Since its introduction in the mid-1990s, combination antiretroviral therapy (ART) therapy has dramatically reduced the morbidity and mortality associated with HIV infection. There has, however, been an increasing awareness of the potential for adverse events related to ART, particularly the problems of metabolic complications. These metabolic complications include insulin resistance, lipid abnormalities such as a reduction in high-density lipoprotein (HDL) cholesterol and an increase in low-density lipoprotein cholesterol, and changes in body fat distribution, such as the loss of peripheral fat and intra-abdominal fat accumulation, all of which have raised concerns about a possible risk of cardiovascular disease (CVD) in HIV-infected patients being treated with ART. In the late 1990s a series of case reports describing severe premature coronary artery disease (CAD) in young HIV-infected patients receiving ART increased these concerns, and combination treatments, especially those containing protease inhibitors (PI), began to be recognized as a possible risk factor for CVD. The improvements in life expectancy in the ART era have not only meant that long-term complications, such as CVD, are becoming more relevant, but also that patients are being treated with ART for longer periods of time, increasing the risk of any exposure-related adverse events. It is becoming imperative therefore to identify the factors associated with CVD in the HIV-infected population and, if possible, to determine which components of combination ART are associated with increased risk, what the underlying mechanisms driving that risk might be, and how these risks should best be managed in the HIV-infected population.
Cardiovascular manifestations of HIV infection
Dilated cardiomyopathy is an important complication of HIV infection, with a reported prevalence of 10–30% by echocardiographic, observational and autopsy studies, which tends to arise late in the course of HIV infection and is usually associated with a significantly reduced CD4 T-cell count . Patients with HIV infection and dilated cardiomyopathy have a much worse prognosis than those without, with a mean survival in the pre-ART era of 101 days [95% confidence interval (CI) 42–146] for individuals with cardiomyopathy compared with 472 days (95% CI 383–560) for those without . The pathogenesis of dilated cardiomyopathy in HIV infection is unclear. A number of causes have been suggested, including direct infection of the heart by HIV itself, toxic effects of ART, particularly potential mitochondrial toxicity with the nucleoside reverse transcriptase inhibitors (NRTI), effects of circulating or systemic toxins, infection of the heart by opportunistic pathogens, toxicity of alcohol, illicit or self-prescribed substances, and nutritional disorders, although it is probable that the underlying cause is multifactorial .
The prevalence of infective endocarditis is similar in HIV-infected patients to that seen in other patients with similar risk behaviors, such as intravenous drug users (IVDU). The incidence of infective endocarditis in HIV-infected IVDU ranges from 6.3 to 34% . For IVDU, presentation and survival rates are similar in HIV-infected and non-HIV-infected patients with endocarditis, although mortality is higher in patients who are more severely immunosuppressed [1,4–6].
Pericardial effusion was one of the most common cardiovascular manifestations in HIV infection before the introduction of ART, with a frequency of between 5% and 46% and an incidence of 11–17% per year [7,8]. Pericardial effusion in HIV infection generally does not have a clear underlying pathology, but is associated with low CD4 cell counts and may be related to opportunistic infections or to malignancy seen in the advanced state of AIDS, although it rarely causes death in these patients . Improved management since the introduction of ART and control of human herpes virus 8 and Epstein–Barr virus infection, both of which are involved in the pathogenesis of HIV-related tumors, may have contributed to the reduced incidence of pericardial effusion in HIV-infected patients in more recent years.
Pulmonary arterial hypertension
Pulmonary arterial hypertension (PAH) has a prevalence of approximately 1/200 000 in the general population, but is more common in HIV-infected patients (∼1/200) . It is a devastating, progressive disease associated with severe cardiac impairment, poor quality of life, right ventricular failure and death. Pulmonary hypertension has been reported in HIV-infected patients without a history of predisposing factors such as thromboembolic disease, intravenous drug use or pulmonary infection. The underlying pathology of HIV-associated PAH appears to share similarities with that of PAH of different etiologies . The pathophysiology of the disease is complex, and is likely to be multifactorial. To date, there are limited data regarding the effects of ART on PAH associated with HIV infection. The prevalence does not change in the ART era. It is more common in young men (mean age 32 years). Intravenous drug use, homosexuality and hemophilia are classic risk factors .
