Association Between Human Immunodeficiency Virus

Infection and Stiffness of the Common Carotid Artery

Eric C. Seaberg, PhD, MPH; Lorie Benning, MS; A. Richey Sharrett, MD, DrPH;
Jason M. Lazar, MD; Howard N. Hodis, MD; Wendy J. Mack, PhD; Mark J. Siedner, MD, MPH;
John P. Phair, MD; Lawrence A. Kingsley, PhD; Robert C. Kaplan, PhD

Background and Purpose—Individuals with human immunodeficiency virus (HIV) who use highly active antiretroviral
therapy (HAART) may have an increased risk for cardiovascular-related events, although the underlying mechanism
remains unclear. We tested the hypothesis that carotid arterial stiffness was higher among persons using HAART
compared to HAART-naïve and HIV-uninfected persons.
Methods—Between 2004 and 2006, we performed high-resolution B-mode ultrasound on 2789 HIV-infected and
HIV-uninfected participants of the Women’s Interagency HIV Study (1865 women) and the Multicenter AIDS Cohort
Study (924 men) and determined carotid arterial distensibility, which is a direct measure of carotid arterial stiffness. We
used generalized estimating equations to evaluate the association between distensibility and HIV infection, CD4⫹ cell
count, and exposure to HAART adjusted for demographic, behavioral, and clinical characteristics.
Results—In multivariable analysis, distensibility was 4.3% lower (95% confidence interval, ⫺7.4% to ⫺1.1%) among
HIV-infected vs uninfected participants. Among HIV-infected participants with ⬍200 CD4⫹ cells, distensibility was
10.5% lower (95% confidence interval, ⫺14.5% to ⫺6.2%) than that among HIV-uninfected participants, and this effect
did not differ significantly by cohort or race. Concurrent HAART use was independently associated with lower
distensibility among Multicenter AIDS Cohort Study participants but not among Women’s Interagency HIV Study
participants.
Conclusions—Our finding that advanced HIV-related immunosuppression was associated with increased carotid arterial
stiffness independent from the effects of traditional atherosclerosis risk factors suggests that the etiologic mechanism
underlying reports of an increased cardiovascular disease risk among HIV-infected individuals might involve
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HIV-related immunosuppression leading to vascular dysfunction and arterial stiffening. (Stroke. 2010;41:2163-2170.)
Key Words: atherosclerosis 䡲 cardiovascular disease 䡲 carotid arteries 䡲 HIV 䡲 epidemiology

T he benefits of highly active antiretroviral therapy

(HAART) for treating human immunodeficiency virus
(HIV) infection are well-established,1,2 but there is mounting
evidence that HAART may also be linked to an increased risk
of cardiovascular disease. Protease inhibitor (PI)-based
HAART appears to be associated with an increased risk of
myocardial infarction,3 perhaps from increased levels of
atherosclerosis.4 Several risk factors for atherosclerosis, in-
cluding hyperglycemia, diabetes, hypertension, and dyslipid-
emia, have been reported to be more common in persons with
HIV, especially among those using PI-containing HAART
regimens.4 – 8 However, the relationship of HIV and HAART
with cardiovascular disease is not clear. Data from the
Strategies for Management of Antiretroviral Therapy trial
suggest that in comparison to patients with HIV managed
using a drug conservation strategy, those receiving uninter-
rupted antiretroviral treatment had a lower risk of vascular
events despite their sustained exposure to HAART.9 Further-
more, a large cohort study recently found that HIV and
HAART were not associated with an increased rate of
cardiovascular events,10 and carotid intima-media thickness
has not been consistently found to be associated with HIV
infection or HAART use.11,12
We previously reported that systolic hypertension, but not
diastolic hypertension, was increased with longer HAART
exposure.13 These findings suggest that the vascular effect of
HAART may involve the “sclerosis” component of athero-
sclerosis that is measured by the stiffness of the arteries,14
which, itself, is only weakly correlated with carotid intima-
media thickness 15 and can predict cardiovascular events and

