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The coexistence of HBsAg and HBsAb is a rare serological pattern of HBV infection, and its underlying mechanism and clinical significance have not been clarified. The prevalence of HBsAg and HBsAb double positives has been reported to be less than 10% globally and about 2.4% - 5.8% on the continental continent. Previous studies have focused on adults with chronic hepatitis B, and there is evidence that patients with HBsAg and HBsAb positive for chronic hepatitis B can achieve clinical cure with pegylated interferon α (PEG IFNα) monotherapy (related links 1 and 2), while current research on children is limited.
The results showed that in children and adolescents with chronic hepatitis B who received antiviral therapy (95% nucleoside combined with interferon α/pegylated interferon α), the proportion of HBsAg and HBsAb double positive children and adolescents with HBsAg and HBsAb was significantly higher in HBsAg and HBsAb positive children and adolescents with HBsAg clearance, HBeAg clearance, and HBV DNA undetectable. In addition, HBsAb levels and age are predictive of HBsAg clearance.
Research Methods:
This retrospective cohort study included children and adolescents aged 1 to 17 years who received antiviral therapy at Hunan Provincial Children's Hospital from June 2016 to April 2023. The children were divided into HBsAb-positive group (HBsAg and HBsAb positive at baseline) and HBsAb-negative group (HBsAg positive at baseline). The threshold for HBsAb positivity is >10 IU/L (1 log10 IU/L).
The primary outcome was HBsAg clearance (two consecutive < 0.05 IU/mL). Other outcomes included HBeAg clearance (<1 COI) and undetectable HBV DNA (<100 IU/mL). Cox proportional hazards regression analysis was used to evaluate the association between HBsAg and HBsAb coexistence and clinical outcomes.
Patient characteristics
A total of 372 children with chronic hepatitis B were enrolled, of whom 62.10% (231) were male, and 23.39% (87) were HBsAg and HBsAb positive. There were no significant differences between the HBsAb-positive group and the HBsAb-negative group in terms of gender, maternal HBV infection status, antiviral treatment regimen, HBV genotype, inflammation grade, fibrosis stage, and HBeAg positive rate. The median levels of HBsAg and HBV DNA in the HBsAb-positive group were significantly lower than those in the HBsAb-negative group, while the median levels of ALT and AST were significantly higher than those in the HBsAb-negative group. The median age at initiation of antiviral therapy in the HBsAb-positive group was significantly smaller than that in the HBsAb-negative group (3 years vs. 5 years, P = 0.003).
All children received antiviral therapy, of which 94.62% were nucleos(t)ide analogues (NAs) combined with IFNα/PEG IFNα, and the rest were monotherapy (NAs monotherapy, IFNα/PEG IFNα monotherapy), and there was no significant difference in the proportion of these two regimens between the HBsAb-positive and negative groups (P = 0.135).
Table 1: Patient characteristics
Findings:
01
Children with HBsAg and HBsAb positive for chronic hepatitis B are more likely to achieve clinical cure
During the follow-up of 407.95 person-years (PYs), the crude incidence of undetectable HBV DNA was 71.58 per 100 PY, which was more common and occurred more rapidly than HBsAg clearance (21.40 per 100 PY, 719.93 PYs) and HBeAg seroconversion (32.88 per 100 PY, 568.73 PYs). At the end of follow-up, 154 children achieved HBsAg clearance, of which 54 (37.46/100 PY) were HBsAb-positive and 100 (17.37/100 PY) were HBsAb-negative.
HBsAb阳性组和HBsAb阴性组的HBeAg清除率和HBV DNA检测不到的比例分别为49.51 vs. 28.66 / 100 PY（HR = 1.73; 95% CI: 1.24 - 2.38）、92.11 vs. 66.54 / 100 PY（HR = 1.38; 95% CI: 1.05 - 1.81），均具有显著差异。
Table 2: Clinical outcomes by HBsAb status
Kaplan-Meier curve analysis showed that the HBsAg clearance, HBeAg clearance and undetectable proportion of HBV DNA in the HBsAb-positive group were significantly higher than those in the HBsAb-negative group during the follow-up period (all P < 0.05).