Coronary artery disease
After the introduction of ART, increases have been observed in the incidence of CAD and myocardial infarction (MI) in HIV-infected patients. Treatment with PI and associated dyslipidemia has been implicated in this increase, and a retrospective analysis reported a fourfold increase in the annual incidence of MI among HIV-infected patients after the introduction of ART regimens including PI compared with patients from the pre-ART period . The underlying pathophysiology of CAD is likely to be multifactorial, and pre-existing cardiovascular risk factors may also play a role in the development of CAD and MI. The identification of vascular risk factors associated with CVD in HIV-infected patients is important in identifying at-risk patients and in improving the management of cardiovascular complications.
Traditional cardiovascular risk factors in HIV-infected patients
There is evidence to suggest that there are specific cardiovascular risk factors associated with HIV infection. Lower HDL-cholesterol, higher triglyceride levels and increased visceral adiposity were found to be significantly more frequent in HIV-infected patients compared with a population-based cohort without CAD  or compared with age-matched controls with CAD . There were significantly more smokers in the HIV-infected cohort in the study by Savès et al.  (56.6 versus 32.7%), but a similar high rate of tobacco consumption in both groups (>80%) when young HIV-infected and uninfected patients with CAD were evaluated in the two case–control retrospective studies by our group [13,14]. Hypertension was reported to be significantly less common in HIV-infected men included in the study by Savès et al.  (5.2 versus 12.8%), although hypertension was defined as blood pressure of 160/90 mmHg in that study, rather than 140/90 mmHg as defined by the General Medical Council, which may explain this finding.
Significantly lower HDL-cholesterol and higher triglyceride levels were also found in patients who had had MI compared with HIV-infected patients without MI in a 5-year cohort study of 840 HIV-infected patients . Interestingly, in that study the mean CD4 T-cell count was lower in the patients who had had MI compared with the HIV-infected patients without MI (284 versus 486 cells/μl). Similar findings were seen in univariate analyses of 16 HIV-infected patients with MI and 32 age and sex-matched HIV-infected patients without MI . Traditional risk factors (elevated cholesterol, family history of CVD, smoking) were more frequent in HIV-infected patients with MI compared with those without. The CD4 T-cell count, the nadir CD4 T-cell count and the duration of low CD4 T-cell count were all related to the risk of MI . The findings from those studies imply that the risk of MI in HIV-infected individuals may be affected by a dual synergistic effect of immuno-incompetence and lipid disturbance. In the large Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study , conventional risk factors for CVD (smoking, hypertension, total cholesterol, increased HDL-cholesterol, increased triglycerides, diabetes and family history) were all significantly associated with MI in HIV-infected patients, but there was no apparent association with CD4 T-cell counts (Table 1).
Although there is some variation between results, those studies suggest that conventional risk factors for CVD, especially total cholesterol, decreased HDL-cholesterol and raised triglyceride levels, are more prevalent in the HIV-infected population, and that these, in combination with other conventional risk factors (including smoking, diabetes and a family history of premature CAD) are associated with an increased risk of MI in HIV-infected patients.
Cardiovascular disease and antiretroviral therapy
Given their known propensity to induce dyslipidemia and insulin resistance , PI are primarily implicated in the possible cardiovascular risk. NRTI may, however, also play a role in CAD because of their potential role in the development of insulin resistance . Several studies have investigated a possible link between ART and the development of CAD and MI in HIV-infected patients (Table 2).
Bozzette and colleagues  performed a retrospective analysis of cardiovascular and cerebrovascular disease in 36 766 patients who received care at US Veterans Affairs facilities between January 1993 and June 2001. Overall, approximately 70% of patients received NRTI, 42% received PI and 26% received non-nucleoside reverse transcriptase inhibitors (NNRTI) over a median treatment period of 17 months, 16 months and 9 months, respectively. In that study, no association was found between the use of PI, NRTI or NNRTI and risk of cardiovascular or cerebrovascular events. There was no effect on the rate of MI in patients being treated with or without PI in another US study . In that case the risk of MI was 6.2 events per 1000 patients per year for patients treated with PI compared with 6.2 events for those not receiving PI, although both of those figures were approximately twice those seen in the general population of the same age from the same area, suggesting that HIV-infected patients have an increased risk of MI.