Received March 9, 2010; final revision received June 10, 2010; accepted June 30, 2010.
From Johns Hopkins Bloomberg School of Public Health (E.C.S., L.B., A.R.S., M.J.S.), Baltimore, Maryland; State University of New York Downstate
Medical Center (J.M.L.), Brooklyn, New York; University of Southern California (H.N.H., W.J.M.), Keck School of Medicine, Los Angeles, California;
Howard Brown Health Center (J.P.P.), Northwestern University, Chicago, Illinois; University of Pittsburgh Graduate School of Public Health (L.A.K.),
Pittsburgh, Pennsylvania; Albert Einstein College of Medicine (R.C.K.), Bronx, New York.
Correspondence to Eric C. Seaberg, PhD, MPH, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe
Street, Room E-7634, Baltimore, MD 21205. E-mail eseaberg@jhsph.edu
© 2010 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.110.583856

2163
 2164 Stroke October 2010
death.16 The current study of ⬎2700 men and women was
designed to investigate the association of HIV infection and
HAART use with arterial stiffness using measurements of
common carotid artery diameter change over the cardiac
cycle.
Subjects and Methods
Study Population
This cross-sectional study included baseline data from HIV-infected
and HIV-uninfected participants enrolled in the Carotid Ultrasound
Substudy of the Multicenter AIDS Cohort Study (MACS) and the
Women’s Interagency HIV Cohort Study (WIHS). MACS and
WIHS are ongoing observational HIV cohort studies comprising
6972 men and 3766 women, respectively, in selected metropolitan
areas across the United States. Recruitment and follow-up proce-
dures have been reported previously.17–20
Between April 2004 and March 2006, 1865 women and 924 men
underwent a baseline carotid ultrasound examination.21 Briefly, all
WIHS participants who attended a study visit during this time period
were eligible for this substudy, whereas MACS participants attend-
ing a study visit during this calendar period were eligible if they were
at least 40 years old, weighed ⬍300 pounds, and had no history of
cardiovascular disease. Among WIHS participants, 84 (4.5%) re-
ported a history of myocardial infarction, congestive heart failure, or
stroke. All participants gave written informed consent before enroll-
ment, and this study was approved by the Institutional Review
Boards at each of the MACS and WIHS institutions.
Study Outcome: Carotid Arterial Distensibility
High-resolution B-mode ultrasound was used to image the right
common carotid artery, internal carotid artery, and carotid bulb as
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previously described.22 Sonographers at each of the WIHS and
MACS sites were trained at the University of Southern California
Atherosclerosis Research Unit Core Imaging and Reading Center,
and all scans were centrally read at the Core Imaging and Reading
Center. The ultrasound assessment included measurements of the
right common carotid artery diameter at systole (DS) and diastole
(DD), and pulse pressure (PP) was measured at the brachial artery.
Using these measurements, we quantified carotid artery stiffness
using the following index of carotid distensibility:
Distensibility ⫽
冉 2共D S ⫺ D D 兲
DD 冊 participants, those infected with HIV were significantly less
PP
where lower values reflect a stiffer carotid artery. Distensibility was
standardized to the units reported by Lage et al23 (10⫺6 ⫻ New-
tons⫺1 ⫻ meters2).
Exposure Variables
HIV infection was determined via serological testing on specimens
obtained at each MACS or WIHS study visit using enzyme-linked
immunosorbent assays and confirmed using Western blot assays.17,19
Antiretroviral therapy use was documented via self-report. Follow-
ing the Department of Health and Human Services/Kaiser Panel24
guidelines, we defined HAART as the reported use of ⱖ3 antiretro-
viral medications, one of which has to be a PI, a non-nucleoside
reverse transcriptase inhibitor, one of the nucleoside reverse tran-