Figure 1: Kaplan-Meier curve analysis of HBsAb-positive group
and clinical outcomes in the HBsAb-negative group
02
Correlation between different HBsAb status and clinical outcomes
Further subgroup analysis found that HBsAb positivity was independently associated with HBsAg clearance in patients with genotype C and inflammation grade 0 to 1 (HR = 3.99, 95% CI: 1.11 to 14.39; HR = 2.40, 95%CI: 1.13 - 5.12）。 Patients with genotype C and inflammation grade 2 to 4 were independently associated with undetectable HBV DNA (HR = 4.03, 95% CI: 1.51 to 10.72; HR = 1.99, 95% CI: 1.10 - 3.61）。 No correlation between HBsAb status and HBeAg clearance was found in any subgroup.
Figure 2: Subgroup analysis of clinical outcomes based on HBsAb status
限制性立方样条分析表明，校正其他协变量后，HBsAb水平与HBsAg清除（P-nonlinear = 0.813, P-overall < 0.001）和HBV DNA检测不到（P-nonlinear = 0.145, P-overall < 0.001）之间存在线性剂量-反应关系。 随着治疗开始HBsAb水平升高，HBsAg清除和HBV DNA检测不到的比例也相应增加。
Figure 3: Restriction cubic spline analysis of the dose-response relationship between HBsAb levels and clinical outcomes
03
HBsAb ≥ 0.84 log10 IU/L且年龄 ≤ 5岁的患者累积HBsAg清除率最高
The area under the curve (AUC) of HBsAb level predicted HBsAg clearance was 0.63 (95% CI: 0.57 - 0.69, P < 0.001). Further, the AUC increased to 0.71 (95% CI: 0.66 to 0.76, P < 0.001), sensitivity 0.77, and specificity 0.47. Patients with HBsAb ≥ 0.84 log10 IU/L and ≤ 5 years of age had the highest cumulative HBsAg clearance (P < 0.001). HBsAb ≥ 0.84 log10 IU/L and age ≤ 5 years predicted a positive predictive value (PPV) of 60.34% and 54.50%, respectively, and the PPV was higher at 68.29%.
Figure 4: Predictive role of HBsAb levels and age on HBsAg clearance.
(A) Receiver operating characteristic curve analysis of HBsAg clearance;
(B) Kaplan-Meier curve analysis predicting HBsAg clearance based on baseline HBsAb and age;
(C) HBsAg clearance was compared against baseline HBsAb and age.
*P < 0.05, **P < 0.01, ***P < 0.001
Liver Linjun has something to say
About 23% of the children and adolescents with chronic hepatitis B included in this study were both HBsAg and HBsAb positive, and the proportion of HBsAg clearance, HBeAg clearance, and HBV DNA undetectable after antiviral therapy was significantly higher. HBsAb-positive children with chronic hepatitis B have lower HBsAg levels and HBV DNA levels, which may be due to HBsAb lowering HBsAg levels by neutralizing HBsAg, and HBsAb production implies a certain immune response in the body, which lowers HBV DNA levels.
In this study, it has been reported that untreated patients with chronic hepatitis B who have both HBsAg and HBsAb may be at higher risk of significant liver fibrosis and cirrhosis (related link), and in this study, young children with high levels of HBsAb are more likely to achieve HBsAg clearance, so it is recommended that these children receive aggressive antiviral therapy for better long-term outcomes.
Bibliography:
Gu YP, Li SJ, Yao ZZ, et al. Characteristics and clinical treatment outcomes of chronic hepatitis B children with coexistence of hepatitis B surface antigen (HBsAg) and antibodies to HBsAg [J]. BMC Med, 2024, 22(1): 77.
Source: Yulu Liver Lin