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Risk of Cardiovascular Disease in a Cohort of HIV-Infected Adults: A Study Using Carotid Intima-Media Thickness and Coronary Artery Calcium Score

  1. Alexandra Mangili1,3,
  2. Jul Gerrior3,
  3. Alice M. Tang3,
  4. Daniel H. O'Leary2,
  5. Joseph K. Polak2,
  6. Ernst J. Schaefer1,
  7. Sherwood L. Gorbach1,3, and
  8. Christine A. Wanke1,3
  1. 1Departments of Medicine, Boston, Massachusetts
  2. 2Departments of Radiology, Tufts-New England Medical Center, Boston, Massachusetts
  3. 3Nutrition Infection Unit, Department of Public Health and Family Medicine, Tufts University School of Medicine, Boston, Massachusetts
  1. Reprints or correspondence: Dr. Alexandra Mangili, Tufts University School of Medicine, Nutrition/Infection Unit, Jaharis 275, 150 Harrison Ave., Boston, MA 02111 (amangili{at}tufts-NEMC.org).
 
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Abstract

Background. There is concern that human immunodeficiency virus (HIV) infection and the use of highly active antiretroviral therapy lead to accelerated atherosclerosis and increased risk of cardiovascular disease. We measured 2 surrogate markers of subclinical atherosclerosis, carotid intima-media thickness (c-IMT) and coronary artery calcium (CAC) scores, in HIV-infected adults.

Methods. A cross-sectional analysis of 242 men and 85 women with HIV infection was used. Carotid ultrasonography and coronary computed tomography were performed, and their associations with cardiovascular risk factors were examined.

Results. Among men, the mean (± standard deviation [SD]) common c-IMT was 0.62 ± 0.2 mm, the mean (±SD) internal c-IMT was 0.76 ± 0.5 mm, and 136 patients (56.1%) had detectable CAC. Among women, the mean (±SD) common c-IMT was 0.59 ± 0.2 mm, the mean (±SD) internal c-IMT was 0.66 ± 0.4 mm, and 40 patients (47.1%) had detectable CAC. Neither the c-IMT nor the CAC score differed by antiretroviral therapy class or individual medications for either sex. For men, age and waist circumference independently predicted common c-IMT; age, systolic blood pressure, and high-sensitivity C-reactive protein level independently predicted internal c-IMT; and age, apolipoprotein B level, and high-sensitivity C-reactive protein level independently predicted CAC score. For women, age and body mass index independently predicted common c-IMT; age independently predicted internal c-IMT; and age and glucose level independently predicted CAC score.

Conclusions. Our participants had more abnormal surrogate markers than expected at a relatively young age, but those were not associated with use of highly active antiretroviral therapy or protease inhibitors. At present, the positive associations were primarily with traditional and novel cardiovascular risk factors. Some HIV-specific (not treatment-specific) factors were observed; they may become more evident with prolonged HIV infection and treatment.

As survival has increased among patients with HIV infection with the use of HAART, there is concern that metabolic and morphological abnormalities associated with HIV infection may predict an increased risk of cardiovascular disease [1, 2]. The metabolic and morphological changes that may occur in individuals with HIV infection include dyslipidemia, insulin resistance, and visceral fat deposition, each of which may contribute to cardiovascular disease [3]. Because the development of atherosclerotic lesions is a slow process, measuring atherosclerotic activity is important for early detection of cardiovascular disease. Surrogate markers obtainable noninvasively may improve the prognostic stratification of HIV-infected persons with risk factors and may clarify some of the pending issues about the risk of cardiovascular disease in HIV infection.

Measurement of carotid intima-media thickness (c-IMT) by ultrasonography is a well-established method to assess subclinical atherosclerosis in HIV-negative populations, and it is currently the only noninvasive imaging recommended by the American Heart Association for inclusion in risk assessment for cardiovascular disease [4]. c-IMT has been shown to predict the incidence of cardiovascular disease [5]. c-IMT of >1 mm has been associated with an increased risk of ischemic heart disease [6]. Although common c-IMT has less measurement variability, internal c-IMT relates more strongly with cardiovascular disease [7]. Previously published studies of cardiovascular disease in HIV infection, using c-IMT, have resulted in variable results about the role of HIV infection or HAART in accelerated atherosclerosis, likely because of variable ultrasonography techniques, the lack of standardized interpretations of c-IMT, and brief follow-up for atherosclerotic progression [8–14].