scriptase inhibitors (either abacavir or tenofovir), an integrase
inhibitor, or an entry inhibitor. HAART exposure was categorized 3
ways for analysis: using vs not using HAART, PI-based vs not
PI-based HAART, and duration of HAART exposure. Other char-
acteristics included in this analysis were demographic/behavioral
factors (eg, age, race, smoking history), clinical factors associated
with atherosclerosis (eg, cholesterol, BMI), and degree of HIV
immunosuppression (eg, CD4⫹ cell count).
Statistical Analysis
We characterized the study population using graphical displays of
the data and descriptive statistics (eg, median, interquartile range),
and the characteristics of the MACS and WIHS cohorts were
compared using a ␹2 test of association. All statistical comparisons
of distensibility were performed using generalized estimating equa-
tions25 to account for clustering within the 10 MACS and WIHS
sites. Multiple regression analyses were performed for the entire
study population and then separately for the MACS and WIHS
cohorts. Distensibility was natural log-transformed to account for its
skewed distribution, and the model results are reported as the percent
difference (PD) in distensibility between those with and those
without the corresponding covariate. Although ⬇90% of participants
had complete data for all study variables other than fasting glucose,
we used multiple imputation26 to account for missing data in the
multiple regression models. Statistical significance was defined as a
2-sided P⬍0.05. All statistical analyses were performed using SAS
9.2 (SAS Institute).
Results
The characteristics of the 2789 study participants are shown
in Table 1; two-thirds were from the WIHS, the median age
was 44.3 years (range, 20.2– 83.0), and 48% were black.
More than one-half of the participants were overweight or
obese (BMI ⬎25), 21% had LDL-c ⬎3.38 mmol/L (130
mg/dL), 30% had HDL-c ⬍1.04 mmol/L (40 mg/dL), and
11% had systolic blood pressure ⬎140 mm Hg. Diabetes
mellitus was documented in 16% of participants, but only 5%
of those who were fasting at the time of the study visit had a
fasting glucose level ⬎6.94 mmol/L (125 mg/dL). Approxi-
mately two-thirds (69%) of participants were infected with
HIV, among whom 13% had a CD4⫹ cell count ⬍200
(cells/mL) and 70% were using HAART at the time of the
ultrasound examination.
In addition to the gender difference between the MACS
and WIHS cohorts, the distributions of all other characteris-
tics included in Table 1 differed significantly between the
cohorts except diabetes, fasting glucose, and the duration of
HAART exposure among those who were using HAART at
the time of the examination. Compared to HIV-uninfected
likely to have education beyond high school, more likely to
have a history of injection drug use, more likely to have a
family history of myocardial infarction, and had significantly
lower BMI, LDL-c, and systolic blood pressure levels (data
not shown).
Overall, the median carotid distensibility was
16.8⫻10⫺6N⫺1m2, and the relationship between distensibil-
ity and age was similar in the 2 cohorts (Figure). In univariate
analyses, distensibility was significantly associated with age,
race/ethnicity, history of injection drug use, family history of
myocardial infarction, and all the clinical characteristics in-
cluded in Table 1. Distensibility was also significantly lower
among persons infected with HIV and among current HAART
users who had initiated HAART ⬎5 years earlier.
HIV infection remained significantly associated with
lower distensibility (PD, ⫺4.3; 95% CI, ⫺7.4 to ⫺1.1) in
the multiple regression analysis (Table 2). The effect of
HIV was greater in the MACS (PD, ⫺5.5) than in the
WIHS (PD, ⫺1.9), but the difference between the cohorts
was not statistically significant (P value for interac-
tion⫽0.24). Other characteristics that were independently
 Seaberg et al HIV and Carotid Arterial Distensibility 2165

