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CLINICAL RESEARCH: HIV AND HEART DISEASE

Endothelial Function in Human Immunodeficiency Virus-Infected Antiretroviral-Naive Subjects Before and After Starting Potent Antiretroviral Therapy

The ACTG (AIDS Clinical Trials Group) Study 5152s

Francesca J. Torriani, MD^_*,_*, Lauren Komarow, MS, Robert A. Parker, ScD, Bruno R. Cotter, MD, FACC^_*, Judith S. Currier, MD, Michael P. Dubé, MD, Carl J. Fichtenbaum, MD^||, Mariana Gerschenson, PhD^¶, Carol K.C. Mitchell, PhD^#, Robert L. Murphy, MD^_**, Kathleen Squires, MD, James H. Stein, MD, FACC^# for the ACTG 5152s Study Team

^_* University of California–San Diego, San Diego, California
Harvard School of Public Health, Boston, Massachusetts
University of California–Los Angeles, Los Angeles, California
Indiana University School of Medicine, Indianapolis, Indiana
^|| University of Cincinnati Medical Center, Cincinnati, Ohio
^¶ University of Hawaii, Honolulu, Hawaii
^# University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
^_** Northwestern University Feinberg School of Medicine, Chicago, Illinois
University of Southern California, Los Angeles, California.

Manuscript received March 27, 2008; accepted April 23, 2008.

^_* Reprint requests and correspondence: Dr. Francesca J. Torriani, University of California–San Diego Infection Prevention and Clinical Epidemiology Unit, 200 West Arbor Drive, MC 8951, San Diego, California 92103. (Email: ftorriani{at}ucsd.edu).

	Abstract

Top Abstract Methods Results Discussion Conclusions References

 
Objectives: This study evaluated the effects of 3 class-sparing antiretroviral therapy (ART) regimens on endothelial function in human immunodeficiency virus (HIV)-infected subjects participating in a randomized trial.

Background: Endothelial dysfunction has been observed in patients receiving ART for HIV infection.

Methods: This was a prospective, multicenter study of treatment-naive subjects who were randomly assigned to receive a protease inhibitor-sparing regimen of nucleoside reverse transcriptase inhibitors (NRTIs) + efavirenz, a non-nucleoside reverse transcriptase inhibitor-sparing regimen of NRTIs + lopinavir/ritonavir, or a NRTI-sparing regimen of efavirenz + lopinavir/ritonavir. The NRTIs were lamivudine + stavudine, zidovudine, or tenofovir. Brachial artery flow-mediated dilation (FMD) was determined by B-mode ultrasound before starting on ART, then after 4 and 24 weeks.

Results: There were 82 subjects (median age 35 years, 91% men, 54% white). Baseline CD4 cell counts and plasma HIV ribonucleic acid (RNA) values were 245 cells/mm³ and 4.8 log₁₀ copies/ml, respectively. At baseline, FMD was 3.68% (interquartile range [IQR] 1.98% to 5.51%). After 4 and 24 weeks of ART, plasma HIV RNA decreased by 2.1 and 3.0 log₁₀ copies/ml, respectively. FMD increased by 0.74% (IQR –0.62% to +2.74%, p = 0.003) and 1.48% (IQR –0.20% to +4.30%, p < 0.001), respectively, with similar changes in each arm (Kruskal-Wallis p value >0.600). The decrease in plasma HIV RNA at 24 weeks was associated with greater FMD (r_s = –0.30, p = 0.017).

Conclusions: Among treatment-naive individuals with HIV, 3 different ART regimens rapidly improved endothelial function. Benefits were similar for all ART regimens, appeared quickly, and persisted at 24 weeks.

