B/F/TAF is a three-drug coformulation that combines bictegravir, an integrase strand transfer inhibitor, with emtricitabine and tenofovir alafenamide, two antiretroviral agents that work through complementary mechanisms. The regimen is considered exceptionally potent, with a high genetic barrier to resistance and reduced renal and bone toxicity compared with older tenofovir formulations. However, as B/F/TAF has become a mainstay of antiretroviral therapy for people living with HIV across diverse populations, its long-term safety profile in real-world settings has remained incompletely characterized. The new study set out to address this gap by systematically mining post-marketing surveillance data accumulated since the drug’s approval.

The researchers extracted adverse event reports from the FAERS database covering the period from the first quarter of 2018 through the first quarter of 2025, including only those reports in which B/F/TAF was identified as the primary suspected drug. After applying the FDA’s official deduplication guidelines to remove duplicate records arising from quarterly data updates, the team retained 6,816 unique case reports encompassing 13,853 individual adverse events. All reported events were mapped to version 27.0 of the Medical Dictionary for Regulatory Activities, the standardized coding system used to classify adverse drug reactions across regulatory agencies worldwide.

To detect safety signals, the team employed four complementary disproportionality algorithms: the reporting odds ratio, the proportional reporting ratio with chi-square statistics, the Bayesian confidence propagation neural network, and the multi-item gamma Poisson shrinker. This combination of frequentist and Bayesian approaches enhances the robustness of signal detection, as each method calculates whether a particular drug-event pair is reported more frequently than would be expected by chance. A signal was considered valid only when specific statistical thresholds were met, such as the lower bound of the 95 percent confidence interval for the reporting odds ratio exceeding one, or the empirical Bayesian geometric mean exceeding two.

The analysis revealed that the highest number of reports fell under the category of injury, poisoning and procedural complications, with 1,792 cases, followed by general disorders and administration site conditions with 1,726 cases, and investigations with 1,499 cases. Only two system organ classes met all four disproportionality criteria simultaneously: congenital, familial and genetic disorders, and pregnancy, puerperium and perinatal conditions. At the level of individual preferred terms, the most frequently reported events were weight increase with 408 cases, product dose omission with 242 cases, and maternal exposure during pregnancy with 202 cases. The strongest signals by reporting odds ratio were viral load increased at 160.14, CD4 lymphocytes decreased at 124.60, and immune reconstitution inflammatory syndrome at 88.12.

Notably, the researchers emphasized that several of the strongest signals likely reflect treatment response rather than drug toxicity. Viral load increased and CD4 lymphocytes decreased are routine monitoring parameters in HIV care, and their high reporting odds ratios likely arise because clinicians report these values when treatment targets are not met, rather than because B/F/TAF directly causes virologic or immunologic deterioration. Similarly, immune reconstitution inflammatory syndrome represents a pathology of immune recovery following viral suppression, in which the reconstituted immune system mounts inflammatory responses against opportunistic pathogens. The team stressed that these pharmacovigilance signals should be distinguished from confirmed adverse drug reactions and interpreted as hypothesis-generating rather than causal.

The metabolic signals identified in the analysis corroborate growing concerns regarding integrase strand transfer inhibitor-associated complications. Weight increase and diabetes mellitus both generated robust signals, consistent with a recent META-INSTI analysis of FAERS data that reported elevated reporting odds ratios for hyperglycemia, new-onset diabetes, and weight gain with bictegravir. However, long-term phase 3 trial data and real-world cohort studies suggest that weight gain is most pronounced in the first year of treatment and in individuals with more advanced HIV disease at baseline, supporting a return-to-health hypothesis rather than a purely drug-driven effect. The renal signal represented by blood creatinine increased reflects the known renal tubular effect of tenofovir alafenamide without necessarily indicating glomerular injury, consistent with the established renal safety profile of this prodrug formulation.

Pregnancy-related signals emerged as particularly noteworthy in the analysis. Maternal exposure during pregnancy, foetal exposure during pregnancy, and spontaneous abortion all demonstrated robust signal generation, and the pregnancy and congenital disorder system organ classes were the only two to meet all four disproportionality criteria. The researchers noted that preliminary pharmacokinetic data support once-daily B/F/TAF without dose adjustment during pregnancy, and available pregnancy outcome data have not shown congenital malformations above the background rate. The spontaneous abortion signal warrants attention but must be interpreted in context, as it may reflect reporting of drug exposure during pregnancy rather than a causal association with pregnancy loss. The team called for continued vigilance and robust pregnancy registries to better characterize the reproductive safety profile of the regimen.

The analysis of time-to-onset data revealed that adverse signals cluster early in treatment but also emerge late. Among 2,064 reports with documented onset times, representing 30.28 percent of all case reports, the median time to onset was 60 days. The first month of therapy alone accounted for 37.94 percent of all reported events, followed by 12.45 percent in the second month and 7.27 percent in the third month. This early clustering underscores the first 90 days of therapy as a critical window for intensified safety monitoring. Importantly, 17.49 percent of events were reported after one year of treatment, challenging the assumption that safety surveillance can be relaxed after the initial phase. Long-term vigilance should focus on metabolic and cardiovascular risks requiring periodic glucose, lipid, and risk-score monitoring, as well as hepatobiliary events that may occur at varying times after initiation or withdrawal.

The researchers acknowledged several limitations inherent to FAERS-based analyses. Confounding by indication, concomitant medications, prior regimen switches, and the higher baseline prevalence of comorbidities among people living with HIV may all influence reported outcomes. Reporting bias may preferentially capture more clinically significant or novel events, and the absence of a comparator group precludes determination of whether observed signals are specific to B/F/TAF or reflect class effects of integrase inhibitors. Additionally, valid onset dates were available in only 30.28 percent of reports, potentially introducing selection bias into the time-to-onset analysis. Despite these constraints, the study provides a comprehensive real-world safety assessment of one of the most widely used antiretroviral regimens globally, reinforcing the necessity of longitudinal pharmacovigilance as B/F/TAF continues to serve an increasingly diverse and aging population of people living with HIV.

Subject of Research: A real-world pharmacovigilance study of FDA adverse event reporting system events for bictegravir/emtricitabine/tenofovir alafenamide

Article Title: A real-world pharmacovigilance study of FDA adverse event reporting system events for bictegravir/emtricitabine/tenofovir alafenamide

Article References: Liu, Y., Zhang, L., Li, X., & Zhao, H. (2026). A real-world pharmacovigilance study of FDA adverse event reporting system events for bictegravir/emtricitabine/tenofovir alafenamide. Frontiers in Pharmacology, 17, Article 1945154. https://doi.org/10.3389/fphar.2026.1945154

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.1945154

Keywords: real-world, pharmacovigilance, adverse, event, reporting, system, events, bictegravir, emtricitabine, tenofovir, alafenamide, scientific research