Ziyue Liu

Effects of switching from efavirenz to raltegravir on endothelial function, bone mineral metabolism, inflammation, and renal function: a randomized, controlled trial.

Abstract:We performed a randomized controlled trial in 30 HIV-infected participants to either continue tenofovir/emtricitabine/efavirenz (Continuation Group) or switch to tenofovir/emtricitabine/raltegravir (Switch Group) for 24 weeks. There were no significant differences in the changes in flow-mediated dilation, 25(OH) vitamin D, or parathyroid hormone levels. Total cholesterol, high sensitivity C-reactive protein, serum alkaline phosphatase, sCD14 levels, and renal function significantly declined in the Switch Group compared with the Continuation Group; however, sCD163 levels significantly increased in the Switch Group. These findings suggest that raltegravir is not inherently more beneficial to endothelial function compared with efavirenz but may impact renal function and monocyte activation.

Transfer of Intracellular HIV Nef to Endothelium Causes Endothelial Dysfunction

With effective antiretroviral therapy (ART), cardiovascular diseases (CVD) are emerging as a major cause of morbidity and death in the aging HIV-infected population. To address whether HIV-Nef, a viral protein produced in infected cells even when virus production is halted by ART, can lead to endothelial activation and dysfunction, we tested Nef protein transfer to and activity in endothelial cells. We demonstrated that Nef is essential for major endothelial cell activating effects of HIV-infected Jurkat cells when in direct contact with the endothelium. In addition, we found that Nef protein in endothelial cells is sufficient to cause apoptosis, ROS generation and release of monocyte attractant protein-1 (MCP-1). The Nef protein-dependent endothelial activating effects can be best explained by our observation that Nef protein rapidly transfers from either HIV-infected or Nef-transfected Jurkat cells to endothelial cells between these two cell types. These results are of in vivo relevance as we demonstrated that Nef protein induces GFP transfer from T cells to endothelium in CD4.Nef.GFP transgenic mice and Nef is present in chimeric SIV-infected macaques. Analyzing the signal transduction effects of Nef in endothelial cells, we found that Nef-induced apoptosis is mediated through ROS-dependent mechanisms, while MCP-1 production is NF-kB dependent. Together, these data indicate that inhibition of Nef-associated pathways may be promising new therapeutic targets for reducing the risk for cardiovascular disease in the HIV-infected population.

Pentoxifylline, Inflammation, and Endothelial Function in HIV-Infected Persons: A Randomized, Placebo-Controlled Trial

Background Untreated HIV may increase the risk of cardiovascular events. Our preliminary in vitro and in vivo research suggests that pentoxifylline (PTX) reduces vascular inflammation and improves endothelial function in HIV-infected persons not requiring antiretroviral therapy. Methods We performed a randomized, placebo-controlled trial of PTX 400 mg orally thrice daily for 8 weeks in 26 participants. The primary endpoint was change in flow-mediated dilation (FMD) of the brachial artery after 8 weeks. Nitroglycerin-mediated dilation (NTGMD) and circulating markers of inflammation, cellular immune activation, coagulation, and metabolism were also assessed. Results The difference in mean absolute change (SD) in FMD after 8 weeks between the placebo [−1.06 (1.45)%] and PTX [−1.93 (3.03)%] groups was not significant (Pu200a=u200a0.44). No differences in NTGMD were observed. The only significant between-group difference in the changes in biomarkers from baseline to week 8 was in soluble tumor necrosis factor receptor-1 (sTNFRI) [−83.2 pg/mL in the placebo group vs. +65.9 pg/mL in the PTX group; Pu200a=u200a0.03]. PTX was generally well-tolerated. Conclusions PTX did not improve endothelial function and unexpectedly increased the inflammatory biomarker sTNFRI in HIV-infected participants not requiring antiretroviral therapy. Additional interventional research is needed to reduce inflammation and cardiovascular risk in this population. Trial Registration ClinicalTrials.gov NCT00796822

Elevated phospholipase A2 activities in plasma samples from multiple cancers.