Key Words: antiretroviral therapy • cardiovascular disease risk • endothelial function • human immunodeficiency virus

Abbreviations and Acronyms   ART = antiretroviral therapy   CVD = cardiovascular disease   FMD = flow-mediated dilation   HIV = human immunodeficiency virus   NNRTI = non-nucleoside reverse transcriptase inhibitor   NRTI = nucleoside reverse transcriptase inhibitor   NTGMD = nitroglycerin-mediated vasodilation   PI = protease inhibitor

	Methods

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Study design.   The ACTG (AIDS Clinical Trials Group) study 5152s is a substudy of ACTG 5142, a prospective, multicenter randomized clinical trial that investigated time to virologic failure among ART-naive subjects who were randomly assigned to receive 1 of 3 ART-sparing regimens: 1) a PI-sparing regimen of NRTIs + the NNRTI efavirenz; 2) an NNRTI-sparing regimen of NRTIs + the PI lopinavir/ritonavir; or 3) an NRTI-sparing regimen of efavirenz + lopinavir/ritonavir. The NRTIs prescribed in this study were lamivudine + stavudine (extended release), zidovudine, or tenofovir. NRTI use was investigator-selected before randomization and was a stratification factor in the parent study. The major inclusion criteria included HIV-1 infection, and plasma HIV ribonucleic acid (RNA) >2.0 log₁₀ copies/ml. Major exclusion criteria included prior use of ART, known CVD, diabetes mellitus, and current (within 6 weeks of enrollment) use of lipid-lowering medications, antioxidant vitamin supplements, or hormones at greater than replacement doses. Pharmacological treatment of diabetes mellitus, dyslipidemia, and changes in doses of angiotensin-converting enzyme inhibitors were not permitted during the study. Subjects participating in ACTG 5142 were recruited consecutively from 6 sites in the U.S. Study procedures were performed at baseline and then after 4 and 24 weeks. Laboratory testing was performed at ACTG Central Metabolic Laboratory (Quest Diagnostics, Baltimore, Maryland). Adiponectin was measured at Northwestern University (Chicago, Illinois). Treatment arms were blinded and coded until completion and presentation of A5142 in August 2006 (9).

Evaluation of endothelial function.   Endothelial function was evaluated by measuring flow-mediated dilation (FMD) of the brachial artery (7,10,11). Brachial artery reactivity studies were performed on the same day as phlebotomy. Subjects were required to be fasting and not use any tobacco-containing products for 8 h before the study. Subjects who were not fasting or who admitted to smoking had their test rescheduled. Subjects were placed in a supine position in a temperature-controlled room for 10 min before imaging. A blood pressure cuff was placed on the widest part of the proximal right forearm approximately 1 cm distal to the antecubital fossa. The arm was extended 90° from the thorax and placed on an arm board with the elbow positioned downward and the hand rotated so the thumb pointed towards the ceiling. Using a high resolution (7 MHz) linear array vascular ultrasound transducer, the brachial artery was located above the elbow and scanned in longitudinal sections with the focus zone set to the depth of the far wall. Time-gain-compensation and overall gain settings were used to optimize images of the lumen/arterial wall interface. Extravascular landmarks in each subject were identified and labeled to assure that the imaged segment of the brachial artery was reproduced within and between studies. After recording baseline B-mode images of the brachial artery and spectral Doppler images of flow, the forearm cuff was inflated to 250 mm Hg for 4.5 min to induce reactive hyperemia. Immediately after deflation, spectral Doppler images were obtained to verify hyperemia. FMD of the brachial artery was measured 1 min after cuff deflation. After a 15-min rest period, nitroglycerin-mediated vasodilation (NTGMD) (a marker of endothelium-independent vasodilation) was measured 3 min after administration of sublingual nitroglycerin (400 µg). FMD was calculated as the ratio of the brachial artery diameter after reactive hyperemia to the baseline diameter and was expressed as a percentage change. NTGMD was calculated in an analogous fashion. Each study was recorded digitally and sent to a core ultrasound laboratory. Brachial artery diameters were measured in triplicate with a digital border tracing tool (Access Point 2004, Freeland Systems, Westfield, Indiana). Measurements were performed by a single reader blinded to subject information and treatment. Using this technique, the median (interquartile range) FMD at the core lab is 5.5% (3.7% to 7.8%), based on studies from 152 nondiabetic individuals without HIV infection (median age 25 years, 25% current smokers, 39% men) performed from May 2002 through May 2005. Among 20 nondiabetic HIV-infected individuals on stable PI-containing ART (median age 43 years, 30% current smokers, 90% men), the median FMD at the core lab was 4.9% (3.3% to 9.1%), based on studies performed from January 2001 through August 2002.

