Progression of carotid artery intima–media thickening in HIV-infected and uninfected adults
Currier, Judith Sa; Kendall, Michelle Ab; Henry, W Keithc; Alston-Smith, Beverlyd; Torriani, Francesca Je; Tebas, Pablof; Li, Yanjieg; Hodis, Howard Ng; for the ACTG 5078 Study Team
From the aCenter for Clinical AIDS Research and Education, David Geffen School of Medicine at the University of California, Los Angeles, California
bStatistical and Data Analysis Center, Harvard School of Public Health, Boston, Massachusetts
cHIV Program, Hennepin County Medical Center, University of Minnesota, Minneapolis, Minnesota
dDivision of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland
eDivision of Infectious Diseases, Department of Medicine, University of California, San Diego, California
fDivision of Infectious Diseases, University of Pennsylvania, Philadelphia, Pennsylvania
gAtherosclerosis Research Unit, Division of Cardiovascular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
Received 3 November, 2006
Revised 6 February, 2007
Accepted 10 February, 2007
Dr J. S. Currier, Center for Clinical AIDS Research and Education, Division of Infectious Diseases, Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, California, USA. E-mail: email@example.com
Objectives: To compare the rate of change in intima–media thickness (IMT) of the carotid artery among uninfected subjects and HIV-infected subjects receiving or not receiving protease inhibitor (PI) regimens over a 144 week period.
Design: This prospective, matched cohort study enrolled 133 subjects into 45 triads (groups of three subjects matched by age, sex, race/ethnicity, smoking status, blood pressure, and menopause) from university based outpatient HIV clinics. Each triad consisted of one subject from each of the following groups: 1, HIV-infected subjects with continuous use of PI therapy for ≥ 2 years; 2, HIV-infected subjects without prior PI use; 3, HIV-uninfected subjects.
Methods: Standardized ultrasound images of carotid IMT were collected at weeks 0, 2, 24, 48, 72, 96, and 144. The main outcome was the yearly progression rate of carotid IMT (mm/year).
Results: The median yearly IMT progression rate in groups 1, 2, and 3 was 0.0096, 0.0058, and 0.0085 mm/year, respectively. There were no statistically significant differences in progression between groups 1 and 2, or between the combined HIV-positive groups and the HIV-negative control group. A multicovariate model examining predictors of progression in carotid IMT among all subjects contained low density lipoprotein cholesterol and homocysteine. Among HIV subjects, predictors included nadir CD4 cell count and ritonavir use.
Conclusions: HIV infection and PI use did not contribute substantially to the rate of carotid IMT progression in our matched study.
Improvements in antiretroviral therapy have greatly extended the life expectancy of people with HIV infection. However, current treatments for HIV infection are associated with metabolic changes that have been associated with an increased risk for atherosclerosis. Well-described lipid abnormalities have been linked with some of the protease inhibitors (PI), non-nucleoside reverse transcriptase inhibitors, and nucleoside analogues [1–8]. In addition, chronic HIV infection is associated with reduced high density lipoprotein (HDL) cholesterol [9,10]. Patients with HIV infection also experience insulin resistance [3,11,12], visceral adiposity [5,13], and chronic immune activation [14,15] associated with elevated levels of C-reactive protein [16–18]. These characteristics are components of the “metabolic syndrome” and are significant risk factors for diabetes and cardiovascular disease in the general population. Observational cohort studies have suggested that exposure to PI therapy and duration of combination antiretroviral therapy are associated with an increased risk of myocardial infaction [19–21].
This prospective, matched cohort study was designed to isolate the role of PI therapy and HIV infection on the risk of development of subclinical atherosclerosis and its progression. Measurement of carotid intima–media thickness (IMT) using non-invasive ultrasound is well documented as a measure of subclinical atherosclerosis. We previously reported the baseline results from our study, demonstrating no difference in carotid IMT between HIV-infected patients treated with PI therapy and those not taking a PI, and between HIV-infected patients and an HIV-uninfected control group, both comparisons matched for traditional cardiovascular risk factors . In this report, we describe the follow-up of our matched cohort study over 144 weeks.