The quantification of coronary artery calcium (CAC) by high-resolution, electrocardiographically synchronized CT is a newer, noninvasive marker of atherosclerosis and is a promising method for the direct visualization of coronary atherosclerosis [15]. Coronary calcification has been shown to be associated with risk of cardiovascular disease, and its prognostic value is currently under investigation [16, 17]. There are few studies correlating CAC score with risk of cardiovascular disease in patients with and/or receiving treatment for HIV infection [18–21]. It has been shown that internal c-IMT and CAC score correlate in the HIV-negative population [22], but to our knowledge, there has been no report to date using both modalities in studies of HIV-infected subjects. The effect of antiretroviral therapies on the promotion of atherosclerosis remains to be clarified, as well, especially because protease inhibitors (PIs) have been inconsistently implicated in causing premature cardiovascular disease [23–25].

Because there are well-known differences in the epidemiology, diagnosis, and clinical manifestations of cardiovascular disease according to sex, investigating atherosclerosis in the HIV-infected population should be stratified by sex [26]. None of the studies of the HIV-infected population to date has performed separate analyses. The interpretation of novel markers of cardiovascular disease, such as lipoprotein particles and high-sensitivity C-reactive protein (hs-CRP) level, in HIV infection also warrants further evaluation, and the correlations of cardiovascular disease with surrogate markers could be useful for future risk assessment [27]. In this study, we assessed the association of c-IMT and CAC measurements with established and newly emerging risk factors for cardiovascular disease in patients with and/or receiving treatment for HIV infection separately in men and women.

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Methods

We enrolled 327 HIV-positive men and women who were followed up in a cohort study (the Nutrition for Healthy Living study) that examined nutritional and metabolic issues in HIV-infected patients at 6-month intervals over a 10-year period. All patients provided informed consent for the Nutrition for Healthy Living study and for this cardiovascular substudy. Both were approved by the Tufts—New England Medical Center Institutional Review Board. Ultrasonography and CT were performed from 23 January 2002 through 31 March 2004.

Patient demographic characteristics, clinical characteristics, and laboratory measurements. Demographic information, medical history, blood pressure, body composition, and laboratory values were obtained within 3 months after the carotid ultrasonography and CT [28]. Levels of plasma total cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol were determined using standard enzymatic methods [29]. Low-density lipoprotein (LDL) cholesterol was measured directly using kits from Roche Diagnostics. Apolipoproteins (Apo) A-1, B, and E and lipoprotein (a) were measured by immunoturbidimetric assays (Wako Diagnostics). Remnant lipoprotein cholesterol was measured by an immunoseparation technique [30]. hs-CRP, fasting glucose, and insulin were measured at the same time as the lipids. The quantitative insulin sensitivity check index (QUICKI), a measure of insulin sensitivity, was calculated with the formula QUICKI = (1 / [log (insulin) + log (glucose)]) [31]. CD4+ cell count was determined by flow cytometry, and HIV RNA level was measured by the Roche assay (Roche Diagnostics; limit of detection, 400 copies/mL). Smoking and injection drug use were reported as past, current, or never. Personal and family cardiovascular and diabetes histories were obtained. HAART was defined as the use of ⩾3 drugs, including ⩾1 PI or a nonnucleoside reverse-transcriptase inhibitor (NNRTI). Receipt of HAART, PIs, and NNRTIs was reported as current use. The total cumulative duration of HAART was reported. HIV transmission categories were determined as per the classification of the Centers for Disease Control and Prevention. All of the above variables were evaluated as predictors in this analysis.

Measurement of surrogate markers. To ensure standardized methods for ultrasonography for c-IMT and its interpretation, we used protocols adapted from the Cardiovascular Health Study [32]. Centrally trained and certified ultrasonographers performed the imaging, and a single reader at a central reading site interpreted the c-IMT. One longitudinal lateral view of the distal 10 mm of the right and left common carotid artery and 3 longitudinal views in different imaging planes (anterior, lateral, and posterior) of the right and left internal carotid artery were obtained. The mean of the maximum of the near- and far-wall c-IMT was used for the final analysis, because it has been shown to have the strongest association with cardiovascular disease risk [33]. To quantify the degree of carotid artery wall thickening, all measures were summarized into 2 variables, 1 for common and 1 for internal carotid artery. c-IMT was used as a continuous measure and stratified as ⩾0.6 mm, ⩾0.8 mm, and ⩾1.0 mm. Quality control analysis of 32 subjects resulted in intraclass correlation coefficients of 0.911 for the common and 0.883 for the internal carotid artery, which is consistent with results of other studies using the same technique in non–HIV-infected populations [34].