Several measures were used to minimize inter- and intrasite variability. All sonographers completed a 2-day training course at the core ultrasound laboratory, which followed standards set by the American Society of Echocardiography (12). After on-site training, each sonographer was required to submit a minimum of 3 paired mock studies to demonstrate adherence to the study protocol and consistent display of high-quality images and reproducibility of landmarks. Before study initiation, ultrasound equipment at each laboratory was evaluated and calibrated using a small parts ultrasound phantom. To evaluate scanning variability, the first 20 subjects that completed week 24 underwent a repeat scan on a separate day within 21 days of the initial 24-week scan. To evaluate reader variability, all scans (weeks 0, 4, 24, and 26) from the first 15 subjects that completed the study were reread, blinded to the original reading.

Data analysis.   The primary objective was to compare brachial artery FMD before and after ART within each of the treatment arms. Secondary objectives were to compare changes in brachial artery FMD between arms. Additional objectives were to evaluate the relationships between levels of CD4 cells, plasma HIV-1 RNA, lipids, inflammatory markers, and markers of insulin sensitivity and their changes to FMD and changes in FMD after 4 and 24 weeks. Randomization in the parent study used a permuted-blocks design stratified on screening plasma HIV-1 RNA, choice of NRTI, and the presence of active hepatitis infection.

All values are reported as medians (interquartile ranges), unless noted otherwise. Changes in brachial artery FMD measurements and laboratory tests are reported as absolute changes from baseline. The Wilcoxon signed rank test was used to assess within-arm changes in FMD and laboratory tests. The Kruskal-Wallis, Wilcoxon rank sum, or Fisher exact test was used for between-arm comparisons at specific time points. Spearman correlations were used to evaluate relationships between pairs of continuous variables and were not adjusted for multiple comparisons. For participants who started lipid-lowering agents while on study, results after the start of lipid-lowering agents were excluded. Correcting for nonparametric testing and an expected 15% loss to follow-up, 25 subjects were needed per arm to achieve 80% power to detect an absolute FMD change of 4% (standard deviation 6%) over 24 weeks with an alpha of 0.05.

	Results

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Between October 2002 and December 2004, 82 treatment-naive individuals were enrolled from 6 institutions: 23 subjects were randomized to the PI-sparing arm, 31 to the NNRTI-sparing arm, and 28 to the NRTI-sparing arm in the parent study.

Baseline characteristics.   Baseline characteristics are shown in Table 1. Subjects were well matched across groups. The median age was 35 (30 to 40) years; 91% were men, 54% were white, 32% black or Asian, and 15% Hispanic. The HIV disease characteristics were similar between groups before starting ART. The baseline median (interquartile range) CD4+ cell count was 245 (119 to 356) cells/mm³, and plasma HIV RNA was 4.8 (4.49 to 5.32) log₁₀ copies/ml. Baseline lipid, glucose homeostasis, and inflammatory markers were similar in each arm before starting ART (Table 2). High-density lipoprotein cholesterol values were similarly low in each arm; however, other median laboratory values were within their normal ranges. Of the 54 individuals that received NRTIs, 9 (16.7%) received stavudine, 27 (50%) received tenofovir, and 18 (33.3%) received zidovudine with a similar distribution between the arms (p = 0.460).