The study was an observational cohort including baseline and longitudinal measurements of carotid IMT in two groups of HIV-infected subjects and one group of HIV-uninfected controls. Study subjects were recruited from eight academic medical centers in the United States. A unique feature of the design was the enrollment of subjects at each site into a triad consisting of one individual from each of the following groups.
Group 1 contained HIV-infected subjects with HIV-1 RNA ≤ 10 000 copies/ml, who were receiving antiretroviral therapy including a PI continuously for ≥ 2 years. Subjects who had received two or more PI drugs must have had a total combined duration of continuous exposure of ≥ 2 years to be eligible. Group 2 contained HIV-infected subjects with HIV-1 RNA ≤ 10 000 copies/ml who were not currently receiving PI therapy (defined as not receiving any PI-containing regimen for more than a total of 3 months at any time prior to study entry). Subjects were not required to be currently receiving antiretroviral therapy but must have been taking non-PI-containing antiretroviral treatment for at least 6 consecutive months sometime in the past. Group 3 contained HIV-uninfected subjects.
The triad of subjects, one subject from each group, was matched on six cardiovascular disease risk factors: age (within 5 years), race/ethnicity, sex, blood pressure status (normal/hypertensive), smoking status (never/current/past), and menopausal status. The matched design was employed to control prospectively for important traditional risk factors for atherosclerosis while attempting to isolate the effects of HIV infection and PI therapy on carotid IMT.
Subjects were excluded if they had any of the following: diabetes mellitus or current use of oral hypoglycemia agents, family history of myocardial infarction (prior to age 55 for first-degree male relatives and prior to age 65 for first-degree female relatives), a history of coronary heart disease or stroke (including a history of angina, myocardial infarction, or abnormal stress test), uncontrolled hypertension, untreated hypothyroidism, or obesity (defined as a body mass index > 30). Subjects requiring systemic chemotherapy, radiation therapy, or systemic steroids were excluded. Subjects with the following laboratory abnormalities were also ineligible: creatine > 15 mg/l, alanine or aspartate aminotransferases > 2.5× upper limit of normal.
Visualization of carotid artery IMT was obtained via non-invasive high-resolution B-mode carotid artery ultrasonography according to the procedure of Hodis et al. [23,24]. Sonographers from six sites were uniformly trained at the University of Southern California Atherosclerosis Research Unit Core Imaging and Reading Center. Prior to study initiation, the ultrasound equipment at each of the eight sites was standardized with a tissue phantom to ensure consistency in pixel calibration necessary for automated edge detection. All subjects underwent ultrasound imaging at baseline and repeated 2 weeks after to determine coefficients of variation. The median coefficient of variation of the repeat baseline measures across all eight sites was 0.53%.
Standardized ultrasound images of the right common carotid artery were captured on SVHS videotape at baseline and at weeks 2, 24, 48, 72, 96 and 144 and sent to the Core Imaging and Reading Center for blinded review and image processing. The distal common carotid artery far wall IMT was measured by automated computerized edge detection using a software package developed in-house (Prowin, patent pending) [25,26].
Fasting glucose, lipids, cardiovascular disease-related measurements, CD4 cell counts and HIV RNA levels were collected every 24 weeks. Metabolic measurements included homocysteine, high-sensitivity C-reactive protein, and insulin.
The primary objective evaluated the pairwise differences in the yearly rate of change in IMT between groups. A clinically relevant difference of 0.02 mm/year between the groups was the basis for the power calculation. Previous studies have documented that each 0.03 mm increase per year in carotid IMT is associated with a statistically significant increase in the risk of clinical cardiovascular events . An SD of 0.026 was conservatively assumed on this measurement. Using the standard t-test approximation, and adjusting for two comparisons (α/2 = 0.025 per comparison) and a planned non-parametric analysis, 33 subjects per group were required to detect a 0.02 mm/year difference with 80% power. However, with 44 subjects per group and an observed SD of 0.0122, there was 80% power to detect a difference of 0.0085 mm/year between groups.
