Among the Indiana cohort on ART there was a negative correlation between LPS and brachial FMD (r=?0.33, p=0.02) but no correlation with sCD14 (Table 2). After limiting the analysis to only those Indiana subjects with undetectable viral load (N=38) a similar, significant inverse correlation between LPS and endothelial function not was observed (r=?0.36, p=0.03), but there was no significant relationship between FMD and sCD14. Table 2 Pearson Correlation Coefficients of Markers of Microbial Translocation with Brachial Artery Flow- Mediated Dilation. When controlling for gender, baseline brachial artery diameter, heart rate, systolic blood pressure and ART use, LPS remained an independent predictor of FMD in those Indiana subjects on ART (p=0.02).

There was a progressive step-wise decrease in median % FMD across increasing tertiles of LPS levels (Figure 1) which was statistically significant (p=0.037 by ANOVA). In the highest tertile of LPS levels (median 44.6 pg/ml [IQR 38.4, 62.8]), FMD was markedly impaired (median 2.76%). Figure 1 Median % flow mediated dilation by tertile of plasma lipopolysaccharide levels among ART treated subjects in the IU study. Discussion In subjects on prolonged ART (mean of 40 months) we observed a statistically significant negative correlation between LPS levels and FMD, suggesting that increased microbial translocation is associated with endothelial dysfunction in chronically ART-treated subjects. A significant relationship between LPS levels and FMD was not seen in those individuals not on ART or in those on short-term (24 weeks) ART.

Soluble CD14 levels were not significantly correlated with FMD in any analyses. However, LPS is directly involved in the causal pathway of endothelial dysfunction [16], [17] and thus may be a superior marker for this effect than a marker of monocyte activation such as sCD14 which does not directly activate endothelial cells. We speculate that the effect of LPS on endothelial function was seen only among those on longer term ART because it may require a longer duration of ART for the effects of persistent microbial translocation to be detected without the influence of other HIV-related disease complications and their associated inflammation. Further studies will need to be completed in order to make any definitive conclusions. LPS levels did not decrease and unexpectedly increased after 24 weeks of ART in the ACTG subjects, which may be an insufficient duration of treatment to detect reduced microbial translocation as was reported by Brenchley [14] who studied subjects after 48 weeks of ART. Most [20], [21], [22], [23], but not all [24], [25], studies have shown that microbial translocation Entinostat is greater with more advanced HIV infection.