Table 1. Cohort Characteristics at the Time of the Carotid Ultrasound Evaluation and Univariate Comparisons of Each Characteristic
With Carotid Distensibility
Carotid Distensibility (10⫺6 * N⫺1 * m2)
MACS WIHS All
Interquartile
N % N % N % Median Range P*
All 924 100 1865 100 2789 100 16.8 12.1–22.8
Cohort
WIHS 0 ... 1865 100 1865 67 17.7 12.2–24.9 0.13
MACS 924 100 0 ... 924 33 15.2 11.7–19.1
Age, y†
⬍40 (WIHS only) 0 ... 864 46 864 31 21.9 15.2–29.3 0.003
40–49 477 52 714 38 1189 43 16.4 12.6–21.5
50–59 365 40 244 13 609 22 14.0 10.2–18.0
ⱖ60 82 9 45 2 127 5 12.3 9.6–15.2
Race/ethnicity†
Black 249 27 1099 59 1348 48 16.0 11.2–22.4 0.03
Hispanic 71 8 532 28 603 22 18.9 14.0–26.6
White/other 604 65 234 13 838 30 16.3 12.5–21.2
Education beyond high school†
No 170 19 1276 69 1446 52 17.1 12.0–24.0 0.34
Yes 731 81 585 31 1316 48 16.4 12.1–21.7
Smoking†
Current 276 30 857 46 1133 41 16.9 12.2–23.4 0.19
Former 310 34 416 22 726 26 16.0 11.2–21.3
Never 329 36 579 31 908 33 17.4 12.6–23.9
History of injection drug use†
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No 807 87 1384 74 2191 79 17.0 12.3–23.5 ⬍0.0001

Yes 117 13 481 26 598 21 15.7 11.2–21.1
Family history of myocardial infarction†
No 690 77 1202 83 1892 80 16.7 12.1–22.7 0.03
Yes 209 23 250 17 459 20 15.7 11.5–20.9
Diabetes
No 761 82 1505 84 2266 83 17.1 12.4–23.5 ⬍0.0001
Yes 163 18 286 16 449 17 14.5 10.2–19.4
Fasting glucose (mmol/L), mg/dL
ⱕ6.94 (125) 691 94 1431 95 2142 95 16.9 12.2–23.1 0.0002
⬎6.94 (125) 42 6 75 5 121 5 13.7 10.1–19.3
BMI, kg/m2†
⬍18.5 18 2 50 3 68 3 17.2 11.9–24.8 0.02
18.5–24.9 369 42 573 31 942 35 17.8 12.8–24.7
25.0–29.9 351 40 530 29 881 33 16.8 12.5–22.4
ⱖ30.0 133 15 677 37 810 30 15.5 10.9–21.4
LDL-c (mmol/L), mg/dL†
ⱕ3.38 (130) 649 72 1452 82 2101 78 17.0 12.3–23.5 0.0002
⬎3.38 (130) 254 28 324 18 578 22 15.8 11.1–20.6
HDL-c (mmol/L), mg/dL†
ⱖ1.04 (40) 586 65 1249 71 1835 69 17.0 12.3–23.4 0.02
⬍1.04 (40) 317 35 522 29 839 31 16.4 11.5–21.8
(Continued)
 2166 Stroke October 2010

Table 1. Continued
Carotid Distensibility (10⫺6 * N⫺1 * m2)
MACS WIHS All
Interquartile
N % N % N % Median Range P*
Systolic blood pressure, mm Hg†
ⱕ120 364 39 1131 61 1495 54 19.5 14.3–26.6 0.006
121–140 462 50 518 28 980 35 14.9 11.2–19.3
⬎140 98 11 216 12 314 11 12.2 9.0–16.2
Using blood pressure medication†
No 666 76 1484 80 2150 78 17.6 12.9–24.3 ⬍0.0001
Yes 207 24 374 20 581 21 13.9 10.1–18.1
Using cholesterol-lowering medication†
No 651 75 1747 94 2398 88 17.1 12.3–23.6 0.0007
Yes 222 25 111 6 333 12 15.2 10.9–18.6
HIV status†
Negative 324 35 534 29 858 31 17.0 12.3–24.0 0.001
Positive 600 65 1331 72 1931 69 16.6 11.9–22.2
HIV status/CD4 level, cells/mL†
HIV-negative 324 36 534 29 858 31 17.0 12.3–24.0 0.06
HIV-positive/CD4 ⱖ200 536 59 1113 60 1649 60 16.7 12.1–22.4
HIV-positive/CD4 ⬍200 48 5 202 11 250 9 16.1 11.9–22.0
HAART use among HIV-positive
participants†
Never used HAART 69 12 219 17 288 15 17.0 11.6–22.8 0.84
Former HAART use 73 13 209 16 282 15 17.5 11.8–22.9
Current HAART use 420 75 897 68 1317 70 16.5 12.0–22.1
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Current PI use among current HAART