Calculation of rates
For each subject, a simple linear regression model was fitted using the subject's IMT data from weeks 0, 24, 48, 72, 96, and 144 to obtain a yearly rate of change in carotid IMT. Twenty-nine subjects had < 144 weeks of follow-up. However, the design of the study assumed that the yearly rate of change would not vary over time. This was tested by calculating the yearly rates of change during the first, second, and third years of follow-up for each subject using simple linear regression. The within-subject differences in the yearly rates of change during the first, second, and third years were not significantly different from zero in a non-parametric analysis. Therefore, rates based on < 144 weeks of data were included in the analyses.
The primary objective was to investigate the difference in the yearly rate of change in carotid IMT between groups. The comparison of groups 1 and 2 assessed the effect of PI therapy on the rate of change in IMT in the HIV-infected subjects. The comparison of groups 2 and 3 (or groups 1 plus 2 with group 3 if there was no difference between groups 1 and 2) assessed the effect of HIV infection on the rate of change in IMT. Within each triad, the subjects were paired according to group membership and differences were assessed with the Wilcoxon signed-rank test. If there was no difference between groups 1 and 2, the subjects in groups 1 and 2 were combined before comparing them with the subjects in group 3. A variation on the Wilcoxon signed-rank test was used to compare the two HIV-infected subjects with the control subject . Triads missing subjects or containing subjects with missing data were excluded as appropriate from the analyses.
The secondary objective was to evaluate the association between progression of IMT and covariates via conditional logistic regression modeling for matched pairs data. The logistic models were stratified by triad; the subjects were matched on HIV-disease status in the analysis of all subjects and PI use in the analysis of HIV-infected subjects. Progression was defined a posteriori as a yearly rate of change of at least 1 SD (i.e., ≥ 0.0122 mm/year). The baseline covariates considered for all subjects were fasting lipid measurements [total cholesterol, low density lipoprotein (LDL) cholesterol, HDL cholesterol, triglycerides, and non-HDL cholesterol], fasting glucose, body mass index, waist circumference, waist/hip ratio, metabolic syndrome, and metabolic measurements (insulin, high-sensitivity C-reactive protein, and homocysteine). For the HIV-infected subjects, additional covariates included PI use, ritonavir exposure, CD4 cell count, nadir CD4 cell count, and plasma HIV-1 viral load. All subjects with complete data were included in the regression model analysis. The results of the univariate analysis were used as a guide for the multicovariate analysis. Covariates univariately associated with progression (P ≤ 0.10) were examined together via conditional logistic regression modeling for matched pairs data.
Baseline data from the study were reported previously . Briefly, 134 subjects in 45 triads were accrued between February 2001 and May 2002. The median age of the subjects was 42 years at entry. There were 40 male and 5 female triads. Participants were 76% white (34 triads) 16% Hispanic (seven triads), 4% Black (two triads) and 4% Asian/Pacific Islander (two triads). All but one subject had normal blood pressure at entry. Nearly half (74/134 or 55%) of the subjects had never smoked. Smokers were evenly matched across groups and the median duration of smoking was 17.2, 16.4, and 14.8 years for the PI, non-PI, and HIV-negative groups, respectively.
In 2004, an interim analysis of the data at 48 weeks showed low rates of IMT change. The original 96 week study was extended to include a visit at week 144. Subjects completing the week 96 visit were eligible for the extension. Eight subjects prematurely discontinued follow-up during the first 96 weeks of the study and 22 (17% of the 126 eligible for the extension visit) opted not to remain on study after week 96. The age, race/ethnicity, and group membership of the subjects who did not remain in the study did not differ from those who completed the week 144 visit. Overall, 103/104 subjects who entered the extension at week 96 completed the final assessment at week 144. Completion rates for the IMT scans were excellent throughout the study, with 97%, 91%, 86%, 92% and 96% of scans completed at weeks 24, 48, 72, 96, and 144, respectively.
