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Improvement in HIV-related endothelial dysfunction using the anti-inflammatory agent salsalate: a pilot study
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[Research Letters]
This pilot study demonstrates that anti-inflammatory therapy has the potential to improve endothelial dysfunction in HIV-infected subjects not receiving CART.
AIDS:Volume 22(5)12 March 2008p 653-655
Gupta, Samir K; Johnson, Raymond M; Saha, Chandan; Mather, Kieren J; Greenwald, Martha L; Waltz, Jeffrey S; Rehman, Jalees; Dube, Michael P
Indiana University School of Medicine, Indianapolis, Indiana, USA.
Abstract
We hypothesized that heightened systemic inflammation contributes to the increased rate of cardiovascular events in HIV-infected patients not receiving combination antiretroviral therapy. We performed a pilot trial to assess the effects of the nuclear factor-κB inhibitor salsalate on flow-mediated dilation of the brachial artery, a measure of endothelial function. Flow-mediated dilation significantly improved after 8 weeks of salsalate. However, hepatotoxicity occurred frequently. Research using alternative agents is warranted to examine the role of inflammation in HIV-related cardiovascular disease.
Recent data suggest that a strategy of combination antiretroviral therapy (CART) interruption may unexpectedly increase the risk of cardiovascular events compared to continued treatment [1]. Untreated HIV infection may also be associated with impaired endothelial function, a precursor to atherosclerosis, although underlying mechanisms remain unknown [2].
Because HIV is a chronic pro-inflammatory condition [3], and because inflammation is associated with endothelial dysfunction [4], we hypothesized that systemic inflammation is associated with endothelial dysfunction in HIV-infected subjects. Specifically, we explored the possibility that reduction of systemic inflammation with salsalate would improve flow-mediated dilation (FMD) of the brachial artery, a measure of endothelial function.
We performed this pilot study to determine the potential effect size of salsalate in order to better inform the design of future controlled trials. Because salsalate had not previously been studied in HIV-infected subjects, we only enrolled a small number to examine the safety of this drug before exposing larger numbers of subjects to any potential toxicity. Salsalate was used as our interventional agent because of its ability to inhibit nuclear factor-κB [5] while having little platelet [6] or cyclo-oxygenase inhibition [7]. Assuming that any possible effect of salsalate would be dose-dependent, we chose to use the maximum FDA-allowed dosage of salsalate, 1500 mg orally twice daily, in order to determine the largest possible effect size. To reduce possible confounding from the effects of antiretrovirals on endothelial function [2,8], only subjects not receiving CART were studied. FMD and nitroglycerin-mediated dilation (NTGMD) were measured according to established guidelines [9] at baseline and after 4 and 8 weeks of study drug. Changes in FMD and inflammatory markers were assessed using the Wilcoxon signed-rank test. This study was approved by the Indiana University School of Medicine Institutional Review Board. All participants provided their written, informed consent.
All subjects were at least 18 years of age, had documented HIV infection with a CD4 cell count ≥ 350/μl within 1 month of screening, and had been free of antiretroviral treatment for at least 6 months prior to screening. Subjects were excluded for known vascular disease, diabetes mellitus or hypertension; pro-inflammatory conditions (hepatitis B or C co-infection was allowed); estimated creatinine clearance < 50 ml/min, hemoglobin < 9.0 mg/dl, hepatic aminotransferase more than three-fold the upper limit normal, or total bilirubin > 2.5-fold the upper limit normal at screening; fever or recent treatment of infection at screening or any main study visit; or receipt of other anti-inflammatory, investigational, or lipid-lowering drugs within 28 days prior to screening.
The baseline characteristics of the 11 subjects enrolled into this study are shown in Table 1. Two subjects experienced symptomatic grades 3 and 4 hepatic transaminase elevation at weeks 3 and 2, respectively; salicylate levels at these time points were 11 mg/dl in each subject. Salsalate was immediately discontinued, and transaminases returned to normal. Two additional subjects were found to have asymptomatic grades 1 and 2 transaminase elevation at the week 4 visit, with salicylate levels of 17 mg/dl and 21 mg/dl, respectively. A dose reduction by 750 mg resulted in normalization of these abnormalities, and both subjects completed the study without interruption of study drug. In addition, one subject without any known adverse events was lost to follow-up after completing the week 4 study visit. Therefore, nine and eight subjects, respectively, completed the week 4 and week 8 visit procedures.
Median FMD in the 11 subjects prior to initiation of salsalate was low at 2.7% (range = 0.2-7.1%), and NTGMD was normal at 18%. These results suggest the study group had impaired endothelium-dependent vasodilation with intact endothelium-independent vasodilation at baseline. There was a nonsignificant (P = 0.4) increase in median absolute FMD in the nine subjects assessed at week 4 (+1.2%; range = -2.3-10.6%). Median absolute FMD continued to improve at 8 weeks in the eight subjects who completed the trial (+4.2%; range = -2.1-12.9%), which is a significant increase (P = 0.02). Seven of these eight subjects had an improvement in FMD. FMD was measured 8 weeks after salsalate discontinuation in the two subjects with the greatest improvement in FMD during the trial (+12.5% and +12.9%) and who continued to be free of CART or anti-inflammatory drug use; FMD returned to predrug baseline levels in both. No significant changes or correlations with FMD occurred with respect to plasma viral load or the inflammatory markers (i.e. soluble tumour necrosis factor receptor 1, high-sensitivity C-reactive protein, interleukin-6, monocyte chemoattractant protein 1, soluble vascular cell adhesion molecule-1, or soluble intercellular adhesion molecule-1).
Several lines of evidence suggest that HIV itself may promote endothelial dysfunction [10,11]. Our data provide support for the concept that HIV, via systemic inflammation, may promote atherosclerosis independent of CART. For example, it is possible that salsalate may counteract the pro-stimulatory effects of HIV on nuclear factor-κB [12]. We did not find evidence in this small study that circulating inflammatory biomarkers were significantly affected by salsalate. It is possible that serum levels may not accurately reflect the activity of salicylates at the level of the endothelium, and therefore would not correlate with physiologic measures of endothelial function.
We found a surprisingly high rate of hepatocellular toxicity in this small trial. Although salicylates are well known to cause liver damage, this toxicity is considered uncommon, in the order of < 0.1% in the general population. This rate may be higher in those with pro-inflammatory conditions [13]. In a previous pilot study of choline magnesium salicylate for the treatment of lipodystrophy [14], one out of six subjects experienced transaminase elevations; similar to two of the subjects in our trial, this subject also had resolution with reduction in dosage.
This pilot study demonstrates that anti-inflammatory therapy has the potential to improve endothelial dysfunction in HIV-infected subjects not receiving CART. Future studies should evaluate either lower doses of salsalate or other anti-inflammatory agents with the goal of reducing cardiovascular events in this population.
Acknowledgements
This study was presented in part at the Ninth International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV; Sydney, Australia; 19-21 July 2007. This work was supported by NIH K23 HL073682 (to S.K.G.), an Indiana University Research Support Funds Grant (to S.K.G.), NIH R01 HL72711 (to M.P.D.), and the Indiana University General Clinical Research Center (NIH M01 RR00750).
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