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Future Virology

Review

Cardiovascular disease in patients with HIV Andreas Knudsen*1,2, Ulrik Sloth Kristoffersen2, Andreas Kjær2 & Anne‑Mette Lebech1 Department of Infectious Diseases, Hvidovre University Hospital, Kettegaard Allé 30, 2650 Hvidovre, Denmark Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet University Hospital & Cluster for Molecular Imaging, University of Copenhagen, Copenhagen, Denmark *Author for correspondence: Tel.: +45 3862 6054 n [email protected] 1 2

The introduction of combination antiretroviral therapy (cART) has substantially decreased mortality among the HIV-infected population. In this setting, cardiovascular disease (CVD) has become a leading cause of morbidity and mortality. Compared with the general population, higher rates of myocardial infarction as well as a high prevalence of subclinical coronary atherosclerosis have been found in the HIV-infected population. It has been suggested that in HIVinfected patients, the atherosclerotic burden is not based solely on traditional cardiovascular risk factors. The interplay of other mechanisms such as chronic inflammation, effects of cART or immune activation after initiation of cART may predispose to accelerated and increased risk of CVD. Effective treatment are available today to reduce CVD in at-risk patients, and therefore early detection of subclinical coronary atherosclerosis is important. However, the mechanisms behind the development of CVD in HIV-infected patients may limit the usefulness of the traditional noninvasive screening tools for CVD used in the general population. This review will focus on the different plausible mechanisms behind the increased risk of CVD and the noninvasive methods by which atherosclerosis may be assessed in the HIV-infected population. Background

Since the introduction of combination antiretroviral therapy (cART) in the mid-1990s, HIV has changed from a death sentence to a chronic but manageable condition in the western world, with free access to antiretroviral medicine. With this medical triumph, survival has been shown to be the same for the HIV-infected population with no comorbidities as for the general population in a recent Danish cohort study [1] . With this improvement in survival rate, the HIV-infected population is growing older and larger since the incidence is currently stable in western countries, and it is estimated that by the year 2015, over half of the American HIVinfected population will be over 50 years of age [2] . With the HIV-infected population growing older, it is facing new challenges in the form of comorbidities that are well known in the aging general population, such as non-AIDS-defining cancer, renal dysfunction, osteoporosis and cardiovascular diseases (CVDs). Of further concern are the data indicating that these comorbidities seem to develop earlier in life within the HIV-infected population. Of special concern among the comorbidities are CVDs, which are now one of the leading causes of death in the HIV-infected population on cART, as well as in the general population [3] . Recent data from the Swiss HIV cohort study concerning 10.2217/FVL.12.25 © 2012 Future Medicine Ltd

the older HIV-infected population support the importance of comorbidities, including CVD, in HIV-infected patient care [4] . This review will focus on the different plausible mechanisms behind the increased risk of CVD and the noninvasive methods by which atherosclerosis and CVD can be assessed in the HIV-infected population. Risk of CVD in patients with HIV

The close relationship between HIV, cART and CVD has been well known for a decade, with substantial epidemiological evidence (Table 1) [5–7] . In a recent study, over 81,000 HIV-infected and HIV-uninfected individuals from the Virtual Cohort of the Veterans Aging Cohort Study were followed from 2003 to 2008. Results showed that, after accounting for other risk factors, HIV infection resulted in a twofold increased risk of clinically confirmed myocardial infarction (MI) [8] . However, in a recent study of 20,775 HIV-infected and 215,158 HIV-uninfected individuals, HIV infection seemed only to be correlated with a higher risk of coronary heart disease when CD4 cell counts were less than 200 cells/µl, whereas HIV-infected patients with CD4 cell counts over 500 had a similar risk to the general population [9] . Future Virol. (2012) 7(4), 413–423

Keywords antiretroviral therapy biomarker n carotid intima–media thickness n cholesterol n coronary artery calcium scoring n HIV n lipid n

n atherosclerosis n

part of

ISSN 1746-0794

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Knudsen, Kristoffersen, Kjær & Lebech

Table 1. Hard end point studies showing increased cardiovascular risk in HIV‑infected patients versus the general population. Study

Study duration Patients (n) Study design Main findings

Ref.

