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

Area of Science:

• Immunology
• Hepatology
• Virology

Background:

• Chronic hepatitis B (CHB) impacts 260 million globally, with functional cure rates remaining low despite antiviral therapies.
• The PD-1/PD-L1 immune checkpoint pathway contributes to hepatitis B virus (HBV)-specific T-cell exhaustion, hindering viral clearance.
• Reinvigorating T-cell responses via PD-1/PD-L1 blockade is a potential strategy for CHB functional cure.

Purpose of the Study:

• To evaluate the efficacy of PD-1/PD-L1 inhibitors in achieving functional cure for CHB.
• To assess the impact of PD-1/PD-L1 blockade on HBsAg levels and T-cell responses in CHB patients.
• To explore combination therapy benefits, particularly with pegylated interferon, for enhancing functional cure rates.

Main Methods:

• Analysis of early clinical trials involving PD-1/PD-L1 inhibitors in CHB patients, including those on nucleos(t)ide analogues.
• Assessment of HBsAg level reduction and functional cure achievement in response to PD-1/PD-L1 blockade.
• Evaluation of combination regimens, specifically with pegylated interferon, for improved outcomes.

Main Results:

• PD-1/PD-L1 inhibitors significantly reduced HBsAg levels in CHB patients with viral suppression.
• A subset of patients, especially those with low baseline HBsAg, achieved functional cure.
• Combination therapy with pegylated interferon resulted in a 30% functional cure rate.

Conclusions:

• PD-1/PD-L1 blockade is a promising approach to overcome immune exhaustion and achieve functional cure in CHB.
• Combination regimens involving PD-1/PD-L1 inhibitors and pegylated interferon show enhanced efficacy.
• Further large-scale trials are needed to optimize treatment, identify predictors, and manage adverse events for widespread clinical application.