CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

percentage of median fluorescence intensity vs. control group (100%) and are expressed as media ± SEM. Statistical analysis was performed with one-way ANOVA and a Newman- Keuls post-hoc test, with significance *p<0.05 (vs. control) and + p<0.05 (vs. abacavir), n ≥ 4. Results: Clinical concentrations of abacavir (10 m mol/L, 24h) produced an increase in ICAM-1 expression on HUVEC (abacavir 10 m mol/L: 189.8 ± 18.3** vs. 100% control) and HUAEC (abacavir 10 m mol/L: 156.3 ± 6.1** vs. 100% control). When cells were pre-treated with P2X 7 receptor antagonists, this ICAM-1 overexpression was reverted on HUVEC [(oxATP 600 m mol/L: 121.9 ± 20.8 + vs. 100% control) or (A804598 1 m mol/L: 122.7 ± 10.4 ++ vs. 100% control)] or HUAEC [(oxATP 600 m mol/L: 104.1 ± 7.2 ++ vs. 100% control) or (A804598 1 m mol/L: 113.8 ± 3.9 ++ vs. 100% control)]. Conclusions: Our results suggest that the increased levels of ATP induced by abacavir and its interaction with its P2X 7 receptors promote overexpression of ICAM-1 in the venular and arterial endothelium. This process may be responsible for the leukocyte recruitment observed in the vascular damage associated with atherosclerosis and myocardial infarction in HIV patients treated with abacavir. Background: Abacavir has been linked with cardiovascular disease but the mechanism by which this may occur is unknown. Alterations in platelet function may be involved as the active anabolite of abacavir, carbovir triphosphate, affects intra-platelet guanylyl cyclase activity. This pilot study was performed to determine the impact of abacavir on known and novel markers of platelet function. Methods: An open label trial was performed in 20 HIV positive adult males on a stable non-abacavir containing regimen for more than 6 months with an undetectable HIV viral load. Patients taking antiplatelets, with known platelet disorders or who were at high cardiovascular risk (Framingham risk score >20%) were excluded. Abacavir (600mg once daily) was added to their usual antiretroviral regimen for 15 days. Blood samples were drawn at baseline, day 15 and day 43 (at completion of 28 day washout). Platelet function was assessed using the FACS-based phosphorylated vasodilator stimulated phosphoprotein (p-VASP) assay and through measurement of the expression and shedding of the pro- thrombotic platelet-specific collagen reception, glycoprotein VI (GPVI). Platelet surface GPVI (pGPVI) was assessed using a fluorescent, phycoerythrin (PE)-conjugated anti-GPVI monoclonal antibody (PE-1G5), plasma levels of shed soluble GPVI (sGPVI) by ELISA. Results: Participants were 90% Caucasian, mean age 42.2 years (range 29-62), median CD4+ T cell count 660 (IQR 576 – 863). 4 (20%) current smokers. Baseline median platelet count: 198 x 10 9 /L (IQR 177-224) with no change over the study period. There was a statistically significant decrease in p-VASP index from baseline to day 15 (median at baseline; 79.1 (95%CI 59.7 - 87.4) vs day 15; 32.6 (95%CI -2.15 - 50.8) p=0.01) which returned to baseline following the 28 day washout period (day 43; 76.3 (95% CI43.7 – 86.8, p=0.71). There was no statistically significant change between baseline and day 15 sGPVI (baseline; 72.5 ng/ml (95% CI 58.3 -81.5) vs Day 15; 45.0 ng/ml (95% CI 33.0 – 98.2) p=0.79) or pGPVI (baseline: 8.38 (95%CI 5.3 – 15.7) vs 7.8 (95%CI 5.7 – 9.7) p=0.81). These results were unaffected by baseline ART (9 on NNRTI, 9 Raltegravir, 6 Protease inhibitor). Conclusions: Abacavir administration was associated with alterations in the platelet cAMP/cGMP inhibitory pathway which were reversed by cessation and an appropriate washout period. These results require confirmation in a larger heterogeneous population and further work to determine the clinical implications. 