Coronary Heart Disease in HIV-infected Patients Marshall J. Glesby, MD, PhD

Address Division of International Medicine and Infectious Diseases Department of Medicine, Weill Medical College of Cornell University 525 E. 68th St., Box 566, New York, NY 10021, USA. E-mail: [email protected] Current HIV/AIDS Reports 2005, 2:68–73 Current Science Inc. ISSN 1548-3568 Copyright © 2005 by Current Science Inc.

Increased risk of coronary heart disease has emerged as a long-term concern among HIV-infected patients receiving antiretroviral therapy. HIV-infected patients may have modifiable risk factors for heart disease that are associated with HIV itself, antiretroviral therapy, or factors unrelated to HIV. Dyslipidemia, insulin resistance, and diabetes mellitus are often multifactorial in origin. Patients with lipodystrophy frequently have a constellation of metabolic changes that may predispose them to accelerated atherosclerosis. There is also concern about contributions of chronic inflammation and prothrombotic tendencies in the pathogenesis of coronary heart disease in the HIV-infected population. Several epidemiological studies support an increased relative risk of myocardial infarction in HIV-infected patients on highly active antiretroviral therapy. Although absolute risk appears low in the short term, patients may accrue significant risk over time. Clinicians are advised to assess coronary heart disease risk in HIV-infected patients and to intervene to reduce the impact of modifiable risk factors.

Introduction Cardiovascular complications of HIV disease were recognized early in the course of the AIDS epidemic. Investigators have reported a wide spectrum of manifestations, including dilated cardiomyopathy, myocarditis, endocarditis, pericardial disease, and pulmonary hypertension. In recent years, with decreased mortality from AIDS as a consequence of more potent antiretroviral therapy, coronary heart disease has emerged as a longer-term concern in this patient population. This review will focus on coronary heart disease in HIV-infected patients, with an emphasis on new developments in the past year.

Coronary Heart Disease Risk Factors Risk factors for coronary heart disease can be categorized as nonmodifiable and modifiable. Nonmodifiable risk

factors include family history of premature coronary heart disease and increasing age, the latter of which is of increasing importance for HIV-infected patients who are living longer as a result of effective antiretroviral therapy. HIVinfected patients may have modifiable risk factors that are associated with HIV itself, antiretroviral therapy, or factors unrelated to HIV. Investigators have studied several of these modifiable risk factors extensively in recent years, though the pathogenesis of some of them, such as dyslipidemia, is not fully understood.

Dyslipidemia Data from the early 1990s indicated that untreated, advanced HIV disease is associated with abnormalities in lipid metabolism that may result in abnormally low highdensity lipoprotein cholesterol (HDL-C), high triglycerides, and low levels of low-density lipoprotein cholesterol (LDL-C), with elevated levels of the atherogenic small, dense LDL subtype [1]. However, competing mortality from AIDS in that era made this atherogenic lipid profile merely an academic concern, until the availability of protease inhibitor (PI)-based antiretroviral regimens. A wealth of data has since implicated many of the PIs in causing dyslipidemia, including hypertriglyceridemia and, in some cases, elevated LDL-C with minimal, if any, favorable effects on HDL-C. Postulated mechanisms by which PIs affect lipid metabolism include interactions between the drugs and various lipoproteins, inhibition of apolipoprotein B degradation in proteasomes, and increased synthesis of cholesterol as a result of inhibition of hydrolysis of transcription factors such as sterol regulatory element-binding proteins [2]. There are differences within the PI class with regard to the propensity to cause lipid abnormalities, and several newer drugs, such as atazanavir and fosamprenavir, generally do not have unfavorable effects on lipids. Recent studies have demonstrated that the non-nucleoside reverse transcriptase inhibitors (NNRTIs) have favorable effects on lipids by increasing levels of HDL-C. For example, in the two non-nucleoside reverse transcriptase inhibitors (2NN) study [3] in which antiretroviral-naïve patients were randomized to receive nevirapine, efavirenz, or both in combination with stavudine and lamivudine, HDL-C increased 42.5% and 33.7% from baseline in the nevirapine and efavirenz arms, respectively, at 48 weeks. Although LDL-C and triglycerides also

