Introduction

With effective antiretroviral therapy (ART), human immunodeficiency virus (HIV) has become a largely manageable disease with a growing burden of chronic, non-communicable diseases. People living with HIV have elevated risks for coronary artery disease (CAD) for several potential reasons, including chronic HIV-related inflammation and immune activation. This article aims to identify the epidemiology, mechanisms, and presentation of CAD in HIV with the ultimate goal of informing management in this admittedly data-sparse area.

MI in HIV: Epidemiology and Risk Factors

Studies in large cohorts have revealed significantly greater risks for myocardial infarction (MI) among HIV-infected persons compared with uninfected controls. When adjusting for atherosclerotic cardiovascular disease (ASCVD) risk factors, HIV-infected (HIV+) persons have a 1.5-fold to twofold increased risk of having CAD.^1,2 Furthermore, compared with uninfected persons, HIV+ persons presenting with a first episode of acute coronary syndromes (ACS) are, on average, a decade younger.^3-5 An overview of factors that contribute to CAD in HIV is provided in Figure 1 and discussed in more detail below.

Figure 1: Mechanisms of Atherosclerosis and MI in HIV

HIV-Specific Factors Associated With MI: HIV Severity, Concomitant Comorbidities, and Medications

HIV viremia and immune dysfunction (as indicated by CD4+ T cell counts) are associated with elevated risks for MI even after adjusting for demographics and traditional ASCVD risk factors.^6,7 Furthermore, HIV+ persons may have concomitant comorbidities, such as hepatitis C virus, that further contribute to inflammation and atherosclerotic disease risk.^4,5 Specific ART regimens may also contribute somewhat to atherosclerotic disease through dyslipidemia and insulin resistance.^8,9 Abacavir, a nucleoside reverse transcriptase inhibitor, has been associated with elevated rates of MI in studies from the large, multinational Data collection on Adverse events of Anti-HIV Drugs cohort as well as other cohorts; however, this finding was not reproduced in an analysis of the pooled AIDS Clinical Trials Group cohort.^10-12

Traditional ASCVD Factors Associated With MI

Some ASCVD risk factors are substantially more common among HIV+ versus uninfected persons. HIV+ persons are twice as likely to smoke tobacco as the general population; 42% of HIV+ persons are current smokers, and 20% are former smokers. Of note, current HIV+ smokers may be less likely to quit than uninfected persons.^1,5,13 These disparate quit rates persist among smokers who have had an ASCVD event. In a single-center study following HIV+ and uninfected persons with ACS, 51% of HIV+ smokers quit smoking after ACS compared with 80% of smokers in the uninfected group.⁵ Dyslipidemia is also common among HIV+ persons. HIV+ persons on ART, especially protease inhibitors, tend to have elevated triglycerides and low high-density lipoprotein cholesterol levels.¹⁴

Pathophysiology of CAD and MI in HIV

Chronic inflammation and immune dysfunction appear to accelerate the progression of cholesterol plaque erosion and rupture in HIV.¹⁵ In chronic HIV infection, there appears to be preferential macrophage differentiation into M1-type macrophages, which can increase cholesterol accumulation and disrupt the fibrous cap (compared with M2-differntiated macrophages, which may contribute to plaque instability). Factors that can enhance this preferential M1 differentiation in HIV include soluble CD14 and soluble CD163 proteins, both of which are elevated in HIV.^6,15,16 Moreover, macrophages also contribute to platelet aggregation, which can in turn lead to coronary occlusion in ACS through the release of tissue factor from foam cells within the plaque.¹⁶ Thus, this increased activity of macrophages expedites the formation of arterial plaques, increases their instability, and potentially amplifies their deleterious effects upon rupture in HIV+ persons. To better understand this elevated CAD risk, we will next look further upstream and evaluate the pathophysiology of subclinical atherosclerosis in HIV.

Subclinical Atherosclerosis

There is growing evidence that persons with HIV, whether on ART or not, develop subclinical atherosclerosis.^6,10,14,17 HIV+ persons in MACS (Multicenter AIDS Cohort Study) were significantly more likely than uninfected matched controls to have non-calcified arterial plaque even after adjustment for traditional ASCVD risk factors.¹⁴ HIV+ persons also had 1.4 times greater odds of having >50% stenosis of a coronary artery in this study, and low CD4 counts were associated with greater likelihood of >50% stenosis independent of demographics (though not traditional ASCVD risk factors).¹⁴ Arterial inflammation also appears to be more common among HIV+ persons than matched uninfected controls.^16,18 One study specifically evaluated endothelial inflammation by ¹⁸flourine-2-deoxy-D-glucose positron emission tomography uptake in the aorta: compared with uninfected individuals without ASCVD, a higher level of inflammation was apparent in HIV+ persons similar to uninfected persons with known atherosclerotic disease.¹⁶ The elevated incidence of non-calcified arterial plaque and chronic arterial inflammation, specifically in the HIV population with perceived low ASCVD risk, enables CAD pathogenesis and progression in a manner that is "under the radar" of our traditional screening and risk prediction tools.

