PD-1/PD-L1 blockade as part of combination strategies toward functional cure of chronic hepatitis B

Chronic hepatitis B (CHB) affects 260 million people worldwide. Despite advances in antiviral therapies, functional cure, characterized by sustained loss of hepatitis B surface antigen (HBsAg) and durable viral control after treatment cessation, remains infrequent. The PD-1/PD-L1 immune checkpoint pathway plays an important role in the exhaustion of hepatitis B virus (HBV)-specific T cells, thereby limiting the immune system's ability to clear HBV. Blocking the PD-1/PD-L1 pathway has emerged as a promising strategy to overcome this immune exhaustion to some extent and reinvigorate antiviral T-cell responses in CHB patients. Early clinical trials, particularly among patients who have achieved viral suppression with nucleos(t)ide analogues, have demonstrated that PD-1/PD-L1 inhibitors can significantly reduce HBsAg levels. Notably, a subset of patients has achieved functional cure, particularly among those with low baseline HBsAg levels. These effects have been further enhanced in combination with pegylated interferon, resulting in a functional cure rate of 30%. While challenges remain, such as optimizing dosing regimens, selecting patients, identifying response predictors and managing immune-related adverse events, these findings emphasize the potential of combination regimens involving PD-1/PD-L1 blockade as a means of achieving a functional cure in CHB patients. Future large-scale randomized controlled trials are essential to fully assess the approach's efficacy and safety, and to refine its clinical application.