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Difference in Aortic Stiffness Between Treated Middle-Aged HIV Type 1–Infected and Uninfected Individuals Largely Explained by Traditional Cardiovascular Risk Factors, With an Additional Contribution of Prior Advanced Immunodeficiency

Kooij, Katherine W. MD; Schouten, Judith MD; Wit, Ferdinand W. N. M. MD, PhD; van der Valk, Marc MD, PhD; Kootstra, Neeltje A. PhD; Stolte, Ineke G. PhD; van der Meer, Jan T. M. MD, PhD; Prins, Maria PhD; Grobbee, Diederick E. MD, PhD; van den Born, Bert-Jan H. MD, PhD; Reiss, Peter MD, PhD

JAIDS Journal of Acquired Immune Deficiency Syndromes: September 1, 2016 - Volume 73 - Issue 1 - p 55–62
doi: 10.1097/QAI.0000000000001024
Clinical Science
Free

Background: Patients with HIV, even with suppressed viremia on combination antiretroviral therapy, are at increased risk for cardiovascular disease. The underlying pathophysiology remains to be clarified. Aortic stiffness, known to be associated with cardiovascular disease in the general population, was investigated in a cohort of HIV type 1 (HIV 1)–infected and similar but uninfected individuals.

Methods: Aortic stiffness was assessed by measuring pulse wave velocity (PWV) with an Arteriograph. Five hundred seven HIV-uninfected and 566 HIV 1–infected individuals, predominantly with suppressed viremia on combination antiretroviral therapy, aged ≥45 years, participating in the ongoing AGEhIV Cohort Study were included in the analysis. Multivariable linear regression was used to investigate whether HIV was independently associated with aortic stiffness, adjusting for traditional cardiovascular risk factors.

Results: Study groups were comparable in demographics; smoking and hypertension were more prevalent in HIV-infected participants. PWV was higher in the HIV-infected group (7.9 vs. 7.7 m/s, P = 0.004). After adjustment for mean arterial pressure, age, gender, and smoking, HIV status was not significantly associated with aortic stiffness. In HIV-infected participants, having a nadir CD4+ T-cell count ≤100 cells per cubic millimeter was independently associated with a higher PWV.

Conclusions: The increased aortic stiffness in HIV-infected participants was largely explained by a higher prevalence of traditional cardiovascular risk factors, particularly smoking. Although HIV itself was not independently associated with higher aortic stiffness, a prior greater degree of immunodeficiency was. This suggests a detrimental effect of immunodeficiency on the aortic wall, possibly mediated by inflammation.

*Department of Global Health, Amsterdam Institute for Global Health and Development and Academic Medical Center, Amsterdam, the Netherlands;

Department of Neurology, Academic Medical Center, Amsterdam, the Netherlands;

Division of Infectious Diseases, Center for Infection and Immunity Amsterdam, Academic Medical Center, Amsterdam, the Netherlands;

§HIV Monitoring Foundation, Amsterdam, the Netherlands;

Department of Experimental Immunology, Academic Medical Center, Amsterdam, the Netherlands;

Department of Infectious Diseases, Public Health Service of Amsterdam, Amsterdam, the Netherlands;

#Julius Global Health, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; and

**Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.

Correspondence to: Katherine W. Kooij, MD, Amsterdam Institute for Global Health and Development, PO Box 22700, 1100 DE Amsterdam, the Netherlands (e-mail: k.kooij@amc.uva.nl).

Supported by the Netherlands Organisation for Health Research and Development (ZonMW) together with AIDS Fonds (Grant nrs 300020007 and 2009063, respectively). Additional unrestricted scientific grants were received from Gilead Sciences, ViiV Healthcare, Janssen Pharmaceutica N.V., Bristol-Myers Squibb, and Merck & Co.

Presented in part at the 14th European AIDS Conference, joint session with 15th International Workshop on Co-Morbidities and Adverse Drug Reactions in HIV, October 17, 2013, Brussels, Belgium.