Currier et al.

1994–2000

28,513

Retrospective case–cohort

Increased risk of CVD in young HIV-infected versus HIV-uninfected individuals (men aged 18–24 years: RR: 6.8; men aged 25–34 years: RR: 2.2; women aged 18–24 years: RR: 2.5; women aged 25–34 years: RR: 1.5)

[7]

Triant et al.

1996–2001

3851


Increased risk of MI in HIV-infected versus HIV-uninfected individuals (RR: 1.75)

[6]

Obel et al.

1995–2004

3953


Increased risk of hospitalization for CVD after initiation of cART in HIV-infected versus HIV-uninfected patients (RR: 1.4)

[5]

Lang et al.

2000–2006

74,958


Increased risk of MI in HIV-infected versus HIV-uninfected men and women with respective standardized morbidity ratios of 1.4 and 2.7

[111]

Durand et al.

1985–2007

7053


Increased risk of MI in HIV-infected versus HIV-uninfected individuals (RR: 1.72)

[112]

Hasse et al.

2008–2010

8844

Prospective observational cohort

Increased risk of MI in HIV-infected patients versus the general population

[4]

cART: Combination antiretroviral therapy; CVD: Cardiovascular disease; MI: Myocardial infarction; RR: Relative risk.

Potential mechanisms behind increased CVD risk in patients with HIV

The pathophysiology behind the increased risk of CVD in patients with HIV is still unclear, but important work has been carried out in the last decade. Theory suggests several mechanisms are responsible for the increased risk of CVD: the virus itself, high-risk lifestyle with an increase in risk factors, the antiretroviral medicine and/or an immune reconstitution syndrome due to a rapid transit from a very weak immune system to a fully functional one in weeks, and of course the complicated interplay between these factors. The virus per se

Inflammation is known to play a pivotal role in the development of atherosclerosis and CVD [10,11] , and as a viral infection, HIV is known to drive an inflammatory response, with elevated levels of inflammation markers such as hs-CRP and IL-6, and markers of endothelial (dys)function such as sICAM-1, sVCAM-1, E-selectin, tPAI-1, MPO and MMP9 being detected in both treatmentnaive individuals and in patients on cART [12,13] . The ways in which HIV enables the inflammatory response are diverse and include direct action by HIV RNA [14] and via the HIV-associated proteins Tat and gp120, which promote both dysfunction and apoptosis in the endothelium [15,16] . The levels of the biomarkers of inflammation and endothelial dysfunction seem to correlate with the HIV viral load, but whether the viral load itself or the increased levels of biomarkers are responsible for the CVD risk is unknown. 414

Future Virol. (2012) 7(4)

T cells have been shown to play a important role in the development of atherosclerotic plaques and thereby CVD [17] , and since the virus inhibits these key players, it is tempting to speculate that a link might exist. Data are now indicating that HIV, as well as other viruses, seems to induce changes via the activation of T cells into a so-called immunosenescent and more atherogenic phenotype, which correlates with findings of subclinical carotid lesions [18,19] . Other recent work has shown correlations between the monocyte/macrophage-specific lineage marker sCD163 and atherosclerotic lesions in both the general and the HIV-infected population, indicating another inflammatory activation driven by HIV [20,21] . There are also data suggesting that HIV causes alterations in cholesterol metabolism by redirecting cholesterol to extrahepatic tissues and impairing the efflux of cholesterol from macrophages, which can lead to accelerated foam cell formation [22,23] . Finally, HIV causes inflammation by the rapid loss of gut-associated lymphoid tissue by depletion of T cells during the infection, which causes translocation of microbial products such as lipopolysaccharide into the bloodstream. These products are highly immunogenic and cause a systemic response via the activation of TLR4 upon binding of sCD14, thus leading to a state of chronic inflammation [24,25] . Traditional risk factors

