Hepatitis B virus (HBV) reactivation is a clinically significant challenge in disease management. This review explores the immunological mechanisms underlying HBV reactivation, emphasizing disease progression and management. It delves into host immune responses and reactivation's delicate balance, spanning innate and adaptive immunity. Viral factors' disruption of this balance, as are interactions between viral antigens, immune cells, cytokine networks, and immune checkpoint pathways, are examined. Notably, the roles of T cells, natural killer cells, and antigen-presenting cells are discussed, highlighting their influence on disease progression. HBV reactivation's impact on disease severity, hepatic flares, liver fibrosis progression, and hepatocellular carcinoma is detailed. Management strategies, including anti-viral and immunomodulatory approaches, are critically analyzed. The role of prophylactic anti-viral therapy during immunosuppressive treatments is explored alongside novel immunotherapeutic interventions to restore immune control and prevent reactivation. In conclusion, this comprehensive review furnishes a holistic view of the immunological mechanisms that propel HBV reactivation. With a dedicated focus on understanding its implications for disease progression and the prospects of efficient management strategies, this article contributes significantly to the knowledge base. The more profound insights into the intricate interactions between viral elements and the immune system will inform evidence-based approaches, ultimately enhancing disease management and elevating patient outcomes. The dynamic landscape of management strategies is critically scrutinized, spanning anti-viral and immunomodulatory approaches. The role of prophylactic anti-viral therapy in preventing reactivation during immunosuppressive treatments and the potential of innovative immunotherapeutic interventions to restore immune control and proactively deter reactivation.

Hepatitis B is a major global health problem. More than 90% of hepatitis B-vaccinated immunocompetent adults become fully immune. The main purpose of vaccination is immunization. Whether non-responders have a lower percentage of total or antigen-specific memory B cells in comparison with responders is still controversial. We aimed to assess and compare the frequency of various B cell subpopulations in non-responders and responders.

Fourteen responders and 14 non-responders of hospital healthcare workers were enrolled in this study. We used flow cytometry to evaluate various CD19+ B cell subpopulations using fluorescent-labeled antibodies against CD19, CD10, CD21, CD27 and IgM and ELISA to evaluate total anti-HBs antibodies.

We found no significant differences in the frequency of various B cell subpopulations between the non-responder and responder groups. Furthermore, the frequency of the isotype-switched memory B cell population was significantly higher in the atypical memory B cell subset compared with the classical memory B cell subset in the responder and total groups (p=0.010 and 0.003, respectively).

Responders and non-responders to HBsAg vaccine had comparable memory B cell populations. Whether anti-HBs Ab production has a correlation with the level of class switching in B lymphocytes in healthy vaccinated individuals needs further investigation.

Several effective antiviral drugs are now available; however, the risk of liver-related complications is still present. Low-level viremia (LLV), defined as a hepatitis B virus (HBV) deoxyribonucleic acid (DNA) load lower than 2000 IU/mL, is one of the major factors responsible for these complications. It has been reported that 22.7-43.1% of patients with HBV experience LLV. Herein, we aimed to explore the risk factors for very LLV (VLLV) during antiviral treatment.

We collected data of patients with chronic hepatitis B (CHB) who received nucleos(t)ide analog treatment from October 2016 to April 2021. VLLV was defined as an HBV DNA load of 9-20 IU/mL. A total of 139 patients with LLV were matched with 139 patients with a sustained virological response at a 1:1 ratio according to age and gender.

Seropositivity rates for hepatitis B e antigen (HBeAg) (45.3% vs. 17.3%, P < 0.001) and hepatitis B surface antigen (HBsAg, 3.11 ± 0.68 lg IU/mL vs. 2.54 ± 1.04 lg IU/mL, P < 0.001) and alanine aminotransferase levels (30.34 ± 15.08 U/L vs. 26.15 ± 16.66 U/L, P = 0.040) in the two groups were significantly different. The multivariate analysis showed that both HBeAg seropositivity (adjusted odd ratio (aOR), 3.63; 95% confidence interval (CI): 1.98-6.64; P < 0.001) and HBsAg levels (aOR, 2.21; 95% CI: 1.53-3.20; P < 0.001) are independent risk factors for VLLV. During the multivariate analysis in the subgroup of HBeAg-positive patients, male gender (aOR, 3.68; 95% CI: 1.23-10.76; P = 0.017) and high HBsAg (aOR, 4.86; 95% CI: 1.73-13.64; P = 0.003) levels were significantly correlated with VLLV. However, this was not the case in HBeAg-negative patients (P > 0.050). HBeAg seropositivity (aOR, 5.08; 95% CI: 2.15-12.02; P < 0.001 vs. aOR, 2.78; 95% CI: 1.16-7.00; P = 0.022) and HBsAg levels (aOR, 2.75; 95% CI: 1.41-5.37; P = 0.003 vs. aOR, 2.10; 95% CI: 1.27-3.46; P = 0.004) significantly increased the risk of VLLV, irrespective of the age group. Both HBsAg (area under the receiver operating characteristic curve (AUC), 0.681; 95% CI: 0.623-0.736; P < 0.001) and HBeAg (AUC, 0.640; 95% CI: 0.581-0.697; P < 0.001) had certain predictive value for VLLV.

HBeAg seropositivity and higher HBsAg levels were not only risk factors for VLLV but also predicted its occurrence. When a patient with CHB remains HBeAg seropositive with high HBsAg levels after antiviral treatment for 48 weeks, emphasis should be placed on the potential occurrence of VLLV, warranting the use of highly sensitive HBV DNA detection methods.