Only in recent years have phospholipase A2 enzymes (PLA2s) emerged as cancer targets. In this work, we report the first detection of elevated PLA2 activities in plasma from patients with colorectal, lung, pancreatic, and bladder cancers as compared to healthy controls. Independent sets of clinical plasma samples were obtained from two different sites. The first set was from patients with colorectal cancer (CRC; nu200a=u200a38) and healthy controls (nu200a=u200a77). The second set was from patients with lung (nu200a=u200a95), bladder (nu200a=u200a31), or pancreatic cancers (nu200a=u200a38), and healthy controls (nu200a=u200a79). PLA2 activities were analyzed by a validated quantitative fluorescent assay method and subtype PLA2 activities were defined in the presence of selective inhibitors. The natural PLA2 activity, as well as each subtype of PLA2 activity was elevated in each cancer group as compared to healthy controls. PLA2 activities were increased in late stage vs. early stage cases in CRC. PLA2 activities were not influenced by sex, smoking, alcohol consumption, or body-mass index (BMI). Samples from the two independent sites confirmed the results. Plasma PLA2 activities had approximately 70% specificity and sensitivity to detect cancer. The marker and targeting values of PLA2 activity have been suggested.

A randomized, controlled trial of the effect of rilpivirine versus efavirenz on cardiovascular risk in healthy volunteers

OBJECTIVESnThe HIV NNRTI rilpivirine is being evaluated as a possible agent for HIV pre-exposure prophylaxis. We have recently shown that the NNRTI efavirenz may impair endothelial function assessed as flow-mediated dilation (FMD), but whether this impairment is also found with rilpivirine is unknown. We sought to compare cardiovascular risk profiles between efavirenz and rilpivirine in healthy volunteers.nnnMETHODSnWe performed a prospective, randomized, open-label trial in 40 HIV-uninfected healthy volunteers who were randomized 1: 1 to either efavirenz or rilpivirine. Vascular indices, metabolic parameters, inflammatory biomarkers and oxidative stress were measured before and after 4 weeks of treatment. This study is registered at ClinicalTrials.gov (NCT01585038).nnnRESULTSnThere were no significant differences in 4 week mean (SD) changes in FMD between efavirenz and rilpivirine [0.089 (3.65)% versus 0.63 (2.42)%; P = 0.77]. There were also no significant differences in 4 week changes in high-sensitivity C-reactive protein, IL-6, soluble vascular cell adhesion molecule-1, HDL-cholesterol, triglycerides or homeostasis model assessment-insulin resistance. However, efavirenz led to significant increases in total cholesterol [19.39 (23.9) versus -5.78 (16.5) mg/dL; P < 0.001], LDL-cholesterol [13.29 (19.5) versus -2.24 (13.4) mg/dL; P = 0.009] and F2-isoprostanes [92.7 (178.6) versus -101.4 (215.7) pg/mL; P = 0.019] compared with rilpivirine. Two participants from each study group discontinued prematurely for adverse events.nnnCONCLUSIONSnThere were no significant differences in the changes in endothelial function over 1 month between the efavirenz and rilpivirine groups, although efavirenz had worse lipid changes compared with rilpivirine. Longer-term studies are required for confirmation.

Endothelial, inflammatory, coagulation, metabolic effects and safety of etravirine in HIV-uninfected volunteers.

The innate proatherosclerotic properties of non-nucleoside reverse transcriptase inhibitors have not previously been examined. Therefore, we performed a pilot study of etravirine (ETR) in healthy volunteers over 28 days. This investigation also allowed us to evaluate the safety of ETR over a period commonly used for HIV postexposure prophylaxis. ETR 200 mg twice daily was given to 28 healthy HIV-uninfected volunteers over 28 days. Flow-mediated dilation (FMD) of the brachial artery and circulating markers of inflammation, coagulation, and metabolism were measured at entry and at day 28. These circulating markers were also measured at day 35. Of the initial 28 subjects, 23 completed both entry and day 28 procedures. Two subjects were discontinued due to development of rash. No other major toxicities developed. The change in FMD over 28 days was minimal and not significant (0.03 [-3.21, 0.97] %; p=0.36). The post hoc estimated detectable absolute change in FMD with the 23 subjects in our study was 2.26%, which is an effect size that has been associated with future cardiovascular event rates in the general population; thus our study had sufficient power to find clinically relevant changes in FMD. In addition, there were no significant changes in any of the circulating markers from entry to day 28 or from day 28 to day 35. ETR did not demonstrate any innate proatherosclerotic properties over 28 days in these HIV-uninfected volunteers. ETR was generally well tolerated. Larger studies are warranted to confirm that ETR can be used safely as part of HIV postexposure prophylaxis regimens.

A pilot trial of pentoxifylline on endothelial function and inflammation in HIV-infected patients initiating antiretroviral therapy.