HIV is known to have a large impact on blood lipids, and dyslipidemia is well described in HIV-infected patients prior to cART [26,27] . The future science group

Cardiovascular disease in patients with HIV

studies show an overall lipid profile of decreased low-density lipoprotein (LDL) cholesterol, highdensity lipoprotein (HDL) cholesterol and total cholesterol, and increased levels of triglycerides. This is not an archetypal atherogenic lipid profile, but the decrease in HDL cholesterol has been shown to be correlated with CVD events in the general population, as well in HIV-infected patients on cART [28–30] , probably due to the loss of atheroprotective mechanisms exerted by HDL cholesterol [23,31] . Whether the increase in triglycerides is correlated with CVD events remains controversial, both in the general and the HIV-infected population [32–34] . Smoking, however, has a well-established heavy impact on CVD and is still very common in the HIVinfected population, in which its prevalence has been found to be up to threefold higher compared with the general population [35,36] . The cessation of smoking shows significant results in both HIV-infected patients and the general population [37–39] . Furthermore, other known risk factors for the development of early CVD are over-represented in the HIV-infected population, such as hypertension [40] and diabetes [41] . Finally, the metabolic syndrome, defined as a cluster of cardiovascular risk factors including insulin resistance, increased abdominal circumference, elevated triglycerides, low HDL cholesterol and hypertension, is of concern in the HIV-infected population, with a growing incidence and a well-established correlation with CVD [42] . Antiretroviral therapy

In the first observational study to extensively focus on CVD in HIV patients, a very rapid annual increase in cardiovascular risk of 26% was found within the first 4 years of exposure to cART, and compared with cART-naive HIVinfected individuals, patients initiating cART increased their risk of MI fourfold within the first year of cART exposure [43] . These findings suggesting a period of particular vulnerability to CVD within the first years of cART are supported in other epidemiological studies [5] . These findings could support the theory of immune reconstitution, according to which the very rapid recovery of the immune system affects the arterial walls in an atherogenic manner. The undesired effects of the rapid immune reconstitution following the initiation of cART are well known as the immune reconstitution inflammatory syndrome. This syndrome is a condition that affects approximately 16% of all HIV patients who initiate cART, characterized by paradoxical future science group

Review

worsening of treated opportunistic infections or chronic conditions, or the unmasking of subclinical and therefore untreated infections [44] . Since atherosclerosis is considered to be a chronic inflammatory condition in which T cells play an important role [45] , theory suggests a possible link between this exaggerated immune response and the development of atherosclerotic lesions. Results from the SMART trial show that for patients in the CD4-guided intermittent treatment group, risk of CVD event was increased by 60% [46] and associated with increased levels of inflammatory markers [47] , which could support the hypothesis that initiating cART intermittently poses special risk. An alternative explanation is that intermittent cART is less effective in viral suppression and therefore increases the viral contribution to CVD. Studies in patients initiating cART that consisted of different regimens show rapid decreases in both coronary and peripheral endothelial function [48–51] , which are known to precede atherosclerosis and predict future cardiovascular events [52–54] . The first studies to describe the connection between cART and CVD primarily showed associations with the use of protease inhibitors (PIs) [55–57] . Part of this association is most likely explained by the dyslipidemia induced by the PIs. The lipid profile created by these drugs is characterized by higher levels of total cholesterol, LDL cholesterol and triglycerides, and decreased levels of HDL cholesterol [58–60] , which is considered to be the classical atherogenic profile. Indeed, the risk associated with the use of PIs seems to be connected to these lipid abnormalities in the epidemiological studies. A study of coronary and endothelial function in two groups of HIV patients with high and normal total cholesterol on stable cART compared with healthy volunteers did, however, indicate that lipids are not the main pathophysiological mechanism in the development of CVD in patients receiving PIs, since no differences were found between the two groups [61] . Another aspect of cART, especially PI-based cART, is the effect on insulin resistance, which is a component in the metabolic syndrome and an independent risk factor for the development of CVD [62] . Experimental studies on PIs and their possible damage to the cardiovascular system are many and the conclusions plenty, including a decrease in nitric oxide production and an increase in superoxide production and subsequent oxidative stress [63–65] . More recently, associations have been made between the use of the nucleoside reverse transcriptase inhibitor abacavir and an increase in the risk of CVD [66–68] . www.futuremedicine.com

