Calza, Leonardo MD; Cascavilla, Alessandra MD; Pocaterra, Daria MD; Manfredi, Roberto MD; Colangeli, Vincenzo MD; Chiodo, Francesco MD
Highly active antiretroviral therapy (HAART) has dramatically changed the natural history of HIV infection, leading to a very significant reduction in mortality and morbidity.1 However, long-term toxicity of antiretroviral drugs is becoming recognized and widely assessed, therefore detecting a wide range of side effects including lipodystrophy and metabolic alterations, which have frequently been associated with new combination therapies, particularly when they are based on protease inhibitors (PIs).2
Because new PI-containing antiretroviral regimens have led to a notable extension of life expectancy in HIV-positive patients, prolonged lipid and glucose metabolism abnormalities could significantly act on the long-term prognosis and outcome of HIV-infected persons. In the post-HAART era, long-term cardiovascular complications, including myocardial infarction (MI), peripheral vascular diseases, and stroke, have been frequently reported, and an increasing concern is mounting particularly about the increased risk of acute coronary syndromes associated with new potent antiretroviral combinations.3
Moreover, recent data suggest that endothelial dysfunction, impaired fibrinolysis, and excess inflammation are more common in HIV-positive patients than in general population and may contribute to an increased cardiovascular risk.4 At the same time, carotid intimal-media thickness and coronary calcification assessments suggest increased incidence of atherosclerotic disease and premature occurrence of arterial atherosclerotic lesions among HIV-infected individuals.5
However, the relationship between coronary heart disease and the use of HAART in HIV-infected patients is still a matter of debate. Several studies have investigated a possible association between antiretroviral treatment and cardiovascular disease using various statistical approaches, but they often reported inconsistent and noncomparable results.
Eight HIV-1-infected patients with a diagnosis of MI performed during a 6-year period among HIV-1-infected persons referring to our university center of infectious diseases are reported and discussed.
PATIENTS AND METHODS
A chart review of HIV-1-infected patients followed up in our clinic was performed, and those with a diagnosis of MI referring to our institution from January 2001 to December 2006 were included in the present study. Diagnosis of MI was performed using standard consensus definitions, including acute chest pain, electrocardiographic changes, and/or increases in troponin and creatine kinase enzyme blood levels.
Eight patients (6 men and 2 women; mean age, 49 years [SD, 9 years]; range, 37-71 years) were enrolled into the study. All subjects underwent laboratory examinations, including hematology testing, measurement of plasma glucose, triglycerides, total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels, CD4 lymphocyte count, and HIV-1 RNA viral load. Case history, traditional risk factors for coronary artery disease (CAD), clinical presentation of MI, physical examination, and presence of lipodystrophy syndrome and/or metabolic syndrome were carefully evaluated. All patients underwent transthoracic echocardiography and coronary angiograms (a coronary stenosis was defined as a luminal diameter stenosis ≥50%). The Framingham equation was applied to estimate the 10-year risk for MI in all considered patients just before the occurrence of acute coronary syndrome. Medical and/or surgical treatment for MI, subsequent cardiovascular complications, and midterm follow-up were also evaluated.
Traditional risk factors for CAD were defined as follows: age (men >45 years old and women >55 years old), family history of premature CAD (men <55 years old and women <65 years old), active cigarette smoking (≥1cigarette smoking in the past month), hypercholesterolemia (fasting serum total cholesterol level >225 mg/dL or fasting serum LDL cholesterol level >160 mg/dL), decreased HDL cholesterol (fasting serum levels <40 mg/dL), hypertriglyceridemia (fasting serum triglyceride levels >150 mg/dL), arterial hypertension (blood pressure ≥140/90 mm Hg or use of antihypertensive drugs), diabetes mellitus (fasting serum glucose levels ≥126 mg/dL or use of hypoglycemic drugs), and obesity (body mass index ≥30 kg/m2).
A lipodystrophy syndrome was diagnosed in patients with peripheral fat loss, central fat accumulation, or a mixed form (peripheral lipoatrophy and central lipohypertrophy), as assessed at physical examination. Metabolic syndrome was defined as the occurrence of 3 or more of the following abnormalities: abdominal obesity (waist circumference >102cm for men and >88 cm for women), hypertriglyceridemia (fasting serum triglyceride levels >150 mg/dL), decreased HDL cholesterol (fasting serum levels <40 mg/dL for men and <50 mg/dL for women), arterial hypertension (systolic blood pressure >130 mg/dL and/or diastolic blood pressure >85 mm Hg), and hyperglycemia (fasting glucose levels ≥100 mg/dL).