After 24 weeks, glucose increased in the PI-sparing and NRTI-sparing arms (p = 0.040). The differences between the 3 arms were significant (p_KW = 0.040) with less increase in glucose in the NNRTI-sparing arm than in each of the other 2 arms (p 0.042). Significant between-arms differences in insulin were seen at 4 but not 24 weeks due to higher values in the NRTI-sparing arm (p 0.018). Adiponectin levels decreased in the NRTI-sparing arm after 24 weeks (p = 0.040); however, this change was not significantly different than observed in the other arms (p_KW = 0.442). C-reactive protein increased after 4 weeks (p < 0.01) without differences between arms, but differences from baseline after 24 weeks were not significant (p = 0.810).

Brachial artery reactivity studies.   Technically usable brachial reactivity scans were obtained from 75 subjects at baseline (Table 4). The resting brachial artery diameter was similar in each arm (4.35 [3.85 to 4.63] mm, p_KW = 0.186). Before starting ART, FMD was similar in each arm (3.68% [1.9% to 5.51%], p_KW = 0.815), as was NTGMD (14.7% [11.5% to 17.6%], p_KW = 0.132). After 4 weeks of ART, the resting brachial artery diameter increased by 0.03 mm (–0.02 to +0.12 mm, p = 0.003) from baseline, with no difference between arms (p_KW = 0.648). Despite the increase in resting brachial diameter, after 4 weeks of ART, FMD increased significantly (0.74% [–0.62% to +2.74%], p 0.01), with no difference between arms (p_KW = 0.609). After 24 weeks of ART, the resting brachial artery diameter increased by 0.06 mm (–0.03 to +0.19 mm, p = 0.002) from baseline, but there was a difference between arms (p_KW = 0.002), as significant resting diameter increases were observed in the PI-sparing (p < 0.001) and NNRTI-sparing arms (p = 0.024), but not the NRTI-sparing arm (p = 0.498). Despite the increases in baseline brachial diameter, after 24 weeks of ART, FMD increased significantly (1.48% [–0.20% to +4.30%], p < 0.001). The improvement in each arm was of a similar magnitude (p_KW = 0.778). There was no significant difference between treatment groups in FMD, even after adjustment for changes in brachial artery diameter and the slight decrease in heart rate observed at week 24 (p_adj = 0.935) (Fig. 1). Reactive hyperemic flow was similar in each arm at each week (Table 4). There was a small, statistically significant increase in the time-velocity integral of reactive hyperemic flow after 24 weeks (p = 0.01), with a significant increase in the NRTI-sparing arm (p < 0.01); however, there was no significant difference between treatment groups in FMD after adjustment for reactive hyperemia flow (p_adj = 0.802).

View larger version (18K): [in this window] [in a new window] [Download PPT slide]   Figure 1 Changes in Brachial Artery Flow-Mediated Dilation From Baseline to Week 24 Thick bars = medians; box edges = 25th and 75th percentiles; error bars = 95% confidence intervals. EFV = efavirenz; FMD = flow-mediated dilation; LPV/r = lopinavir/ritonavir; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor. *p 0.005, #p = 0.015 within arm, compared with baseline (between groups, p = 0.828).

There were no within- or between-arms changes in NTGMD after 4 (p = 0.431, p_KW = 0.560) or 24 weeks (p = 0.363, p_KW = 0.142). Neither CD4 cell counts nor log RNA were significantly correlated with FMD at baseline. There was a weak correlation between triglycerides and FMD at baseline (r_s = 0.24, p = 0.043) but not at 24 weeks. Significant correlations between FMD and the other variables in Tables 1 and 2 were not observed at baseline. The change in FMD from baseline to week 24 correlated inversely with the change in log RNA (r_s = –0.30, p = 0.017) and positively with adiponectin (r_s = 0.26, p = 0.041). Significant correlations between changes in FMD and changes in the other variables in Tables 1 and 2 were not observed after 24 weeks.

