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Previously, the team of Professor Wu Chao from the Drum Tower Hospital of Nanjing University School of Medicine and the team of Professor Zhu Chuanwu from the Infectious Disease Hospital of Soochow University discussed the disease progression of patients with chronic hepatitis B with normal ALT but detectable HBV DNA, and the results showed that this group of people had a greater risk of disease progression (related link).
Recently, they published a multicenter, real-world cohort study that explored the clinical outcomes of treatment-naïve HBeAg-negative chronic HBV patients with HBsAg < 100 IU/mL, undetectable HBV DNA, and normal ALT, suggesting that patients with low HBsAg levels (<≥ 100 IU/mL) had higher HBsAg clearance and a lower risk of significant liver fibrosis compared with patients with high HBsAg levels ( 100 IU/mL), and the optimal cut-off value for predicting HBsAg clearance was 1.1 log10 IU/mL。
Research Methods:
This study retrospectively included treatment-naïve HBeAg-negative chronic HBV patients with undetectable HBV DNA and normal ALT who attended three medical institutions in China from January 2016 to July 2023. Patients were divided into low-level HBsAg (< 100 IU/mL) and high-level HBsAg (≥ 100 IU/mL). The upper limit of normal (ULN) for ALT is 40 U/L. Non-invasive tests (NITs) were used to evaluate liver fibrosis, and transient elastography was used to measure liver stiffness. None of the patients received antiviral therapy during the follow-up period. The primary clinical outcomes were significant incidence of liver fibrosis and HBsAg clearance.
Definition of important clinical events:
- Significant liver fibrosis (meeting any criteria): APRI ≥ 1.5, or FIB-4 ≥ 3.25, or liver stiffness value (LSM) ≥ 8.0 kPa;
- Cirrhosis (meeting any criteria): APRI ≥ 2.0, FIB-4 ≥ 6.5, LSM value ≥ 11.0 kPa or cirrhosis on ultrasound;
- HBsAg clearance: HBsAg < 0.05 IU/mL, regardless of HBsAb status;
- HBsAg血清学转换:HBsAg < 0.05 IU/mL且HBsAb ≥ 10 mIU/mL;
- 病毒再激活:ALT > 40 U/L且HBV DNA ≥ 2000 IU/mL。
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Clinical outcomes in different patients
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In the total population, patients in the low-HBsAg group were significantly older at baseline, and the proportion of HBsAg < 100 IU/mL was higher with older patients
A total of 1218 patients with undetectable HBV DNA and normal ALT were included in the treatment-naïve HBeAg-negative chronic HBV infection, of which 41.1% (501 cases) were in the low-level HBsAg group. The median age of the patients was 41.5 (IQR 32.0, 53.0) years, and 51.3% were male. In 8.9% and 4.4% of patients in the total population, respectively, were diagnosed with significant liver fibrosis and cirrhosis.
Compared with the HBsAg high level group, the patients in the HBsAg low group were significantly older (45.0 vs. 40.0 years, P < 0.001), and the proportion of males (56.9% vs. 47.4%, P = 0.001) and GGT levels (18.3 U/L vs. 17.0 U/L, P = 0.007) were significantly higher in the HBsAg group, and other clinical indicators were similar between the two groups (P >). 0.05) (Table 1). In order to adjust for confounding factors, propensity score matching (PSM) was used to match age and gender, and a total of 482 matching groups were obtained. After PSM, APRI, FIB-4, LSM values, significant liver fibrosis and cirrhosis were similar between the two groups.
Table 1 Total population, low/high levels of HBsAg
Comparison of clinical features in patients with chronic HBV infection
The older the patient, the higher the proportion of HBsAg < 100 IU/mL. The proportion of HBsAg < 100 IU/mL was also higher in male patients (Figure 1).
Fig. 1 Distribution of HBsAg < 100 IU/mL by age (A) and sex (B).
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During the follow-up period, the group with low HBsAg levels had a lower risk of significant liver fibrosis and a higher spontaneous HBsAg clearance
An analysis of 309 patients with no significant liver fibrosis at baseline (138 in the low-level HBsAg group and 171 in the high-level HBsAg group) showed that compared with the high-level HBsAg group, the patients in the low-level HBsAg group were significantly older (45.0 vs. 38.0 years, P = 0.001), AST (21.0 vs. 19.9 U/L, P = 0.015), APRI (0.28 vs. 0.26, P =). 0.041) and FIB-4 (1.09 vs. 0.91, P = 0.003) were significantly higher. The median follow-up was similar between the two groups (25.7 vs. 25.3 months, P = 0.632).
At the end of follow-up, compared with the HBsAg high level group, the proportion of patients with significant liver fibrosis in the HBsAg low level group (2.2% vs. 7.0%, P = 0.049) and the proportion of patients with HBV DNA > 2000 IU/mL (2.9% vs. 9.9%, P = 0.014) were significantly lower than those in the HBsAg high group, and the spontaneous HBsAg clearance rate was significantly higher in the HBsAg low level group (13.0% vs. 0%, P < 0.001), of which 3 patients (2.2%) were in the low HBsAg group HBsAg seroconversion was achieved in the patient (Table 2).
