Post-marketing safety profile of bictegravir/emtricitabine/tenofovir alafenamide: a FAERS pharmacovigilance study with EudraVigilance validation and mechanistic investigation of pancreatitis.

backgroundBictegravir/Emtricitabine/Tenofovir alafenamide (BIC/FTC/TAF) has demonstrated strong efficacy and favorable tolerability as a first-line HIV treatment. However, there is a lack of long-term safety data from large-scale studies and real-world settings. This study aimed to evaluate the post-marketing safety of BIC/FTC/TAF using the FAERS database, with external validation in EudraVigilance, and to further explore the potential mechanisms underlying the pancreatitis signal.

methodsA retrospective pharmacovigilance analysis was conducted using data from FAERS from 2018 to 2025. deduplication, disproportionality analyses were performed using the reporting odds ratio and Bayesian confidence propagation neural network methods, with Bonferroni correction for multiple testing. Sex-stratified analyses, time-to-onset analyses, and sensitivity analyses were additionally performed. Key findings were externally validated using EudraVigilance. Because pancreatitis emerged as an unexpected and clinically important signal, logistic regression, network pharmacology, molecular docking, and transcriptomic validation were further applied to explore its potential biological basis.

resultsA total of 5,815 adverse drug (ADE) reports were identified in FAERS, Reports were more frequently submitted for male patients. Several identified positive ADEs were consistent with the drug label, such as weight increase (n = 526, ROR 10.32), headache (n = 239, ROR 1.56), immune reconstitution inflammatory syndrome (IRIS) (n = 113, ROR 76.26). Unexpected signals included "pancreatitis" (n = 51, ROR 4.37), "dysphagia" (n = 104, ROR 4.47), and "mental disorder (n = 33, ROR 3.3). Sex-stratified analyses showed more positive signals in males than in females, with differences in the signal spectrum between subgroups. Among 813 reports with valid time-to-onset data, most adverse events occurred within the first month, although approximately one-quarter were reported after 1 year. External validation in EudraVigilance identified 75 overlapping signals with FAERS, including weight increased, insomnia, dysphagia, diabetes mellitus, pancreatitis, and acute pancreatitis. Mechanistic analyses suggested that BIC/FTC/TAF-associated pancreatitis may involve inflammatory and metabolic pathways, particularly the PI3K-Akt signaling pathway, with hub targets including NFKB1, AKT1, STAT3, and MMP9.

conclusionThis study expands the post-marketing safety profile of BIC/FTC/TAF by identifying both recognized and potentially emerging adverse event signals in real-world pharmacovigilance data. Cross-database replication supported the robustness of several findings, particularly metabolic, psychiatric, renal, hepatobiliary, and pancreatic signals. Although these findings are hypothesis-generating rather than evidence of causality, they support continued clinical vigilance during both early and long-term BIC/FTC/TAF treatment, especially in patients with polypharmacy or metabolic vulnerability.