In the 20 subjects who underwent repeat scans within 16 days of the week 24 scan, the difference in FMD was only 0.26% (–0.43% to +0.72%, p = 0.498). The difference in NTGMD also was small (0.66% [–3.51% to +1.09%], p = 0.599). Blinded rereading of 57 scans revealed strong correlations of 0.97 to 0.99 (p < 0.001) and small median differences of –0.14% to +0.09% at each week. There were no outliers on visual inspection limits of agreement analyses (13).

	Discussion

Top Abstract Methods Results Discussion Conclusions References

 
This is the first study of HIV-infected patients where assignment to ART was randomized and a validated marker of arterial function was followed prospectively. Patients with HIV infection who met criteria for starting ART experienced a rapid improvement in endothelial function. The effect of ART on brachial artery FMD was of similar magnitude for all 3 ART regimens, appeared after 4 weeks, and persisted at 24 weeks. It persisted after adjustment for the changes in heart rate, brachial artery diameter, and reactive hyperemia observed with ART.

Our findings of improved endothelial function with ART appear to contradict some cross-sectional studies in which use of ART-containing regimens was associated with endothelial dysfunction (7,14,15), a study demonstrating that administration of a PI (indinavir) impaired endothelial function in healthy men (8), and several studies that identified cellular or molecular mechanisms of endothelial dysfunction associated with the use of PIs (16–18). Other investigators, however, have variably found that viral load, CD4 cell count, cardiovascular risk factors, injection drug use, and alcoholism were associated with impaired arterial function, rather than ART (19–22). Although several observational studies have demonstrated that ART and specifically the use of PI-containing regimens are associated with increased CVD risk (2–4), short-term decreases in CVD risk and overall mortality have been observed after initiation of ART (23), and the recent SMART (Strategies for Management of Anti-Retroviral Therapy) study demonstrated that total mortality and possibly CVD risk are increased when ART is discontinued or HIV replication is not suppressed (24). This prospective study helps shed light on this apparent contradictory literature (2–4,23,24) by demonstrating a rapid, consistent, and reproducible improvement in FMD of the brachial artery in 3 randomly assigned class-sparing ART regimens that were sustained over 24 weeks. In this study, FMD improved despite increases in total cholesterol, low-density lipoprotein cholesterol, triglycerides, and lipoprotein(a); however, high-density lipoprotein cholesterol improved with ART. Changes in an overall measure of lipid change—the total/high-density lipoprotein cholesterol ratio—were small and similar in each arm. None of these parameters, or changes in levels of traditional or inflammatory markers of cardiovascular risk, correlated significantly with changes in FMD. Some studies suggest that HIV infection may directly or indirectly impair arterial function (25–27). Human immunodeficiency virus has been shown to infect endothelial cells; patients with HIV infection have increased vascular cell adhesion molecule-1 and E-selectin expression from aortic endothelium, and increased circulating markers of endothelial activation (25–27). Although the change in HIV viral load had the strongest association with the change in FMD, the correlation was modest (r_s = –0.30). This may be explained by the robust and homogeneous response of our subjects to each of the ART regimens with 67% of participants having plasma HIV RNA levels below the limit of detection after 24 weeks. This study could not determine if the inverse association between viral load and FMD was due to a direct adverse effect of viremia, a marker of receiving effective treatment, or even a chance finding, since HIV viral load was not associated with the degree of endothelial dysfunction at baseline. The correlation between changes in adiponectin and FMD was of marginal statistical significance, and is difficult to interpret in light of the small changes in glucose, insulin, and body mass index.