Presentation and Management of CAD

Several studies have evaluated the management and outcomes of interventions for CAD among HIV+ persons. Studies from the early 2000s demonstrated similar outcomes following percutaneous coronary intervention (PCI) with bare-metal stents (BMS) for HIV+ versus uninfected persons.^5,19 The first direct comparison of drug-eluting stents (DES) versus BMS for HIV+ persons, a single center retrospective study, found that HIV+ persons treated with DES were less likely to have target vessel and lesion revascularization compared with those treated with a BMS.³ Importantly, whether the HIV+ persons in this study received a BMS or DES, they fared similarly to the general population regarding target lesion revascularization, target vessel revascularization, and major adverse cardiac events.³

Recent data from 23 cardiac intensive care units in France showed no difference between HIV+ and uninfected persons after their first PCI in major adverse cardiac or cerebral events, reduction in left ventricular ejection fraction, or target vessel revascularization. However, HIV+ persons had a 4.6-fold increased risk of having recurrent ACS at 1 year with more frequent urgent PCIs.⁵ Coronary artery bypass graft surgery has also shown similar efficacy between HIV+ and uninfected persons with similar rates of immediate post-operative death, MI, stroke, and mediastinitis.²⁰ Notably, HIV+ persons did have a higher long-term incidence of revascularization via PCI of native arteries, which corroborates the findings of other studies looking at outcomes post-PCI.^5,20

Prevention and Screening of CAD

ASCVD Prediction and Risk Stratification

Given the elevated rates of ASCVD among HIV+ persons, several studies have evaluated CVD risk prediction tools in the HIV+ population. The ASCVD Pooled Cohort Equations, derived from multicenter US cohorts with low prevalence of HIV, appear to consistently under-predict MI risk in the low-to-moderate predicted risk group (<10% 10-year predicted ASCVD risk) when applied in a large multicenter US HIV cohort.²¹ Other studies of models incorporating HIV-specific variables such as inflammatory markers and ART regimens for CVD risk prediction have demonstrated somewhat a better fit than general population ASCVD risk prediction models; however, the external validity of these models is unclear, as is their applicability in the setting of evolving ART regimens.^6,22 Thus, although we know that HIV+ persons tend to have 1.5-fold to twofold greater risk for ASCVD than uninfected persons, optimal methods to integrate ASCVD risk prediction in the care of HIV+ persons remain unclear.^1,2

Statin Use in HIV and Pharmaco-Prevention of ASCVD

Statins are widely used in the general population to reduce ASCVD risk. Since the early ART era, there has been some reluctance to co-administer statins and ART given potential interactions with the cytochrome P450 system.²³ Lovastatin and simvastatin, and to a lesser extent atorvastatin, may be particularly prone to drug-drug interactions with boosted ART regimens (particularly ritonavir- or cobicistat-boosted regimens) because these regimens, by definition, inhibit drug metabolism by the cytochrome P450 system. However, pitavastatin, rosuvastatin, and pravastatin appear to have fewer interactions with boosted protease inhibitor regimens because they rely less on the CYP450 system for metabolism.²⁴ In a systematic review of 18 trials from 2002 to 2015 evaluating the use of statins in HIV+ individuals, statins other than simvastatin and lovastatin appeared to maintain a favorable safety profile while also effectively reducing low-density lipoprotein cholesterol.²³ Accordingly, it is appropriate that simvastatin and lovastatin are contraindicated in the setting of HIV on ART but other statins appear to be acceptable in the appropriate clinical settings.

In addition to cholesterol reduction, statins have also been shown to reduce chronic immune activation and arterial inflammation associated with subclinical CAD in HIV+ persons.²⁵ The largest study to date investigating the use of statins in the HIV+ population was INTREPID (HIV-Infected Patients and Treatment With Pitavastatin vs Pravastatin for Dyslipidemia); it included 252 patients randomized to pitavastatin 4mg or pravastatin 40mg daily. As expected given its greater potency, pitavastatin had a greater effect, reducing oxidized low-density lipoprotein by 27% and soluble CD14 levels by 10%.¹⁸ Still, no large randomized trials have evaluated the efficacy of statins on reducing hard clinical endpoints in the HIV+ population. The first of these, REPRIEVE (Evaluating the Use of Pitavastatin to Reduce the Risk of Cardiovascular Disease in HIV-Infected Adults), is underway and on track to recruit 6,500 patients with an average follow up of 48 months.²⁶ Data from this study may be instrumental in informing approaches to CVD prevention in the HIV+ population.

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Keywords: Acquired Immunodeficiency Syndrome, Acute Coronary Syndrome, Antigens, CD, Anti-HIV Agents, Aorta, Arteries, Atherosclerosis, Cardiovascular Diseases, CD4 Lymphocyte Count, CD4-Positive T-Lymphocytes, Cell Differentiation, Cholesterol, HDL, Cholesterol, LDL, Cohort Studies, Comorbidity, Constriction, Pathologic, Coronary Artery Bypass, Coronary Artery Disease, Coronary Occlusion, Cytochrome P-450 Enzyme System, Deoxyglucose, Dideoxynucleosides, Drug Interactions, Drug-Eluting Stents, Dyslipidemias, Factor X, Foam Cells, Follow-Up Studies, Hepacivirus, HIV Infections, HIV-1, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Insulin Resistance, Intensive Care Units, Lovastatin, Mediastinitis, Myocardial Infarction, Percutaneous Coronary Intervention, Platelet Aggregation, Positron-Emission Tomography, Pravastatin, Prevalence, Protease Inhibitors, Quinolines, Receptors, Cell Surface, Retrospective Studies, Reverse Transcriptase Inhibitors, Risk Assessment, Risk Factors, Ritonavir, Simvastatin, Smoke, Smoking, Stroke, Stroke Volume, Thromboplastin, Tobacco, Triglycerides, Viremia

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