusions and myocardial involvement of HIV-associated malignancies and coinfections [1]. However, a careful cardiac screening is warranted for patients who are being evaluated for or who are receiving HAART regimens, especially those with other known underlying cardiovascular risk factors, as the atherogenic effects of PI-including HAART may synergistically promote the acceleration of coronary and cerebrovascular disease and increase the risk of death from myocardial infarction and stroke. A close collaboration between cardiologists and infectious disease specialists may be useful for decisions regarding use of antiretrovirals and other therapies for a careful stratification of cardiovascular risk and cardiovascular monitoring.


   Notes
 
Time for primary review 29 days.


   References
Top
 Abstract
 1. Introduction
 2. HIV infection and...
 3. Antiretroviral therapy and...
 4. Antiretroviral therapy and...
 5. Conclusions
 References
 

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