Efficacy and Safety of Tenofovir plus Entecavir Combination Therapy versus Tenofovir Monotherapy in Chronic HBV Patients with Resistance or Partial Response to Entecavir: A Systematic Review and Meta-Analysis

Abstract

Background and Objectives
Chronic Hepatitis B Virus (HBV) remains a significant cause of liver disease in the developing world, leading to sequelae such as hepatocellular carcinoma. While ETV (Entecavir) serves as a first-line treatment, its growing resistance rates underscore the need to explore viable alternatives. Tenofovir disoproxil fumarate (TDF) monotherapy and entecavir plus tenofovir (TDF+ETV) combination therapy are both employed as treatments, but one’s efficacy over another is in question. This meta-analysis aims to investigate any primacy of either treatment.

Methods
We conducted a comprehensive literature search across PubMed/Medline, Embase, Cochrane Central, Web of Science, and CNKI from inception till 7th October 2024. Studies comparing the safety and efficacy of TDF monotherapy versus TDF+ETV combination therapy in patients resistant to entecavir were considered. Data about the virologic response (VR), virologic breakthrough, HbeAg seroconversion, HbeAg/HbsAg seroclearance, and ALT normalisation were extracted. Relative Risks (RR) and their corresponding 95% Confidence Intervals (CIs) were calculated, pooled, and analysed in a random-effects model. P-value < 0.05 was regarded as significant for all analyses.

Results
9 studies, comprising 335 patients undergoing monotherapy and 352 patients undergoing combination therapy, satisfied the criteria. TDF+ETV combination therapy was found slightly advantageous to TDF monotherapy stimulating a VR at 48 weeks (RR 1.081 95% CI [1.001-1.167] p=0.046, I2= 0%), along with the HbeAg seroconversion rate (RR 1.711 95% CI [1.005-2.913] p=0.048, I2= 0%). There were no significant adverse events in individual studies to warrant a meta- analysis.

Conclusions
TDF+ETV shows slightly better efficacy to TDF monotherapy over a 48-week treatment regimen, with minimal safety concerns. However, further high-quality studies like randomised controlled trials are needed to further solidify conclusions, with this meta-analysis only achieving borderline significances.

Registration
This review is registered on the PROSPERO database (ID: CRD42024581443)