users†
Current PI HAART 210 50 533 41 743 56 16.4 12.2–21.9 0.28
Current non-PI HAART 210 50 364 59 574 44 16.7 11.9–22.5
Time since HAART initiation among
current HAART users
⬍5 years 124 30 269 30 393 30 17.2 12.9–23.4 0.01
ⱖ5 years 296 70 628 70 924 70 16.3 11.9–21.9
*Univariate P were generated using generalized estimating equation models to account for clustering at the 10 MACS and WIHS sites.
†The distribution of these characteristics differ significantly (P⬍0.05) between MACS and WIHS.
HAART indicates highly active antiretroviral therapy; HIV, human immunodeficiency virus; MACS, Multicenter AIDS Cohort Study; PI, protease inhibitor; WIHS,
Women’s Interagency HIV Study.

associated with lower distensibility in this model were
older age, black and Hispanic race/ethnicity, higher BMI,
higher LDL-c, lower HDL-c, and higher systolic blood
pressure. We then added covariates for the use of blood
pressure medications and cholesterol-lowering medica-
tions to the regression models, but these cofactors were not
independently associated with distensibility (data not
shown) and their inclusion did not alter any inferences
taken from the results in Table 2.
To examine the association between HIV-related immuno-
suppression and distensibility, we stratified the HIV-infected
subgroup by CD4⫹ cell count. HIV-infected participants with
⬍200 CD4⫹ cells had significantly less distensible carotid
arteries (PD, ⫺10.5; 95% CI, ⫺14.5 to ⫺6.2; (Table 3,
model 1) compared to those who were not infected with HIV,
and the association between advanced HIV-related immuno-
suppression and distensibility did not differ significantly
between MACS (PD, ⫺6.9) and WIHS (PD, ⫺9.2; P for
interaction⫽0.46) or between blacks (PD, ⫺9.9) and non-
blacks (PD, ⫺9.5; P for interaction⫽0.42).
Among the 1931 HIV-infected participants, distensibil-
ity was significantly lower among those using HAART in
the MACS (PD, ⫺4.2; 95% CI, ⫺7.0 to ⫺1.4), but not in
the WIHS or in the overall model (Table 3, model 2).
Among the 1317 HAART users, distensibility was also
significantly lower in MACS participants who had been
using HAART for ⬎5 years (PD, ⫺4.6; 95% CI, ⫺8.5 to
⫺0.6), but duration of HAART use was not significantly
associated with distensibility in the WIHS or overall
models (Table 3, model 3). Finally, distensibility was
similar among participants using PI-based and not PI-
based HAART regimens (Table 3, model 4).
 Seaberg et al HIV and Carotid Arterial Distensibility 2167