Table 2 Low/high levels of HBsAg with follow-up data
Comparison of clinical features in patients with chronic HBV infection
The baseline serum HBsAg level was significantly lower in patients with HBsAg clearance than in patients without HBsAg clearance (P < 0.001), and the serum HBsAg level at baseline was significantly higher in patients with significant liver fibrosis (P = 0.041) and HBV DNA > 2000 IU/mL (P = 0.004) (Fig. 2).
Fig.2 Comparison of baseline HBsAg levels in patients with HBsAg clearance (A), significant liver fibrosis (B), and HBV DNA > 2000 IU/mL (C).
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Analysis of relevant factors for each clinical outcome
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Low levels of HBsAg were inversely associated with a significant risk of liver fibrosis
In multivariate analysis, HBsAg < 100 IU/mL was inversely associated with a significant risk of liver fibrosis compared with serum HBsAg ≥ 100 IU/mL (HR 0.010, 95% CI 0.001, 0.177, P = 0.002). Kaplan-Meier survival analysis showed that the cumulative incidence of significant liver fibrosis was significantly higher in the HBsAg high level group than in the low HBsAg group (P = 0.020) (Fig. 3A).
Figure 3A Cumulative incidence of significant liver fibrosis at different HBsAg levels
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Low levels of HBsAg are associated with higher spontaneous HBsAg clearance
Multivariate analysis showed that HBsAg level was negatively correlated with HBsAg clearance (HR 0.213, 95% CI 0.125, 0.364, P < 0.001). The cumulative HBsAg clearance rate in the low-level HBsAg group was significantly higher than that in the high-level HBsAg group (P < 0.001) (Fig. 3B).
Figure 3B Cumulative incidence of HBsAg clearance at different HBsAg levels
More than half of the 18 patients with HBsAg clearance were younger than 50 years of age, and most were male. The majority of patients (88.9%) had very low baseline HBsAg levels (< 10 IU/mL), and no significant liver fibrosis and cirrhosis occurred at baseline or at the last follow-up. At the end of follow-up, 3 patients achieved HBsAg seroconversion, all of whom were in the low-level HBsAg group. The optimal cut-off value of HBsAg for predicting HBsAg clearance was 1.1 log10 IU/mL, and the area under the receiver operating characteristic curve, sensitivity and specificity were 0.934, 83.2% and 94.4%, respectively.
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HBsAg ≥ 100 IU/mL与HBV DNA > 2000 IU/mL呈正相关
During the follow-up period, a total of 21 patients developed HBV DNA > 2000 IU/mL regardless of ALT level, including 4 patients in the low-level HBsAg group and 17 patients in the high-level HBsAg group. Multivariate analysis showed that serum HBsAg ≥ 100 IU/mL was associated with a significantly higher risk of HBV DNA > 2000 IU/mL (HR 4.587, 95% CI 1.430, 14.712, P = 0.010). Patients in the HBsAg low level group had a significantly higher cumulative incidence of HBV DNA > 2000 IU/mL compared to the low HBsAg group (P = 0.016) (Figure 3C).
Figure 3C Cumulative incidence of HBV DNA > 2000 IU/mL at different HBsAg levels
Two patients in the HBsAg high level group had viral reactivation during follow-up, namely ALT > 40 U/L and HBV DNA ≥ 2000 IU/mL, while no patients in the HBsAg low group had viral reactivation. The cumulative incidence of ALT and AST elevation was similar between the high-level and low-HBsAg groups. During the follow-up period, no patients developed liver cancer.
Liver Linjun has something to say
This multicenter, real-world retrospective cohort study found that serum HBsAg levels were associated with clinical outcomes in treatment-naïve HBeAg-negative patients with undetectable HBV DNA and normal ALT. In these patients, patients with low HBsAg levels (< 100 IU/mL) have a lower risk of liver fibrosis and are more likely to achieve spontaneous HBsAg clearance, with the optimal HBsAg threshold for predicting HBsAg clearance in these patients being 1.1 log10 IU/mL.
Although the guidelines do not recommend antiviral therapy for this population, more clinical studies have shown that this population can achieve high HBsAg clearance after antiviral therapy, and for inactive HBsAg carriers with very low HBsAg levels, the clinical cure rate of pegylated interferon α (PEG IFNα) can exceed 90% (related links 1, 2, 3), therefore, people with inactive HBsAg carrier state can consider receiving short-term PEG IFNα therapy according to their own needs and benefits to pursue clinical cure as soon as possible.
Bibliography:
Wang J, Zhu L, Zhang S, et al. Clinical outcomes of treatment-naïve HBeAg negative patients with chronic hepatitis B virus infection with low serum HBsAg and undetectable HBV DNA[J]. Emerg Microbes Infect. 2024, 13(1): 2339944.
Source: Yulu Liver Lin