EACS2023: 496 Bictegravir alters glucose tolerance and metabolism L. Gisbert-Ferrándiz , P. García-Martínez , Á. Álvarez , J.V. Esplugues , A. Blas-García Universitat de València, Farmacología, 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, Universitat de València, Fisiología, Valencia, Spain General data Abstract category: Antiretroviral drugs preclinical Abstract body Purpose: Metabolic alterations and/or a higher risk of insulin resistance have been reported in patients receiving combined antiretroviral therapy containing Integrase Strand Transfer Inhibitors (INSTIs) and/or tenofovir alafenamide (TAF). This study evaluates the individual impact of these drugs on key aspects of glucose metabolism. Method: Dolutegravir (DTG, 10mg/kg), bictegravir (BIC, 10mg/kg), tenofovir disoproxil fumarate (TDF, 50mg/kg), TAF (5mg/kg), lamivudine (3TC, 60mg/kg) or vehicle were orally administered to C57BL/6J mice for 16 weeks as monotherapy. Doses were calculated by allometric scaling and were equivalent to those used in patients. Glucose tolerance tests (GTT) were performed after finalizing treatment, and the area under the curve (AUC) of mean glucose curves compared. The human hepatoma cell line Hep3B was treated with clinically relevant concentrations of drugs to evaluate glucose uptake (2-NBDG Assay) and gene expression of key enzymes involved in glucose metabolism and homeostasis (RT-qPCR). One-way ANOVA was used for statistical analysis (n≥5). Results: No differences in fasting glucose concentrations were observed following the in vivo treatments. However, mice treated with BIC exhibited higher glucose levels and a slower decrease of glucose during GTT than those treated with vehicle or other drugs (AUC =20857±2957 versus AUC =16538±2877, AUC =16791±1433, AUC =15185±2463, AUC =15488±1815, AUC =17475±2494 min.mg/dL; p=0,001). Likewise, BIC (1,10,20mM) concentration-dependently decreased glucose uptake in hepatocytes, both in basal conditions (-21±1.6%, p=0.0204; -25±6.5%, p=0.0113; -48±4.6% p<0.0001, respectively) and post-insulin stimulation (-5±4.1%, p=0.7390; -18±3.7%, p=0.0390; -33±5.0%, p=0.0015, respectively). Furthermore, mRNA expression in human Hep3B cells incubated 48h with BIC revealed significant alterations in enzymes implicated in glucose synthesis ( G6PC1), glycolysis ( GKC), or glycogen storage ( GYS2). Conclusions: Chronic administration of BIC impairs glucose tolerance in mice and affects glucose metabolism in human hepatocytes in vitro compared to other antiretroviral drugs. These results support clinical reports associating BIC with changes in glucose metabolism. 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 1 1,2 1,2,3 4,2,3 1 2 3 4 BIC veh 3TC DTG TDF TAF 78 19TH EUROPEAN AIDS CONFERENCE | WARSAW 2023
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