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HIV infection is associated with progression of subclinical carotid
atherosclerosis.....61% Greater Risk....viral load & CD4 are risks
 
 
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Clinical Infectious Diseases
Advance Access published April 22, 2015
 
David B. Hanna et al
bring to your attention Appendix Table 1 below, where despite that CCA-IMT progression was not associated with HIV......Statistically significant predictors of CCA-IMT increase in multivariable analyses included black race, Hispanic ethnicity, and crack/cocaine use and Table 4 showing CD4 risks bt gradient of CD4 tables at bottom
 
"We assessed the association between HIV serostatus and progression of subclinical atherosclerosis, adjusting for demographic, behavioral, and cardiometabolic risk factors "......"Our data support earlier ART initiation, before CD4+ counts decline, which may mitigate HIV-associated increased CVD risks.......
 
Using non-invasive carotid B-mode ultrasonography.....HIV-infected women and men had a 61% greater risk of new focal carotid artery plaque formation over seven years compared with uninfected controls, regardless of baseline vascular phenotype and after controlling for cardiometabolic risk factors......Focal plaque prevalence increased from 8% to 15% in women and 25% to 34% in men over 7 years......
 
Increased plaque occurred even among persistently virologically suppressed HIV-infected individuals compared with uninfected individuals (RR 1.56, 95% CI 1.07-2.27)......suggesting that sustained suppression of circulating HIV RNA to below detectable limits does not eliminate excess CVD risk in the treated HIV-infected population.....HIV-infected participants with the lowest CD4+ count at baseline (i.e., <200 cells/μL) had the greatest risk (aRR 2.57, 95% CI 1.48-4.46) compared with HIV-uninfected participants, with a gradient of decreasing risk by increasing categories of CD4+ count (Table 4).....However, HIV-infected individuals with high (>500) CD4+ counts were not significantly different from HIV-uninfected individuals in changes in carotid artery measures over time. ......The HIV-associated risk was higher than that associated with smoking......

 
Current smoking was associated with a 42% increase in focal plaque formation (95% CI 1.03-1.96) (Table 3).....Other associated factors in fully-adjusted analyses included use of antihypertensive medications, higher total cholesterol, and older age
 
.........We did not find differences in CCA-IMT progression over the seven years by HIV serostatus, consistent with smaller studies......HIV infection was not associated with the magnitude of CCA-IMT increase over time (Figure 1). Multivariable models adjusting for demographic, behavioral, and cardiometabolic risk factors showed no significant difference in CCA-IMT change by HIV serostatus (adjusted ß=0.2 μm/year higher in HIV-infected persons, 95% CI -0.6-1.0). Statistically significant predictors of CCA-IMT increase in multivariable analyses included black race, Hispanic ethnicity, and crack/cocaine use (Appendix Table 1). Use of of antihypertensive medications was associated with a decrease in CCA-IMT ........
 
........Our findings are consistent with a growing body of evidence linking HIV infection with CVD...... these findings add strong support to the hypothesis that development of atherosclerosis in HIV-infected individuals involves endothelial shear stress preferentially occurring at vascular branch points,[19] which may represent a common pathway with atherosclerosis arising from other conditions such as rheumatoid arthritis.[29]"
 
.....HIV-infected participants with CD4+
counts ≥500 cells/μL at baseline had a risk of new focal plaque formation that was not statistically different from HIV-uninfected participants (aRR 1.28, 95% CI 0.85-1.94)...
 
......Our data support earlier ART initiation, before CD4+ counts decline, which may mitigate HIV-associated increased CVD risks
 
......HIV-infected participants with the lowest CD4+ count at baseline (i.e., <200 cells/μL) had the greatest risk (aRR 2.57, 95% CI 1.48-4.46) compared with HIV-uninfected participants, with a gradient of decreasing risk by increasing categories of CD4+ count (Table 4)
 
We identified 199 HIV-infected participants who were receiving ART and persistently virologically suppressed (16% of HIV-infected women, N=92; 29% of HIV-infected men, N=107) (Table 4 and Appendix Table 2). Among this selected group, increased risk of new focal plaque formation compared with the HIV-uninfected group remained (aRR 1.77, 95% CI 1.13-2.77).
 
We found a slightly elevated association between exposure to protease inhibitors and new focal plaque formation among men but not women, consistent with our cross-sectional findings.
 