participants and for both blacks and non-blacks. Distensibility

Figure. Natural log-transformed carotid arterial distensibility by
age, stratified by cohort (blue: Women’s Interagency HIV Study
[WIHS]; black: Multicenter AIDS Cohort Study [MACS]). The ver-
tical dashed line corresponds to age 40, which was an eligibility
criterion for MACS. N, Newtons; m, meters.
Discussion
In this study, the largest study of the association between HIV
disease and arterial stiffness performed to date to our knowl-
edge, carotid arterial distensibility was significantly lower in
HIV-infected vs HIV-uninfected participants after adjusting
for the demographic, behavioral, and clinical characteristics
of the study population. Distensibility was lowest among
HIV-infected participants with advanced HIV-related immu-
nosuppression, and this was true for both MACS and WIHS
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was also significantly lower among HIV-infected HAART
users in MACS, especially among men who had initiated
HAART ⬎5 years earlier, but it was not associated with
HAART use in the WIHS, nor did it differ between those
using PI-containing HAART vs HAART without a PI in
either cohort. Thus, our study provides stronger support for
an effect of HIV-related immunosuppression, compared to
that of HAART, on carotid distensiblity.
Much of the research linking HIV disease with cardiovas-
cular disease has focused on the effects of HIV therapy on
metabolic-related factors such as hyperglycemia, insulin re-
sistance, dyslipidemia, and fat redistribution, which contrib-
ute to arterial disease8,27,28 and may account for some of the
increased risk of cardiovascular disease observed among
HIV-infected persons using HAART.4,29,30 However, if these
factors were to mediate the association between HIV disease
and atherosclerosis, then we would have expected that ad-
justing for them would nullify the association between HIV
and distensibility in our analysis; this was not the case.
Moreover, BMI, LDL-c, HDL-c, and systolic blood pressure
were all independently associated with distensibility in the
expected direction, which supports the validity of our results.
Arterial stiffness is associated with impaired endothelial
function,31 and it has been proposed that HIV may affect the
vasculature directly via endothelial damage,32 promoting
arterial stiffness33–35 and contributing to atherogenesis.36
Consistent with this hypothesis, HIV infection was associated

Table 2. Carotid Arterial Distensibility by HIV Adjusted for Demographic, Behavioral, and Clinical Cofactors
Overall MACS WIHS

Percent Percent Percent

Difference 95% CI Difference 95% CI Difference 95% CI
WIHS (vs MACS) ⫺0.2 (⫺17.2, 20.3)
Age per 10 years ⫺17.1† (⫺19.4, ⫺14.7) ⫺12.1† (⫺13.7, ⫺10.5) ⫺19.1† (⫺21.5, ⫺16.6)
Race/ethnicity
White and other races* 0 0 0
Black ⫺10.4† (⫺12.7, ⫺8.1) ⫺5.8† (⫺9.2, ⫺2.4) ⫺11.0† (⫺14.3, ⫺7.6)
Hispanic ⫺8.9† (⫺11.0, ⫺6.8) ⫺6.6 (⫺14.4, 1.8) ⫺9.2† (⫺12.8, ⫺5.4)
More than high school education 1.2 (⫺2.3, 4.7) 5.6 (⫺6.5, 19.6) ⫺0.1 (⫺2.8, 2.7)
Smoking status
Never smoked* 0 0 0
Former smoker ⫺0.9 (⫺5.2, 3.6) 3.6 (⫺2.2, 9.9) ⫺3.5 (⫺8.3, 1.5)
Current smoker ⫺0.1 (⫺3.5, 3.5) ⫺0.6 (⫺4.1, 3.0) 0.2 (⫺5.0, 5.6)
History of injection drug use ⫺2.6 (⫺5.7, 0.6) ⫺3.3 (⫺8.3, 1.9) ⫺0.1 (⫺4.7, 4.0)
Family history of myocardial infarction 0.3 (⫺2.8, 3.5) ⫺3.8 (⫺8.1, 0.6) 2.9 (⫺1.7, 7.7)
Body mass index per 5 kg/m2 ⫺4.4† (⫺5.5, ⫺3.3) ⫺5.9† (⫺9.3, ⫺2.3) ⫺4.1† (⫺5.3, ⫺3.0)
LDL-c per 0.52 mmol/L (20 mg/dL) ⫺0.9† (⫺1.4, ⫺0.3) ⫺1.0 (⫺2.2, 0.2) ⫺0.5 (⫺1.2, 0.3)
HDL-c per 0.13 mmol/L (5 mg/dL) 0.5† (0.1, 1.0) ⫺0.2 (⫺1.2, 0.9) 0.8† (0.4, 1.1)
Systolic blood pressure per 10 mm Hg ⫺8.1† (⫺9.4, ⫺7.1) ⫺8.8† (⫺10.1, ⫺7.5) ⫺8.0† (⫺9.4, ⫺6.7)
Diabetes ⫺2.1 (⫺5.1, 1.0) ⫺3.0 (⫺7.8, 2.1) ⫺1.7 (⫺5.7, 2.5)
HIV positive vs negative ⫺4.3† (⫺7.4, ⫺1.1) ⫺5.5† (⫺9.9, ⫺1.0) ⫺1.9 (⫺6.2, 2.6)
*Reference.
†P⬍0.05.
HIV, human immunodeficiency virus; MACS, Multicenter AIDS Cohort Study; WIHS, Women’s Interagency HIV Study.
 2168 Stroke October 2010