Study limitations.   Although our study provides further support for the hypothesis that control of HIV replication initially improves endothelial function, our study had only 24 weeks of follow-up. Prolonged and uncorrected lipid abnormalities after ART ultimately may lead to deterioration of endothelial function, and thus to higher cardiovascular risk in the longer term (2–4,7). Also, the effects of ART on arterial function in previously treated patients, or in those whose viremia is less suppressed, are not known. Another limitation is that randomization was performed in the larger, parent study (ACTG 5142) before voluntary enrollment in our substudy. While we believe this minimized treatment bias, this study was not, in the strictest sense, a randomized clinical trial. This study was designed to detect differences in FMD from baseline through 24 weeks within the treatment arms, not to detect between-group differences. The absence of differences between groups should be interpreted cautiously, especially in regard to FMD. Although this study was relatively large in regard to the longitudinal assessment of changes in FMD, it was underpowered to detect correlations <0.35 between changes in the parameters studied and changes in FMD.

This study did not have a control group, so the possibility that regression to the mean contributed to some of the improvement in FMD cannot be excluded. Because it would be unethical to withhold ART from individuals who require treatment, it would not have been possible to have had an HIV-infected, untreated control group. Using a group of HIV-infected patients who do not require ART would not be appropriate due to differences in the stage of HIV disease. It also would not be ethical to treat HIV-negative individuals with ART for 24 weeks, given the possible toxicities of these medications. To the extent that measurement variability can contribute to regression to the mean, we have demonstrated highly reproducible measurements of FMD and NTGMD at all time points. Biological variability cannot be excluded; however, the consistent, incremental improvements in FMD seen in each arm, at each time point, and their magnitude suggest that the observations in this study were related to ART.

	Conclusions

Top Abstract Methods Results Discussion Conclusions References

 
Patients with HIV infection who met criteria for starting ART had impaired endothelial function. Use of 3 different ART regimens rapidly improved endothelial function in treatment-naive patients with HIV infection. Improvements were similar for all ART regimens, appeared quickly, and persisted over 24 weeks. It is unclear if the improvements were due to ART, suppression of viremia, or changes in factors not measured in this study, such as immune activation or biological variation. Larger, prospective, controlled studies of longer duration are needed to determine the long-term effects of ART on endothelial function and ultimately on atherosclerosis and CVD events.

	Acknowledgments

 
The authors gratefully acknowledge the contributions of the other members of ACTG 5152s protocol team. The following ACTG sites and staff participated in this study: Indiana University: Janet L. Hernandez, RN, Gina Bonner; Northwestern University: Baiba Berzins, RN, Karen Coleman, Bonnie Kane, Beverly Smulevitz; University of California–Los Angeles/University of Southern California: Eric Daar, MD, Hannah Edmondson, RN, MPH, Luis M. Mendez, Howard Hodis, MD, Sadia Shaik; University of California–San Diego: Susan Cahill, RN, Julie Hoffman, RN, Oi-Ling Kwan, RDCS, FASE; University of Cincinnati: Jenny Baer, RN, Betty Glasscock; University of Hawaii: Nancy Hanks, RN, Pua Kondo, Todd Seto, MD, Pearl Whitaker; Frontier Science & Technology Research Foundation, Inc.: Dave Rusin, MT, Mary Dobson. The authors also acknowledge the assistance of Tamara J. LeCaire, MS, and Mari Palta, PhD, for providing the data on normal control subjects from the CARDIO-DIAB study (NIH HL62897). The authors would also like to posthumously acknowledge Robert Zackin, ScD, who served as the senior biostatistician until his death on September 2, 2004. Dr. Zackin was instrumental in the design and development of this study.