K.W.K. received travel grants from Gilead Sciences and ViiV Healthcare, was a speaker at an event sponsored by Gilead Sciences and served on a scientific advisory board for Gilead Sciences for which her institution received remuneration. J.S. received travel grants from Gilead Sciences, ViiV Healthcare, Boehringer Ingelheim. F.W.N.M.W. received travel grants from Gilead Sciences, ViiV Healthcare, Boehringer Ingelheim, AbbVie, Bristol-Myers Squibb. M.V. received consultancy fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Johnson & Johnson; received nonfinancial support by MSD. P.R. through his institution received independent scientific grant support from Gilead Sciences, Janssen Pharmaceuticals Inc, Merck & Co, Bristol-Myers Squibb, ViiV Healthcare; served on scientific advisory board for Gilead Sciences; serves on data safety monitoring committee for Janssen Pharmaceuticals Inc; chaired a scientific symposium by ViiV Healthcare, for which his institution received remuneration. The remaining authors have no funding or conflict of interest to disclose.

None of these funding bodies had a role in the design or conduct of the study, the analysis and interpretation of the results, or the decision to publish.

K.W.K. and J.S. shared first authorship.

The members of the AGEhIV Cohort Study Group are listed in Appendix 1.

Received November 16, 2015

Accepted March 28, 2016

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INTRODUCTION

HIV infection has been associated with an increased risk of adverse cardiovascular outcomes.1–3 The pathogenesis of cardiovascular disease (CVD) in the context of HIV infection is not fully clarified. It is likely that lifestyle factors, including smoking, contribute to the increased cardiovascular risk in patients with HIV. Chronic immune activation and inflammation, partly driven by gut microbial translocation and persistent low-level viral replication, and exposure to particular antiretroviral agents may also be involved.4,5

Aortic stiffening is a degenerative process, associated with loss of elastin and increased deposition of collagen and other structural proteins within the extracellular matrix of the arterial wall. This process typically occurs with aging and is accelerated by hypertension, metabolic changes, and inflammation.6–9 Aortic stiffness, assessed by measuring aortic pulse wave velocity (PWV), is independently associated with cardiovascular events and mortality in the general population.10–12 Previous studies on the association between HIV and aortic stiffness are inconsistent,13–18 possibly due to small sample sizes and suboptimal control groups. In addition, several of these studies included untreated or inadequately treated HIV-infected patients.

We cross sectionally compared aortic stiffness in a well-characterized cohort of HIV type 1 (HIV 1)–infected individuals predominantly with suppressed viremia on long-term combination antiretroviral therapy (cART), and HIV-uninfected individuals with similar behavioral and demographic characteristics, all aged ≥45 years. We assessed whether HIV infection was associated with higher aortic PWV, independent of traditional cardiovascular risk factors. In addition, we explored possible determinants of aortic PWV in the whole cohort, including behavioral, metabolic, and inflammatory markers, as well as HIV-related virological, immunological, and clinical factors in the HIV-infected group.

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METHODS

Subjects and Clinical Variables

The AGEhIV Cohort Study, an ongoing prospective comparative cohort study, aims to assess and compare prevalence, incidence of and risk factors for age-associated comorbidities and organ dysfunction among HIV 1–infected individuals and HIV-uninfected controls. Between 2010 and 2012, 598 HIV 1–infected individuals were recruited at the HIV outpatient clinic of the Academic Medical Center (AMC) in Amsterdam, the Netherlands. Five hundred fifty HIV-uninfected individuals were recruited from the sexual health clinic and the Amsterdam Cohort Studies on HIV/AIDS at the Amsterdam Public Health Service, with similar socio-demographic and behavioral (risk) factors.19 Inclusion criteria were: age ≥45 years, laboratory-confirmed presence (HIV 1–infected participants), or absence of HIV 1 infection (HIV-uninfected controls). Written informed consent was obtained from all participants; the study was approved by the local ethics review board (clinicalTrials.gov identifier NCT01466582).