Our analyses did not find any association of nadir CD4+ count, history of AIDS, and duration of ART use with new focal plaque formation. We found a slightly increased risk of plaque formation with greater exposure to protease inhibitors among men (aRR 1.12 per year of cumulative use at baseline, 95% CI 1.01-1.25) but not among women. No other associations between other ART classes and focal plaque formation were found, nor were any HIV-related parameters associated with increased CCA-IMT progression (Appendix Table 3).
 
"Using non-invasive carotid B-mode ultrasonography, we demonstrated that HIV-infected women and men had a 61% greater risk of new focal carotid artery plaque formation over seven years compared with uninfected controls, regardless of baseline vascular phenotype and after controlling for cardiometabolic risk factors. The HIV-associated risk was higher than that associated with smoking.
 
Furthermore, the elevated risk persisted among ART-treated individuals with persistent HIV viral suppression, suggesting that sustained suppression of circulating HIV RNA to below detectable limits does not eliminate excess CVD risk in the treated HIV-infected population. However, HIV-infected individuals with high CD4+ counts were not significantly different from HIV-uninfected individuals in changes in carotid artery measures over time.....Our findings are consistent with a growing body of evidence linking HIV infection with CVD
.....To our knowledge, our study is the largest and longest examining whether HIV infection is associated with incidence and progression of subclinical carotid atherosclerosis, with >1,800 study participants recruited across 10 U.S. locations. By design, our comparison group of HIV-uninfected participants had similar sociodemographic and behavioral characteristics as participants with HIV infection ......We did not find differences in CCA-IMT progression over the seven years by HIV serostatus, consistent with smaller studies.....Moreover, prior studies that have measured several carotid artery segments have found that IMT in the internal carotid artery and carotid bifurcation have been more consistently associated with HIV infection than CCA-IMT.[16,19] The increased rate of plaque progression in disease-prone segments of the carotid arterial tree that we found among HIV-infected participants corroborates these previous findings. Collectively, these findings add strong support to the hypothesis that development of atherosclerosis in HIV-infected individuals involves endothelial shear stress preferentially occurring at vascular branch points,[19] which may represent a common pathway with atherosclerosis arising from other conditions such as rheumatoid arthritis.[29] ......While HIV infection was the factor most strongly associated with formation of new focal plaque, elevated risk was seen with smoking and increased total cholesterol levels, both of which are amenable to modification.[30] Over one-third of our HIV-infected participants were current smokers. Thus, our findings, consistent with other studies among both HIV-infected individuals and the general population,[15,31] support recommendations promoting smoking cessation for HIV-infected individuals.[32] ......Use of antihypertensive medications appeared to be associated with decreased CCA-IMT progression but increased plaque. While antihypertensive medication through its effects on blood pressure may reduce wall hypertrophy in the CCA,[33] it may not reduce or correct turbulent blood flow, so it may appear as though such medications associate with plaque formation. Most of the plaque we detected was found in the bifurcation and ICA segments, which are affected more by turbulent flow, supporting this premise. Alternatively, antihypertensive medication could serve as a marker for longstanding hypertension that has led to plaque formation. .....Our finding that participants who maintained HIV suppression still had an increased risk of new focal plaque formation suggests that vigilance with respect to the long-term adverse consequences of ART remains warranted for all HIV-infected individuals. This elevated risk may be due in part to low-level HIV replication and inflammation that persists despite reductions in viral load.[10,34,35] Future work should confirm our findings and further explore the extent to which these factors play a role in CVD development. .....
 
....We found a slightly elevated association between exposure to protease inhibitors and new focal plaque formation among men but not women, consistent with our cross-sectional findings.[21] Concerns about protease inhibitor use initially arose based on data from the D:A:D Study, in which an elevated risk of myocardial infarction among protease inhibitor users was observed.[8] Given the small magnitude of our effect estimate (aRR 1.12 per year of cumulative use) and improvements in risk profiles of available ART drugs since this study was initiated, our finding should be interpreted with caution. The overwhelming benefits of ART should not be minimized, since participants with CD4+ counts in the normal range (≥500 cells/μL) had atherosclerotic risks similar to HIV-uninfected participants. In fact, CD4+ count was the single HIV-related factor conferring a linear, monotonic risk of plaque formation, supporting treatment guidelines that advocate early ART initiation, allowing for better CD4+ maintenance.
 