CAC score was obtained by ultrafast coronary calcium CT, as described elsewhere [35, 36]. An electrocardiographic data file acquired during the CT was used to select a single image for each group of readings to minimize image degradation caused by heart motion. The initial image selection was done automatically using rules based on position within the group of readings. After the selection was complete, the particular pixel regions were identified within the images that were to be considered for calcium scoring. Calcification scores were computed using standardized scoring techniques [37]. For our analysis, extent of CAC was used as a continuous variable or stratified as 0, 1–100, or >100. Any detectable score was defined as >0.

Statistics. This is a cross-sectional analysis of 327 participants stratified by sex. Analyses were performed with SAS for Windows, version 9.0 (SAS Institute). After distribution assumptions were tested, nonnormally distributed variables were transformed by taking the natural logarithm. Because the normal CAC value is 0, 1 was added before log-transformation. Comparisons between groups were conducted using Student's t tests and analysis of variance for continuous variables and the χ2 test for binary variables. Univariate associations between c-IMT and CAC score were analyzed by Pearson correlation coefficients. Univariate logistic regression was conducted for all predictor variables. Separate multivariate models were fit using c-IMT and CAC score as the dependent variables. All predictor variables with P < .20 in the univariate analyses were included in the initial multivariate models. The final models were determined using stepwise linear regression techniques. P < .05 was considered to be statistically significant.

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Results

General characteristics. The demographic and clinical characteristics of the 327 participants, according to sex, are shown in table 1. Of the participants, 26% were female. Blacks represented the largest racial group among women (48.2%), whereas men were predominantly white (59.5%). Women had a higher body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters) than men, but weight and waist circumferences did not significantly differ by sex. Women had higher levels of HDL, ApoA-1, and fasting insulin than men. A larger percentage of women were smokers. Triglyceride, ApoB, and remnant lipoprotein cholesterol levels were all significantly higher in men than in women.

Table 1
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Table 1

Demographic and clinical characteristics in a study of coronary disease risk markers and HIV infection and treatment.

HIV and treatment history. HIV-specific parameters listed in table 1 did not significantly differ by sex. Of the treatment regimens, 76% of men and 66% of women were undergoing HAART; 46% of men and 40% of women were receiving a PI-containing regimen; and 35% of men and 26% of women were receiving an NNRTI-containing regimen. The mean duration of HAART (±SD) for men was 32 ± 26 months; for women, it was 28 ± 25 months. For men, the most common HIV transmission category was having sex with men, followed by injection drug use. For women, the main modes of HIV transmission were heterosexual sex and injection drug use.

c-IMT and CAC scores. The mean common c-IMT (±SD) was 0.62 ± 0.2 mm in men and 0.59 ± 0.2 mm in women (P = .173); the mean internal c-IMT (±SD) was 0.76 ± 0.5 mm in men and 0.66 ± 0.4 mm in women (P = .109). Although not statistically significant, common and internal c-IMT measurements tended to be greater in men than in women. Further, internal c-IMT was generally greater than common c-IMT for both sexes. Twenty-four men (10%) and 6 women (7%) had common c-IMT of >0.8 mm; 39 men (16%) and 9 women (11%) had internal c-IMT >1 mm.

There was a trend for CAC score to be higher in men than in women. The mean log CAC score (±SD) was 1.4 ± 1.9 in men and 1.0 ± 1.6 in women (P = .073). Detectable CAC was found in 136 men (56.1%) and 40 women (47.1%); 21 men (8.6%) and 5 women (6.0%) had CAC scores of >100. Both men and women with higher CAC scores had significantly greater common and internal c-IMT (table 2). Carotid measures were positively correlated with CAC in men and women (Pearson correlations for common c-IMT and CAC score, r = 0.30 and P < .001 for men and r = 0.20 and P = .062 for women; Pearson correlations for internal c-IMT and CAC score, r = 0.32 and P < .001 for men and r = 0.42 and P < .001 for women).

Table 2
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Table 2

Carotid intima-media thickness (c-IMT) in millimeters by sex and by coronary artery calcium score cut points.

Mean common or internal c-IMT measurements did not significantly differ by HAART, PI, or NNRTI use in either men or women. In men, CAC was detectable in 57% undergoing HAART versus 56% not undergoing HAART (P = .84) and in 49% undergoing PI treatment versus 63% not undergoing PI treatment (P = .07). In women, CAC was detectable in 50% undergoing HAART versus 43% not undergoing HAART (P = .73) and in 53% undergoing PI treatment versus 44% not undergoing PI treatment (P = .34).

