Clinical utility of hepatitis B surface antigen kinetics in treatment-naïve chronic hepatitis B patients during long-term entecavir therapy

Abstract

Aim: To investigate the utility of hepatitis B surface antigen (HBsAg) kinetics in chronic hepatitis B patients during long-term entecavir treatment.

Methods: This retrospective study included treatment-naïve chronic hepatitis B patients who received at least 2 years of consecutive entecavir treatment. Patients were followed up at three to six month intervals with liver biochemistry, hepatitis B virus DNA, and abdominal sonography. In hepatitis B e antigen (HBeAg)-positive patients, HBeAg levels were assessed every three to six month until results became negative. Serum HBsAg levels were determined at the baseline, one-year and five-year time points. Liver cirrhosis was diagnosed through liver biopsy, imaging examinations, or clinical findings of portal hypertension. Hepatocellular carcinoma was diagnosed by histological examination or dynamic image studies.

Results: A total of 211 patients were enrolled. The median treatment time was 5.24 (2.00-9.62) years. Multivariate analysis showed that lower baseline HBsAg levels were associated with an earlier virological response, earlier hepatitis B e antigen (HBeAg) seroconversion, and earlier biochemical response in HBeAg-positive patients (cut-off value: 4 log IU/mL) and an earlier virological response in HBeAg-negative non-cirrhotic patients (cut-off value: 2.4 log IU/mL). Although HBsAg levels decreased slowly during long-term entecavir treatment, higher HBsAg decrease rates were found in the first year for HBeAg-positive non-cirrhotic patients, and patients with higher baseline HBsAg levels. More favorable clinical outcomes were not observed by a rapid HBsAg decline per se, but depended on lower baseline HBsAg levels.

Conclusion: Baseline HBsAg can be used to predict treatment responses. HBsAg levels and decrease rates should be considered together according to disease status while interpreting HBsAg changes.

Keywords: Chronic hepatitis B; Entecavir; Hepatitis B e antigen; Hepatitis B surface antigen; Kinetics.

Figure 1

Cumulative incidence of virological response. A: Cumulative incidence of virological response in HBeAg-positive patients; B: Cumulative incidence of virological response in HBeAg-positive non-cirrhotic patients; C: Cumulative incidence of virological response in HBeAg-negative patients; D: Cumulative incidence of virological response in HBeAg-negative non-cirrhotic patients.

Figure 2

Cumulative incidence of HBeAg serological response. A: Cumulative incidence of HBeAg seroclearance; B: Cumulative incidence of HBeAg seroconversion.

Figure 3

HBsAg kinetics during entecavir treatment. A: HBsAg levels at different time points, categorized by baseline HBeAg and cirrhosis status; B: Annual HBsAg changes in different periods, categorized by baseline HBeAg and cirrhosis status; C: HBsAg levels and annual HBsAg changes, categorized by baseline HBsAg < 3 log IU/mL and ≥ 3 log IU/mL; D: HBsAg levels and annual HBsAg changes, categorized by time to virological response < 6 mo and ≥ 6 mo; E: HBsAg levels and annual HBsAg changes, categorized by HBeAg seroconversion in HBeAg-positive non-cirrhotic patients. Error bars represent 95% confidence intervals. Comparisons between different time points or periods for one patient group: ^aP < 0.05, ^bP < 0.005, ^cP < 0.001; Comparisons between different groups at one specific time point or period: ^dP < 0.05, ^eP < 0.005, ^fP < 0.001.

Figure 4

Possible mechanisms for HBsAg decline after nucleos(t)ide analogue treatment. A: Nucleos(t)ide analogues inhibit the activity of HBV reverse transcriptase; B: The production of relaxed circular DNA; C and D: The package andrelease of complete virions, and the replenishment of cccDNA. cccDNA: Covalently closed circular DNA; HBc: Hepatitis B core protein; HBsAg: Hepatitis B surface antigen; L/M/S proteins: Large, middle, and small envelope proteins; HBV: Hepatitis B virus.