Efficacy and safety of Tenofovir disoproxil fumarate (TDF) or Entecavir (ETV) combined with interferon for the treatment of chronic hepatitis B: a systematic review and meta-analysis.

BACKGROUND

Whether tenofovir disoproxil fumarate (TDF) or entecavir (ETV) combined with pegylated interferon offers superior functional cure potential in chronic hepatitis B remains unclear.

OBJECTIVE

To compare the efficacy and safety of TDF plus interferon versus ETV plus interferon against their respective monotherapies.

METHODS

Systematic review and meta-analysis of 16 randomized controlled trials from six databases (inception to January 2026).

INTERVENTIONS: TDF (300 mg/day) or ETV (0.5 mg/day) plus pegylated interferon alfa-2a/2b (180 µg/week) versus monotherapy.

PRIMARY OUTCOMES: HBsAg reduction and HBeAg seroconversion. Risk of bias: Cochrane RoB 2; Certainty: GRADE.

PROSPERO: CRD42025632412.

RESULTS

2,575 patients were included. TDF plus interferon achieved markedly superior HBsAg reduction versus TDF monotherapy (OR 5.16, 95% CI 2.71-9.84; ARD 4.9%, 95% CI 2.0-9.9; NNT 20, 95% CI 10-50), whereas ETV plus interferon showed no significant benefit (OR 1.16, 95% CI 0.56-2.40; P = 0.006 for interaction). HBeAg seroconversion similarly favored TDF-based regimens (OR 2.25 vs. 1.63). HBV DNA negativity improved overall, although this effect was confined to TDF-based regimens. Safety data were highly heterogeneous (I² > 80% within both regimen subgroups) and derived from variable reporting standards; no reliable pooled estimate was constructed. Descriptive synthesis revealed no consistent excess toxicity for TDF-based or ETV-based combinations, though certainty remains very low. Sensitivity analyses excluding high-risk trials demonstrated robustness. GRADE certainty: moderate for serological outcomes, low for HBV DNA, very low for safety.

CONCLUSIONS

TDF-based combination regimens were associated with superior functional cure potential compared with ETV-based alternatives, suggesting a potential efficacy hierarchy that prior pooled analyses obscured. TDF may represent a potential backbone option for patients seeking HBsAg loss, with ETV combinations remaining an appropriate alternative, particularly for those with TDF contraindications or baseline renal impairment or osteopenia. However, these findings are descriptive rather than prescriptive, derive specifically from predominantly HBeAg-positive Asian populations, and should not be generalized to other demographic or disease-stage groups without further validation. The moderate-to-low certainty of evidence, substantial methodological limitations, lack of blinded trials, and insufficient safety data to exclude differential renal or bone toxicity between backbones preclude definitive treatment recommendations. Confirmation in double-blind trials is needed.