Within the PI and non-PI groups, the choice of baseline antiretroviral therapy varied. In the PI group, 26 (59%) received a single PI (13 nelfinavir, 10 indinavir, and three other PI), four received lopinavir/ritonavir, and 13 received a dual PI combination (three did not include ritonavir). Overall, 30% of subjects were receiving ritonavir as part of their therapy. In the non-PI group, 76% were receiving a combination of non-nucleoside reverse transcriptase inhibitors and nucleoside analogues, 18% nucleoside analogues only, and 6% were receiving no antiretroviral therapy.
The HIV groups had comparable CD4 cell counts and HIV viral loads at entry. The median CD4 cell count was 530 cells/μl in the PI group and 481 cells/μl in the non-PI group (P = 0.59). HIV RNA values were < 400 copies/ml in 75% of the PI group and in 69% of the non-PI group (P = 0.64). In addition, 40% of the PI group had a CD4 cell count nadir of < 200 cells/μl compared with 31% of the non-PI group (P = 0.50).
There were five subjects in the PI group who temporarily stopped taking PI drugs during study follow-up. All five of these subjects were taking a PI at the last follow-up visit. There were six subjects in the non-PI group who initiated therapy with a PI during follow-up; one subject took a PI temporarily (24 weeks) and the other five subjects started PI therapy after week 85. The data were analyzed in three ways, giving similar findings: (1) including these 11 subjects, (2) “truncating” the data at the PI-status change, and (3) excluding these 11 subjects. The results discussed are from the analysis that included these 11 subjects.
Baseline and longitudinal values for metabolic parameters are summarized in Table 1. Subjects in the HIV-positive groups had higher triglycerides than the HIV-negative group during the first 96 weeks on study (all P ≤ 0.01). Over time, values for triglycerides did not change within the HIV groups (P = 0.3). HDL cholesterol was significantly lower in the HIV groups at week 72 (all P ≤ 0.01), without a significant change over time within any group (P > 0.3). Insulin levels were higher in the PI group when compared with the non-PI and HIV-negative groups (all P ≤ 0.01) without a significant change over time (P > 0.8). There were increases over time within the non-PI group for fasting glucose (P = 0.03) and within the PI group for high-sensitivity C-reactive protein (P = 0.02).
Overall, 18% of the study subjects met the definition for metabolic syndrome as defined by National Cholesterol Education Program (NCEP) criteria. A higher proportion of the PI group (32%) had metabolic syndrome at baseline compared with the non-PI (18%) and HIV-negative groups (5%) (P = 0.003 and P < 0.0001, respectively). There were no significant trends over time within any group (P > 0.5).
At baseline, lipid-lowering therapy was being used by 13 subjects in the PI group, seven in the non-PI group, and by none in the HIV-negative group. Of the subjects not using lipid-lowering therapy at baseline, four subjects in the PI group, five of the non-PI group and two subjects in the HIV-negative group started new lipid-lowering therapy during follow-up. Lipid-lowering therapy was used more commonly in the combined HIV-positive groups compared with the HIV-negative group, with no significant difference between the two HIV groups. Use of lipid-lowering therapy was not associated with progression of IMT, although the small numbers of subjects may limit our power to detect an association.
Carotid intima–media thickness changes
The median rate of change in IMT in the PI group was 0.0096 mm/year, compared with 0.0058 and 0.0085 mm/year in the non-PI and HIV-negative groups, respectively (Fig. 1). The median paired difference in IMT change between the PI and non-PI subjects, 0.0027 mm/year, did not reach statistical significance (P = 0.19). When the HIV-positive groups were combined and compared with the HIV-negative group, the difference in progression was not statistically significant in a matched analysis (P = 0.71).
