EACS2023: 616 Bictegravir and dolutegravir influence leukocytes and/or platelets in a way that promotes a proinflammatory milieu which favors cardiovascular toxicity J.V. Esplugues , V. Collado-Díaz , S. Fernández-Rodríguez , A. Blas-García , Á. Álvarez University of Valencia, Department of Pharmacology, Valencia, Spain, CIBERehd (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas), Valencia, Spain, FISABIO (Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana), Valencia, Spain, University of Valencia, Department of Physiology, Valencia, Spain General data Abstract category: Antiretroviral drugs preclinical Abstract body Purpose: Recent studies have associated integrase strand transfer inhibitors (INSTIs) with an increased risk of cardiovascular diseases, but the underlying mechanisms are unclear. Activation of leukocytes and platelets–which enables both cell types to interact with the endothelium –can lead to thrombi formation and other vascular disorders. This study evaluates how leukocytes and platelets are influenced by three of the most widely employed INSTIs [dolutegravir (DTG), bictegravir (BIC), raltegravir (RAL)], and compares their actions with those of a NRTI (abacavir; ABC) known to produce CV toxicity and a NNRTI (doravirine, DOR), both of which were used as controls. Method: Human blood from healthy donors (n≥5) was incubated (4h) with clinically relevant concentrations (µM) of DTG (10, 20), BIC (10, 15, 20), RAL (5, 10), DOR (2.5, 5) or ABC (20). Neutrophil activation was analyzed (flow cytometry) by quantifying the expression of the two subunits of the integrin Mac-1 (CD11b/CD18) responsible for the interaction of neutrophils with the endothelium and platelets. Platelet activation was assessed by measuring P-selectin expression (responsible for their interaction with the endothelium) in platelet-rich plasma (PRP) treated (15min) with the same concentrations of the drugs, in the presence or absence of the positive stimulus ADP (40µM,5min). Results: BIC, but not DTG, RAL or DOR, induced a significant dose-dependent increase of both CD11b and CD18 in neutrophils ( table 1) that exceeded the increase induced by ABC. In addition, and despite not inducing the expression of P-selectin in platelets, 20µM of BIC or DTG (112.4±1.9% and 116.6±2.1% vs. ADP: 100%, p<0.01; respectively) potentiated ADP-induced P-selectin expression. Table 1. Expression of leukocyte adhesion molecule subunits CD11b and CD18 in neutrophils Drug μM CD11b CD18 DTG 10 110.9 ± 7.8 105.5 ± 6.7 DTG 20 105 ± 6.7 101.4 ± 4.7 BIC 10 107.7 ± 9.1 105.2 ± 8.4 BIC 15 158.4 ± 25.1* 119.4 ± 9.4* BIC 20 179.2 ± 12.7*** 140.2 ± 6.9*** RAL 5 105.1 ± 9.5 107.4 ± 12.4 RAL 10 98.6 ± 7.4 87.5 ± 6.2 DOR 2.5 103.3 ± 17.1 94.3 ± 12.0 DOR 5 82.8 ± 5.3 95.5 ± 8.0 ABC 20 125.9 ± 6.2* 117.4 ± 12.0 Whole blood from healthy donors was incubated with the various compounds and thereafter treated with antibodies against CD11b or CD18 conjugated with phycoerythrin (PE) and fluorescein isothiocyanate (FITC), respectively. Results are expressed as mean ± SEM of the percentage of CD11b or CD18 median fluorescence intensity compared with vehicle (100%). n≥5. *p<0.05, ***p<0.001 vs corresponding value in vehicle-treated group, One-way ANOVA followed by post hoc Tukey´s test. Conclusions: There are differences in the actions of the INSTIs evaluated: BIC influences the activation of leukocytes, whereas both BIC and DTG potentiate that of platelets. Both actions are implicated in the development of a vascular inflammatory environment, which in turn favors thrombi formation. General conditions 1. I confirm that I previewed this abstract and that all information is correct. I accept that the content of this abstract cannot be modified or corrected after the submission deadline and I am aware that it will be published exactly as submitted.: Yes 2. I confirm that the submission of the abstract constitutes my consent to publication (e.g. conference website, programmes, other promotions, etc.). : Yes 3. I herewith confirm that the contact details saved in this system are those of the corresponding author, who will be notified about the status of the abstract. The corresponding author is responsible for informing the other authors about the status of the abstract.: Yes 4. I agree that all data provided may be used (saved, stored, processed, transmitted and deleted) in compliance with the privacy policy to provide the services described.: Yes 1,2,3 1 1 2,3,4 1,2 1 2 3 4 79
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