Coronary Heart Disease in HIV-infected Patients • Glesby

increased in both arms, the net effect on lipid profiles appeared favorable as assessed by reduction in the total cholesterol to HDL-C ratios. Nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) may also affect lipids. For example, in the Gilead 903 trial [4], antiretroviral-naïve subjects were randomized to receive stavudine or tenofovir, each with lamivudine and efavirenz. Subjects in the stavudine arm had significantly greater increases in total cholesterol, LDLC, and triglycerides at week 144 compared to those in the tenofovir arm [4]. A recent retrospective analysis of 50 HIV seroconverters from the Multicenter AIDS Cohort Study (MACS) has suggested that some of the adverse changes in lipids that have been attributed to direct effects of antiretrovirals may, in fact, be partly due to a return to pre-HIV–infection levels and age-related changes. In this elegant study, nonfasting serum lipid profiles were retrospectively obtained from stored preseroconversion blood and additional timepoints prior to initiating and while on highly active antiretroviral therapy (HAART). The authors demonstrated decreases in total cholesterol, LDL-C, and HDL-C between the time of seroconversion and initiation of HAART, and subsequent increases in total cholesterol and LDL-C on HAART. The end result was that much of the increases in total cholesterol and LDL-C on HAART appeared to represent returns to baseline, pre-HIV infection levels plus the effects of increasing age. Notably, HDL-C remained lower than baseline, suggesting that the net effect on lipids may be adverse with respect to coronary heart disease risk.

Insulin resistance and diabetes mellitus Insulin resistance is prevalent among HIV-infected patients, and the age-adjusted incidence of diabetes mellitus is higher than controls without HIV infection [5]. Both diabetes and insulin resistance itself are risk factors for coronary heart disease. The etiology of insulin resistance in the HIV-infected patient is frequently multifactorial. Certain PIs, such as indinavir, directly cause peripheral insulin resistance in healthy volunteers [6], possibly through inhibition of the GLUT4 glucose transporter [7]. Recent data also suggest that indinavir may worsen insulin sensitivity in the liver and increase hepatic glucose production presumably by a different mechanism [8]. Other treatment-related factors contributing to insulin resistance in HIV-infected patients may include lipoatrophy, visceral adiposity, and hepatic steatosis. Co-infection with hepatitis C virus predisposes to diabetes [9], as do traditional risk factors, such as obesity and family history of diabetes [10]. Hypertension The relationship, if any, between antiretroviral therapy and hypertension is unclear. Retrospective studies of blood pressure in association with HAART use in general have yielded conflicting results [11,12], but two retrospective studies suggest that indinavir use is associated with hyper-

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tension [13,14], possibly mediated by vasoconstriction [15]. Several studies have suggested that elevated blood pressure is seen in association with other metabolic disorders in patients with lipodystrophy [16–18].

Inflammation Diseases characterized by chronic inflammation, such as some collagen vascular diseases, are associated with accelerated atherosclerosis. Although some controversy exists, markers of inflammation, such as high sensitivity C-reactive protein (hsCRP), may be independently associated with atherosclerotic risk. Preliminary data from the Adult AIDS Clinical Trials Group (AACTG) suggest that patients with suppressed HIV viral loads for over 3 years on indinavir-based HAART regimens continue to have higher than expected hsCRP levels [19]. While hsCRP has not been validated as a marker of atherosclerotic risk in this patient population, there is concern that even well-controlled HIV disease may be a chronic inflammatory state that could predispose to acclerated atherosclerosis. Endothelial dysfunction Endothelial dysfunction has emerged as an early marker of atherosclerosis and can be assessed noninvasively by methods such as measurement of brachial artery reactivity [20]. Use of PIs was associated with impaired flow-mediated vasodilatation of the brachial artery, an indicator of endothelial dysfunction, in association with atherogenic dyslipidemia in a cross-sectional study [21]. Administration of indinavir to healthy HIV-uninfected controls for 4 weeks resulted in endothelial dysfunction, as assessed by invasive monitoring of femoral artery blood flow in response to various stimuli [22]. Of note, indinavir did not cause dyslipidemia or hypertension in this study, suggesting that insulin resistance or direct vascular effects may have been the culprit. The clinical implications of these findings are uncertain, though the implications of endothelial dysfunction in the general population raise concern about this potential association with some PI-based regimens. A substudy of the ongoing AACTG A5142 protocol examining longitudinal changes in brachial artery reactivity among antiretroviral-naïve subjects who initiated therapy with two NRTIs plus efavirenz, two NRTIs plus lopinavir/ ritonavir, or efavirenz plus lopinavir/ritonavir should clarify the effects of various class-sparing regimens on endothelial function. Prothrombotic state A number of investigators have reported abnormalities in coagulation in association with HIV infection including one report of a correlation between HIV viral load and hypercoagulability [23]. More recently, elevated levels of markers of impaired fibrinolysis, specifically plasminogen activator inhibitor type-1 (PAI-1) and tissue plasminogen activator (tPA), were found in patients with lipodystrophy compared with age-, sex-, and body mass index-matched

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controls from the Framingham Offspring Study [24]. Others have reported elevated PAI-1 and fibrinogen levels among HIV-infected patients receiving PI-containing HAART, with or without other features of the metabolic syndrome [25]. Elevated homocysteine levels, which may adversely affect vascular function and coagulation, have also been reported in HIV-infected patients receiving HAART compared to healthy controls [26]. Although the potential role of a prothrombotic state in the pathogenesis of coronary heart disease or myocardial infarction (MI) in HIV-infected patients is unproven, recent reports suggest that reocclusion rates after angioplasty or coronary artery stenting procedures are higher than expected, which is consistent with disordered coagulation [27,28].

