The BTLA/HVEM axis as a key regulator for stratified functional cure in chronic hepatitis B.

BACKGROUND: Functional cure rates in chronic hepatitis B (CHB) remain below 10% after long-term nucleos(t)ide analogue (NA) therapy, and PD-1/PD-L1 blockade achieves HBsAg clearance in approximately 30% of selected patients with low baseline HBsAg (≤100 IU/mL). This shortfall reflects an oversimplified view of T-cell exhaustion that neglects nonredundant checkpoints operating in parallel with PD-1. MAIN ARGUMENTS: We synthesize emerging evidence (2019-2025) to position the B and T lymphocyte attenuator (BTLA)/herpesvirus entry mediator (HVEM) axis as an emerging candidate hub for layered therapeutic strategies in HBV infection. BTLA preferentially recruits SHP-1 (versus PD-1-predominant SHP-2) and signals via PI3K-AKT to sustain terminal exhaustion independently of PD-1 status. BTLA preferentially recruits SHP-1 (Src homology region 2 domain-containing phosphatase-1) [versus PD-1-predominant SHP-2 (Src homology region 2 domain-containing phosphatase-2)] and signals via PI3K-AKT to constrain TPEX proliferation and effector differentiation independently of PD-1 status. In CHB, BTLA is upregulated on peripheral and intrahepatic CD4+ and CD8+ T cells, correlating with ALT/AST and histologic activity; however, this correlation should be interpreted cautiously, as elevated liver enzymes primarily reflect immune-mediated hepatocellular injury during active inflammation rather than purely antiviral immune dysfunction. In HBV-related acute-on-chronic liver failure (HBV-ACLF), CD4+ T-cell BTLA expression independently predicts 90-day mortality and secondary infections. Soluble BTLA has emerged as a candidate minimally invasive biomarker for risk stratification in resource-limited settings. CONCLUSION: Under low antigen load following long-term NA suppression (HBsAg <100 IU/mL), biomarker-guided combination therapy targeting BTLA/HVEM alongside PD-1 may expand functional cure rates beyond the ceiling of single-checkpoint blockade. We outline an adaptive Phase I trial concept with predefined stratification thresholds to enable reproducible translation in HBV-endemic regions.