Pharmacovigilance analysis of metabolic and nutritional adverse reactions associated with entecavir and tenofovir using the FDA adverse event reporting system database.

Abstract

Introduction: Entecavir and tenofovir are the first-line therapies for chronic hepatitis B. Although effective, long-term use may cause adverse drug reactions (ADRs), affecting the metabolic and nutritional systems. However, many such risks are not comprehensively reflected in the current drug labels.

Aim: This study aimed to systematically detect and validate metabolic and nutritional ADR signals associated with entecavir and tenofovir using the US FDA Adverse Event Reporting System (FAERS) database.

Method: The FAERS reports from Q1 2004 to Q3 2024 were extracted. Reports that listed entecavir (4820 cases) or tenofovir (76,452 cases) as the primary suspect drugs were screened for metabolic and nutritional ADRs coded by the Medical Dictionary for Regulatory Activities (MedDRA). Disproportionality analysis (reporting odds ratio [ROR], proportional reporting ratio [PRR]) and the Bayesian Confidence Propagation Neural Network (BCPNN) were applied. Positive signals were defined as fulfilling three criteria: ROR 95% CI lower bound > 1, PRR ≥ 2 with χ² ≥ 4, and IC025 > 0.

Results: Eight positive ADR signals were detected for entecavir, and the top five in descending order of the number of reports are: lactic acidosis [46 reports; ROR(95%CI) = 10.06(7.53-13.44)], metabolic acidosis [11 reports;ROR(95%CI) = 2.36(1.3-4.26)], hypophosphatemia [9 reports;ROR(95%CI) = 8.3(4.32-15.97)], cell death [5 reports;ROR(95%CI) = 16.58(6.89-39.9)], and hyperlactacidaemia [5 reports;ROR (95%CI) = 13.63(5.67-32.8)]. For tenofovir, 16 positive signals were identified, with vitamin D deficiency[1,149 reports;ROR(95%CI) = 27.7(26.03-29.48)], hypophosphatemia [270 reports;ROR(95%CI) = 7.88(6.98-8.9)], dyslipidaemia [72 reports; ROR(95%CI) = 2.85(2.26-3.6)], mitochondrial toxicity [66 reports; ROR(95%CI) = 17.68(13.73-22.76))],and fat redistribution [30 reports; ROR(95%CI) = 28.81(19.59-42.37)] being the most prominent. Most signals were not addressed in the existing labels.

Conclusion: Entecavir and tenofovir exhibit under-recognized risks of mitochondrial toxicity, electrolyte imbalance, and bone metabolism disorders. Routine monitoring of the serum phosphorus, vitamin D, and lactate levels is recommended. Drug labeling should be updated to include newly identified risks such as hypokalemic alkalosis and fat redistribution. Further research on mitochondrial mechanisms and gender-based differences is needed to optimize individualized therapy for chronic hepatitis B patients.