An analysis of 18 603 HIV-infected patients treated with ART over a median of 3.49 years showed an only marginally significant increase in the risk of MI with PI, and no increased risk with atherosclerotic disease overall . In a cohort of 5672 outpatients with HIV-1 seen at nine US HIV clinics between January 1993 and January 2002, however, the frequency of MI significantly increased after the introduction of PI in 1996 . The hazard ratio for MI after exposure to PI was 7.1 (95% CI 1.6–44.3) in an unadjusted model and 6.5 (95% CI 0.9–47.8) when adjusted for smoking, sex, age, diabetes, hyperlipidemia and hypertension. In a retrospective analysis of HIV-infected men included in the French Hospital database on HIV, exposure to PI was associated with a higher risk of MI (relative hazard 2.56; 95% CI 1.03–6.34) . The standardized mortality ratio relative to the French general male population was 0.8 (95% CI 0.5–1.3) for men exposed to PI for less than 18 months, 1.5 (95% CI 0.8–2.5) for men exposed for 18–29 months and 2.9 (95% CI 1.5–5.0) for those exposed for 30 months or more (Fig. 1). These results demonstrate a duration-related effect relationship between PI and MI, with a higher MI incidence rate among men exposed to PI for 18 months or more.
Overall, the data from those studies indicate a probable association between PI use, the duration of PI use, and increased cardiovascular risk. There are, however, several factors that need to be taken into account when assessing CAD risk as a potential adverse event, including the fact that atherosclerosis is a slow process that may take many years to exert clinical effects, and the relatively low incidence of the disease in the young population (<50 years of age). To confirm this association, large, adequately powered studies that rigorously characterize and confirm adverse events with the ability to control for conventional risk factors are required. One such study, the DAD study, has been reported.
Initiated in 1999, the DAD study was a prospective, observational collaboration between 11 existing prospective cohort studies that were ongoing when the study was first initiated [17,27]. The study enrolled 23 437 patients and followed their progress up until February 2005. The primary outcome of the study was MI, as defined by the criteria applied in the World Health Organization Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) study . Initial findings from the study were reported in 2003 . Overall, the risk of MI was found to increase with longer exposure to combination ART (adjusted relative rate per year of exposure 1.26; 95% CI 1.12–1.41; P < 0.001) with a 26% relative increase in the rate of MI per year of exposure during the first 4–6 years of use. At this preliminary stage, however, there were insufficient data to identify differences between drug classes. The full data from this study were recently published . The patient population in the DAD study was young, with a median age of 39 years (interquartile range 34–45), and approximately a quarter of patients were women. The median CD4 T-cell count was 420 cells/μl at enrolment; the median HIV-RNA level was 2.6 log10 copies/ml. At baseline, almost 70% of the population had been exposed to PI for a median of 1.6 years, and 18% were naive to ART. Exposure to NNRTI as a class was considerably less common, at approximately 35%. By the end of follow-up 93.6% of patients had been exposed to some form of ART, with a median exposure of 6.9 years. Incidence rates of MI between study initiation in 1999 and last follow-up in 2005 were relatively stable, with an incidence of approximately 3.7 per 1000 person-years of follow-up. A linear increase in the incidence of MI was seen with longer duration of exposure to combination therapy with antiretroviral drugs. The relative rate per year of exposure after adjustment for other factors (sex, mode of HIV transmission, race, age, body mass index, family history of CVD, smoking status and previous cardiovascular event) was 1.16 per year of exposure (95% CI 1.09–1.23). A linear trend of increasing MI was also seen with increasing exposure to PI (relative rate per year of exposure 1.16; 95% CI 1.10–1.23). With NNRTI there was no clear pattern of risk association. There was, however, an increased risk of 16% per year of additional PI exposure in NNRTI-treated patients. The association between exposure to PI and an increased risk of MI was confirmed when patients treated with PI only (i.e. those naive to other antiretroviral drugs) were analyzed; the risk of MI in these patients was 1.15 (95% CI 1.06–1.25).
Increased total cholesterol and reduced HDL-cholesterol, increased triglyceride levels and a diagnosis of hypertension or diabetes are risk factors for coronary heart disease that have been reported to be associated with ART. These factors were also associated with MI in the cohort of patients included in unadjusted analyses from the DAD study. When lipids were added to the adjusted model, the estimate for the risk of MI with increasing exposure to PI was reduced from 1.16 to 1.10, and 1.05 to 1.00 for exposure to NNRTI. This analysis suggests that only some of the PI effect on CVD risk can be explained by lipid levels as measured. Diabetes and hypertension were strong predictors of CVD or MI, whereas markers of HIV infection (nadir CD4 T-cell count and peak HIV-RNA level) were not. In that study, the lack of increase in the risk of MI in later years appears to be at least partly explained by improvements in the extent of dyslipidemia in the targeted population over time.