The univariate and multivariate association of risk factors with c-IMT and CAC score for men and women are shown in tables 3 and 4. Univariate predictors of common c-IMT for men were age; systolic and diastolic blood pressure; waist circumference; BMI; lipoprotein (a), ApoE, and insulin levels; smoking; and CD4+ cell count. There was a trend for triglyceride levels and duration of HIV infection to be associated with common c-IMT in men. For women, univariate predictors of common c-IMT were age, systolic blood pressure, and diastolic blood pressure. There was a trend for BMI, lipoprotein (a) and hs-CRP levels, duration of HIV infection, and duration of HAART to be associated with common c-IMT in women. Univariate results were similar for the internal c-IMT, but there were fewer significant associations in men and women. In men only, duration of HAART was positively associated with internal c-IMT, and there was a trend for CD4+ cell count to be associated with internal c-IMT. Univariate predictors of CAC score for men were age; systolic blood pressure; and triglyceride, total cholesterol, ApoB, ApoE, remnant lipoprotein cholesterol, and hs-CRP levels. There was a trend for duration of HAART to be associated with CAC in men. In women, univariate predictors of CAC score were age and triglyceride and glucose levels. There was a trend for CAC score to be associated with systolic blood pressure in women.

Table 3
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Table 3

Variables correlating with surrogate markers by univariate and multivariate analysis in men.

Table 4
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Table 4

Variables correlating with surrogate markers by univariate and multivariate analysis in women.

In the multivariate analysis for men, age and waist circumference independently predicted common c-IMT; age, systolic blood pressure, and hs-CRP level independently predicted internal c-IMT; and age, ApoB level, and hs-CRP level independently predicted CAC score. For women, age and BMI independently predicted common c-IMT; age independently predicted internal c-IMT; and age and glucose level independently predicted CAC score. Other variables included in the multivariate analyses were current PI use and injection drug use, but these were not significant predictors for any of the surrogate markers for either sex.

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Discussion

Our data show that subclinical atherosclerosis is common among HIV-infected patients. At a relatively young age and compared with historical age-matched, HIV-negative controls, abnormal c-IMT and CAC scores in our HIV-positive population were greater than expected [16, 38]. Although certain lipid levels were higher among men and women undergoing HAART or PI treatment than they were among those not undergoing these treatments [39], we did not see a significant difference in c-IMT or CAC score between these groups. Traditional and some newly emerging risk factors correlated most strongly with surrogate markers of cardiovascular disease in this population. Only a few HIV-specific factors independently predicted surrogate markers in the univariate analysis, but these may become more evident with prolonged HIV infection and treatment.

Methodological issues in c-IMT measurements in previously published studies might have contributed to the conflicting results regarding the prognostic value of c-IMT as a surrogate marker for subclinical atherosclerosis in HIV. A greater prevalence of premature carotid vessel lesions (c-IMT of >1 mm) was reported in subjects treated with PIs for >1 year (52.7%) compared with PI-naive (14.9%) and HIV-negative controls (6.7%) [8]. In contrast, in another study, traditional risk factors, but not HIV infection or PI therapy, contributed significantly to the presence of peripheral atherosclerosis (c-IMT of >1.2 mm) [9]. In a large cross-sectional study of HIV-positive subjects, c-IMT was significantly greater with older age, male sex, high BMI, waist/hip ratio, elevated systolic blood pressure, elevated total cholesterol level, glucose and homocysteine abnormalities, smoking and alcohol, lipodystrophy, and HAART use, but only traditional risk factors independently predicted c-IMT [10]. Another study reported mean c-IMT to be significantly greater in PI-treated than PI-naive or HIV-negative patients [11]. HDL, triglyceride, and ApoB levels were significantly higher in PI-treated subjects in that study. Furthermore, a small HIV-positive, antiretroviral therapy–treated group had 8% greater c-IMT than did controls matched for lipid and glucose measurements [12]. These investigators found independent positive associations of c-IMT with ratio of total to HDL cholesterol levels and waist circumference in the HIV-positive, antiretroviral therapy–treated group. Another study reported significantly greater c-IMT in HIV-positive subjects than in HIV-negative subjects (mean c-IMT [±SD], 0.91 ± 0.33 mm vs. 0.74 ± 0.17 mm) [13]. In addition to traditional risks, HIV infection independently predicted c-IMT. One-year follow-up showed that HIV-infected persons had a greater rate of c-IMT progression than did HIV-negative control subjects. Most recently, in a large case-control study, a higher prevalence of premature carotid lesions was shown in PI-treated patients (52.4%) than in the NNRTI-treated patients (15.2%) and nucleoside reverse-transcriptase inhibitor–only or antiretroviral therapy–naive groups (14.3%) (P < .001) [14]. PI use most strongly predicted the risk for developing vascular lesions (P = .001). A standardized protocol similar to that used in the HIV-negative population is needed to facilitate the comparison of these highly variable results. Using the standardized technique described in our study will ultimately improve the prognostic power of c-IMT in HIV infection and clarify its association with treatment regimens.