Table 3. Carotid Arterial Distensibility by CD4ⴙ Cell Count and HAART Use
Overall MACS WIHS

Percent Percent Percent

Difference 95% CI Difference 95% CI Difference 95% CI
Full cohort (n⫽2789)
Model 1. HIV infection and CD4⫹ cell count
HIV-negative* 0 0 0
HIV-positive, CD4 ⱖ200 ⫺3.5 (⫺6.9, 0.1) ⫺5.3† (⫺9.3, ⫺1.1) ⫺0.7 (⫺5.5, 4.2)
HIV-positive, CD4 ⬍200 ⫺10.5† (⫺14.5, ⫺6.2) ⫺6.9 (⫺19.0, 7.0) ⫺9.2† (⫺13.2, ⫺5.1)
HIV-infected only (n⫽1931)
Model 2. Current HAART use
No* 0 0 0
Yes ⫺2.2 (⫺5.7, 1.5) ⫺4.2† (⫺7.0, ⫺1.4) ⫺0.8 (⫺5.8, 4.4)
Current HAART users only (n⫽1317)
Model 3. HAART use ⬎5 years
No* 0 0 0
Yes 0.9 (⫺3.3, 5.4) ⫺4.6† (⫺8.5, ⫺0.6) 3.6 (⫺1.2, 8.6)
Model 4. Current PI-based HAART use
No* 0 0 0
Yes 1.2 (⫺1.5, 4.0) 1.0 (⫺5.1, 7.4) 0.8 (⫺2.7, 4.3)
*Reference.
†P⬍0.05.
All results are adjusted for cohort (overall models only), age, race/ethnicity, education, smoking, injection drug use, family history of myocardial
infarction, body mass index, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, and diabetes.
HAART indicates highly active antiretroviral therapy; HIV, human immunodeficiency virus; MACS, Multicenter AIDS Cohort Study; PI, protease
inhibitor; WIHS, Women’s Interagency HIV Study.
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with increased arterial stiffness among children.37 The AIDS
Clinical Trials Group Study 5152s reported that initiating
antiretroviral treatment improves endothelial reactivity, with
a direct correlation between the improvement in vascular
function and the viral and immunologic response to therapy.38
Data from the Strategies for Management of Antiretroviral
Therapy trial suggest that, in terms of vascular disease, the
risks associated with occasional adverse metabolic effects of
antiretroviral therapies may be outweighed by the benefits of
maintaining good immunologic function.9 A previous study
from our group found that advanced HIV-related immuno-
suppression was independently associated with an increased
prevalence of carotid lesions but not with carotid intima-
media thickness.21 Together with our results, these findings
suggest that the etiologic pathway connecting HIV infection
to arterial stiffness may directly involve HIV-related immu-
nosuppression rather than, or in addition to, antiretroviral
therapy and atherosclerosis risk factors. However, caution is
urged when interpreting our data because CD4⫹ cell count
was a marker of the immunologic status at the time of the
ultrasound evaluation, whereas arterial stiffness may stem
from multiple processes operating over many years.39
Our finding that HAART was associated with increased
carotid artery stiffness in the MACS and that stiffness
increased with prolonged HAART use is consistent with our
previous MACS study13 in which men who had prolonged
exposure to HAART had a higher prevalence of systolic
hypertension. It is unclear, however, why this association
existed only among the MACS participants in the current
study. Although the effect of antiretroviral therapies on the
vasculature might differ between men and women, it is also
possible that differences in the course or treatment of HIV
infection between the MACS and WIHS cohorts or, more
generally, between men and women40 may have led to these
results. Nevertheless, in comparison to HIV-related immuno-
suppression, HAART was not as strongly or as consistently
associated with increased carotid stiffness.
The strengths of the current study include the large sample
size, being nested within 2 ongoing HIV cohorts, and the
analysis of standardized data from 10 different sites. The
