Serum hepatitis B surface antigen (HBsAg) in patients with chronic hepatitis B correlated with inhibitory receptor expression, hepatitis B virus (HBV)-specific CD4+ T-cell responses, and augmentation by checkpoint blockade, according to results of a study published in Scientific Reports.

The functional cure of CHB is defined as a sustained loss of HBsAg; however, there have not been much data gathered known about pre-treatment levels as an indicator of potential immunity. To investigate this, researchers aimed to study the comparisons between the phenotypes and HBV-specific response of lymphocytes in patients with CHB stratified by serum HBsAg levels <500 or >50,000 IU/mL via immunologic assays (flow cytometry, intracellular cytokine staining, and enzyme-linked immune absorbent spot). Patients with high HBsAg levels were defined as >50,000 IU/mL and low levels as <500.

Patients with high HBsAg expressed higher levels of inhibitory programmed cell death (PD)-1 on CD4+ T cells, particularly among the TEMRA subset, and higher FcRL5 expression on B cells. After hepatitis core and surface antigen stimulation, 85% and 60% of patients with low HBsAg had interferon (IFN)γ+ tumor necrosis factor (TNF)α+ and IFNγ+ interleukin (IL)2+ CD4+ T-cell responses, respectively; among patients with high HBsAg, these were 33% and 13%. Checkpoint blockade with αPD-1 improved HBV-specific CD4+ T-cell function was found only in patients with low HBsAg. There was no difference in response between groups in terms of HBsAg-specific antibody-secreting cell response. However, αPD-1 treatment resulted in significantly higher-fold change in HBsAg-specific antibody-secreting cells among patients with HBsAg levels <100 IU/mL compared to patients with HBsAg levels >5000 IU/mL.

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However, the sample sizes here were too small for making full conclusions applicable for all patients with chronic HBV. This is especially true considering the large patient heterogeneity in the general population of patients with chronic HBV. The investigators also noted that because HBsAg can be derived from cccDNA or integrated DNA, it is possible that that this distinction might interfere with the current findings. The study was also unable to assess the breadth of HBV-specific T-cell responses. Finally, whereas the study focused on the role of HBsAg levels, there are other biomarkers that could also be correlative to HBV-specific immune function.

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Despite these limitations, the investigators concluded that these results, “suggest that subjects with pre-existing low HBsAg levels may be more poised to re-awaken HBV-specific immune responses either by antiviral or immunotherapeutic approaches or a combination approach.” They further recommend that studies investigating multidimensional immune function and phenotypes associated with HBsAg levels might lead to better designing immunotherapies for CHB.


Kim JH, Ghosh A, Ayithan N, et al. Circulating serum HBsAg level is a biomarker for HBV-specific T and B cell responses in chronic hepatitis B patients. Sci Rep. 2020;10:1835.