Univariate conditional logistic regression models for matched pairs data were used to explore the relationship between baseline variables of interest and progression in IMT. Higher total cholesterol (P = 0.02), higher non-HDL cholesterol (P = 0.02), and higher LDL cholesterol (P = 0.04) were individually associated with progression of carotid IMT. Within the groups of HIV-positive subjects, higher nadir CD4 cell count (> 200 versus ≤ 200 cells/μl; P = 0.04) was associated with progression. Multicovariate conditional logistic regression models for matched pairs data further explored the relationship between the covariates identified in the univariate analysis; covariates associated with progression were included (P ≤ 0.10, Table 2). Since total cholesterol, non-HDL cholesterol, and LDL cholesterol are highly correlated with each other, these covariates were considered separately: one model for each of the cholesterol covariates (best model determined by Akaike's information criterion). Considering all subjects, higher LDL cholesterol (P = 0.07) and higher homocysteine (P = 0.08) predicted progression of IMT. Among HIV-positive subjects, higher nadir CD4 cell count (> 200 versus ≤ 200 cells/μl; P = 0.04) and ritonavir use (P = 0.06) predicted progression. The results of the univariate and multicovariate models are summarized in Table 2.
Our prospective, matched cohort study in HIV-infected adults was conducted to determine the contribution of antiretroviral therapy and HIV infection to the yearly rate of progression of carotid IMT during 3 years of follow-up. The yearly rate of progression among the HIV-infected groups was not statistically different from the HIV-uninfected individuals.
In the overall study population, only higher homocysteine and LDL cholesterol predicted progression of carotid IMT. These observations suggest that, after control for traditional risk factors for atherosclerosis, HIV or treatment-related factors may be less important as contributors to progression of carotid IMT. This does not mean, however, that antiretroviral therapy may not contribute to IMT progression. Although there were few ritonavir users, given any two subjects in the same nadir CD4 cell count category, the subject taking ritonavir at baseline had a 14 times greater risk of progressing (defined as IMT increase of ≥ 0.0122 mm/year) relative to a subject not taking ritonavir.
Several groups have examined the relationship between antiretroviral therapy, HIV, and carotid IMT in cross-sectional and longitudinal studies, with variable results [28–35]. Several cross-sectional studies have found a positive correlation between PI exposure and carotid IMT [28,30,36] using both presence of plaque and carotid IMT as an endpoint, while others have found that, after control for traditional cardiovascular risk factors, PI therapy was no longer a statistically significant predictor of plaque or IMT [29,31]. Most recently, Jercio et al. . reported results of a cross-sectional study that compared the prevalence of subclinical atherosclerosis among groups of HIV patients with varying cardiovascular risk as assessed by the Framingham risk score. Multivariable models identified the use of combination antiretroviral therapy as a predictor of subclinical atherosclerosis independent of the Framingham risk score.
Longitudinal studies of changes in carotid IMT in HIV-infected individuals have produced conflicting results. Hsue et al.  reported rapid progression of carotid IMT among 121 HIV-infected patients compared with 27 controls matched for age and sex. The 1-year rate of progression in this study (0.074 ± 0.13 mm) in the HIV group was extraordinarily high, nearly 10-fold greater than the control group (−0.006 ± 0.05 mm). Older age, Latino race, and lower CD4 cell count nadir were multivariable predictors of progression of carotid IMT. Mercie et al.  reported an increase in the common carotid artery of 0.020 mm (95% confidence interval, 0.012–0.029) in a 1-year follow-up study of 342 HIV-infected patients. Higher CD4 cell count at baseline was strongly and positively associated with higher progression rates for IMT at 1 year; however, no association was found with type or duration of antiretroviral exposure and progression of IMT. This study did not include an HIV-uninfected comparison group.
