CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

Poster and Themed Discussion Abstracts

609

PROTHROMBOTIC EFFECTS OF ABACAVIR IN AN IN VIVO MODEL Isabel Andujar 1 , Victor Collado-Diaz 2 , Samuel Orden 1 , Ainhoa Sanchez-Lopez 2 , Maria Angeles Martinez-Cuesta 2 , Angeles Alvarez 2 , Juan V. Esplugues 2 1 FISABIO, Valencia, Spain, 2 Univ of Valencia, Valencia, Spain Background: The controversy surrounding the association between Abacavir (ABC) and cardiovascular disease is fuelled by the lack of a convincing mechanism of action. ABC shares structural similarities with endogenous purines; i.e. ATP or ADP, signalling molecules capable of triggering prothrombotic/proinflammatory programmes. We

have previously reported that ABC induces platelet-leukocyte-endothelial cell interactions through a mechanism involving interference with the purinergic system, specifically ATP-P2X7 receptors. The present study expands these concepts and assesses whether clinically relevant concentrations of ABC generate a pro- thrombotic environment in a validated animal model of thrombosis. Methods: Male wild-type C57BL/6 and P2X7 homozygous knock-out mice (B6.129P2-P2rx7tm1Gab/J) were pretreated with ABC or TDF (2.5–7.5 µg/ mL and 0.3 µg/mL intrascrotally 4h), or rofecoxib (0.1 mg/kg, i.p. 2h). In some cases mice were pre-treated (30 min) with ATP-P2X7 (A804598) or ATP-P2X2/3 (A317491) receptor antagonists. Arteries of the cremaster muscle were visualized with an intravascular microscope and their blood flow analyzed with a Doppler velocimeter. The endothelium-damaging agent Ferric chloride was superfused at a concentration (25 mM), which does not itself modify blood flow, but predisposes arterioles to thrombosis when additional vascular deleterious agents are present. Images were recorded until blood flow ceased, or for 8 min if no vessel occlusion occurred. Results: ABC treatment did not affect blood flow in the absence of ferric chloride. However, treatment with ABC significantly accelerated vessel occlusion in a dose-dependent manner after superfusion of ferric chloride (Figure 1). Selective blockade of P2X7 receptors, but not of other purinergic receptors, reverted the pro-thrombotic effect of ABC. The pro-thrombotic effect of ABC was non-existent in P2rx7 KO mice. TDF had no effect, whereas inhibition of COX-2 with rofecoxib induced a level of thrombosis similar to that produced by the highest dose of ABC evaluated. Conclusion: Exposure to ABC dose-dependently increases thrombus formation in vivo through interference with ATP-P2X7 receptors. These results suggest that ABC induces a pro-inflammatory vascular environment.

610 A SWITCH TO RALTEGRAVIR DOES NOT LOWER PLATELET REACTIVITY IN HIV-INFECTED ADULTS Wouter A. van der Heijden , Marjolein Bosch, Reinout van Crevel, Monique Keuter, André van der Ven, Quirijn de Mast Radboud Univ Med Cntr, Nijmegen, Netherlands

Background: HIV infection is associated with platelet hyperreactivity and increased platelet-monocyte aggregation (PMA), which may contribute to the excess cardiovascular risk. In a cross-sectional study we recently showed that individuals using a raltegravir-based regimen have reduced platelet reactivity and PMA compared to other antiretroviral regimens. The aim of this study was to investigate whether switching a non-nucleoside reverse transcriptase inhibitor (NNRTI)- or protease inhibitor (PI)-based regimen to a raltegravir-based regimen reduces platelet reactivity and/or PMA. Methods: This study was designed as an investigator initiated, single-center, prospective randomized, open-label, blinded endpoint (PROBE) trial. We enrolled 40 adult HIV- infected individuals with undetectable (<40 copies/mL) viral load receiving a standard backbone of two NRTI’s (either TDF/FTC or ABC/3TC) with either a NNRTI (EFV or RPV) or a boosted PI (DRV/r, ATZ/r or LPV/r). Participants were randomized (1:1) to continue the same ART regimen or to switch to raltegravir during 3 months. The primary outcome was the change (Δ) in platelet reactivity at 3 months. This was determined using a flow-cytometry based assay by measuring platelet expression of the platelet granule protein P-selectin

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