"......HIV infection was not associated with the magnitude of CCA-IMT increase over time (Figure 1)......Statistically significant predictors of CCA-IMT increase in multivariable analyses included black race, Hispanic ethnicity, and crack/cocaine use. Use of antihypertensive medications was associated with a decrease in CCA-IMT. ......HIV infection was associated with an unadjusted 66% increase in new focal plaque formation (relative risk [RR] 1.66, 95% CI 1.18-2.34) (Table 2). After adjusting for demographic, behavioral, and cardiometabolic risk factors, this association remained significant (adjusted RR [aRR] 1.61, 95% CI 1.12-2.32). Similar associations were observed among males (aRR 1.65, 95% CI 1.03-2.66) and females (aRR 1.53, 95% CI 0.85-2.76)......Current smoking was associated with a 42% increase in focal plaque formation (95% CI 1.03-1.96) (Table 3). Other associated factors in fully-adjusted analyses included use of antihypertensive medications, higher total cholesterol, and older age......We identified 199 HIV-infected participants who were receiving ART and persistently virologically suppressed (16% of HIV-infected women, N=92; 29% of HIV-infected men, N=107) (Table 4 and Appendix Table 2). Among this selected group, increased risk of new focal plaque formation compared with the HIV-uninfected group remained (aRR 1.77, 95% CI 1.13-2.77).......HIV-infected participants with CD4+ counts ≥500 cells/μL at baseline had a risk of new focal plaque formation that was not statistically different from HIV-uninfected participants (aRR 1.28, 95% CI 0.85-1.94). HIV-infected participants with the lowest CD4+ count at baseline (i.e., <200 cells/μL) had the greatest risk (aRR 2.57, 95% CI 1.48-4.46) compared with HIV-uninfected participants, with a gradient of decreasing risk by increasing categories of CD4+ count (Table 4). ......Our analyses did not find any association of nadir CD4+ count, history of AIDS, and duration of ART use with new focal plaque formation. We found a slightly increased risk of plaque formation with greater exposure to protease inhibitors among men (aRR 1.12 per year of cumulative use at baseline, 95% CI 1.01-1.25) but not among women. No other associations between other ART classes and focal plaque formation were found, nor were any HIV-related parameters associated with increased CCA-IMT progression (Appendix Table 3). "
 
----------------------
 
Clinical Infectious Diseases Advance Access published April 22, 2015
 
David B. Hanna1, Wendy S. Post2,3, Jennifer A. Deal3, Howard N. Hodis4, Lisa P. Jacobson3, Wendy J. Mack5, Kathryn Anastos1,6, Stephen J. Gange3, Alan L. Landay7, Jason M. Lazar8, Frank J. Palella9, Phyllis C. Tien10, Mallory D. Witt11, Xiaonan Xue1, Mary A. Young12, Robert C. Kaplan1, Lawrence A. Kingsley13,14
 
Preliminary findings were presented at the American Heart Association Epidemiology and Prevention Scientific Sessions, San Francisco, CA, March 18-21, 2014
 
Abstract
 
Background.
HIV-infected individuals live longer as a result of effective treatment, but long-term consequences of infection, treatment, and immunological dysfunction are poorly understood.
 
Methods. We prospectively examined 1011 women (74% HIV-infected) in the Women's Interagency HIV Study and 811 men (65% HIV-infected) in the Multicenter AIDS Cohort Study who underwent repeated B-mode carotid artery ultrasound imaging in 2004-2013. Outcomes included changes in right common carotid artery intima-media thickness (CCA-IMT) and new focal carotid artery plaque formation (IMT >1.5 mm) over median 7 years. We assessed the association between HIV serostatus and progression of subclinical atherosclerosis, adjusting for demographic, behavioral, and cardiometabolic risk factors.
 
Results. Unadjusted mean CCA-IMT increased (725 to 752 μm in women, 757 to 790 μm in men), but CCA-IMT progression did not differ by HIV serostatus, either in combined or sex-specific analyses. Focal plaque prevalence increased from 8% to 15% in women and 25% to 34% in men over 7 years. HIV-infected individuals had 1.6-fold greater risk of new plaque formation compared with HIV-uninfected individuals (RR 1.61, 95% CI 1.12-2.32), adjusting for cardiometabolic factors; the association was similar by sex. Increased plaque occurred even among persistently virologically suppressed HIV-infected individuals compared with uninfected individuals (RR 1.56, 95% CI 1.07-2.27). HIV-infected individuals with baseline CD4+ ≥500 cells/μL had plaque risk not statistically different from uninfected individuals.
 
