The Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
The Department of Radiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Front Immunol. 2022 May 27;13:903685. doi: 10.3389/fimmu.2022.903685. eCollection 2022.
There is no effective treatment for occult hepatitis B virus infection (OBI) patients, and immunotherapy may be one of the most promising options. We aim to investigate the underlying mechanism and therapeutic potential of hepatitis B vaccine immunotherapy for OBI patients.
Outpatient OBI patients were screened and randomly divided into treatment (Group A) and control (Group B) groups. At weeks 0, 4, and 24, patients in Group A received a subcutaneous/intramuscular injection of hepatitis B vaccine (Engerix-B, 20 μg/time) according to the standard vaccination schedule; patients in Group B served as blank control. The patients were followed for 36 weeks, with clinical, biochemical, virological, immunological, and imaging data collected and analyzed at weeks 0, 12, 24, and 36, respectively, and the relation between the virology and immunology results was analyzed.
Of the 228 OBI patients, 28 were excluded, and 200 were enrolled for observation. In the end, 44 patients were included in Group A and 39 in Group B after excluding lost cases. At week 0 (baseline), some patients in two groups had liver disease symptoms, HBV-related liver function damage, and liver fibrosis. 86.36% (38/44) and 82.05% (32/39) patients were positive for serum hepatitis B surface antibodies (anti-HBs) in Group A and Group B, respectively, with the median (quartile) of 42.47 (16.85, 109.1) and 39.27 (16.06, 117.4) mIU/ml, respectively. Reduced peripheral blood CD4T, CD8T, and B lymphocytes were found in some patients in two groups. These results were not statistically different between Group A and Group B (0.05). At week 36, all patients were serum anti-HBs (+) in Group A, with a median (quartile) of 1000 (483.9, 1000) mIU/ml, which was significantly higher than that at week 0 (<0.05) and that in Group B (<0.05). Compared to week 0, the number of CD8 T and B lymphocytes increased significantly and were significantly higher than Group B at the same point. Two patients in Group B were found to have hepatitis B virus reactivation from week 12 to week 36.
Anti-HBs in Group A patients were positively correlated with B lymphocytes (r=0.3431, 0.3087, and 0.3041, respectively) and positively correlated with CD8 T lymphocytes (r=0.4954, 0.3054, and 0.3455, respectively) at weeks 12, 24, and 36.
Virological reactivation is a risk for OBI patients. Serum hepatitis B surface antibodies were significantly increased after hepatitis B vaccine treatment, the same as the numbers of peripheral blood B and CD8 T lymphocytes; changes in hepatitis B surface antibody levels were positively correlated with the changes in peripheral blood B and CD8 T lymphocytes.
目前针对隐匿性乙型肝炎病毒感染（OBI）患者尚无有效的治疗方法，免疫疗法可能是最有前途的选择之一。本研究旨在探讨乙型肝炎疫苗免疫疗法治疗 OBI 患者的潜在机制和治疗潜力。
筛选门诊 OBI 患者并随机分为治疗（A 组）和对照组（B 组）。在 0 周、4 周和 24 周时，A 组患者按标准接种方案皮下/肌内注射乙型肝炎疫苗（安在时，20μg/次）；B 组患者作为空白对照。患者随访 36 周，分别在 0 周、12 周、24 周和 36 周收集并分析临床、生化、病毒学、免疫学和影像学数据，并分析病毒学和免疫学结果之间的关系。
在 228 例 OBI 患者中，有 28 例被排除，200 例患者被纳入观察。最终，A 组有 44 例患者纳入研究，B 组有 39 例患者纳入研究，排除失访病例。在第 0 周（基线）时，两组部分患者存在肝病症状、HBV 相关肝功能损害和肝纤维化。A 组和 B 组分别有 86.36%（38/44）和 82.05%（32/39）的患者血清乙型肝炎表面抗体（抗-HBs）阳性，中位（四分位距）值分别为 42.47（16.85，109.1）和 39.27（16.06，117.4）mIU/ml。两组部分患者外周血 CD4T、CD8T 和 B 淋巴细胞减少。两组间差异无统计学意义（0.05）。在第 36 周时，A 组所有患者血清抗-HBs 均为阳性，中位（四分位距）值为 1000（483.9，1000）mIU/ml，与第 0 周相比明显升高（<0.05），且高于 B 组（<0.05）。与第 0 周相比，A 组 CD8 T 和 B 淋巴细胞数量明显增加，且在同一时间点均高于 B 组。B 组有 2 例患者在第 12 周至第 36 周出现乙型肝炎病毒再激活。
A 组患者的抗-HBs 与 B 淋巴细胞（r=0.3431、0.3087 和 0.3041）和 CD8 T 淋巴细胞（r=0.4954、0.3054 和 0.3455）在第 12、24 和 36 周时均呈正相关。
病毒学再激活是 OBI 患者的风险因素。乙型肝炎疫苗治疗后血清乙型肝炎表面抗体明显升高，与外周血 B 淋巴细胞和 CD8 T 淋巴细胞数量相同；乙型肝炎表面抗体水平的变化与外周血 B 淋巴细胞和 CD8 T 淋巴细胞的变化呈正相关。
