Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.
Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China.
JAMA Netw Open. 2022 Jun 1;5(6):e2216485. doi: 10.1001/jamanetworkopen.2022.16485.
Coexistence of hepatitis B surface antigen (HBsAg) and antibody against HBsAg (anti-HBs) constitutes an atypical serological profile in chronic hepatitis B virus infection, and the association between coexistent HBsAg and anti-HBs with severe liver fibrosis and cirrhosis in patients with chronic hepatitis B (CHB) remains unclear.
To investigate the association of coexistent HBsAg and anti-HBs with severe liver fibrosis and cirrhosis in patients with CHB.
DESIGN, SETTING, AND PARTICIPANTS: Consecutive treatment-naive patients with CHB from 2 medical institutions in China were enrolled between January 10, 2015, and March 31, 2021. Severe liver fibrosis and cirrhosis were identified using the aspartate transaminase (AST) to platelet ratio index (APRI), the fibrosis index based on 4 factors (FIB-4; factors comprise age, AST level, alanine aminotransferase [ALT] level, and platelet count), transient elastography, or ultrasonography. Data were analyzed from August 1, 2021, to April 15, 2022.
The primary outcomes were rates of severe liver fibrosis and cirrhosis among patients with vs patients without coexistant HBsAg and anti-HBs. Severe liver fibrosis was defined as an APRI score of 1.5 or higher, a FIB-4 score of 3.25 or higher, or a liver stiffness measurement of 8 kPa or higher; cirrhosis was defined as an APRI score of 2.0 or higher, a FIB-4 score of 6.5 or higher, a liver stiffness measurement of 11 kPa or higher, or ultrasonographic findings suggestive of cirrhosis.
Of 6534 enrolled patients, 4033 patients (61.7%) were male, and the median (IQR) age was 41.0 (33.0-52.0) years. A total of 277 patients (4.2%) had coexistent HBsAg and anti-HBs. Patients with vs without anti-HBs were older (median [IQR], 46.0 [33.0-55.5] years vs 41.0 [33.0-52.0] years) and had a higher proportion of hepatitis B e antigen (HBeAg) positivity (123 of 277 patients [44.4%] vs 2115 of 6257 patients [33.8%]; P < .001), higher ALT levels (median [IQR], 45.1 [24.6-119.0] U/L vs 36.7 [22.0-77.0] U/L; P = .001) and AST levels (median [IQR], 35.0 [23.5-68.4] U/L vs 28.3 [21.6-51.0] U/L; P < .001), and lower platelet counts (median [IQR], 173.0 × 103/μL [129.0-212.5 × 103/μL] vs 185.0 × 103/μL [141.0-224.0 × 103/μL]; P = .004), albumin levels (median [IQR], 4.37 [4.11-4.56] g/dL vs 4.43 [4.17-4.61] g/dL; P = .02), and HBsAg levels (median [IQR], 2.8 log10 [1.6-3.4 log10] IU/mL vs 3.3 log10 [2.6-3.9 log10] IU/mL; P < .001). Compared with patients without anti-HBs, those with anti-HBs had higher APRI scores (median [IQR], 0.5 [0.3-1.4] vs 0.4 [0.3-0.9]; P < .001), FIB-4 scores (median [IQR], 1.4 [0.9-2.6] vs 1.1 [0.7-2.1]; P < .001), and liver stiffness values (median [IQR], 7.5 [6.2-9.8] kPa vs 6.3 [5.2-8.1] kPa; P = .003). Patients with anti-HBs also had higher proportions of severe liver fibrosis (102 of 277 patients [36.8%] vs 1397 of 6207 patients [22.5%]; P < .001) and cirrhosis (87 of 277 patients [31.4%] vs 1194 of 6213 patients [19.2%]; P < .001) compared with patients without anti-HBs. The coexistence of HBsAg and anti-HBs was independently associated with severe liver fibrosis (odds ratio [OR], 2.29; 95% CI, 1.56-3.38; P < .001) and cirrhosis (OR, 1.73; 95% CI, 1.12-2.68; P = .01) in the multivariate analysis. However, the association of coexistent HBsAg and anti-HBs with cirrhosis was only observed in patients with HBeAg negativity (OR, 1.66; 95% CI, 1.05-2.62; P = .03) and not in patients with HBeAg positivity (OR, 1.45; 95% CI, 0.87-2.43; P = .16).
In this cross-sectional study, the coexistence of HBsAg and anti-HBs was unusual in hepatitis B virus infection and was associated with more advanced liver diseases, such as severe liver fibrosis and cirrhosis, especially among patients with HBeAg negativity. These results suggest that close monitoring for liver fibrosis and cirrhosis is warranted in patients with CHB who have this serological profile.