Conclusions. HIV infection is associated with greater increases in focal plaque among women and men, potentially mediated by factors associated with immunodeficiency or HIV replication at levels below current limits of detection.
 
EXCERPTS
 
RESULTS
 
Participant characteristics.
There were 1,011 women (74% HIV-infected) and 811 men (65% HIV-infected) who met study inclusion criteria and had at least two vascular substudy visits. Median follow-up time (years) was 6.5 for women and 7 for men, corresponding to 4 and 3 vascular assessments. Baseline characteristics are shown in Table 1. Median age (years) was 40 in women and 49 in men. Women were more likely to be of black race or Hispanic ethnicity than men (89% versus 35%). At baseline, women were more likely to report current cigarette smoking (47% versus 30%) and have higher BMI (median 28.2 versus 25.4 kg/m2) than men. Men had higher systolic blood pressures (124 versus 116 mmHg) and total cholesterol levels (194 versus 172 mg/dL), and were more likely to be current users of anti-hypertensive (23% versus 18%) or lipid-lowering medications (24% versus 5%). HIV-infected and uninfected participants were generally similar, although HIV-infected participants were more likely to have previously injected drugs and be co-infected with HCV. The majority of HIV-infected individuals reported using ART at baseline (67% among women; 76% among men).
 
Predictors of new focal plaque formation: HIV serostatus and CVD risk factors. Figure 2 shows the presence of focal carotid artery plaques at the baseline and last vascular substudy visits by HIV serostatus. Plaques were more common among the older men (24% with at least one plaque at baseline and 34% at the last visit) than the younger women (8% and 15%). The older men were also more likely to have an increase over time in number of plaques (22% versus 11%). Focal plaque was more commonly observed at the carotid artery bifurcation compared with the ICA, and least commonly observed at the CCA.
 
HIV-infected participants with higher CD4+ counts. HIV-infected participants with CD4+ counts ≥500 cells/μL at baseline had a risk of new focal plaque formation that was not statistically different from HIV-uninfected participants (aRR 1.28, 95% CI 0.85-1.94). HIV-infected participants with the lowest CD4+ count at baseline (i.e., <200 cells/μL) had the greatest risk (aRR 2.57, 95% CI 1.48-4.46) compared with HIV-uninfected participants, with a gradient of decreasing risk by increasing categories of CD4+ count (Table 4).
 
Other HIV-related predictors. Our analyses did not find any association of nadir CD4+ count, history of AIDS, and duration of ART use with new focal plaque formation. We found a slightly increased risk of plaque formation with greater exposure to protease inhibitors among men (aRR 1.12 per year of cumulative use at baseline, 95% CI 1.01-1.25) but not among women. No other associations between other ART classes and focal plaque formation were found, nor were any HIV-related parameters associated with increased CCA-IMT progression (Appendix Table 3).
 
DISCUSSION
 
Using non-invasive carotid B-mode ultrasonography, we demonstrated that HIV-infected women and men had a 61% greater risk of new focal carotid artery plaque formation over seven years compared with uninfected controls, regardless of baseline vascular phenotype and after controlling for cardiometabolic risk factors. The HIV-associated risk was higher than that associated with smoking. Furthermore, the elevated risk persisted among ART-treated individuals with persistent HIV viral suppression, suggesting that sustained suppression of circulating HIV RNA to below detectable limits does not eliminate excess CVD risk in the treated HIV-infected population. However, HIV-infected individuals with high CD4+ counts were not significantly different from HIV-uninfected individuals in changes in carotid artery measures over time.
 
Our findings are consistent with a growing body of evidence linking HIV infection with CVD. To our knowledge, our study is the largest and longest examining whether HIV infection is associated with incidence and progression of subclinical carotid atherosclerosis, with >1,800 study participants recruited across 10 U.S. locations. By design, our comparison group of HIV-uninfected participants had similar sociodemographic and behavioral characteristics as participants with HIV infection. This is a major strength, given the well-known threats to validity when making comparisons of age-related disease outcomes that may stem from health behaviors (e.g., drug use, smoking) in HIV-infected individuals that differ from those in the general population.[20]
 
We did not find differences in CCA-IMT progression over the seven years by HIV serostatus, consistent with smaller studies.[17,18] Moreover, prior studies that have measured several carotid artery segments have found that IMT in the internal carotid artery and carotid bifurcation have been more consistently associated with HIV infection than CCA-IMT.[16,19] The increased rate of plaque progression in disease-prone segments of the carotid arterial tree that we found among HIV-infected participants corroborates these previous findings.
 