Lipodystrophy HIV-infected patients with the body composition changes referred to as lipodystrophy or fat redistribution, consisting primarily of lipoatrophy and possibly increased truncal/ visceral fat, frequently have a constellation of associated metabolic disorders that may predispose to coronary heart disease. Investigators at Massachusetts General Hospital (Boston, MA) compared 71 HIV-infected patients with lipodystrophy to 213 controls from the Framingham Offspring Study, matched on age, sex, and body mass index [16]. The patients with lipodystrophy had a higher prevalence of impaired glucose tolerance and diabetes mellitus on oral glucose tolerance testing. Furthermore, they had higher diastolic blood pressure, higher triglycerides, higher total cholesterol, and lower HDL-C. These findings, and work by others, suggest that patients with lipodystrophy have a metabolic syndrome or clustering of coronary heart disease risk factors that may predispose them to accelerated atherosclerosis. Epidemiology of coronary heart disease To address whether HIV-infected patients have increased rates of coronary heart disease, investigators have conducted epidemiological investigations of rates of MI among HIV-infected patients. The Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group [29••] examined rates of MI in a compilation of 11 prospective cohorts of HIV-infected patients in Europe, Australia, and the United States. In their analysis of 23,648 patients who contributed 36,199 person-years of observation, there was a statistically significant trend for increased risk of MI by duration of exposure to combination antiretroviral therapy, defined as a three-drug combination that included a PI or NNRTI. In a multivariate analysis that adjusted for other risk factors, the risk of MI increased by 26% per year of exposure to combination antiretroviral therapy. Of note, the maximal rate of MI, found in patients with over four years of exposure to antiretrovirals, was only approximately 5.5 events per 1000 person-years. In contrast, retrospective data from the Veterans Affairs medical system in the United States failed to

demonstrate increased rates of admissions for or death from cardiovascular or cerebrovascular disease over time in association with increased use of HAART [30•]. This analysis of 36,766 patients who contributed close to 122,000 person-years of observation was limited by relatively short exposure to antiretrovirals; 70% took antiretrovirals for a median of 15 months, and 42% took PIs for a median duration of 16 months. The authors concluded that the mortality benefit from HAART was not abrogated by increased rates of MI or cerebrovascular disease and that fear of atherosclerotic complications in the short term should not lead to withholding antiretroviral therapy when it is otherwise indicated. Other studies support an increased relative risk of MI in HIV-infected patients receiving PIs. A retrospective analysis from France showed increased risk of MI with increased exposure to PIs [31]. A retrospective analysis of data from the Northern California-based Kaiser Permanente health maintenance organization (HMO) initially found an increased rate of hospitalization for coronary heart disease among HIV-infected men, irrespective of PI use, relative to those without known HIV infection [32]. With further followup, a trend for increased risk of coronary heart disease in relation to duration of exposure to PIs has emerged [33]. Lastly, an analysis of data from the California Medicaid program found an increased incidence of coronary heart disease among young HIV-infected men (< 34 years of age) and women (< 44 years of age) relative to HIV uninfected controls [34]. Young (age 18–33 years) patients receiving antiretroviral therapy also had an increased risk of coronary heart disease compared to those not receiving antiretroviral therapy. Taken together, the bulk of the available data suggest that HIV-infected patients receiving HAART have an increased relative risk of MI or coronary heart disease compared to either the general population or HIV-infected patients not receiving HAART. The absolute risk appears to be low with short-term followup, but this risk is expected to increase over time as the population ages and further risk accrues.

Management of risk factors dyslipidemia Published guidelines for managing dyslipidemia in HIVinfected patients exist [35••]. The recommended approach is based on the National Cholesterol Education Program (NCEP) Panel guidelines and advocates targeting interventions based on risk stratification of patients using the Framingham risk calculations. Lifestyle modification in the form of diet and exercise counseling is a first-line approach for patients with dyslipidemia. Although there is a paucity of data on the efficacy of lifestyle modification, clinical experience suggests that many patients will require pharmacologic intervention to achieve desired levels of lipids. Statin drugs are recommended for patients whose predominant lipid

