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HIV, atherosclerosis and inflammation: implications for treatment.


Atherosclerosis is characterised by a chronic inflammatory state with upregulation of many immunomodulatory paracrine, humoral and cellular factors along the inflamed dysfunctional vascular endothelium [1]. This inflammatory process ultimately results in formation of atherosclerotic plaques along the vascular tree, which are prone to atherothrombotic sequelae [2]. Although the acquired immunodeficiency syndrome is associated with profound immunosuppression, human immunodeficiency virus (HIV) infection in its early stages and immune reconstitution following highly active antiretroviral therapy (HAART) are more associated with chronic immune activation and dysregulation that may accelerate atherosclerosis already occurring in these patients. Beyond the deleterious chronic inflammatory effects of HIV infection, the adverse metabolic effects of HIV therapy and the disproportionately increased burden of traditional cardiovascular risk factors among these patients [3-5] may contribute to the increased incidence of atherosclerosis observed in this group [6]. This article highlights recent progress made in our understanding of the pathophysiology of atherosclerosis and cardiovascular disease (CVD) in HIV-infected patients, and also discusses potential therapeutic strategies in this group of patients.


In the pre-HAART era (before 1996), the cardiac manifestations of HIV were mainly due to the toxic and inflammatory effects of HIV and included cardiomyopathy, pancarditis and pulmonary hypertension leading to heart failure [7] (Table 1). However, even as early as 1992 autopsy case reports describing coronary lesions among HIV-infected patients began to appear [8,9]. Seminal cases of acute coronary syndromes in HIV-infected patients were first reported in 1998 [10] and histopathological analysis of atheromas suggested a distinctive form of diffuse atherosclerosis characterised by proliferation of smooth muscle cells, mixed with abundant elastic fibres, resulting in endoluminal protrusions [11].

The pathogenesis of atherosclerosis in HIV-infected patients remains speculative and is likely multifactorial in aetiology, as in the non-HIV setting (Figure 1). Case reports in the pre-HAART era suggested that HIV itself maybe pro-atherogenic, perhaps due to the increased systemic inflammatory response it perpetuates, as well as that caused by concomitant infections and endothelial injury [12,13]. We have recently described another mechanism by which HIV may contribute to foam cell formation by impairing cholesterol efflux [14]. However, most of the evidence linking HIV with accelerated atherosclerosis has emerged in the post-HAART era.

Although several observational studies have shown an association between lipodystrophy and HAART with the development of subclinical atherosclerosis in HIV-infected patients (independent of traditional cardiovascular risk factors) as detected by coronary calcium [15,16], other studies have not reported such an association [17].

Similarly, results from retrospective studies linking HAART with CVD have published conflicting results. Several studies [18] reported significant associations but the largest, of 36,766 patients who received care for HIV infection at Veterans Affairs facilities between January 1993 and June 2001, showed no increase in the rate of cardiovascular or cerebrovascular events or related mortality [19]. However, all these studies suffer from the inherent biases of retrospective studies, including the lack of a control group.

Most prospective studies have reported a significant, albeit small, increased risk in development of CVD with HAART. Friis-Moller and colleagues from the DAD study group reported a 26% relative increase in the rate of myocardial infarction per year of exposure to HAART during the first 4-6 years of use but the absolute risk was low and should be balanced against the benefits of antiretroviral treatment [20]. This risk seems to be driven by increased exposure to protease inhibitors (PIs), which is partly explained by dyslipidaemia, rather than by concomitant non-nucleoside reverse transcriptase inhibitors (NNRTI) [3]. These findings have been corroborated in other studies [12,13,21,22].

Taken together, the weight of current evidence supports an increased risk of CVD among HIV-infected patients but this risk may be outweighed by the benefits gained from HAART as reported by SMART investigators [23]. Nevertheless, excess CVD (6-15% of all deaths in HIV-infected patients [24,25]) remains an important impediment to the health of people who are now living longer with HIV and improvements in our understanding of its pathophysiology will allow better treatment strategies to be devised for primary and secondary prevention purposes.