primary limitation of our study was its cross-sectional design
that made it impossible for us to tease apart the etiologic
importance of HIV-related immunosuppression vs therapy, to
describe changes in arterial stiffness across time, or to
evaluate the effect of increased stiffness on cardiovascular
outcomes. Finally, the unique demographic and clinical
characteristics of the MACS and WIHS participants must be
considered when interpreting the results from this study.
Conclusion
HIV-related immunosuppression was associated with in-
creased carotid stiffness among both MACS and WIHS
participants, whereas HAART use was associated with ca-
rotid stiffness among the MACS participants only. The
mechanisms underlying these findings remain unknown, but
these results suggest that the etiologic pathways may be
independent from traditional atherosclerosis risk factors. Our
study contributes to a growing volume of research supporting
 Seaberg et al
the hypothesis that HIV-related immunosuppression impacts
the risk of cardiovascular disease and underscores the need
7.
for further exploration of cardiovascular disease risk among
persons infected with HIV.
8.
Acknowledgments 9.
Data in this manuscript were collected by the Multicenter AIDS
Cohort Study (MACS) and the Women’s Interagency HIV Study
(WIHS) Collaborative Study Group with centers (Principal Investi-
gators) located at the following institutions: MACS centers: The
Johns Hopkins Bloomberg School of Public Health, Baltimore,
Maryland (Joseph B. Margolick, Lisa P. Jacobson), Howard Brown 10.
Health Center, Feinberg School of Medicine, Northwestern Univer-
sity, and Cook County Bureau of Health Services, Chicago, Illionis
(John P. Phair, Steven M. Wolinsky), University of California, Los
Angeles, California (Roger Detels), and University of Pittsburgh, 11.
Pittsburgh, Pennsylvania (Charles R. Rinaldo). WIHS centers: New
York City/Bronx Consortium, New York, New York (Kathryn
Anastos); Brooklyn, NY (Howard Minkoff); Washington DC, Met-
ropolitan Consortium (Mary Young); The Connie Wofsy Study
Consortium of Northern California (Ruth Greenblatt), San Francisco, 12.
Calif; Los Angeles County/Southern California Consortium (Alex-
andra Levine), Los Angeles, Calif; Chicago Consortium (Mardge
Cohen), Chicago, Illionis; Data Coordinating Center (Stephen 13.
Gange), Johns Hopkins Bloomberg School of Public Health, Balti-
more, Md.
Sources of Funding 14.
The WIHS is funded by the National Institute of Allergy and
Infectious Diseases (UO1-AI-35004, UO1-AI-31834, UO1-AI- 15.
34994, UO1-AI-34989, UO1-AI-34993, and UO1-AI-42590) and by
the Eunice Kennedy Shriver National Institute of Child Health and
Human Development (UO1-HD-32632). The study is co-funded by
16.
Downloaded from http://ahajournals.org by on September 25, 2020
the National Cancer Institute, the National Institute on Drug Abuse,
and the National Institute on Deafness and Other Communication
Disorders. Funding is also provided by the National Center for
Research Resources (UCSF-CTSI grant number UL1 RR024131). 17.
This project was also funded in part by grants from the National
Heart, Lung, and Blood Institute (1R01HL083760-04 and
5R01HL095140-03 to R.K.). The MACS is funded by the National 18.
Institute of Allergy and Infectious Diseases, with additional supple-
mental funding from the National Cancer Institute. UO1-AI-35042,
5-MO1-RR-00052 (GCRC), UO1-AI-35043, UO1-AI-35039, UO1- 19.
AI-35040, and UO1-AI-35041.
Disclosure
20.
J.P. is a consultant to Pfizer. There are no other conflicts to report.
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