Patients and controls underwent standardized screening for age-associated comorbidities and organ dysfunction. Details concerning study procedures have been reported previously.20 In short, participants completed an extensive standardized questionnaire. Self-reported comorbidities were validated using AMC hospital records of HIV-infected participants and general practitioners' records of HIV-uninfected participants, provided that the latter gave consent to contact their general practitioner. Data were available on the following CVD: angina pectoris, myocardial infarction, peripheral arterial disease, and cerebrovascular disease. Participants were asked whether they had used recreational drugs in the past 6 months. If so, they were asked to select the types of drugs they had used from a list and indicate the frequency of usage for each drug type. Physical activity was defined according to Dutch guidelines for healthy physical activity (Combinorm).21 Height, weight, and waist/hip-circumference were measured. Hypertension was defined as a mean systolic blood pressure (SBP) ≥140 mm Hg, mean diastolic blood pressure (DBP) ≥90 mm Hg (3 measurements, recorded by the Arteriograph), or use of antihypertensive medication. For both HIV-infected and uninfected participants, all laboratory tests were performed centrally in the AMC. Diabetes mellitus type 2 was defined as a hemoglobin A1c [International Federation of Clinical Chemistry and Laboratory Medicine (IFCC)] level ≥48 mmol/mol and/or blood glucose (fasting/nonfasting) ≥7.0 mmol/L/≥11.1 mmol/L, and/or use of antidiabetic medication. We assessed levels of high- and low-density lipoprotein (HDL and LDL) cholesterol, total cholesterol and triglycerides, and use of statins as markers of dyslipidemia. Hepatitis B virus and hepatitis C virus infection status, CD4+ T-cell counts (CD4 counts) and markers of inflammation [high-sensitivity (hs) C-reactive protein (CRP)], monocyte activation [soluble (s) CD163, sCD14] and coagulation (D-dimer) were determined for all participants, as well as plasma HIV 1 viral load for HIV-infected participants.

Detailed information concerning HIV infection and ART history was obtained from the HIV Monitoring Foundation registry.22

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Aortic Stiffness as Measured by PWV

Blood pressure (BP) and aortic PWV was measured at both study sites using the Arteriograph (Tensiomed Kft., Budapest, Hungary) in a standardized manner by trained study staff. The Arteriograph uses an oscillometric method to register pressure curves by an upper arm BP cuff. PWV measurements with the Arteriograph are highly correlated with invasive PWV measurements, and correlate well with aortic PWV obtained by magnetic resonance imaging and carotid-femoral PWV.23–25 PWV is measured after an oscillometric BP reading is taken, and the pressure cuff is overinflated to 35–40 mm Hg above SBP to occlude the brachial artery. The technology makes use of the 2 pressure waves during the cardiac cycle; the first is generated by the ejection of blood into the aorta during systole and the second by the reflection of the first wave from the aortic bifurcation. The Arteriograph registers these pressure fluctuations through the upper arm cuff. Aortic PWV is calculated using the time difference between the beginning of the first and the second wave and the estimated distance from the heart to the aortic bifurcation, which is estimated by measuring the distance from the jugulum to the pubic symphysis using a tape measure. PWV measurements were performed in a quiet room after at least 15 minutes of supine rest. Measurements were discarded if the SD of the analyzed pulse waves exceeded the cutoff (>1.0 m/s and >15% of the measured PWV value) or if the PWV value differed >15% from the other 2 PWV measurements. The average of 3 consecutive PWV and BP [DBP, SBP, and mean arterial pressure (MAP)] measurements was used for analysis.

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Statistical Analysis

Characteristics of HIV-infected and uninfected groups were compared using χ2, Student t, and Wilcoxon rank-sum tests where appropriate.

The association between HIV status and aortic PWV, adjusted for possible confounders, was assessed by multivariable linear regression; a covariate was considered a significant confounder if its introduction into the model changed the regression coefficient of HIV by ≥10%. Possible determinants of aortic PWV were explored; these included demographic, behavioral, and metabolic CVD risk factors, including those potentially influenced by exposure to HIV and/or ART. hsCRP, D-dimer, sCD163, and sCD14 were explored to assess the contribution of inflammatory and coagulation parameters on differences in aortic PWV. Covariates with a P-value <0.1 and significant confounders were kept in the model. A second model, only including HIV-infected individuals, explored the role of HIV- and ART-related clinical variables. In an additional third analysis, we compared the HIV-infected group, stratified according to nadir CD4 count (cutoff: ≤100 cells per cubic millimeter), with the entire HIV-uninfected group.

We used multiple imputation to handle missing observations of independent variables, generating 5 sets with complete covariate values. We assessed nonlinearity of relationships using categorization and transformation of continuous covariates. To investigate whether associations differed significantly according to HIV status, we explored biologically plausible interactions with HIV-infected status. All models were adjusted for MAP because aortic stiffness is directly affected by BP at the time of PWV measurement.26 Statistical analysis was performed using STATA version 12 (StataCorp LP, College Station, TX). All reported P-values are 2 sided.

