Subjects infected with human immunodeficiency virus (HIV) have increased risk for atherosclerosis. Carotid artery intima-media thickness (IMT) assessed using ultrasound and coronary artery calcium (CAC) detected using computed tomography predict cardiovascular risk in the general population; however, their usefulness and comparability in patients with HIV are less well defined. The purpose of this study was to compare IMT and CAC in the detection of atherosclerosis in subjects with HIV. CAC and IMT were measured in 253 HIV-infected and 58 uninfected adults. Associations among HIV-related factors, traditional risk factors, and CAC and IMT were evaluated. The distribution of IMT among subjects with and without CAC was compared. Among the patients with HIV, 37% had detectable CAC compared to 28% of controls (p = 0.19); 16% of the patients with HIV had CAC >100 compared to 5% of controls (p = 0.03). With either detectable or undetectable CAC, HIV-infected subjects had higher IMT compared to controls (1.02 ± 0.34 vs 0.78 ± 0.12 mm, p <0.0001), even after adjustment for traditional risk factors. Among those with undetectable CAC, 34% of patients with HIV had markedly increased IMT (≥1 mm) compared to no controls (p <0.0001). HIV-related factors were associated with IMT but not with CAC. In conclusion, patients with HIV and controls had similar rates of detectable CAC, while absolute CAC scores were modestly higher in the HIV group. Conversely, carotid IMT detected advanced subclinical atherosclerosis in patients with HIV even in the absence of CAC. Thus, with HIV, IMT is associated with disease-related factors and may be a more sensitive indicator of subclinical atherosclerosis than CAC.
Coronary artery calcium (CAC) is an accepted measure of atherosclerosis burden and a robust predictor of clinical outcomes in the general population. The prevalence of CAC is also higher in patients with human immunodeficiency virus (HIV) than would be expected for their age. Limited data are available comparing carotid artery intima-media thickness (IMT) and CAC in patients with HIV. Therefore, we compared these 2 measurements prospectively in a large cohort of patients with HIV and in a control group of uninfected subjects. As previous studies have revealed that no CAC is detected in ≥1/2 of patients with HIV, we were particularly interested in analyzing IMT measurements according to whether or not CAC was detected. In addition, we wished to determine the associations of HIV-related factors with CAC and with IMT.
Methods
Patients for the study were recruited from a clinic-based HIV cohort at San Francisco General Hospital (Study of the Consequences of the Protease Inhibitor Era [SCOPE]). Study participants were confirmed to be HIV infected using HIV antibody testing, letters of diagnosis, or medical records. Patients with histories of coronary heart disease (CHD) or atrial fibrillation were excluded. We recruited our control group through advertisements placed around the hospital and community. All control participants were HIV antibody negative. Study participants were selected independently of their cardiovascular risk factor profile. This study was approved by the University of California, San Francisco, Committee on Human Research, and all participants provided written informed consent.
We performed detailed interviews of all study participants, focusing on cardiovascular risk factors, past and present medication use, and illicit drug use. We calculated 10-year risk for CHD using the Framingham risk calculator. For the patients with HIV, we recorded antiretroviral therapy use by chart review, as well as history of opportunistic infections, CD4 counts, and HIV viral loads.
Blood was drawn in the fasting state and used to measure total cholesterol, high-density lipoprotein cholesterol, and triglycerides. Low-density lipoprotein cholesterol was calculated using Friedewald’s formula except when triglycerides were ≥400 mg/dl, in which case it was measured directly. CD4 + T-cell counts were measured at the respective clinical laboratories associated with each of the SCOPE cohort clinic sites. The nadir CD4 + T-cell count was the lowest laboratory-confirmed value before the date of computed tomography.
Multislice computed tomography to assess CAC score was performed using a 16-detector Philips MX8000 scanner (Philips Medical Systems, Andover, Massachusetts). Imaging used a slice thickness of 3 mm and electrocardiographic gating was used to trigger axial multislice scan acquisitions. Using this technique, a gantry rotation time of 420 ms results in a temporal resolution of 210 ms. CAC was measured using the Philips scoring software program and calculated as described by Agatston et al. The sum of the scores for all arterial lesions was used to provide an overall score for each subject. The radiologists interpreting the scans were blinded with respect to the participants’ HIV status.
We assessed carotid IMT using the GE Vivid 7 system (GE Healthcare, Milwaukee, Wisconsin) and a 10-MHz linear-array probe as described previously. IMT was measured in a total of 12 segments in the near and far walls of the common carotid, bifurcation region, and internal carotid region according to the standardized protocol of the Atherosclerosis Risk in Communities (ARIC) study. A single experienced technician who was blinded to the subjects’ HIV status performed all the IMT studies and caliper measurements of the digital images. The CAC and carotid IMT studies were performed during the same time period.
