Carotid Intima-Media Thickness Progression in HIV-Infected Adults Occurs Preferentially at the Carotid Bifurcation and Is Predicted by Inflammation.

BackgroundShear stress gradients and inflammation have been causally associated with atherosclerosis development in carotid bifurcation regions. The mechanism underlying higher levels of carotid intima-media thickness observed among HIV-infected individuals remains unknown.Methods and resultsWe measured carotid intima-media thickness progression and development of plaque in the common carotid, bifurcation region, and internal carotid artery in 300 HIV-infected persons and 47 controls. The median duration of follow-up was 2.4 years. When all segments were included, the rate of intima-media thickness progression was greater in HIV-infected subjects compared with controls after adjustment for traditional risk factors (0.055 vs. 0.024 mm/year, P=0.016). Rate of progression was also greater in the bifurcation region (0.067 vs. 0.025 mm/year, P=0.042) whereas differences were smaller in the common and internal regions. HIV-infected individuals had a greater incidence of plaque compared with controls in the internal (23% vs. 6.4%, P=0.0037) and bifurcation regions (34% vs. 17%, P=0.014). Among HIV-infected individuals, the rate of progression in the bifurcation region was more rapid compared with the common carotid, internal, or mean intima-media thickness; in contrast, progression rates among controls were similar at all sites. Baseline hsCRP was elevated in HIV-infected persons and was a predictor of progression in the bifurcation region.ConclusionsAtherosclerosis progresses preferentially in the carotid bifurcation region in HIV-infected individuals. hsCRP, a marker of inflammation, is elevated in HIV and is associated with progression in the bifurcation region. These data are consistent with a model in which the interplay between hemodynamic shear stresses and HIV-associated inflammation contribute to accelerated atherosclerosis. (J Am Heart Assoc. 2012;1:jah3-e000422 doi: 10.1161/JAHA.111.000422.)Clinical trial registrationURL: http://clinicaltrials.gov. Unique identifier: NCT01519141

The association of CD4+ T-cell counts and cardiovascular risk in treated HIV disease

ObjectiveHIV-infected individuals are at high risk of developing cardiovascular disease. Whether earlier initiation of HIV therapy at higher CD4 cell counts has any effect on cardiovascular risk as assessed by endothelial function is unknown.DesignCross-sectional study of 74 antiretroviral-treated men with undetectable plasma HIV RNA levels.MethodsParticipants underwent noninvasive assessment of endothelial function using brachial artery flow-mediated dilation (FMD). The association of nadir and current CD4 T-cell count with FMD was assessed using multivariable linear regression.ResultsThe median age was 47 years [interquartile range (IQR) 42-55], median current CD4 T-cell count was 659 cells/μl (IQR 542-845), and nadir CD4 cell count was 314 cells/μl (IQR 150-490). Twenty-eight percent had hypertension, and 32% hyperlipidemia. Nadir CD4 T-cell count less than 350 cells/μl was associated with lower FMD in age-adjusted and race-adjusted analyses and remained an independent predictor of FMD after adjustment for cardiovascular risk factors (hypertension, diabetes, smoking, hyperlipidemia) and HIV-related characteristics (HIV duration, HAART duration). After multivariable adjustment, individuals with nadir CD4 T-cell count less than 350 cells/μl had a 1.22% lower FMD compared with those with higher T-cell counts [95% confidence interval (CI) -2.20 to -0.19, P=0.02]. Proximal CD4 T-cell count showed little association with FMD.ConclusionAmong treated HIV-infected individuals, nadir CD4 T-cell count less than 350 cells/μl is independently associated with lower FMD, suggesting that delayed therapy results in sustained harm to endothelial function. Our data support future prospective studies evaluating cardiovascular effects of HAART initiation at higher CD4 cell counts

Carotid Intima-Media Thickness Progression in HIV-Infected Adults Occurs Preferentially at the Carotid Bifurcation and Is Predicted by Inflammation.

Shear stress gradients and inflammation have been causally associated with atherosclerosis development in carotid bifurcation regions. The mechanism underlying higher levels of carotid intima-media thickness observed among HIV-infected individuals remains unknown. We measured carotid intima-media thickness progression and development of plaque in the common carotid, bifurcation region, and internal carotid artery in 300 HIV-infected persons and 47 controls. The median duration of follow-up was 2.4 years. When all segments were included, the rate of intima-media thickness progression was greater in HIV-infected subjects compared with controls after adjustment for traditional risk factors (0.055 vs. 0.024 mm/year, P=0.016). Rate of progression was also greater in the bifurcation region (0.067 vs. 0.025 mm/year, P=0.042) whereas differences were smaller in the common and internal regions. HIV-infected individuals had a greater incidence of plaque compared with controls in the internal (23% vs. 6.4%, P=0.0037) and bifurcation regions (34% vs. 17%, P=0.014). Among HIV-infected individuals, the rate of progression in the bifurcation region was more rapid compared with the common carotid, internal, or mean intima-media thickness; in contrast, progression rates among controls were similar at all sites. Baseline hsCRP was elevated in HIV-infected persons and was a predictor of progression in the bifurcation region. Atherosclerosis progresses preferentially in the carotid bifurcation region in HIV-infected individuals. hsCRP, a marker of inflammation, is elevated in HIV and is associated with progression in the bifurcation region. These data are consistent with a model in which the interplay between hemodynamic shear stresses and HIV-associated inflammation contribute to accelerated atherosclerosis. (J Am Heart Assoc. 2012;1:jah3-e000422 doi: 10.1161/JAHA.111.000422.) URL: http://clinicaltrials.gov. Unique identifier: NCT01519141

A Randomized Controlled Trial Assessing the Effects of Raltegravir Intensification on Endothelial Function in Treated HIV Infection

ObjectivesTo determine whether intensification with raltegravir improves endothelial function in antiretroviral-treated HIV-infected individuals.Design: Randomized, double-blinded, placebo-controlled study.MethodsFifty-six subjects with treatment-mediated viral suppression for at least 1 year were randomized to add 400 mg of raltegravir twice daily or matching placebo for 24 weeks. The primary endpoint was the difference in rate of change in endothelial function [as assessed by flow-mediated vasodilation (FMD) of the brachial artery] from baseline to week 24 between the raltegravir and placebo groups. Linear mixed models were used to evaluate the association of treatment group with changes in FMD, immune activation, and measures of viral persistence.ResultsAt baseline, the median CD4 T-cell count was 498 cells/mm, nadir CD4 T-cell count was 191 cells/mm, duration of HIV infection was 18 years, FMD was 3.3%, and hyperemic velocity (a marker of microvascular function) was 68.3 cm. There were no significant differences between treatment groups in rate of change in FMD (raltegravir group: +0.032% per week, placebo group: +0.023% per week; P = 0.60). There were also no differences between treatment groups in rate of change in hyperemic velocity, immune activation, or viral persistence. In multivariable analysis, older age, longer duration of HIV infection, and current abacavir use were associated with lower FMD. Lower CD4 T-cell count and current abacavir use were associated with lower hyperemic velocity.ConclusionsThe addition of raltegravir to suppressive antiretroviral therapy did not have a significant impact on cardiovascular risk, as assessed by endothelial function (ClinicalTrials.gov NCT00843713)