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There is a broad consensus on the treatment guidelines for chronic hepatitis B (CHB) at home and abroad, and the realization of HBsAg clearance has become the main goal of clinical cure. However, no studies with follow-up of more than 10 years have demonstrated that the long-term risk of liver decompensation and liver cancer (HCC) is reduced after HBsAg clearance. Recently, the team of Professor Huang Lihong of Hong Kong University Chinese published a study in the Journal of Hepatology, "Risk of hepatic decompensation but not hepatocellular carcinoma decreases over time in patients with hepatitis B surface antigen loss" Using a territory-wide real-world cohort study, they found that the risk of liver decompensation in patients after HBsAg clearance decreased significantly over time, while the risk of HCC persisted, suggesting that long-term HCC monitoring is still necessary in patients with cirrhosis and other high-risk patients.
Research methods
The study included CHB patients who had HBsAg clearance in Hong Kong between January 2000 and December 2020 and completed 12 years of follow-up. Exclusion criteria: age< 18 years; incomplete demographic data; Acute hepatitis B; with other liver diseases; HIV infection; HCC or liver transplantation occurs before HBsAg clearance. The primary endpoint was the occurrence of HCC; Secondary endpoints were hepatic decompensation events, including ascites, variceal bleeding, hepatic encephalopathy, hepatorenal syndrome, spontaneous bacterial peritonitis, liver transplantation, and liver-related death.
In addition, observation of HCC excluded patients with HCC during 6 months of follow-up, and observation of decompensatory events excluded patients with decompensatory events during 6 months of follow-up.
Study results
Between January 2000 and December 2020, 13,021 CHB patients received HBsAg clearance. HCC observation cohort, excluding 3252 cases, for a total of 9769 cases included in the analysis (Figure 1A); The decompensation observation cohort, excluding 3381 cases, for a total of 9640 cases were included in the analysis (Figure 1B).
Figure 1. HBsAg clears the patient's entry chart
(Quoted from references)
HCC was observed in the HCC observation cohort, with a total of 106 (1.1%) HCC cases during 12 years of follow-up, and 84 and 22 cases of HCC during 0-7 years and 8-12 years, respectively. The cumulative incidence of HCC (95% CI) at 5, 7, and 12 years in patients with HBsAg clearance was 0.9% (0.7% to 1.1%), 1.3% (1.0% to 1.6%), and 2.2% (1.8% to 2.8%), respectively (Figure 2A). Patients with HCC are older, have a higher proportion of males and cirrhosis, have higher alanine aminotransferase (ALT) and creatinine, and lower albumin and platelet counts than those without HCC.
The average cumulative incidence of HBsAg clearance per year around 7 years was 0.20% and 0.19%, respectively (Figure 2A). From 0-1 to 11-12 years, the annual crude incidence of HCC after HBsAg clearance ranged from 1.7% to 3.2%, with a slight decrease of 0.04% (95% CI: 0.13%-0.04%) (p = 0.265) over time (Figure 3A). Univariate analysis found that HBsAg clearance over 7 years was not associated with HCC risk reduction (Subdistribution Risk Ratio (SHR): 1.03; 95%CI: 0.64-1.66; P = 0.898）。 Multivariate analysis further found that older age, male sex, cirrhosis, and low platelet count were associated with a higher risk of HCC after HBsAg clearance, while HBsAg clearance over 7 years was not associated with a reduced risk of HCC (adjusted SHR: 1.35; 95%CI: 0.83-2.19; P = 0.230）。
Figure 2. Cumulative incidence of HBsAg clearance in CHB patients
(Quoted from references)
In the decompensation observation cohort, a total of 124 (1.1%) cases of decompensation events occurred during 12 years of follow-up, and 111 cases and 13 cases of HCC occurred during 0-7 years and 8-12 years, respectively. The cumulative incidence of HCC (95% CI) at 5, 7, and 12 years in patients with HBsAg clearance was 1.2% (1.0% to 1.5%), 1.7% (1.4% to 2.1%), and 2.3% (1.9% to 2.8%), respectively (Figure 2B). Patients with decompensation are older, have higher rates of cirrhosis and diabetes, higher ALT, total bilirubin, and creatinine, and lower albumin and platelet counts than non-decompensated patients.
The average cumulative incidence of HBsAg clearance per year around 7 years was 0.26% and 0.12%, respectively (Figure 2B). The annual incidence of decompensation after HBsAg clearance ranged from 0-1 to 11-12 years, with a decrease of 0.23% (95% CI: 0.40% to 0.06%) (p = 0.012) per year (P = 0.012). Univariate analysis found that HBsAg clearance over 7 years was associated with a reduced risk of decompensation (SHR 0.46, 95% CI 0.26-0.83, p = 0.009). Multivariate analysis further demonstrated that HBsAg clearance over 7 years was independently associated with a reduced risk of decompensation (adjusted SHR: 0.55, 95% CI: 0.31-0.97, p = 0.039). Cirrhosis and lower albumin are associated with a higher risk of liver decompensation. In subgroup analysis, a similar correlation occurred between years after HBsAg clearance and the development of liver decompensation in patients with and without cirrhosis.
Figure 3. Long-term trends in annual crude incidence
(Quoted from references)
Conclusion of the study
The risk of decompensation in CHB patients decreases over time 12 years after HBsAg clearance, however, there is still a non-negligible risk of liver cancer, especially in men with cirrhosis. This suggests that patients with long-term clearance of HBsAg in clinical practice, especially those with cirrhosis and other high-risk groups, still need long-term HCC monitoring.
参考文献：Yip TC, et al. Risk of hepatic decompensation but not hepatocellular carcinoma decreases over time in patients with hepatitis B surface antigen loss. J Hepatol. 2022 Dec 2:S0168-8278（22）03314-1.
Source: Hepatobiliary Intelligence Officer