The debate on the impact of the immunovirological status and CVD has been raised by the recent results of the SMART study . This randomized, non-blinded trial evaluated two therapeutic strategies in more than 5000 HIV-infected patients, with one group undergoing continuous ART (viral suppression arm) and one group receiving treatment interruptions (drug conservation arm or episodic use). Episodic use involved the deferral of therapy until the CD4 cell count decreased to less than 250 cells/μl and then the use of therapy until the CD4 cell count increased to more than 350 cells/μl. The study was stopped after an average treatment period of 16 months follow-up, with the drug conservation arm being switched to continuous therapy before the predefined study end because of increased mortality in the episodic therapy group. The risk of fatal or non-fatal CVD was marginally statistically significantly elevated in the drug conservation arm compared with the viral suppression arm (hazard ratio 1.6; 95% CI 1.0–2.5; P = 0.05). During follow-up, however, the absence of treatment was not associated with an increased cardiovascular risk. There was also no association between the current HIV-1-RNA level or CD4 cell count levels and CVD risk in the drug conservation arm. Overall, there was a greater rate of unfavorable lipid changes in the drug conservation arm compared with the viral suppression arm, which may explain the increased CVD risk.
Non-traditional cardiovascular risk factors in HIV-infected patients
In addition to the traditional risk factors found in the HIV-infected population, there is increasing evidence to suggest that chronic HIV infection, low-grade chronic inflammation and immunological status are also involved in the development of atherosclerosis and atherothrombosis . The underlying mechanisms of these interactions between immunovirological status and cardiovascular risk remain to be elucidated. T cells are present in atherosclerotic lesions and could produce cytokines, leading to inflammation and acceleration of atherosclerosis. Cytomegalovirus has been associated with cardiac allograft vasculopathy in heart transplanted non-HIV-infected patients. Hsue and colleagues  demonstrated that HIV-infected patients had higher carotid intima media thickness (IMT) compared with uninfected controls and that cytomegalovirus-specific T-cell responses were independently associated with IMT. The impact and exact role of the specific immune responses on atherosclerosis in HIV-infected patients requires further investigation.
As data become available there is a need to improve measures to identify HIV-infected individuals at risk of CAD through the refinement of current conventional prediction models. Analysis of data from the DAD study suggested that models such as the Framingham equation can be used in this population, although greater accuracy would be achieved in a prediction model based on HIV-infected patients .
Prognosis of coronary artery disease and coronary revascularization
The prognosis of CAD in HIV-infected patients has been evaluated in a small number of studies [33–36]. Matetzky et al.  compared the characteristics and long-term course of 24 HIV-infected patients with acute MI with age and sex-matched non-HIV patients with MI. The in-hospital course was similar, with no deaths or re-infarctions arising. After a 15-month follow-up, however, HIV-infected patients had a higher incidence of re-infarction, recurrent cardiovascular events, and target vessel revascularization independently of the type of ART used. In accordance with these findings, a case–control study by Hsue et al.  reported a higher rate of coronary re-stenosis after percutaneous coronary intervention (PCI) in HIV-infected patients compared with non-HIV-infected patients with acute coronary syndrome (52%; 15/22 patients versus 14%; 3/21 patients; P = 0.032). There was, however, no significant difference in the subgroup of patients who had stenting (50 versus 18%; P = 0.078).
Ambrose et al.  reported the outcome of 51 HIV-infected patients with acute coronary syndrome. Forty-five had coronary angiography and 25 had PCI, with an excellent initial result and no hospital death in the PCI subgroup. We have previously reported the results of a case–control study comparing baseline characteristics, the rate of procedural success and clinical outcome at 20 months [major adverse cardiac events (MACE): death from cardiac cause, MI, target lesion or vessel revascularization] between 50 consecutive HIV-infected and 50 HIV-uninfected patients matched for age and sex who underwent PCI . The procedural success rate was achieved in 98% of cases with a high rate of stenting (76% versus 96%, P = 0.004). The in-hospital course was uneventful in both groups. Clinical re-stenosis including revascularization of the entire target vessel was not significantly different between HIV-positive and HIV-negative patients at follow-up (20 months) (14 versus 16%, respectively; P = 0.78). Rates of occurrence of first MACE and MI at 20 months were similar in both groups (20 versus 16%; P = 0.64, and 8 versus 0%; P = 0.12, respectively). We concluded that PCI represents an adequate and safe therapeutic strategy for coronary revascularization in HIV-positive patients without significant differences in terms of clinical re-stenosis and MACE compared with the control population.