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These findings are supported by a subanalysis of the SMART study finding elevated risk of MI with the use of abacavir, correlated with higher levels of IL-6 and hs‑CRP [69] . Other studies have produced similar results, showing increased levels of biomarkers of cardio vascular risk after switching to an abacavir-containing cART regimen [70,71] and lower levels of flow-mediated dilation (FMD) in abacavirtreated patients [72] , suggesting that pathogenesis occurs due to inflammation and endothelial dysfunction. However, in May 2011, the US FDA released a safety report based on data from 26 randomized clinical trials conducted from 1996 to 2010, with 16 trials from the drug manufacturer database, five from the AIDS Clinical Trials Group (ACTG) and five from academic centers, stating that no risk of MI is connected to the use of abacavir [73] . These findings are further supported by a recent large cohort study [74] and a meta-analysis [75] of the use of abacavir relating to MI and hard end point CVD. Some of the important studies regarding MI and cART in patients with HIV are listed in Table 2 . Assessment of CVD in patients with HIV

Regardless of the controversy on hard end points such as MI, several studies indicate that HIV patients on stable cART show signs of early, subclinical atherosclerosis [76,77] . Therefore, the monitoring of early signs of atherosclerosis may be of importance for identifying and monitoring at-risk HIV-infected patients. Below, we will discuss the currently available methods for such monitoring in the general population, with a focus on studies performed in HIV-infected patients (Figure 1) . Biomarkers of early atherosclerosis

Since HIV-infected patients typically have blood samples taken every 3–6 months to monitor the effect of cART, an obvious choice for screening is a blood-borne marker. In the general population, biomarkers for screening for CVD are subject to much attention. First and foremost, hs‑CRP has been thoroughly studied both as a marker of present CVD and also as a predictor of future events [78] resulting in a recommendation from the American Heart Association (AHA)/CDC of hs‑CRP measurement in patients with an intermediate risk of coronary heart disease (Framingham risk score [FRS] of 10–20%) in order to improve risk stratification [79] . The use of hs‑CRP in the HIV-infected population is subject to debate, since levels are elevated pre-cART and during 416


therapy regardless of regimen, and seem to either remain elevated despite normalized CD4 cell count and suppressed viral load [13,80] , or decrease even though the risk is thought to lie in the exposure to cART [12] . However, hs‑CRP may still be useful in patients on steady cART with normalized CD4 cell counts and suppressed viral load, since changes in therapy regimen in some studies are associated with increases in hs‑CRP [69,81] . Other biomarkers associated with an increased risk of CVD in the general population are markers of endothelial (dys)function such as E-selectin, sICAM-1, sVCAM-1, tPAI‑1, MMP9 and MPO [82] , which also seem to decrease after initiation of cART. Their role in predicting CVD in the HIV-infected population remains unclear [81,83] . Several other biomarkers are currently being evaluated (e.g., markers of thrombotic activity such as d-dimer and fibrinogen, as well as NT-proBNP, which showed an independent association with CVD in an HIV-infected population) [84–86] . A biomarker that is new to HIV is sCD163, which has recently been shown to decrease to normal levels after initiation of cART in patients with early HIV, but remains elevated in chronic HIV [87] ; results that correspond well to previous endothelial biomarker findings made by others [12] . Furthermore, sCD163 seems to be closely related to the degree of noncalcified plaque burden in asymptomatic, HIV-infected men, and since this is a lesion type that deserves a great deal of attention in this group, sCD163 could prove very useful in the assessment of cardiovascular risk [21,76] . An important goal in future research will be to clarify whether biomarkers of CVD can prove useful on an individual basis in the risk stratification of HIV-infected patients. Carotid intima–media thickness