Cardiovascular complications were defined as congestive heart failure, ischemic recurrence, coronary revascularization, stroke, and cardiovascular death. Follow-up was carried out by periodic interview and clinical examination (every 3 months), including blood tests, electrocardiography, transthoracic echocardiography (every 6 months), and stress testing (stress echocardiography or myocardial scintigraphy every year). No patient was lost to follow-up.
Eight patients (6 men and 2 women; mean age, 49 years [SD, 9 years]; range, 37-71 years) were enrolled into the study. Because a mean of 997 patients per year were followed up in our clinic during this period, the mean incidence of MI was 1.33 events per 1000 patients per year. Their age was younger than 55 years in 7 cases (87%) and ranged from 37 to 55 years, whereas the older subject was aged 71 years. Demographic, epidemiological, clinical, and laboratory features of the evaluable patients are depicted in Table 1.
Among these 8 subjects, one was naive to all antiretroviral agents, whereas the remaining 7 received HAART: 5 had received 1 or more previous antiretroviral treatments, whereas 2 were receiving their first antiretroviral association. The median duration of current antiretroviral therapy was 5.6 years (range, 3.5-7.9 years), whereas the median total duration of antiretroviral treatment was 9.8 years (range, 6.2-14.5 years). Current HAART included a PI in 5 cases (lopinavir/ritonavir in 2, saquinavir/ritonavir in 2, and nelfinavir in one), and a nonnucleoside reverse transcriptase inhibitor (NNRTI) in 2 cases (efavirenz in both subjects). The associated nucleoside-nucleotide dual combination included zidovudine plus lamivudine in 3 cases, stavudine plus lamivudine in 1 case, and tenofovir plus lamivudine in 3 cases. The total median duration of PI-based, NNRTI-based, and NRTI-based therapy was 8.5 years (range, 5.6-12.1 years), 7.2 years (range, 4.4-10.6 years), and 9.8 years (range, 6.2-14.5 years), respectively. One patient received hypolipidemic therapy (pravastatin), and 1 patient was treated with antidiabetic drugs (metformin), before the occurrence of MI.
The examination of case records showed an advanced stage of HIV infection in most subjects (mean duration of HIV infection was 14.6 years and a previous AIDS-defining illness diagnosed in 5 cases), although the immunovirological parameters generally disclosed a good immunologic recovery with complete virological suppression (mean CD4 lymphocyte count of 500 cells/μL and HIV RNA <50 copies/mL in 5 patients).
All the evaluated patients had at least 3 traditional risk factors for CAD, including cigarette smoking in 7 subjects (87%), hypertriglyceridemia in 6 (75%), hypercholesterolemia in 5 (62%), arterial hypertension in 3 (37%), and family history of premature coronary disease in 3 (37%). Four patients (50%) had lipodystrophy syndrome (3 cases of lipoatrophy and one of mixed form), and 1 subject had a metabolic syndrome (defined by the association of abdominal obesity, hypertriglyceridemia, and arterial hypertension) (Fig 1). No cases of hyperglycemia were observed. The mean 10-year risk for coronary events calculated by the Framingham equation just before the diagnosis of IMA was 7.6% (SD, 2.4%), and it was greater than 20% in only 1 patient, ranging from 10% to 20% in 3, and lower than 10% in 4 subjects.
Clinical, instrumental, and therapeutic features of IMA are summarized in Table 2. The mean time between the onset of chest pain and hospitalization was 12 hours (range, 3-21 hours). During the acute phase, electrocardiogram revealed an elevation of ST segment in 7 cases, and the heart involvement was anterior in 4 patients (57%), lateral in 2, and inferior in 1 patient; the ST segment was nonelevated in 1 case only. Coronary and ventricular angiographic study disclosed a 1-vessel obstruction in 4 patients (50%), and mean left ventricular ejection fraction was 51%. Four patients (50%) were treated with thrombolysis, 4 (50%) had a percutaneous coronary angioplasty with stenting (guided by the result of stress testing), and 3 (37%) had a coronary artery bypass shunt. Transthoracic echocardiographic study showed heart valve dysfunctions in 4 cases, represented by a mitral, aortic, or tricuspid regurgitation. There were no deaths during initial hospitalization.