In a single-arm, open-label, eight week, pilot study, we reported that pentoxifylline (PTX) reduced circulating levels of interferon-γ-induced protein 10 (IP-10) and soluble vascular cell adhesion molecule-1 (sVCAM-1) and improved endothelial function (measured as flowmediated dilation (FMD) of the brachial artery) in HIV-infected patients not receiving ART [4]. However, in a randomized, placebo-controlled trial of PTX in a similarly untreated population, we did not confirm that PTX reduced inflammation or improved endothelial function [5]. In fact, PTX unexpectedly led to significantly increased circulating soluble tumor necrosis factor-1 (sTNFR1) levels compared to placebo in this trial. However, the potential effects of PTX on FMD and inflammation in a population initiating ART are unknown. Thus, we conducted a randomized, placebo-controlled, single-center pilot trial of PTX 400mg thrice daily given for 48 weeks in patients concurrently initiating ART (ClinicalTrials.gov NCT00864916).

Differences in Circulating Endothelial Progenitor Cells among Childhood Cancer Survivors Treated with and without Radiation.

Radiation during childhood cancer treatment increases the propensity to atherosclerotic cardiovascular disease among adult survivors of childhood cancer. This is thought to be mediated through the damage to the underlying vascular endothelium. Endothelial progenitor cells (EPCs) involved in vascular endothelial repair after its damage may be affected by radiation therapy but have never been investigated in adult survivors of childhood cancer. In this pilot study, utilizing multi-parametric flowcytometry, endothelial colony forming cells (ECFCs), which are the bonafide EPCs, and circulating endothelial cells (CECs), which are not EPCs, were compared between adult survivors of childhood cancer with or without radiation exposure. In addition, their associations with blood-pressure, physical activity and diet were examined. Survivors who received radiotherapy had lower ECFCs and CECs (p<0.05) compared to those without it. Significant positive correlations included physical activity with ECFCs and diet with CECs, while blood-pressure negatively correlated with ECFCs. Further evaluation is needed to examine the effect of radiation and modifiable risk factors on ECFCs and CECs. The preliminary findings from this study suggest evidence of the role of ECFCs as biomarkers of vascular injury following treatment for childhood cancer that may help in early identification of survivors at risk for cardiovascular disease.

Brief report: Endothelial colony-forming cells and inflammatory monocytes in HIV.

Abstract:The relationships between HIV infection, monocyte activation, and endothelial colony-forming cells (ECFCs) are unknown. We compared ECFC, intermediate monocytes (CD14+ CD16+), and nonclassical monocytes (CD14dim CD16++) levels in HIV-infected participants virologically suppressed on antiretroviral therapy, HIV-infected treatment-naive participants, and HIV-uninfected healthy controls. ECFC levels were significantly higher in the HIV-infected virologically suppressed group compared with the uninfected controls. CD14+ CD16+ percentages (but not CD14dim CD16++ cells) were significantly higher in both HIV-infected groups vs. uninfected controls. In the HIV-infected groups, ECFCs and CD14+ CD16+ intermediate monocytes were significantly and inversely correlated. Lower availability of ECFCs may partly explain the relationship between greater intermediate monocytes and atherosclerosis in HIV.

Immune reconstitution in ART treated, but not untreated HIV infection, is associated with abnormal beta cell function

HIV infection has been associated with increased diabetes risk, but prior work has mostly focused on insulin resistance, as opposed to beta cell effects, or included patients on antiretroviral therapies (ART) directly linked to metabolic toxicity. In this analysis, we measured markers of glucose homeostasis and beta cell function, stress, and death in fasting sera from a cross section of HIV+ individuals off ART (n = 43), HIV+ individuals on ART (n = 23), and HIV- controls (n = 39). Markers included glucose, HOMA%S, HOMA%B, proinsulin:C-peptide ratio (PI:C ratio), and circulating preproinsulin (INS) DNA. We performed multiple linear regressions with adjustments for age, sex, race, BMI, and smoking status. Compared to HIV- controls, HIV+ participants off ART exhibited similar beta cell function and insulin sensitivity, without increases in markers of beta cell stress or death. Specifically, in HIV+ participants with CD4 counts <350 cells/μL, PI:C ratios were lower than in HIV- controls (p<0.01), suggesting a reduction in intrinsic beta cell stress among this group. By contrast, HIV+ participants on ART had higher fasting glucose (p<0.0001) and lower HOMA%B (p<0.001) compared to HIV- controls. Among the entire HIV+ population, higher HIV RNA correlated with lower fasting glucose (r = -0.57, p<0.001), higher HOMA%B (r = 0.40, p = 0.001), and lower PI:C ratios (r = -0.42, p<0.001), whereas higher CD4 counts correlated with higher PI:C ratios (r = 0.2, p = 0.00499). Our results suggest that HIV seropositivity in the absence of ART does not worsen beta cell function or glucose homeostasis, but immune reconstitution with ART may be associated with worsened beta cell function.