乙型肝炎表面抗原 (HBsAg) 和抗乙型肝炎表面抗原 (抗-HBs) 共存构成慢性乙型肝炎病毒感染中一种非典型的血清学特征，慢性乙型肝炎 (CHB) 患者中 HBsAg 和抗-HBs 共存与严重肝纤维化和肝硬化之间的关联仍不清楚。
研究 CHB 患者中 HBsAg 和抗-HBs 共存与严重肝纤维化和肝硬化的关系。
设计、地点和参与者：这项连续纳入了来自中国 2 家医疗机构的治疗初治 CHB 患者，研究于 2015 年 1 月 10 日至 2021 年 3 月 31 日进行。采用天门冬氨酸氨基转移酶 (AST) 与血小板比值指数 (APRI)、基于 4 个因素的纤维化指数 (FIB-4；因素包括年龄、AST 水平、丙氨酸氨基转移酶 [ALT] 水平和血小板计数)、瞬时弹性成像或超声检查来确定严重肝纤维化和肝硬化。数据分析于 2021 年 8 月 1 日至 2022 年 4 月 15 日进行。
主要结局为合并 HBsAg 和抗-HBs 的患者与未合并 HBsAg 和抗-HBs 的患者之间严重肝纤维化和肝硬化的发生率。严重肝纤维化定义为 APRI 评分≥1.5、FIB-4 评分≥3.25 或肝脏硬度值≥8 kPa；肝硬化定义为 APRI 评分≥2.0、FIB-4 评分≥6.5、肝脏硬度值≥11 kPa 或超声提示肝硬化。
共纳入 6534 例患者，其中 4033 例（61.7%）为男性，中位（IQR）年龄为 41.0（33.0-52.0）岁。共 277 例（4.2%）患者同时存在 HBsAg 和抗-HBs。与无抗-HBs 患者相比，有抗-HBs 的患者年龄更大（中位 [IQR]，46.0 [33.0-55.5] 岁 vs 41.0 [33.0-52.0] 岁），乙型肝炎 e 抗原 (HBeAg) 阳性率更高（277 例患者中有 123 例 [44.4%] vs 6257 例患者中有 2115 例 [33.8%]；P<0.001），ALT 水平更高（中位 [IQR]，45.1 [24.6-119.0] U/L vs 36.7 [22.0-77.0] U/L；P=0.001）和 AST 水平更高（中位 [IQR]，35.0 [23.5-68.4] U/L vs 28.3 [21.6-51.0] U/L；P<0.001），血小板计数更低（中位 [IQR]，173.0×103/μL [129.0-212.5×103/μL] vs 185.0×103/μL [141.0-224.0×103/μL]；P=0.004），白蛋白水平更低（中位 [IQR]，4.37 [4.11-4.56] g/dL vs 4.43 [4.17-4.61] g/dL；P=0.02），HBsAg 水平更高（中位 [IQR]，2.8 log10 [1.6-3.4 log10] IU/mL vs 3.3 log10 [2.6-3.9 log10] IU/mL；P<0.001）。与无抗-HBs 的患者相比，有抗-HBs 的患者的 APRI 评分更高（中位数 [IQR]，0.5 [0.3-1.4] vs 0.4 [0.3-0.9]；P<0.001），FIB-4 评分更高（中位数 [IQR]，1.4 [0.9-2.6] vs 1.1 [0.7-2.1]；P<0.001），肝脏硬度值更高（中位数 [IQR]，7.5 [6.2-9.8] kPa vs 6.3 [5.2-8.1] kPa；P=0.003）。有抗-HBs 的患者也有更高比例的严重肝纤维化（277 例患者中有 102 例 [36.8%] vs 6207 例患者中有 1397 例 [22.5%]；P<0.001）和肝硬化（277 例患者中有 87 例 [31.4%] vs 6213 例患者中有 1194 例 [19.2%]；P<0.001）。在多变量分析中，HBsAg 和抗-HBs 的共存与严重肝纤维化（比值比 [OR]，2.29；95%CI，1.56-3.38；P<0.001）和肝硬化（OR，1.73；95%CI，1.12-2.68；P=0.01）独立相关。然而，HBsAg 和抗-HBs 的共存与肝硬化的关联仅在 HBeAg 阴性患者中观察到（OR，1.66；95%CI，1.05-2.62；P=0.03），而在 HBeAg 阳性患者中未观察到（OR，1.45；95%CI，0.87-2.43；P=0.16）。
在这项横断面研究中，HBsAg 和抗-HBs 的共存在乙型肝炎病毒感染中并不常见，与更严重的肝脏疾病有关，如严重肝纤维化和肝硬化，尤其是在 HBeAg 阴性患者中。这些结果表明，对患有这种血清学特征的 CHB 患者应密切监测肝纤维化和肝硬化。