At discharge, drug therapy included aspirin and β-blockers in all patients, angiotensin-converting enzyme inhibitors in 3 subjects, statins in 5 patients (3 on pravastatin, 1 on atorvastatin, and 1 on rosuvastatin), and fenofibrate in 1 patient. At follow-up (mean, 25.7 months [SD, 8.5 months]), no deaths were occurred, but 2 patients (25%) had had cardiovascular complications (congestive heart failure with pulmonary edema in 1 subject and recurrent myocardial ischemia with unstable angina in 1 subject). The patient with ischemic recurrence had sustained, at 18-month follow-up, ventricular tachycardia leading to cardioverter-defibrillator implantation and coronary artery bypass surgery. Concomitant antiretroviral therapy was changed in 4 subjects: current PI was replaced with atazanavir/ritonavir in 3 cases and with abacavir in 1 case. In all these patients, undetectable HIV viral load and mean increase in CD4 lymphocyte count were maintained at the end of follow-up.
After an 18-month follow-up, 3 patients were in class I and 5 patients were in class II of the New York Heart Association Classification. Four of 5 patients with hypercholesterolemia normalized total and LDL cholesterol levels, and the average total cholesterol level dropped from 228.4 (SD, 59.2) to 176.5 (SD, 48.7) mg/dL. Similarly, 3 of 6 patients with hypertriglyceridemia attained normal serum triglyceride levels, and the average serum triglyceride levels decreased from 252.5 (SD, 65.7) to 211.4 (SD, 58.1) mg/dL. Six of 7 subjects stopped smoking, and the average body mass index after diet went down from 26.2 (SD, 5.4) to 25.1 (SD, 4.8) kg/m2.
Some retrospective and prospective studies have shown that the incidence of MI tends to be higher in HIV-positive subjects treated with antiretroviral therapy than in the general population, particularly in those receiving a PI-based treatment.6 However, reports from large observational studies demonstrate that considerable controversy still exists over the association of HAART (particularly PI-based combinations) and an increased incidence of coronary heart disease risk.
In a large retrospective study using the Veterans' Affairs database (which included 36,766 patients followed up for an average of 40 months, between the years 1993 and 2001), Bozzette et al7 showed that PI therapy was not associated with an increased risk of coronary heart disease. Patient-level regression analyses indicated that there was no relation between the administration of nucleoside analogs, nonnucleoside analogs, or PIs and the hazard of cardiovascular or cerebrovascular events. On the contrary, in this study, the use of antiretroviral therapy was associated with a decreased risk of death from any cause. However, the median duration of exposure to PIs was only 16 months, and the true cardiovascular disease rate may have been underestimated, because many patients with acute MI may not have been admitted to Veterans' Affairs hospitals.
In contrast, Mary-Krause et al8 assessed the incidence of MI among 34,976 HIV-infected male patients belonging to the French Hospital Database on HIV, who were followed up for a median of 33 months between 1996 and 1999. Myocardial infarction was diagnosed in 60 men among 88,029 person-years, including 49 cases among men receiving PIs. Exposure to PIs was associated with a higher risk of cardiovascular disease, and the MI rates increased in relation to duration of PI therapy (10.8 events per 10,000 person-years in men with <18 months of PI use; 33.8 events per 10,000 person-years in those with >30 months of PI use).
Moreover, recent prospective studies involving large cohorts of HIV-infected patients have documented an increased incidence of MI and cerebrovascular diseases in association with a prolonged exposure to combination antiretroviral therapies, even if the absolute risk of cardiovascular events remains low and should be balanced against the remarkable benefits from HAART in terms of improvement in immune function and related morbidity and mortality.
The Data Collection on Adverse Events of Anti-HIV Drugs study9 is a prospective, observational study of 11 previously established cohorts comprising 23,468 HIV-infected patients followed up in 21 countries in Europe, United States, and Australia. During this study, a total of 126 episodes of MI were diagnosed, leading to a crude incidence rate of 3.5 per 1000 patient-years. The authors showed that the incidence of MI increased significantly with increasing exposure to combination antiretroviral therapy, and the adjusted risk rate per year of exposure ranged from 0.32 for no HAART use to 2.93 for 6 years or longer of HAART use. This suggested that during the first 4 to 6 years of combination antiretroviral treatment, there was approximately a 26% increase in the relative risk of suffering from an MI, but the absolute risk of coronary events was low and must be balanced against the remarkable benefits from antiretroviral therapy. In subjects receiving combination antiretroviral therapy, the observed numbers of MIs during follow-up were similar to or somewhat higher than predicted numbers, whereas in patients who had not received HAART, the observed number of coronary events was fewer than predicted, suggesting that the observed increase in risk may at least in part be explained by HAART-induced changes in conventional risk factors.10
Iloeje et al11 estimated the risk of cardiovascular disease events with PI exposure in a prospective observational study involving a cohort of 7542 HIV-infected patients (77% were exposed to PIs) followed up between 1996 and 2003. The study population was derived from the Centers for Disease Control and Prevention HIV Outpatient Study and additional physician offices and clinics funded by the sponsoring agency, Cerner Corporation. The incidence of cardiovascular complications was significantly higher in subjects exposed to PIs: a total of 127 cardiovascular events were observed, with 112 in the PI group for an adjusted event rate of 9.8 per 1000 person-years of follow-up, and 15 in the non-PI group for an adjusted event rate of 6.5 per 1000 person-years of follow-up (P = 0.0008). In the multivariate analyses, cumulative PI therapy for 60 days or longer was associated with an increased risk of cardiovascular diseases, and the cardiovascular event rates were also higher in the PI group among patients in the 35- to 65-year-old subset. Other independent risk factors were current or past smoking, hypertension, diabetes mellitus, and pre-existing cardiovascular diseases.
