Hepatitis B virus (HBV) is a hepatotropic virus, which damage to hepatocytes is not direct, but through the immune system. HBV specific CD4⁺ T cells can induce HBV specific B cells and CD8⁺ T cells. HBV specific B cells produce antibodies to control HBV infection, while HBV specific CD8⁺ T cells destroy infected hepatocytes. One of the reasons for the chronicity of HBV infection is that it cannot effectively activate adoptive immunity and the function of virus specific immune cells is exhausted. Among them, virus antigens (including HBV surface antigen, e antigen, core antigen, etc.) can inhibit the function of immune cells and induce immune tolerance. Long term nucleos(t)ide analogues (NAs) treatment and inactive HBsAg carriers with low HBsAg level may “wake up” immune cells with abnormal function due to the decrease of viral antigen level in blood and liver, and the specific immune function of HBV will recover to a certain extent, thus becoming the “dominant population” for functional cure. In turn, the functional cure will further promote the recovery of HBV specific immune function, which is also the theoretical basis for complete cure of hepatitis B. In the future, the complete cure of chronic HBV infection must be the combination of three drugs: inhibiting virus replication, reducing surface antigen levels and specific immune regulation, among which specific immunotherapy is indispensable. Here we review the relationship, mechanism and clinical significance between the cure of hepatitis B and immune system.

Background and Aim: Programmed death 1 (PD‐1) and programmed death ligand 1 (PD‐L1) inhibitors have transformed the treatment landscape of advanced hepatocellular carcinoma (HCC), but consistent responses are not observed in all patients, and prognostic biomarkers to guide treatment decisions are lacking. We aimed to evaluate the predictive value of PD‐L1 expression in advanced HCC patients treated with PD‐1/PD‐L1 inhibitors.Methods: A comprehensive search of PubMed, Embase, Web of Science, and the Cochrane Library was conducted. Studies comparing the objective response rate (ORR) and/or disease control rate (DCR) based on the tumor PD‐L1 status of HCC were included.Results: Eleven studies with 1,330 HCC patients treated with PD‐1/PD‐L1 inhibitors were included. Pooled odds ratio (OR) analysis demonstrated a significantly improved ORR in PD‐L1‐positive patients compared with PD‐L1‐negative patients (OR, 1.86, 95% CI, 1.35–2.55). Similar results were observed in the anti‐PD‐1 treatment (p < 0.001) and anti‐PD‐1/PD‐L1 monotherapy (p < 0.001) subgroups. The pooled ORRs in the PD‐L1‐positive and PD‐L1‐negative groups were 26% (95% CI, 20%–32%) and 18% (95% CI, 13%–22%), respectively. For DCR, the pooled OR analysis showed no significant difference between PD‐L1‐positive patients and PD‐L1‐negative patients (66% [95% CI, 55%–76%] vs. 69% [95% CI, 62%–76%]; OR, 0.92, 95% CI, 0.59–1.44). The results were consistent across the drug target and combination treatment subgroups.Conclusion: Positive PD‐L1 expression is associated with a better ORR in advanced HCC patients treated with anti‐PD‐1/PD‐L1‐based therapies. This feature can help to identify HCC patients who will benefit most from PD‐1/PD‐L1 inhibitors.

Background: Nucleos(t)ide analogues (NAs) cessation is not widely practiced and remains a controversial, but highly relevant subject in patients infected with hepatitis B virus (HBV). We aimed to explore the related factors for safe NAs cessation. Methods: This is a multicenter prospective cohort study. Overall, 139 initially HBV e antigen (HBeAg)-positive patients meeting the stopping criteria were included in 12 hospitals in China. Enrolled patients ceased NAs and were followed up every 3 months for 24 months or until clinical relapse (CR). Results: The 24 month cumulative rates of virological relapse (VR), CR, HBeAg reversion and HBV surface antigen (HBsAg) loss were 50.4, 24.5, 11.5 and 9.4%, respectively. Patients with end of treatment (EOT) HBsAg < 100 IU/mL plus negative HBV RNA had the lowest 24 month cumulative VR rate (5 vs 58%, p < 0.001). EOT HBsAg ≥ 2 log₁₀ IU/mL [odds ratio (OR) = 6.686, p = 0.006], EOT positive HBV RNA (OR = 3.453, p = 0.008) and EOT hepatitis B core-related antigen (HBcrAg) ≥ 4log U/mL (OR = 3.702, p = 0.002) were found to independently predict the risk of VR. To predict VR, the area under the receiver-operating characteristic (AUROC) value of the EOT HBsAg < 100 IU/mL plus EOT HBV RNA negative was 0.698 (p < 0.001), which was higher than other parameters alone or combinations. Conclusions: NAs cessation is suitable only for a small and selected patients. An EOT HBsAg < 100 IU/mL and EOT negative HBV RNA identified a patient with low risk of off-treatment VR.

In the era of antiviral therapy, the main goal of treatment has shifted from the persistent inhibition of hepatitis B virus (HBV) replication to the pursuit of serological clearance of HBs surface antigen (HBsAg). Based on the life cycle of HBV, HBsAg originates from covalently closed circular DNA (cccDNA) and integrated HBV DNA, thus reflecting their transcriptional activity. Complete HBsAg loss may mean elimination or persistent inactivity of the HBV genome including cccDNA and integrated HBV DNA. HBsAg loss improves the recovery of abnormal immune function, which in turn, may further promote the clearance of residual viruses. Combined with functional cure and the great improvement of clinical outcomes, the continuous seroclearance of high-sensitivity quantitative HBsAg may represent the complete cure of chronic hepatitis B (CHB). For many other risk factors besides HBV itself, patients with HBsAg loss still need regular monitoring. In this review, we summarized the evolution of CHB treatment, the origin of serum HBsAg, the pattern of HBsAg seroclearance, and the effect of HBsAg loss on immune function and disease outcomes. In addition, we discuss the significance of high-sensitivity HBsAg detection and its possibility as a surrogate of complete cure.