Probable key processes involved in the pathogenesis of atherosclerosis are depicted in Figure 1. Interest in atherosclerosis as a chronic immune-mediated inflammatory disease was stimulated by the realisation that C-reactive protein (CRP) was elevated in patients with unstable angina [26] and that it could predict future cardiovascular risk even among apparently healthy men and women [27,28]. Moreover, the most prominent T cell type in human atheromas is the CD4+ T cell of the Th1 subset [29,30], the same population infected by HIV. Th1 cells, like macrophages, recognise oxidised low density lipoprotein cholesterol (ox-LDL) and produce interferon (IFN)-[gamma] and tumour necrosis factor (TNF)-[alpha] to further recruit and activate monocytes and macrophages [31,32]. Both Th1 T cells and macrophages are known long-term reservoirs for HIV [33] and thus it is likely that Th1 T cell and macrophage cross-talk within the coronary circulation, in the presence of a dysfunctional endothelium, can contribute to atherogenesis (Figure 1). Below, we outline our current understanding of aetiopathogenic factors involved with atherosclerosis in HIV-infected patients.



High-sensitivity CRP (hsCRP) is an established biomarker of chronic inflammation produced by the liver in response to interleukin 6 (IL-6), a pro-inflammatory cytokine generated by the inflamed vasculature as well as by visceral adipose tissue in patients with the metabolic syndrome and established atherosclerosis [34-36] (Figure 1). Elevations in hsCRP and other pro-inflammatory cytokines (for example IL-1 and IL-6) occur in both atherosclerosis and HIV [37-39]. High CRP concentrations independently predicted an increased acute myocardial infarction risk in HIV-infected patients [5], correlated with the presence of traditional cardiovascular risk factors in HAART-treated patients [40], and were higher among patients receiving HAART [41]. Moreover, hsCRP may also provide further prognostic information for patients with HIV as hsCRP levels have been associated with HIV progression [42].

Whether CRP is merely a marker for vascular inflammation or if it does mediate various aspects of atherogenesis remains to be determined [43]. Mechanistically, CRP can promote LDL uptake in macrophages, stimulate LDL oxidation, and recruit more monocytes to the inflamed endothelium by increasing monocyte chemoattractant protein-1 (MCP-1) production [44]. However, clinical studies of CRP polymorphisms have failed to identify a positive association between genetically elevated CRP levels and raised cardiovascular risk [45,46]. What is not contentious, however, is that hsCRP is a robust marker for CVD risk stratification that needs to be validated in the HIV setting.

Interestingly, the stimuli driving chronic vascular inflammation in HIV have not yet been defined. Is it the HIV itself, HAART, the metabolic and anthropometric abnormalities in chronic HIV infection, traditional cardiovascular risk factors (Figure 2) or some as yet unidentified factor? It has been recently proposed that microbial translocation across the gut mucosa may be one of the causes of low-grade endotoxaemia that contributes to the chronic immune (monocyte) activation and inflammation in HIV-infected patients [47]. Monocytes in HIV-infected patients frequently express activation markers (CD38, CD69, CD11b, HLA-DR) [48-50] and secrete proinflammatory cytokines (e.g. IL-6). Despite prolonged HAART, immune activation has been reported to persist in chronically infected HIV patients suggesting that immune dysregulation (accelerated T cell activation and proliferation) and inflammation remain attractive culprits (and targets) to explain the elevation in CRP and other proinflammatory cytokines [51-54] that ultimately drive the atherosclerotic process in these patients.