We recently reported data from the long-term follow-up (median 41 months, range 34–60 months) of a case–control study comparing 27 HIV-infected patients and 54 non-HIV-infected patients undergoing coronary artery bypass graft for CAD . The results from that study differed from those reported in our earlier study regarding PCI. After 30 days, the rate of postoperative death, MI, stroke, mediastinitis and re-intervention was identical in both groups. At follow-up, however, the rate of occurrence of first MACE was higher in the HIV-positive group compared with the HIV-negative group (11, 42% versus 13, 25%; P = 0.03). This difference was largely caused by the need for repeated PCI revascularization of the native coronary arteries but not of the grafts, in the HIV-positive group in nine (35%) versus six (11%) in the uninfected group (P = 0.02). We could not explain this difference, although the follow-up was longer in the coronary artery bypass graft study compared with the PCI study (41 versus 20 months). In addition, patients were also older (49 ± 8 versus 43 ± 5 years) and had a longer exposure to PI (median 28 versus 24 months), which may have at least partly accounted for the increased atherosclerotic manifestations. The prognosis of coronary revascularization in HIV-infected patients needs to be compared with a larger cohort of HIV-uninfected subjects with a long follow-up .
Non-invasive coronary risk evaluation
A number of non-invasive imaging techniques are available that give an indication of the structural artery, and can act as surrogate markers of subclinical atherosclerosis. These include IMT, which significantly correlates with advancing CAD and coronary artery calcium. The measurement of IMT is a well-established method for the assessment of subclinical atherosclerosis in HIV-negative populations, which has been shown to predict the incidence of CVD. Subclinical atherosclerosis in HIV-infected patients has been reported, with increased IMT and atherosclerotic plaques of the carotid and femoral arteries being correlated with age, dyslipidemia, and tobacco use, although results regarding the impact of PI therapy have been mixed and remain controversial [31,38–42]. Coronary artery calcium visualized using electron beam computed tomography, another surrogate marker and prognostic factor of atherosclerosis, has also been assessed in HIV-infected patients, with controversial results in the HIV-infected population [42–44]. Coronary magnetic resonance angiography and computed tomography could also be further diagnostic tools for detecting coronary atherosclerosis in the near future, although additional technical improvements are required before this technique can be widely implemented .
In conclusion, CVD is an important cause of non-HIV-related death in the ART era, accounting for 6–15% of all deaths in HIV-infected patients [46–49]. Studies show that many of the conventional risk factors for CVD are more prevalent in HIV-infected patients than in the overall population, and especially in those HIV-infected patients who go on to develop CVD. Data from large-scale prospective studies and smaller cohort and retrospective studies have also suggested and confirmed a link between ART, and in particular PI, and MI. PI are known to increase total cholesterol and low-density lipoprotein cholesterol, and would therefore be expected to increase the risk of CAD. In the largest and most comprehensive study to date, however, the risk of MI associated with the use of PI was not fully explained by the lipid changes induced by this class of drugs . The etiology of cardiovascular manifestations in HIV-infected patients is probably multifactorial, with recent studies suggesting a complex interaction between ART, HIV infection itself, immunological and virological factors  and conventional factors.
There is also a need to identify those antiretroviral drugs and interventions that will minimize risk in HIV-infected patients, especially in the at-risk population. There are known to be marked differences between the tendency of particular PI to induce dyslipidemia [50–52], but the impact of these differences on the incidence of cardiovascular manifestations remains to be investigated. Large-scale prospective randomized clinical trials are required to determine the net effect of statins on cardiovascular events in HIV patients, especially given the potential for adverse drug–drug interactions. The optimal selection of ART, together with aggressive management of other modifiable coronary risk factors, may improve cardiovascular risk in HIV-infected patients.
Conflicts of interest: None.
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