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RESULTS

Subject Characteristics

Of the 598 HIV-infected and 550 HIV-uninfected participants of the AGEhIV Cohort Study, 32 and 43 participants, respectively, were excluded from this analysis either because of missing PWV measurements (16 HIV-infected, 22 HIV-uninfected), or because the SD or variation between measurements exceeded the predefined limits (16 HIV-infected, 21 HIV-uninfected). Individuals with missing or invalid PWV data were more often women (16.4% vs. 4.9%, P < 0.001) but did not significantly differ regarding age or BP. Variance between the 3 measurements of each participant did not differ between study sites (P = 0.96).

Age and gender distribution of the 566 HIV-infected and 507 HIV-uninfected individuals included in the analysis did not differ significantly. The majority were men and men who have sex with men. Compared with the HIV-uninfected group, a larger proportion of the HIV-infected group was of African descent. HIV-infected individuals were more often diagnosed with hypertension, had generally less favorable lipid profiles, and were more often smokers. A history of CVD was more prevalent in HIV-infected compared with HIV-uninfected individuals (10.3% vs. 4.7%, P = 0.001). Levels of hsCRP, sCD163, and sCD14 were significantly higher in HIV-infected individuals, and D-dimer in HIV-uninfected individuals (Table 1). Ninety-five percent of the HIV-infected participants were currently on cART; 92.6% of those had suppressed viremia to levels <200 copies per milliliter in the year before enrollment (Table 2).

TABLE 1

TABLE 1

TABLE 2

TABLE 2

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Determinants of Aortic PWV

Unadjusted, aortic PWV was significantly higher in the HIV-infected (7.9 m/s, interquartile range 7.2–9.0) compared with the HIV-uninfected group (7.7 m/s, interquartile range 7.0–8.8) (P = 0.004). After adjusting for age, MAP, and gender, the association between HIV and aortic PWV remained statistically significant (+0.20 m/s, 95% CI: 0.02 to 0.38 m/s, P = 0.03). Further adjustment for the number of pack years of smoking attenuated the regression coefficient of HIV-infected status (adjusted coefficient: +0.12 m/s, 95% CI: −0.06 to 0.29, P = 0.18). Race/ethnicity, use of substances (ecstasy, cocaine, alcohol, or injecting drugs), chronic hepatitis C virus infection, family history of myocardial infarction, and level of physical activity were not independently associated with PWV, nor did they significantly affect the association between HIV and PWV. Subsequent adjustment for use of antihypertensive drugs attenuated the regression coefficient of HIV-infected status further (+0.09 m/s, 95% CI: −0.09 to 0.26, P = 0.33). Compared with a body mass index (BMI) between 18.5 and 25 kg/m2, both a BMI ≥25 kg/m2 and a BMI <18.5 kg/m2 were associated with a higher PWV, whereas waist-to-hip ratio was not. Lower HDL cholesterol levels, as well as higher triglycerides and hsCRP levels were positively associated with aortic PWV, whereas levels of low-density lipoprotein and total cholesterol, D-dimer, sCD163 or sCD14, and the use of statins were not independently associated with PWV (Table 3).

TABLE 3

TABLE 3

We found no statistically significant interactions between any of the investigated covariates and HIV status.

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HIV- and ART-Related Covariates

Including only HIV-infected individuals in the multivariable model, after adjustment for MAP, gender, age, and smoking, a lower nadir CD4 count was significantly associated with a higher aortic PWV (+0.12 m/s per 100 cells per cubic millimeter lower CD4 count, 95% CI: 0.03 to 0.22, P = 0.01). We explored several cutoff values of the nadir CD4 count (100, 200, 350, and 500 cells per cubic millimeter); a cutoff of ≤100 cells per cubic millimeter was most strongly and significantly associated with aortic PWV (+0.33 m/s, 95% CI: 0.06 to 0.61, P = 0.02). This association was not attenuated when use of antihypertensive drugs, BMI and HDL cholesterol were added to the model, but slightly attenuated, when the level of triglycerides (after adjusting: +0.31 m/s, 95% CI: 0.03 to 0.59, P = 0.03) and hsCRP were added to the model (after adjusting: +0.28 m/s, 95% CI: 0.00 to 0.56, P = 0.05). The association was not affected by sCD163, sCD14, or D-dimer. Explored, but not significantly associated with PWV were the cumulative duration of having a reduced CD4 count (using cutoffs of 50, 100, 200, and 350 CD4 cells per cubic millimeter), the known duration of HIV infection, a history of AIDS, the CD4 count, and the HIV-viral load in the year before enrollment. No associations were observed between PWV and being treated with mono/dual antiretroviral therapy before cART initiation, (cumulative) exposure to ART, abacavir, or any drug from the protease inhibitor (PI) class.