Collectively, these findings add strong support to the hypothesis that development of atherosclerosis in HIV-infected individuals involves endothelial shear stress preferentially occurring at vascular branch points,[19] which may represent a common pathway with atherosclerosis arising from other conditions such as rheumatoid arthritis.[29]
 
While HIV infection was the factor most strongly associated with formation of new focal plaque, elevated risk was seen with smoking and increased total cholesterol levels, both of which are amenable to modification.[30] Over one-third of our HIV-infected participants were current smokers. Thus, our findings, consistent with other studies among both HIV-infected individuals and the general population,[15,31] support recommendations promoting smoking cessation for HIV-infected individuals.[32]
 
Use of antihypertensive medications appeared to be associated with decreased CCA-IMT progression but increased plaque. While antihypertensive medication through its effects on blood pressure may reduce wall hypertrophy in the CCA,[33] it may not reduce or correct turbulent blood flow, so it may appear as though such medications associate with plaque formation. Most of the plaque we detected was found in the bifurcation and ICA segments, which are affected more by turbulent flow, supporting this premise. Alternatively, antihypertensive medication could serve as a marker for longstanding hypertension that has led to plaque formation.
 
Our finding that participants who maintained HIV suppression still had an increased risk of new focal plaque formation suggests that vigilance with respect to the long-term adverse consequences of ART remains warranted for all HIV-infected individuals. This elevated risk may be due in part to low-level HIV replication and inflammation that persists despite reductions in viral load.[10,34,35] Future work should confirm our findings and further explore the extent to which these factors play a role in CVD development.
 
We found a slightly elevated association between exposure to protease inhibitors and new focal plaque formation among men but not women, consistent with our cross-sectional findings.[21] Concerns about protease inhibitor use initially arose based on data from the D:A:D Study, in which an elevated risk of myocardial infarction among protease inhibitor users was observed.[8] Given the small magnitude of our effect estimate (aRR 1.12 per year of cumulative use) and improvements in risk profiles of available ART drugs since this study was initiated, our finding should be interpreted with caution. The overwhelming benefits of ART should not be minimized, since participants with CD4+ counts in the normal range (≥500 cells/μL) had atherosclerotic risks similar to HIV-uninfected participants. In fact, CD4+ count was the single HIV-related factor conferring a linear, monotonic risk of plaque formation, supporting treatment guidelines that advocate early ART initiation, allowing for better CD4+ maintenance.
 
Our study has limitations. First, only the right carotid artery was examined; however, other studies have found wall thickness to be correlated bilaterally.[37] Second, the use of long-term cohort studies may induce selection bias, and some participants were not able to attend all vascular study visits. However, we do not have a strong basis to believe that inferences would change as a result (Appendix). Furthermore, the women and men in our study have the same age distribution as the U.S. HIV-infected population,[22,38] supporting the generalizability of our results. We carefully adjusted for many established confounders, including cardiometabolic risk factors, but did not have comprehensive data on diet, physical activity, and other lifestyle factors and therefore cannot rule out the possibility of unmeasured confounding. We used carotid artery B-mode ultrasonography to examine structural measures of atherosclerosis; imaging techniques examining other structural or functional aspects of CVD, such as coronary computed tomographic angiography,[39] provide additional information. Finally, our analysis does not examine clinical CVD outcomes such as myocardial infarction; while subclinical carotid artery disease has been strongly associated with such outcomes in non-HIV studies,[40] this relationship has not yet been replicated in HIV-infected cohorts.
 
More HIV-infected individuals are initiating ART earlier in the course of their infection, with concomitant improvements in long-term virologic control.[41] Our data support earlier ART initiation, before CD4+ counts decline, which may mitigate HIV-associated increased CVD risks. Better understanding of these processes is necessary, both to prevent or delay CVD development and to improve treatment strategies in the growing and increasingly older HIV-infected population.

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