There are several possible explanations for our negative findings in the context of previous studies. First, our study design allowed us better control for underlying cardiovascular risk factors than prior studies. The subjects enrolled in our study had a low cardiovascular risk profile since the study was focused on isolating the effect of HIV infection or PI use on risk for atherosclerosis. We excluded subjects with diabetes, prior coronary heart disease, or a family history of coronary heart disease because we felt these factors would be difficult to match within triads. It is possible that the risk for progression of atherosclerosis associated with PI therapy is most evident in those patients with a higher underlying cardiovascular risk. Second, the endpoints used vary across different studies; some studies have examined plaque or included additional segments of the carotid. Although other IMT assessment methods may account for the difference between our findings and those of others, studies that have used multiple segment measurements have reported results consistent with our data . It is possible that different factors influence the presence of plaque and carotid IMT. Third, in our longitudinal study, there appeared to be changes in lipid parameters over time within our PI group. Total and non-HDL cholesterol appeared to decline over time in the PI group, possibly because of the addition of lipid-lowering therapy as clinicians became aware of cardiovascular risk. Lipid-lowering therapy was utilized during follow-up by 17 subjects in the PI group and 12 in the non-PI group, which may have contributed to the rate of progression within these groups relative to the HIV-uninfected group, where only two subjects took lipid-lowering therapy. Fourth, although our study was powered to detect a difference of 0.02 mm/year in progression between groups, it is possible that the true difference is smaller and, therefore, would require a larger sample size. Our sample size enabled us to detect a clinically significant difference within the range described in other studies. Lastly, it is possible that the PI drugs used in our cohort have a lesser impact on lipid parameters and cardiovascular risk than the ones used in other studies. While our study suggested a possible relationship between ritonavir exposure and carotid IMT, only 30% of the subjects taking a PI were receiving a ritonavir-containing regimen at baseline. Our study was not designed to detect changes within the PI class and risk for progression of carotid IMT; however, this issue will be important to examine in future studies.
The finding that homocysteine and LDL cholesterol were independently associated with progression of carotid IMT is not surprising. Elevated levels of homocysteine have been implicated as a risk factor for vascular disease, including studies of carotid IMT [38–40]. Cross-sectional studies have suggested an association between PI therapy and elevated homocysteine ; however, results have been inconsistent and confounded by folate levels . In our study, median levels of homocysteine (7.6 μmol/l) in the 34 subjects who reported vitamin supplement use were significantly lower than the median (9.8 μmol/l) for the 88 non-users (P < 0.001). After control for vitamin use, the relationship between homocysteine and progression of IMT remained borderline significant.
In conclusion, in this well-matched cohort study, we did not detect a significant difference in the rate of progression of carotid IMT between PI-treated and non-PI-treated patients and between HIV-infected and matched HIV-uninfected controls. Although our study was small, we had adequate statistical power to detect a 0.01 mm/year difference in the rate of progression of carotid IMT. Larger prospective studies are needed to determine the precise contributions of specific antiretroviral agents to the progression of carotid IMT. As the long-term survival of the HIV-infected population continues to improve, it is important that physicians work closely with patients to reduce modifiable cardiovascular risk factors.
Site investigators: Susan Cahill (University of California, San Diego); Kathy Fox (University of Minnesota); Tomasa Maldonado, Suzette Chafey (University of California, Los Angeles); Kathleen Squires, Angela Grbic, Deborah Johnson (University of Southern California); Jeanne Conley (University of Washington); Cecilia Shikuma, Nancy Hanks (University of Hawaii); Joe Quinn (University of Pennsylvania); Michael Basar (Operational Support: Frontier Science and Technology Research Foundation, Inc.); Mira Madans (Social and Scientific Systems, Inc); Philip W. Anthony (Community Constituency Group of the AACTG).
Sponsorship: AIDS Clinical Trials Group; Dr Currier is supported by U01 AI27660 and by K24 AI56933.
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