737 An RCT of Rilpivirine vs Efavirenz on Cardiovascular Risk in Healthy Volunteers Samir K. Gupta 1 ; James E. Slaven 1 ; Ziyue Liu 1 1 Indiana University School of Medicine, Indianapolis, IN, US; 2 Indiana University, School of Medicine, Indianapolis, IN, US Background: Efavirenz (EFV) has recently been shown to impair endothelial function assessed as flow-mediated dilation (FMD), a measure which responds quickly to interventions, but whether this impairment represents an NNRTI class effect is unknown. In the first trial of its kind, we sought to compare endothelial function, metabolic, and inflammatory profiles between EFV and rilpivirine (RPV). The study included healthy volunteers to prevent confounding from HIV infection itself and to allow an evaluation of these drugs’ safety profiles as potential pre-exposure prophylaxis. Methods: We performed a prospective, randomized, open-label trial in 40 HIV-uninfected healthy volunteers who were randomized 1:1 to either EFV or RPV. Vascular indices [FMD, nitroglycerin-mediated dilation (NTGMD), hyperemic volume-time integral (VTI), FMD/VTI of the brachial artery]; metabolic parameters (lipid profiles, HOMA-IR); and inflammatory biomarkers (hsCRP, IL-6, and sVCAM-1) were measured before and after 4 weeks of treatment. Results: Women (63%) and Blacks (38%) were well-represented in the study cohort. Two participants from each study group discontinued prematurely for adverse events [EFV: 1 for rash, 1 for GI abnormalities; RPV: 1 for headache/insomnia, 1 for rash/drowsiness/vivid dreams]. There were no significant differences (all P>0.2) in 4-week mean (SD) changes in FMD between EFV and RPV [0.089 (3.7) vs 0.63 (2.4) %], NTGMD [0.42 (3.4) vs 1.59 (5.7) %], VTI [0.02 (0.3) vs 0.01 (0.3) cm], or FMD/VTI [-0.67 (5.6) vs 0.54 (5.6) %/cm]. There were also no significant differences in 4-week changes in hsCRP, IL-6, sVCAM, HDL-C, or triglycerides. However, EFV led to significant increases in total cholesterol [19.39 (23.9) vs -5.78 (16.5) mg/dL; P<0.001] and LDL-C [13.29 (19.5) vs -2.24 (13.4) mg/dL; P=0.009] and to non-significant decreases in HOMA-IR [-0.43 (1.5) vs 0.60 (1.6); P=0.056] compared to RPV. Both agents were generally well-tolerated without differences in adverse events. Conclusions: We did not detect any differential effects between RPV and EFV on endothelial function, other physiologic vascular indices, inflammatory biomarkers, or safety parameters over 4 weeks in healthy volunteers. However, EFV was associated with significantly greater increases in total cholesterol and LDL-C compared to RPV. These results suggest RPV has an inherently benign cardiovascular safety profile and may be a safe agent to use for PrEP, although longer-term studies are required for confirmation. 738 Elvitegravir Reduces Monocyte Activation and Vascular Inflammation More Than Efavirenz Corrilynn O. Hileman 1 ; Bruce Kinley 1 ;Valeska Scharen-Guivel 2 ; Kathy Melbourne 2 ; Javier Szwarcberg 2 ; Janet Robinson 1 ; Michael M Lederman 1 ; Grace A. McComsey 1 1 Case Western Reserve University, Cleveland, OH, US; 2 Gilead Sciences, Inc., Foster City, CA, US Background: Heightened inflammation and monocyte activation may drive cardiovascular disease and other comorbidities in HIV. Little is known about the differential effects of antiretrovirals on immune activation. Methods: A randomized, double blind trial in ART-naïve HIV-infected adults comparing safety and efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir (EVG/C/F/TDF) and efavirenz/emtricitabine/tenofovir (EFV/F/TDF) was previously performed. From a random sample of participants who achieved HIV-1 RNA of <50 copies/mL at week 48, we conducted a comparison of changes from baseline to week 24 and 48 in biomarkers of monocyte activation (sCD14 and sCD163), systemic (sTNF-RI, IL-6 and hsCRP) and vascular inflammation (Lp-PLA 2 ). Multivariable linear regression was used to determine predictors of change in sCD14 and Lp-PLA 2 . Results: 200 participants were included (100 per group). Baseline demographics and clinical indices were balanced and comparable to the overall population (n=700). Overall, 89%were men, 65% Caucasian, with median age 38 years, CD4 count 372 cells/mm 3 and HIV-1 RNA 64,900 copies/mL. At baseline, biomarkers were similar between groups. Significant differences favoring EVG/C/F/TDF were noted for changes in sCD14 and Lp-PLA 2 and neared significance for hsCRP (see Figure). Weight, lipid and CD4 changes were similar between groups. The 48 week changes in sCD14 and Lp-PLA 2 remained significantly different between groups after adjustment for changes in all clinically important 736 Changes in Platelet Function Following Abacavir Administration: A Pilot Study Janine M. Trevillyan 2 ; Elizabeth E. Gardiner 2 ; Jane F. Arthur 2 ; Jing Jing 2 ; Robert K. Andrews 2 ; Jennifer F. Hoy 2 1 Monash University, Melbourne, Australia; 2 Monash University, Melbourne, Australia

Poster Abstracts

453

CROI 2015