Coronary Heart Disease in HIV-infected Patients • Glesby

abnormality is elevated LDL-C, whereas fibrate drugs are recommended for those whose predominant abnormality is hypertriglyceridemia. In practice, many patients will have abnormalities of both LDL-C and triglycerides, which may necessitate cautious use of both a statin and fibrate, for which there are limited safety data [36]. Clinicians should keep in mind established drug-drug interactions between some statins and antiretrovirals. For example, studies of healthy volunteers have shown dramatic elevations of simvastatin when coadministered with ritonavir/saquinavir or nelfinavir [37,38]. Pravastatin, fluvastatin, and atorvastatin, the latter at low doses, are considered the drugs of choice by many experts. Recent data from the AACTG indicate that simvastatin and atorvastatin exposures decrease significantly in the presence of efavirenz, suggesting that efficacy of these statins may be affected if usual doses are administered along with efavirenz [39]. Other lipid-lowering agents such as niacin, ezetimibe, and fish oils are currently under study in the HIV-infected population. In a pilot dose escalation study, an extended release formulation of niacin lowered triglycerides, total cholesterol, and non-HDL cholesterol significantly over a 14-week period [40]. Insulin sensitivity was reduced, but none of the 14 subjects developed overt diabetes mellitus. In a pilot study [41] in HIV-infected subjects with hypertriglyceridemia, fish oil supplementation was safe and lowered triglycerides modestly compared with placebo. No prospective data are available on ezetimibe, a cholesterol absorption inhibitor, which is commonly used in combination with statins to further lower LDL-C. There is little enthusiasm for using bile acid sequestrants such as cholestyramine in the HIV-infected population because of the potential to exacerbate hypertriglyceridemia and unknown effects on absorption of antiretrovirals. Substituting antiretroviral drugs with neutral or favorable effects on lipids for a drug in an antiretroviral regimen that is likely to cause lipid abnormalities has been a successful approach in a number of clinical trials. The most common approach has been to switch a PI to a NNRTI or abacavir, which has typically resulted in favorable effects on triglycerides and total cholesterol [42–44]. Changing to efavirenz or nevirapine may also increase HDL-cholesterol [42]. Substitution within the PI class, specifically switching nelfinavir to atazanavir, has also resulted in improved lipid profiles in an uncontrolled study [45]. Recent data suggest that substituting tenofovir for stavudine may improve lipid profiles [46,47]. The approach of switching antiretrovirals to manage dyslipidemia should only be undertaken if a patient’s treatment history and resistance profile confer a low probability of virologic failure.

Disordered glucose metabolism Limited data from clinical trials suggest that rosiglitazone, pioglitazone, and metformin have favorable effects on

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insulin sensitivity in HIV-infected patients. There are currently no data, however, to support pharmacologic treatment of insulin resistance or impaired glucose tolerance in this population, though lifestyle modification is indicated. Insulin sensitivity may improve with the discontinuation of certain PIs, and this approach may be tried if there is a temporal relationship between the onset of diabetes and initiation of a PI known to induce insulin resistance. Otherwise, diabetes mellitus should be managed as in the HIV-uninfected patient.

Hypertension There are no clinical trial data to specifically guide the management of hypertension in HIV-infected patients. Of note, a study in healthy volunteers demonstrated significantly increased exposure to amlodipine and modestly increased exposure to diltiazem and its metabolites when these drugs were coadministered with indinavir plus ritonavir [48]. The authors suggest that if used concurrently with indinavir/ritonavir, these calcium channel blockers should be initiated at low doses with careful titration to response and adverse effects. Other interventions Consideration should be given to prescribing aspirin to HIV-infected patients with risk factors for coronary heart disease, though there are no specific data to support this recommendation. Smoking cessation is likely to be the intervention with the greatest potential impact on cardiovascular risk, and absent any data, it is reasonable to approach this in the same manner as someone without HIV infection. Investigational approaches to the management of the lipoatrophy and visceral adiposity compon e n t s of l i p o d ys tr o p hy c ou l d p o t e n t i a l ly re d uc e cardiovascular risk by effects on related metabolic disorders. For example, recombinant human growth hormone has been shown to reduce non-HDL cholesterol in association with reduction of visceral adipose tissue [49].

Conclusions Risk factors for coronary heart disease are prevalent among HIV-infected patients and may be related to underlying HIV infection or antiretroviral therapy. In particular, the subset of patients with changes in fat distribution known as lipodystrophy frequently have an associated metabolic syndrome that raises concern about accelerated atherosclerosis. Although definitive data on the clinical impact of these risk factors are not yet available, several epidemiological studies do support an increased relative risk of MI among HIV-infected patients receiving HAART. Consequently, clinicians should evaluate coronary heart disease risk factors in HIV-infected patients and intervene to reduce long-term risk based on established guidelines.

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Acknowledgement This work was supported by National Institutes of Health grant R01- DK065515.

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