In addition, we constructed a multivariable model comparing both a lower nadir HIV-infected group (nadir CD4 count ≤100 cells per cubic millimeter, n = 190) and a higher nadir HIV-infected group (nadir CD4 count >100 cells per cubic millimeter, n = 376) with the entire HIV-uninfected group (Table 4). In model 1, we adjusted for MAP, gender, age, and smoking: aortic PWV of the subgroup with a lower nadir CD4 count was significantly higher than PWV of the HIV-uninfected group (+0.34 m/s, 95% CI: 0.09 to 0.58, P = 0.007), although there was no difference in PWV between the group with higher CD4 count and the HIV-uninfected group. After additional adjustment for the use of antihypertensive drugs, BMI, HDL cholesterol, and triglyceride level (model 2), the coefficient of the lower nadir CD4 group was attenuated (+0.24 m/s, 95% CI: −0.01 to 0.49, P = 0.06). The coefficient was further attenuated and was no longer statistically significant by adding hsCRP to the model (+0.18 m/s, 95% CI: −0.07 to 0.43, P = 0.16, model 3), but not by addition of sCD163, sCD14, or D-dimer.

TABLE 4

TABLE 4

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Sensitivity Analyses

Multivariable models, adjusted for MAP, gender, age, and pack years of smoking, were repeated excluding individuals with a history of clinical CVD. HIV-infected status was not associated with PWV in this model (+0.01 m/s, 95% CI: −0.17 to 0.19, P = 0.91). The association between being HIV-infected with a nadir CD4 count below 100 cells per cubic millimeter and PWV was no longer statistically significant (+0.20 m/s, 95% CI −0.06 to 0.45, P = 0.13). Repeating the multivariable models excluding all individuals with renal disease (an estimated glomerular filtration rate below 60 mL·min−1·1.73 m−2) showed similar results as models including these individuals. To explore a possible confounding effect of the use of angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists, drugs that may affect arterial stiffness,27 we repeated multivariable models separately adjusting for the use of antihypertensive regimens containing any of these drugs and for use of other antihypertensive regimens. These models showed similar results as models adjusting for antihypertensive drugs in general. Repeating multivariable regression models, only including individuals with complete data, showed similar results as the analyses with multiple imputed data.

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DISCUSSION

Aortic stiffness (aortic PWV) was higher in middle-aged predominantly virologically suppressed HIV-infected individuals than uninfected controls of similar demographic and behavioral background. HIV, however, was not independently associated with higher aortic stiffness. Traditional cardiovascular risk factors, mainly smoking and hypertension, seemed to be the most important determinants of aortic PWV in both HIV-infected and uninfected participants; the higher prevalence of smoking in the HIV-infected subgroup largely explained the observed difference in aortic stiffness.

Within the HIV-infected cohort, having experienced a lower nadir CD4 count was significantly associated with a higher aortic PWV. This confirms previous reports on the association between immunodeficiency and aortic stiffness.13,28,29 Furthermore, HIV-infected individuals with a nadir CD4 count ≤100 cells per cubic millimeter had a significantly higher aortic PWV than HIV-uninfected individuals, while adjusting for behavioral and metabolic risk factors. These results suggest a lasting effect of advanced immunodeficiency on aortic PWV. A higher hsCRP level, associated with higher aortic stiffness in the general population30,31 and in our cohort (both in HIV-infected and uninfected participants), attenuated the coefficient of the group with the lowest nadir CD4 count. This suggests a role for ongoing inflammation in the pathogenesis of aortic stiffness, particularly in HIV-infected individuals with low nadir CD4 counts. Possibly, cytomegalovirus infection may contribute to this proinflammatory state.32,33 In contrast, markers of monocyte/macrophage activation (sCD14 and sCD163), previously associated with atherosclerotic disease in the context of HIV,34,35 were not significantly associated with aortic PWV and did not attenuate the association between the nadir CD4 count and PWV.