	Footnotes

 
This multicenter trial was conducted by the AIDS Clinical Trials Group (ACTG) funded by the National Institute of Allergy and Infectious Diseases and the National Heart, Lung, and Blood Institute. Pharmaceutical support was provided by Abbott Laboratories and Bristol-Myers Squibb Company. The following additional grants were received: NIH AI069424, AI56933, and AI069428 (to Dr. Currier); NIH AI25859, HL72711, RR00750, and RR000750 (to Dr. Dubé); NIH AI069513 (to Dr. Fichtenbaum); NIH AI34853, RR16467, and MD000173 (to Dr. Gerschenson); NIH AI069471 (to Dr. Murphy); NIH AI38855 and AI068634 (to Ms. Komarow); NIH AI38855 and AI068634 (to Dr. Parker); NIH RR16176 and AI25915 (to Dr. Stein); NIH AI69432 (to Dr. Torriani); and NIH AI38558 and NIH AI068636 (to the ACTG leadership). Dr. Torriani is on the advisory board for Abbott. Dr. Currier has received research grants from Merck and Co., Tibotec, GlaxoSmithKline, Theratechnologies, and Schering-Plough; has received honoraria from Gilead, Koronnis, Achillion, and Vertex; and has been a consultant/advisory board member for Bristol-Myers Squibb, Pfizer, Merck, and Gilead. Dr. Dubé has received research grants from Abbott and Bristol-Myers Squibb and has been a consultant to GlaxoSmithKline, Tibotec, Gilead, Bristol-Myers Squibb, and Abbott. Dr. Fichtenbaum has received research grants from Abbott and Bristol-Myers Squibb; has been on the Speakers' Bureaus of Abbott, Bristol-Myers Squibb, and Gilead; and has received honoraria from Abbott, Bristol-Myers Squibb, and Gilead. Dr. Murphy has received research grants from Bristol-Myers Squibb and has been a consultant/advisory board member for Gilead and Bristol-Myers Squibb. Dr. Squires has received a research grant from Bristol-Myers Squibb; has received honoraria from Gilead Sciences, Bristol-Myers Squibb, and Abbott; and has been on the advisory board for Bristol-Myers Squibb, Gilead Sciences, and Abbott. Dr. Stein has received a research grant from Bristol-Myers Squibb and has been a consultant for Abbott. Joseph A. Vita, MD, served as Guest Editor for this article.

	References

Top Abstract Methods Results Discussion Conclusions References

 
1. Palella Jr. FJ, Delaney KM, Moorman AC, et al. HIV Outpatient Study Investigators Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection N Engl J Med 1998;338:853-860.[Abstract/Free Full Text]

2. Friis-Moller N, Reiss P, Sabin CA, et al. Class of antiretroviral drugs and the risk of myocardial infarction N Engl J Med 2007;356:1723-1735.[Abstract/Free Full Text]

3. Obel N, Thomsen HF, Kronborg G, et al. Ischemic heart disease in HIV-infected and HIV-uninfected individuals: a population-based cohort study Clin Infect Dis 2007;44:1625-1631.[CrossRef][Web of Science][Medline]

4. Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease J Clin Endocrinol Metab 2007;92:2506-2512.[Abstract/Free Full Text]

5. Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance Circulation 2007;115:1285-1295.[Free Full Text]

6. Yeboah J, Crouse JR, Hsu FC, Burke GL, Herrington DM. Brachial flow-mediated dilation predicts incident cardiovascular events in older adults: the Cardiovascular Health study Circulation 2007;115:2390-2397.[Abstract/Free Full Text]

7. Stein JH, Klein MA, Bellehumeur JL, et al. Use of human immunodeficiency virus-1 protease inhibitors is associated with atherogenic lipoprotein changes and endothelial dysfunction Circulation 2001;104:257-262.[Abstract/Free Full Text]

8. Shankar SS, Dube MP, Gorski JC, Klaunig JE, Steinberg HO. Indinavir impairs endothelial function in healthy HIV-negative men Am Heart J 2005;150:933.[Medline]

9. Riddler SA, Haubrich R, DiRienzo G, et al. AIDS Clinical Trials Group Study 5142 Class-sparing regimens for initial treatment of HIV-1 infection N Engl J Med 2008;358:2095-2106.[Abstract/Free Full Text]

10. Corretti MC, Anderson TJ, Benjamin EJ, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force J Am Coll Cardiol 2002;39:257-265.[Abstract/Free Full Text]