Endothelial dysfunction, a likely precursor of early atherosclerosis, has been reported in HAART-naive patients and in patients treated with PIs and nucleoside reverse transcriptase inhibitors (NRTIs). The mechanisms for HIV-mediated endothelial dysfunction may be multiple and include HIV-1 envelope glycoprotein 120 upregulation of endothelial intercellular adhesion molecule-1 expression by endothelial cells [55]; HIV tat protein interaction with signal transduction pathways that lead to increased expression of adhesion molecules, vascular endothelial growth factors and platelet activating factor [56,57]; and HIV membrane microparticle inhibition of endothelial nitric oxide synthase expression [58]. Similarly, HAART-mediated endothelial dysfunction has been attributed to a reduction in nitric oxide production or release [59], and an increase in reactive oxygen species production [60,61], as well as impairment of cholesterol efflux and accelerated foam cell formation [62,63].



The aetiology and development of the dyslipidaemic, anthropometric and metabolic changes observed in chronically HIV-infected patients and its interplay with enhanced CVD risk is complex (Figure 3) [64]. These changes often coexist and are modulated by therapy with HAART, genetic and dietary factors and together appear to exert synergistic atherogenic effects on the vasculature.

Lipid abnormalities in early HIV are characterised by low levels of high-density lipoprotein (HDL) and LDL cholesterol and high levels of very low-density lipoprotein (VLDL) and triglycerides [64,65]. Overall, this lipid milieu may be atherogenic due to low HDL levels and an increase in de novo lipogenesis and reduced VLDL clearance [66]. The adverse cardiovascular effects of lipids on endothelium are well known and have been reviewed previously [67]. Various PIs, in particular ritonavir, can cause hypertriglyceridaemia [68] while other agents increase LDL modestly [69]. Carr et al. hypothesised that the catalytic region of HIV-1 protease (the binding site of various PIs) possesses some homology to regions of proteins regulating lipid metabolism (cytoplasmic retinoic acid-binding protein-I and LDL receptor-related protein) so that PI binding to these proteins results in impaired hepatic chylomicron uptake and triglyceride clearance by LDL receptor-related protein-lipoprotein-lipase complex [70,71]. Other mechanisms of PI-induced dyslipidaemia have been described and include inhibition of Apo-B degradation [72].

With the advent of HAART, anthropometric changes in HAART-naive patients were observed following NRTI and PI treatment, which were characterised by early increases in subcutaneous and visceral fat followed by loss of subcutaneous fat (peripheral lipoatrophy) with relative preservation of visceral fat (visceral adiposity) [70,73,74]. Such lipodystrophic changes have been reported in 30-50% of HAART users (particularly with stavudine and didanosine or zidovudine and lamivudine combined with nelfinavir, efavirenz, or both) [75,76] while up to 26% of HIV-infected patients can be diagnosed with metabolic syndrome [77,78]. The pathogenesis of HAART-induced lipodystrophic changes is complex [64] and may involve mitochondrial toxicity [79] and modulation of adipocyte differentiation [80]. Visceral fat accumulation is a pro-inflammatory state because visceral adipose tissue produces and secretes proinflammatory cytokines (TNF-[alpha], IL-6, MCP-1) and adipokines (adiponectin, leptin and resistin) that attract and recruit macrophages to adipose tissue, stimulate hepatic CRP production and exacerbate insulin resistance [77,81]. Once activated, macrophages elaborate further proinflammatory mediators continually driving chronic vascular inflammation [77] (Figure 2).

Metabolic changes, in particular insulin resistance, may result from the developing anthropometric changes as well as from the direct effects of HAART [82]. Diabetes mellitus has been reported to occur in 6-18% of HIV-infected patients [82] whilst the prevalence of insulin resistance may be as high as 50% in those with anthropometric abnormalities [83]. PIs and NRTIs have been most frequently implicated via selectively inhibiting the transport function of Glut4 receptor [84] and inhibiting mitochondrial function in skeletal muscles [85], respectively.

Thus, HAART appears to play a critical role in the development of the dyslipidaemic, anthropometric and metabolic changes in HIV-infected patients [86,87]. Strategies to reduce HAART-related adverse effects are urgently needed.