Carotid intima–media thickness (cIMT) is now well established as being useful in risk stratification and has been given a level IIa recommendation for cardiovascular risk evaluation in the latest edition of the American College of Cardiology Foundation/AHA guidelines [88] . The method has been made easy to apply and highly reproducible by commercial software with automated measuring algorithms. There is an ongoing debate as to the precise methodology of the measurement of cIMT, which we will not elaborate on here, but we recommend the use of an automated edge-detection program designed for the measurement of the far wall of the common carotid artery. future science group


In HIV patients, enlargement of the cIMT has been well investigated over the last decade and substantial evidence shows both an enlargement in cIMT from cross-sectional data and a faster progression of cIMT than normal [19,89–93] . cIMT measurement in HIV-infected patients could prove to be a useful tool in risk stratification of HIV patients, but more longitudinal studies are warranted. Arterial stiffness

Related to cIMT and vascular thickening is the concept of large vessel stiffness, which may also contribute to the pathogenesis of CVD in HIV. As atherosclerosis is not just a disease of the small vessels, noninvasive measurements of the compliance and distensibility of larger vessels may provide evidence of early subclinical disease. These measurements can be made by pulse wave velocity or ultrasound and find proof of changes in distensibility, which may provide evidence of early atherosclerotic disease [94] . Using ultrasound, lower arterial compliance of the carotid arteries has been shown in HIV-infected patients compared with matched controls [95] . Flow-mediated dilation

Endothelial function plays a central role in maintaining healthy vasculature, and dysfunction

Review

develops when the endothelium loses the ability to react adequately to blood flow (shear stress) and vasoactive blood-borne substances and thereby create the appropriate constriction or dilation. The dilation of the artery can be measured with ultrasound of the brachial artery following cuffinduced blood stasis. A set of international guidelines have been developed for reproducibility [96] . Using this method, a strong correlation between FMD and cardiovascular events has been established in HIV-uninfected patients [97], but whether this correlation also exists in HIV-infected patients is currently not known. A small study of FMD in HIV-infected patients found that FMD did not differ between a group of HIV-infected patients with a low overall CVD risk compared with controls and was not correlated with cholesterol levels [61] . In a longitudinal study of HIV-infected patients naive to cART, FMD was measured 5 weeks after initiation of cART, and a considerable decrease in vasomotor function was found, which could be caused by immune reconstitution [48] . This decrease in endothelial function is supported by other studies [72,98] , but an increase was found by the ACTG in a longitudinal study of patients initiating cART [99] . These discrepancies may be due to differences in baseline levels, with the ACTG cohort having very low pre-cART levels, indicating a more diseased HIV population.

Table 2. Hard end point studies showing antiretroviral therapy to be associated with increased cardiovascular risk. Study

Study duration Patients (n) Study design

Main findings

Holmberg et al.

1993–2002

5672


Increased risk of MI in HIV patients on PI-containing cART versus non-PI cART (OR: 7.1)

[56]

Currier et al.