Risk assessment by CAC score is a newer method, and there are only very few published studies of the HIV-infected population to date. One study compared 60 HIV-positive men with historical age-, sex-, and race-matched HIV-negative control subjects. There was no difference in detectable and clinically significant CAC between case patients and control subjects. They further found no association between abnormal CAC score, HIV infection, and PI use [21]. Another study reported that PI use was associated with changes in CAC and atherogenic lipid levels [18]. In the same 98 HIV-infected participants, those treated with nelfinavir, but not with other PIs, had significantly higher mean CAC scores than those of patients not treated with PIs [20]. Finally, a small pilot study involving 17 dyslipidemic HIV-infected patients reported a higher trend for detectable CAC in HIV-positive patients than in HIV-negative patients (76% vs. 63%; P = .09) [19]. Again, no definite conclusion about the usefulness of CAC as a marker among those individuals with HIV infection can be drawn from these studies. Our analysis did show a worrisome percentage of detectable CAC in a relatively young cohort and positive correlations with multiple risk factors, but we could not confirm a difference in CAC scores according to different treatment regimens.

It is believed that c-IMT and CAC score measure different stages of atherosclerosis [40]. This is the first report assessing to what extent extracoronary indices reflect coronary atherosclerosis in HIV infection. We found that the two are moderately positively associated and show a graded association between CAC score and c-IMT. Because the cardiovascular pathophysiology and risk factors differ by sex, we, for the first time, examined markers of atherosclerosis in HIV infection separately for each sex. Because of the large size of our cohort and the high percentage of female participants, we were able to stratify by sex. Despite women being more obese and having higher rates of smoking and higher HDL cholesterol levels, we found that similar risk factors were associated with surrogate markers in women and men.

hs-CRP elevation is of particular interest in HIV infection, because it is a marker of chronic inflammation and recently was determined to be an important cardiovascular disease risk [41]. We found that hs-CRP independently predicted internal c-IMT and the presence of CAC in men and that this correlation might become more evident with prolonged HIV disease and prolonged exposure to treatment.

An important limitation of our study is its cross-sectional nature. An ongoing longitudinal component will assess changes in surrogate markers after 36 months. This has previously been shown to be sufficient time to assess atherosclerotic disease progression in the general population. Change in c-IMT has been shown to be 0.01–0.03 mm per year in the non–HIV-infected population [33]. It has also been demonstrated that a 0.19-mm increment in c-IMT was significantly associated with an elevated risk of cardiovascular events [6]. Previous studies involving HIV infection have indicated an accelerated progression of atherosclerosis in patients undergoing PI therapy, but the short duration of follow-up greatly limited the generalizability of these findings [13].

Because many coronary events occur in asymptomatic people, assessment of cardiovascular risk using surrogate markers is useful in HIV-infected patients. The relatively brief duration of HIV disease and short exposures to treatment remain limiting factors in the identification of surrogate markers in HIV infection. Our study confirms that interventions should focus on traditional risk factors without jeopardizing HIV treatment. The potential interplay of personal risk of cardiovascular disease with HIV infection and with specific antiretroviral medications is intriguing and requires more examination. In attempting to reduce modifiable risks, smoking cessation programs should be a component of risk reduction, because an alarmingly high percentage of HIV-infected persons smoke. The role of advancing age, the consequences of prolonged survival, the importance of other risk factors, the direct effect of HIV infection, and the direct effect of HAART in relation to surrogate markers of atherosclerosis will become clearer with increasing time and further study.

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Acknowledgments

Financial support. National Institutes of Health (T32Al07438-11, 5R01HL065947-04, and 5P01DK045734-10).

Potential conflicts of interest. All authors: no conflicts.

  • Received May 2, 2006.
  • Revision received August 10, 2006.
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  1. Clin Infect Dis. (2006) 43 (11): 1482-1489. doi: 10.1086/509575
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