Accumulation of oxLDL cholesterol in macrophages due to unregulated uptake by CD36 scavenger receptors leads to foam cell formation. There is evidence that HIV [88] and PIs can upregulate the macrophage CD36 scavenger receptors to promote cholesterol ester accumulation [62,63,77].

Usually macrophages have the ability to release excessive cholesterol by means of cholesterol efflux pathways. However, we have previously reported that HIV-1 infection can inhibit cholesterol efflux from macrophages via HIV nef-mediated inhibition of ATP-binding cassette transporter A1 (ABCA1)-dependent cholesterol efflux from macrophages [14,89] (Figure 1). Through hijacking the cholesterol metabolism pathway in macrophages to increase its virulence, the HIV may inadvertently destroy the macrophages' capacity to expel cholesterol leading to accelerated foam cell formation [90].

In the current HAART era, PI-based regimens are common and have been associated with elevations in VLDL and LDL levels [91-93], which may translate into greater clinical risk of CVD [3]. More recently, we have shown that HIV itself, rather than the commonly used antiretroviral compounds (stavudine, efavirenz, nevirapine, lopinavir, amprenavir, nelfinavir and ritonavir), impairs cholesterol efflux [94]. This implies that HAART promotes atherosclerosis mainly by enhancing forward cholesterol transport and delivery of LDL and oxLDL to macrophages, while HIV appears responsible for the inhibition of reverse cholesterol transport.


Despite mounting evidence of increased CVD in the HIV population over the last decade, rigorous clinical trial data are still insufficient to recommend a different screening and treatment approach for HIV-infected patients from that of non-HIV-infected patients [95-97]. The use of the Framingham risk equation for CVD screening has been well established in the non-HIV setting but its use in the HIV-infected population requires further validation. Recently, the DAD study group reported that the Framingham risk equation underestimated CVD risk especially in smokers [96]. A multidisciplinary conference convened in 2007 suggested that the development of an appropriate CVD risk prediction model was a major unmet need in the management of HIV-infected patients and that this model should incorporate some newer markers beyond traditional cardiovascular risk factors such as the type and duration of HAART, hsCRP levels, and other inflammatory or metabolic surrogate markers [96].


General primary prevention risk reduction strategies such as smoking cessation, appropriate dietary advice and exercise prescription should be implemented for all HIV-infected patients given that there is a high prevalence of traditional cardiovascular risk factors among this group of patients [4,5].


In the non-HIV setting, measuring hsCRP provides additive value to global cardiovascular risk stratification, irrespective of LDL levels [27,28,98-100], once again suggesting that the fundamental pathophysiology of atherosclerosis is based on inflammation. By corollary, it has been shown that the benefits of targeting inflammation (measured by hsCRP) parallels the reduction in hsCRP levels among apparently healthy persons [101], patients with stable coronary artery disease [102] and those presenting with acute coronary syndrome [103-105]. Numerous studies have reported that statins can lower median CRP levels by 15-30% independent of the magnitude of lipid-lowering [106]. The most provocative prospective randomised outcome study of statin therapy in primary prevention, which looked at patients with high hsCRP ([greater than or equal to] 2.0mg/L) without hyperlipidaemia (LDL <3.4mmol/L), was terminated prematurely after a median follow-up of 1.9 years. The rates of the combined primary end points of myocardial infarction, stroke, arterial revascularisation, hospitalisation for unstable angina or death from cardiovascular causes were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin: 0.56; 95% confidence interval: 0.46-0.69; P < 0.00001) [107].