Although HIV-infected individuals with a nadir CD4 count below 100 cells per cubic millimeter had significantly higher aortic PWV than HIV-uninfected controls, this was not the case for HIV-infected individuals with a higher nadir CD4 count. Furthermore, although in unadjusted analysis, HIV-infected individuals had a higher aortic PWV than uninfected controls, being HIV-infected was no longer significantly associated with a higher PWV after adjusting for traditional cardiovascular risk factors. Our observations corroborate results of several smaller studies comparing aortic PWV in treated HIV-infected patients to uninfected controls.15,18,29 Discrepancies with some other studies may be explained by their relatively small sample size (maximum sample size was 50),13,14,16,17 which increases the risk for type I errors and limits the ability to adjust for potential confounders. Moreover, some of the earlier studies recruited hospital staff as a control group, which was likely suboptimal as they did not share many of the characteristics and lifestyle factors with the patients studied.13,14,16 Our findings suggest a relatively small role for aortic stiffening in the observed increased CVD risk in well-treated HIV infection.

PI (particularly lopinavir and ritonavir) strongly affect lipid metabolism, thereby potentially contributing to aortic stiffening. In our study, we found the levels of HDL cholesterol and triglycerides, both markers of lipid metabolism, to be associated with aortic PWV. However, we did not confirm earlier findings associating PI exposure with PWV.13 This may be because a large proportion (72.5%) of PI-based regimens used in our study population contained (boosted) atazanavir or darunavir, both PIs with a relatively favorable lipid profile.36 Furthermore, the usual ritonavir boosting dose in these regimens is lower than in ritonavir-boosted lopinavir.

To ensure the robustness of our conclusions, we performed several sensitivity analyses. Excluding all individuals with a history of overt CVD resulted in smaller estimates of the association between being HIV-infected with a nadir CD4 count below 100 cells per cubic millimeter and PWV, and a decrease in the level of statistical significance. This may in part be due to a loss of power, resulting from a decrease in group size, and in part to the exclusion of the individuals with the most extreme PWV values. However, a near-significant trend toward a higher PWV in HIV-infected with the lowest nadir CD4 count remained present, suggesting that the high PWV in this subgroup is not driven solely by individuals with overt CVD. This study is subject to several limitations. Inherent to its cross-sectional and observational design, it does not allow us to draw conclusions regarding causality. Although we collected data on many possible confounders, effects of any residual unmeasured confounders cannot be excluded. We cannot exclude the possibility that the selection of our controls may have led to an underestimation of the effect of HIV on aortic stiffness. The HIV-infected patients included in this study were regularly monitored at the HIV outpatient clinic of our hospital, whereas the healthy controls were generally not monitored regularly by a physician. Conditions potentially affecting aortic stiffness, such as dyslipidemia and hypertension, may have been diagnosed and treated at an earlier stage in the HIV-infected patients, thereby limiting their negative effect on aortic stiffness. Furthermore, to include controls with a similar behavioral and demographic background as the patients, we recruited them from a sexual health clinic. As a result, they may have recently suffered from sexually transmitted diseases associated with a proinflammatory state. However, the lifetime incidence of sexually transmitted diseases is likely at least as high in the HIV-infected group.

In conclusion, we show a higher aortic stiffness in HIV-infected individuals on antiretroviral therapy. The observed higher aortic PWV in the HIV-infected participants was largely explained by a higher prevalence of traditional risk factors. Overall, the factors most strongly associated with higher aortic stiffness in this population include both traditional (and modifiable) risk factors: smoking, hypertension, and dyslipidemia, each of which is highly prevalent among HIV-infected individuals. Being HIV-infected by itself was not independently associated with a higher aortic PWV, but a prior greater degree of immunodeficiency, particularly having experienced a nadir CD4 count less than 100 cells per cubic millimeter, was. The relation between immunodeficiency and aortic stiffness should optimally be investigated in the context of a randomized controlled trial, such as the arterial elasticity substudy within the Strategic Timing of AntiRetroviral Treatment (START) trial.37 Results from that study and longitudinal follow-up of the AGEhIV Cohort Study will hopefully provide more insight in the effect of HIV infection and ART on age-related changes in aortic stiffness, as well as on the predictive value of aortic stiffness for clinical CVD in the HIV-infected population.