Kwong et al12 evaluated the relative hazards of atherosclerotic disease and death in 18,603 HIV-infected patients from 2 established cohorts with a median follow-up of 3.49 years. Traditional risk factors (older age, hypertension, diabetes mellitus, and smoking) were significantly associated with increased risk of atherosclerotic disease, whereas PI- and NNRTI-containing regimens significantly reduced the joint risk of either coronary syndromes or death from other causes compared with nucleoside reverse transcriptase inhibitor (NRTI)-only regimens or stopping therapy. Protease inhibitor- and NNRTI-based combinations were associated with a borderline significantly increased risk of MI, but not with increased risk of atherosclerotic disease compared with NRTI-only regimens or stopping therapy. In this study, overall benefits of PI- and NNRTI-based antiretroviral therapy in reducing mortality remarkably outweigh any risk of atherosclerotic complications in the short-term follow-up.
Endothelial dysfunction, reduced flow-mediated arterial dilatation, and premature atherosclerotic lesions have been reported with increasing frequency among HIV-infected patients receiving HAART.13-16 However, whether the increased cardiovascular risk in HIV-positive subjects is due to HIV infection itself, to antiretroviral therapy, or to a synergistic interaction between these factors remains to be established. Although both HIV disease and HAART are associated with a lipid and glucose profile known to increase the risk of coronary and cerebrovascular complications, these metabolic factors do not fully account for the premature atherosclerotic lesions observed in these patients, suggesting that other mechanisms or mediators might be involved. Recent data support the hypothesis that both HIV infection and antiretroviral treatment promote atherosclerosis and its clinical manifestations through inflammatory mechanisms involving endothelial cells, either directly or indirectly, also by the lipid alterations induced by these underlying factors.17-18
The activation of the endothelium induced by either HIV infection itself or by a leukocyte-mediated inflammatory cascade triggered by the same virus leads to the increased expression of endothelial cellular adhesion molecules, such as intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1, E selectin, P selectin, thrombomodulin, tissue plasminogen activator, and plasminogen activator inhibitor 1. A significant association between increasing serum concentrations of adhesion molecules and risk of future MI has been shown in apparently healthy men and women, and these molecules are now considered as soluble biomarkers of endothelial inflammation and early atherosclerosis.14,15,19
Increased serum levels of ICAM-1, vascular adhesion molecule 1, E selectin, and thrombomodulin were demonstrated in patients with advanced HIV infection and opportunistic diseases, and a correlation between ICAM-1 concentrations and the progression of disease as well as the reduction of CD4 lymphocyte count was also reported. If circulating adhesion molecules indicate vascular endothelium injury, it seems clear that endothelium injury is associated with the progression and severity of HIV disease.19,20 Moreover, the available evidence demonstrates that certain PIs could induce endothelial dysfunction, including a decrease of endothelium-dependent vasorelaxation, inhibition of the nitric oxide synthase system, increase of oxidative stress, and activation of mitogen-activated protein kinases.21
In our study, an advanced stage of HIV infection was found in most subjects; 7 the 8 observed patients were on HAART, and a prolonged mean duration of antiretroviral treatment with previous therapies including multiple combinations of NRTIs, NNRTIs, and PIs was generally reported. All the evaluated individuals had 3 or more conventional risk factors for MI, mostly represented by smoking, hyperlipidemia, hypertension, and family history of premature coronary disease, whereas no cases of diabetes mellitus were reported. The heart involvement was anterior in most cases with elevation of ST segment at the electrocardiogram, and the angiographic study disclosed a 1-vessel obstruction in the majority of cases. The acute coronary disease was treated with thrombolysis, surgical treatment (percutaneous coronary angioplasty with stenting or coronary artery bypass shunt), and medical therapy (aspirin, β-blockers, angiotensin-converting enzyme inhibitors, and hypolipidemic drugs), and no deaths occurred after a mean follow-up of 26 months.
