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).
We found no statistically significant interactions between any of the investigated covariates and HIV status.
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.
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.
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.
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.
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).
S. Zaheri, M.M.J. Hillebregt, Y.M.C. Ruijs, D.P. Benschop, P.R. (HIV Monitoring Foundation).
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).
Project Management and Administrative Support
F.R. Janssen, M. Heidenrijk, W. Zikkenheiner, L. Boumans (AIGHD), M. Wezel, C.S.M. Jansen-Kok (AMC).
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).
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:Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
cardiovascular disease; aortic stiffness; pulse wave velocity; HIV; immunodeficiency