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ACKNOWLEDGMENTS

The authors thank Yolanda Ruijs-Tiggelman, Lia Veenenberg-Benschop, Tieme Woudstra, Sima Zaheri, and Mariska Hillebregt at the HIV Monitoring Foundation for their contributions to data management. The authors thank Aafien Henderiks and Hans-Erik Nobel for their advice on logistics and organization at the Academic Medical Center. The authors thank Rosan van Zoest, Barbara Elsenga, Aafien Henderiks, Jane Berkel, Sandra Moll, and Marjolein Martens for running the study program and capturing our data with such care and passion.

The authors thank their colleagues at the Department of Experimental Immunology at the Academic Medical Center for the excellent collaboration both logistically and scientifically.

The authors thank all HIV physicians and HIV nurses at the Academic Medical Center and all Public Health Service Amsterdam personnel for their efforts to include HIV-infected and uninfected participants into the AGEhIV Cohort Study.

The authors thank all study participants without whom this research would not be possible.

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AGEhIV COHORT STUDY GROUP MEMBERS Scientific Oversight and Coordination

P.R. (principal investigator), F.W.N.M.W., M.v.d.V., J.S., K.W.K., R.A. van Zoest, B.C. Elsenga [Academic Medical Center (AMC), Department of Global Health and Amsterdam Institute for Global Health and Development (AIGHD)]. M.P. (coprincipal investigator), M. Martens, S. Moll, J. Berkel, M. Totté, G.R. Visser, S. Kovalev (Public Health Service Amsterdam, Infectious Diseases Research Cluster).

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Data Management

S. Zaheri, M.M.J. Hillebregt, Y.M.C. Ruijs, D.P. Benschop, P.R. (HIV Monitoring Foundation).

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Central Laboratory Support

N.A.K., A.M. Harskamp-Holwerda, I. Maurer, M.M. Mangas Ruiz, A.F. Girigorie, E. van Leeuwen (AMC, Laboratory for Viral Immune Pathogenesis and Department of Experimental Immunology).

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Project Management and Administrative Support

F.R. Janssen, M. Heidenrijk, W. Zikkenheiner, L. Boumans (AIGHD), M. Wezel, C.S.M. Jansen-Kok (AMC).

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Participating HIV Physicians and Nurses

S.E. Geerlings, M.H. Godfried, A. Goorhuis, J.W.R. Hovius, J.T.M.v.d.M., F.J.B. Nellen, T. van der Poll, J.M. Prins, P.R., M.v.d.V., W.J. Wiersinga, F.W.N.M.W.; J. van Eden, A.M.H. van Hes, M. Mutschelknauss, H.E. Nobel, F.J.J. Pijnappel, A.M. Westerman (AMC, Division of Infectious Diseases).

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Others Collaborators

J. de Jong, P.G. Postema (AMC, Department of Cardiology); P.H.L.T. Bisschop, M.J.M. Serlie (AMC, Division of Endocrinology and Metabolism); P. Lips (Free University Medical Center Amsterdam); E. Dekker (AMC, Department of Gastroenterology); S.E.J.A. de Rooij (AMC, Division of Geriatric Medicine); J.M.R. Willemsen, L. Vogt (AMC, Division of Nephrology); J.S., P. Portegies, B.A. Schmand, G.J. Geurtsen, J.A. ter Stege, M. Klein Twennaar (AMC, Department of Neurology); B.L.F. van Eck-Smit, M. de Jong (AMC, Department of Nuclear medicine); D.J. Richel (retired) (AMC, Division of Clinical Oncology); F.D. Verbraak, N. Demirkaya (AMC, Department of Ophthalmology); I. Visser, H.G. Ruhé (AMC, Department of Psychiatry); P.T. Nieuwkerk (AMC, Department of Medical Psychology); R.P. van Steenwijk, E. Dijkers (AMC, Department of Pulmonary medicine); C.B.L.M. Majoie, M.W.A. Caan, T. Su (AMC, Department of Radiology); H.W. van Lunsen, M.A.F. Nievaard (AMC, Department of Gynaecology); B.J.H.v.d.B., E.S.G. Stroes (AMC, Division of Vascular Medicine); W.M.C. Mulder (HIV Vereniging Nederland).

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Keywords:

cardiovascular disease; aortic stiffness; pulse wave velocity; HIV; immunodeficiency

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