It appears that the pleiotropic effects of statin therapy may go beyond lipid lowering and may also encompass anti-inflammation and vascular protection [108,109]. Driven by compelling clinical data in the non-HIV setting, trials of statin treatment in HIV patients are accumulating. Statin therapy has been shown to improve surrogate markers such as endothelial function and lipid profiles in HAART-treated patients [110,111] but larger outcome studies are lacking. In general, HIV-infected patients with abnormal lipid levels should be managed according to the National Cholesterol Education Program guidelines [112] or the European guidelines on cardiovascular disease prevention in clinical practice [112,113]. Special consideration should also be given to interactions of various statins with PIs as most statins and all PIs undergo CYP450 3A4 metabolism [114]. Commonly used statins with HAART include pravastatin, atorvastatin and rosuvastatin whereas simvastatin is usually not recommended. The use of fibrates for hypertriglyceridaemia has not been well studied in the HIV setting whilst there is preliminary data to suggest that ezetimibe may be used safely in dyslipidaemic HIV-infected individuals as an adjunct to statins [115].


Although it is attractive to treat metabolic abnormalities in HIV-infected patients with different medications, the potential for drug-drug interaction is great. Insulin-sensitising agents, for example metformin, may moderate insulin resistance associated with HAART and also reduce central fat accumulation [116] but they can also precipitate lactic acidosis. Lifestyle interventions have also been shown to be modestly effective in reducing haemoglobin A1C levels over 6 months [117].


While statin therapy may ameliorate vascular inflammation and adverse lipid changes in patients with HIV, modification of HAART (especially abacavir-based regimens) to less lipodystrophic and dyslipidaemic regimens appears critical [70,118]. Recent evidence supports the use of NNRTI-based regimens due to the propensity of this drug class to increase HDL cholesterol [119,120], whereas patients treated with PI-based HAART had an increased risk of CVD, in part attributable to changes in lipids [3]. A small study of 12 HIV-1-infected patients treated with zidovudine/lamivudine/abacavir for [greater than or equal to] 6 months suggested that the addition of nevirapine may provide some antiatherogenic effects by increasing apoA-1 levels, and therefore HDL production [121].


It is important to recognise that atherosclerosis and the atherothrombotic sequelae of CVD in HIV-infected patients remain incompletely elucidated. Based on our current (or lack thereof) understanding, the process is complex and fundamentally based on vascular inflammation, chronic immune activation, abnormal lipid metabolism and traditional cardiovascular factors, notwithstanding the superimposed effects of chronic HIV infection and adverse lipid effects mediated by HAART, which may accelerate any atherosclerotic tendency. Clearly, the need for greater understanding of this disease process is important in developing more effective treatment strategies and improving the quality of life of HIV-infected patients who are now living longer. So far JUPITER has given us some insight into the significance of reducing vascular inflammation, however, other strategies aimed at improving the dyslipidaemic profile in HAART-treated patients appear more paramount than ever.


Dr Chan was supported by a postgraduate scholarship from the National Health and Medical Research Council of Australia and a support grant from GlaxoSmithKline Australia. Professor Dart and Associate Professor Sviridov are Research Fellows of the National Health and Medical Research Council of Australia.


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Correspondence to: Anthony M Dart Heart Centre, Alfred Hospital, 3rd Floor, WS Philip Block Commercial Road, Melbourne 3004 Victoria, Australia Email:

William Chan, Dmitri Sviridov and Anthony M Dart

Department of Cardiovascular Medicine, Alfred Hospital and Baker IDI Heart and Diabetes Institute, Melbourne, Australia
Table 1. Cardiovascular effects of HIV and HAART

Cardiovascular effects       Cardiovascular effects of HAART
  of HIV infection

Toxic                        Lipodystrophy

* Pericardial effusion       * Peripheral lipoatrophy

* Dilated cardiomyopathy     * Central visceral fat
* Pulmonary hypertension
                             * Metabolic syndrome-like
* Pancarditis                  effects


                             Insulin resistance


* Dyslipidaemia

* Coronary artery disease
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Title Annotation:LEADING ARTICLE
Author:Chan, William; Sviridov, Dmitri; Dart, Anthony M.
Publication:Journal of HIV Therapy
Article Type:Report
Geographic Code:8AUST
Date:Nov 1, 2009
Previous Article:Inflammation and gut permeability.
Next Article:SILCAAT and ESPRIT: taking stock.

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