11. Sorensen KE, Celermajer DS, Spiegelhalter DJ, et al. Non-invasive measurement of human endothelium dependent arterial responses: accuracy and reproducibility Br Heart J 1995;74:247-253.[Abstract/Free Full Text]

12. Gottdiener JS, Bednarz J, Devereux RM, et al. Recommendations for use of echocardiography in clinical trials: a report from the American Society of Echocardiography's Nomenclature and Standards Committee and The Task Force on Echocardiography in Clinical Trials J Am Soc Echocardiogr 2004;17:1086-1119.[Web of Science][Medline]

13. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement Lancet 1986;1:307-310.[CrossRef][Web of Science][Medline]

14. Charakida M, Donald AE, Green H, et al. Early structural and functional changes of the vasculature in HIV-infected children: impact of disease and antiretroviral therapy Circulation 2005;112:103-109.[Abstract/Free Full Text]

15. Blanco JJ, Garcia IS, Cerezo JG, et al. Endothelial function in HIV-infected patients with low or mild cardiovascular risk J Antimicrob Chemother 2006;58:133-139.[Abstract/Free Full Text]

16. Wang X, Chai H, Yao Q, Chen C. Molecular mechanisms of HIV protease inhibitor-induced endothelial dysfunction J Acquir Immune Defic Syndr 2007;44:493-499.[CrossRef][Web of Science][Medline]

17. Grubb JR, Dejam A, Voell J, et al. Lopinavir-ritonavir: effects on endothelial cell function in healthy subjects J Infect Dis 2006;193:1516-1519.[CrossRef][Web of Science][Medline]

18. Zhong DS, Lu XH, Conklin BS, et al. HIV protease inhibitor ritonavir induces cytotoxicity of human endothelial cells Arterioscler Thromb Vasc Biol 2002;22:1560-1566.[Abstract/Free Full Text]

19. Solages A, Vita JA, Thornton DJ, et al. Endothelial function in HIV-infected persons Clin Infect Dis 2006;42:1325-1332.[CrossRef][Web of Science][Medline]

20. van Wijk JP, de Koning EJ, Cabezas MC, et al. Functional and structural markers of atherosclerosis in human immunodeficiency virus-infected patients J Am Coll Cardiol 2006;47:1117-1123.[Abstract/Free Full Text]

21. Nolan D, Watts GF, Herrmann SE, French MA, John M, Mallal S. Endothelial function in HIV-infected patients receiving protease inhibitor therapy: does immune competence affect cardiovascular risk? QJM 2003;96:825-832.[Abstract/Free Full Text]

22. Blum A, Hadas V, Burke M, Yust I, Kessler A. Viral load of the human immunodeficiency virus could be an independent risk factor for endothelial dysfunction Clin Cardiol 2005;28:149-153.[CrossRef][Web of Science][Medline]

23. Bozzette SA, Ake CF, Tam HK, et al. Cardiovascular and cerebrovascular events in patients treated for human immunodeficiency virus infection N Engl J Med 2003;348:702-710.[Abstract/Free Full Text]

24. El Sadr WM, Lundgren JD, Neaton JD, et al. CD4+ count-guided interruption of antiretroviral treatment N Engl J Med 2006;355:2283-2296.[Abstract/Free Full Text]

25. Bussolino F, Mitola S, Serini G, Barillari G, Ensoli B. Interactions between endothelial cells and HIV-1 Int J Biochem Cell Biol 2001;33:371-390.[CrossRef][Web of Science][Medline]

26. Zietz C, Hotz B, Sturzl M, Rauch E, Penning R, Lohrs U. Aortic endothelium in HIV-1 infection: chronic injury, activation, and increased leukocyte adherence Am J Pathol 1996;149:1887-1898.[Abstract]

27. Shankar SS, Dube MP. Clinical aspects of endothelial dysfunction associated with human immunodeficiency virus infection and antiretroviral agents Cardiovasc Toxicol 2004;4:261-269.[CrossRef][Medline]

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