1994–2000

28,513


Increased risk in HIV patients on cART versus not on cART (RR: 2.1)

[7]

Friis-Møller et al. 1999–2002

23,468


Increased risk of MI in HIV patients on cART versus not on cART and RR increased 26% per year in the first 4 years of cART exposure

[43]

7542


Increased risk of CVD in HIV patients on PI-containing cART versus non-PI cART (RR: 1.71)

Friis-Møller et al. 1999–2005

23,437


Adjusted increased risk of MI of 16% per year for patients on PI-containing cART versus non-PI cART

[57]

1999–2005

33,347


Increased risk of MI in HIV patients on abacavir- or didanosine-containing cART versus non-abacavir or non-didanosine cART (RR: 1.5)

[67]

SMART/INSIGHT 2002–2007 and D:A:D Study Groups

2752


Increased risk of major CVD events in HIV patients on abacavir-containing cART versus non-abacavir cART (HR: 1.8)

[69]

Obel et al.

1995–2005

2952


Increased risk of MI in HIV patients after initiating abacavir-containing cART (RR: 2.22)

[66]

Choi et al.

1997–2007

10,931


Increased risk of CVD with recent use of abacavir within 6 months (HR: 1.48)

[68]

Iloeje et al.

Sabin et al.

1991–2002

Ref.

[113]

cART: Combination antiretroviral therapy; CVD: Cardiovascular disease; HR: Hazard ratio; MI: Myocardial infarction; OR: Odds ratio; PI: Protease inhibitor; RR: Relative risk.

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Normal

Inflammation

Endothelial dysfunction

Fatty streaks

Increased intima–media thickness

Plaque formation

Plaque rupture

Stable plaque

Myocardial infarction

Stable angina

Biomarkers E-selectin

ICAM-1

MPO

tPAI-1

hs-CRP VCAM-1

MMP-9

Examinations FMD and PET

IMT

CACS

MPS

ECG

Future Virol. © Future Science Group (2012)

Figure 1. Development of ischemic heart disease. Schematic representation of the development of ischemic heart disease with approximate time points for biomarker changes and relevant examinations. CACS: Coronary artery calcium scoring; FMD: Flow-mediated dilation; IMT: Intima–media thickness; MPS: Myocardial perfusion scintigraphy.

Coronary endothelial function & flow reserve studied with PET

Although the study of peripheral endothelial function by FMD is valuable, a direct measurement of the coronary flow reserve and myocardial perfusion reserve seems more relevant with regard to later cardiac events. The technique measures myocardial perfusion (ml/g/min) in absolute values using PET. Normally, either 13NH3 or 15O-H2O is used as the PET tracer and dynamic PET imaging is performed, allowing for kinetic modeling of perfusion. These methods have been extensively validated in non-HIV populations and found to be extremely reproducible and powerful for studying even minor changes in myocardial flow and thereby changes in integrated coronary vasomotor function [100] . Using this modality, HIV-infected patients on cART have similar myocardial perfusion reserves to those found in the general population, but in a longitudinal study of treatment-naive HIV-infected patients, myocardial perfusion reserve declined upon initiation of cART [48] . Myocardial perfusion PET may be used for research purposes in HIV-infected patients if exact information on myocardial perfusion and coronary endothelial function is needed. For now, however, the modality remains experimental due to both the 418


cost and the ionizing radiation, limiting its use for the widespread screening of asymptomatic individuals. Coronary artery calcium scoring

In the general population, coronary artery calcium scoring (CACS) has been thoroughly evaluated, and the AHA suggests it as a potential supplement to FRS to modify risk prediction and alter therapy in individuals with an intermediate risk [101] . Studies using this technique to identify early atherosclerosis in HIV-infected patients have revealed a higher burden of calcified coronary plaques than would be expected for their age when compared with the general population [102–104] . However, studies comparing CACS and other noninvasive methods suggest that the amount of coronary calcium may not fully reflect the total level of atherosclerotic disease. In support of this, a recent study found that almost 25% of HIV-infected patients with coronary stenosis on computed tomography (CT) angiography had a coronary calcium score of zero [76] . CT angiography revealed that these plaques were softer and were therefore thought to be more vulnerable than the calcified plaques. In a recent study of 55 asymptomatic HIV-infected patients with a FRS of future science group