Given 80% power and a 2-tailed α value of 0.05, the sample size required for this study was 159 patients with HIV and 40 controls, assuming a standard deviation of 20 and a difference in CAC score of 10. Because a major goal of our study was to compare predictors of CAC and IMT specifically in patients with HIV, we enrolled more of them compared to controls. Descriptive statistics including medians, interquartile ranges, and percentages were used to summarize all variables. We first compared characteristics of HIV-infected and controls using Mann-Whitney U tests for continuous variables and Pearson’s chi-square tests for categorical variables. Mean IMT was compared using Student’s t tests, and median values were compared using Mann-Whitney U statistics. Although only mean values are shown for IMT in the “Results” section, results obtained using Mann-Whitney U statistics were similar. All p values were 2 sided.
To assess the association of HIV status with any detectable CAC and with CAC >100, multiple logistic regression analyses adjusting for appropriate risk factors was used to estimate odds ratios and confidence intervals. Candidate covariates for a final model were determined by logistic regression with CAC (detectable or >100) as the response variable, HIV status as the explanatory variable, and each of the following risk factors 1 at a time: age, gender, race, antihypertensive medication, blood pressure, diabetes, ever smoked, years of cigarette smoking, family history of cardiovascular disease, use of lipid-lowering medication, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, C-reactive protein, Framingham risk score, body mass index, intravenous drug use, cocaine use, and methamphetamine use. Only risk factors significant in the smaller models (p <0.05) were included in the final multiple logistic regression model. A separate multiple logistic regression of patients with HIV was carried out to assess the independent associations of antiretroviral use and other HIV-specific factors with detectable CAC. This analysis considered the aforementioned risk factors and HIV-specific risk factors. To evaluate the independent associations of HIV-specific risk factors and the increased prevalence of high levels of detectable CAC in HIV-infected subjects compared to controls (chi-square p = 0.0042), a separate but parallel multiple logistic regression analysis of high levels of detectable calcium (>100 vs ≤100) was carried out in HIV patients only.
Results
The clinical features of the 253 patients with HIV and 58 uninfected controls are listed in Table 1 . The calculated 10-year Framingham CHD risk was low and similar in the 2 groups (HIV group: median 4%, interquartile range 2% to 6%; controls: median 3%, interquartile range 0.5% to 6%, p = 0.09). The median duration of HIV infection was 15 years, and most subjects were being actively treated with antiretroviral therapy.
| Characteristic | Patients With HIV | Controls |
|---|---|---|
| (n = 253) | (n = 58) | |
| Age (years) | 49 (43–53) | 47.5 (42–55) |
| Men | 225 (89%) | 48 (83%) |
| Race | ||
| European American | 158 (63%) | 36 (62%) |
| African American | 55 (22%) | 12 (21%) |
| Latino | 25 (10%) | 2 (3%) |
| Other | 15 (6%) | 8 (14%) |
| Hypertension | 70 (28%) | 12 (21%) |
| Diabetes mellitus | 16 (6%) | 1 (2%) |
| Low-density lipoprotein cholesterol (mg/dl) | 108 (83–128) | 113 (92–147) |
| High-density lipoprotein cholesterol (mg/dl) | 43 (36–50) | 48 (42–55) |
| Triglycerides (mg/dl) | 144 (86–215) | 107 (70–145) |
| Injection drug use | ||
| Ever but not current | 59 (23%) | 5 (9%) |
| Current | 11 (4.3%) | 0 (0%) |
| Cigarette smoking (ever) | 164 (65%) | 32 (55%) |
| Hepatitis C | 56 (22%) | 1 (2%) |
| Duration of HIV infection (years) | 15 (10–19) | — |
| Use of antiretroviral medication | — | |
| Ever | 193 (76%) | |
| Current | 172 (68%) | |
| Duration of nucleoside reverse transcriptase inhibitor use (years) | 6.1 (0–19) | — |
| Duration of non-nucleoside reverse transcriptase inhibitor use (years) | 0 (0–15) | — |
| Duration of protease inhibitor use (years) | 3.3 (0–13) | — |
| CD4 + T cells/mm 3 | 471 (3–1960) | — |
| Nadir CD4 + T cells/mm 3 | 185 (0–1200) | — |
| Plasma HIV ribonucleic acid copies/ml, % <75 | 146 (58%) | — |
CAC was detected in 63% of patients with HIV and 72% of controls (p = 0.19). Among those with detectable CAC, patients with HIV had higher CA scores compared to controls, as shown in Figure 1 ; for example, 40 of the patients with HIV (16%) compared to only 3 of the controls (5%) had CAC >100 (p = 0.03).
The mean IMT was higher in all patients with HIV (1.02 ± 0.34 mm) compared to all uninfected controls (0.78 ± 0.12 mm, p <0.0001), a difference that persisted even after adjusting for traditional risk factors and Framingham risk score (p <0.0001). Among all subjects after adjustment for risk factors, HIV infection was independently associated with higher IMT, as was older age, male gender, and hypertension (p <0.05 for all). Among the patients with HIV, older age, hypertension, and the HIV-related factors of lower nadir CD4 cell count and duration of antiretroviral therapy were associated with higher IMT (p <0.05).
Among patients with HIV, those with detectable CAC had higher IMT compared to those with no detectable CAC (1.17 ± 0.38 vs 0.93 ± 0.28 mm, respectively, p <0.0001). As shown in Figure 2 , CAC and IMT were correlated (p <0.0001 for trend).