In conclusion, maintaining virological suppression should still be considered today as the main concern in HIV-infected patients treated with HAART because short-term rates of cardiovascular complications remain quite low and are significantly lower than death rates for AIDS-related conditions in subjects with virological failure and immunologic impairment. However, owing to the notable extension of life expectancy in HIV-positive subjects on antiretroviral therapy, cardiovascular complications are expected to become significantly more frequent and require a routine and appropriate monitoring and management of the broad spectrum of risk factors supporting cardiovascular complications.
1. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med
2. Calza L, Manfredi R, Chiodo F. Dyslipidaemia associated with antiretroviral therapy in HIV-infected patients. J Antimicrob Chemother
3. Holmberg SD, Moorman AC, Williamson JM, et al. Protease inhibitors and cardiovascular outcomes in patients with HIV-1. Lancet
4. Koppel K, Bratt G, Schulman S, et al. Hypofibrinolytic state in HIV-1-infected patients treated with protease inhibitor-containing highly active antiretroviral therapy. J Acquir Immune Defic Syndr
5. Maggi P, Lillo A, Perilli F, et al. Colour-Doppler ultrasonography of carotid vessels in patients treated with antiretroviral therapy: a comparative study. AIDS
6. Vittecoq D, Escaut L, Monsuez JJ. Vascular complications associated with use of HIV protease inhibitors. Lancet
7. Bozzette SA, Ake CF, Tam HK, et al. Cardiovascular and cerebrovascular events in patients treated for human immunodeficiency virus infection. N Engl J Med
8. Mary-Krause M, Cotte L, Simon A, et al. Increased risk of myocardial infarction with duration of protease inhibitor therapy in HIV-infected men. AIDS
9. Friis-Møller N, Sabin CA, Weber R, et al. The Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group: combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med
10. Law MG, Friis-Møller N, El-Sadr WM, et al. The use of Framingham equation to predict myocardial infarctions in HIV-infected patients: comparison with observed events in the D:A:D: Study. HIV Med
11. Iloeje UH, Yuan Y, L'Italien G, et al. Protease inhibitor exposure and increased risk of cardiovascular disease in HIV-infected patients. HIV Med
12. Kwong GP, Ghani AC, Rode RA, et al. Comparison of the risks of atherosclerotic events versus death from other causes associated with antiretroviral use. AIDS
13. Jager A, Van Hinsbergh VW, Kostense PJ, et al. Increased levels of soluble vascular cell adhesion molecule I are associated with risk of cardiovascular mortality in type 2 diabetes: the Hoorn study. Diabetes
14. Wolf K, Tsakiris DA, Weber R, et al. Antiretroviral therapy reduces markers of endothelial and coagulation activation in patients infected with human immunodeficiency virus type 1. J Infect Dis
15. De Gaetano Donati K, Rabagliati R, Tumbarello M, et al. Increased soluble markers of endothelial dysfunction in HIV-positive patients under highly active antiretroviral therapy. AIDS
16. De Gaetano Donati K, Rabagliati R, Iacoviello L, et al. HIV infection, HAART, and endothelial adhesion molecules: current perspectives. Lancet Infect Dis
17. Depairon M, Chessex S, Sudre P, et al. Premature atherosclerosis in HIV-infected individuals-focus on protease inhibitor therapy. AIDS
18. Kamin DS, Grinspoon SK. Cardiovascular disease in HIV-positive patients. AIDS
19. Galea P, Vermot-Desroches C, Le Contel C, et al. Circulating cell adhesion molecules in HIV-1-infected patients as indicator markers for AIDS progression. Res Immunol
20. Boccara F, Ederhy S, Janower S, et al. Clinical characteristics and mid-term prognosis of acute coronary syndrome in HIV-infected patients on antiretroviral therapy. HIV Medicine
21. Wang X, Chai H, Yao Q, et al. Molecular mechanisms of HIV protease inhibitor-induced endothelial dysfunction. J Acquir Immune Defic Syndr
. January 22, 2007 [Epub ahead of print].
© 2008 Lippincott Williams & Wilkins, Inc.