Regression of liver fibrosis after HBsAg loss: A prospective matched case-control evaluation using transient elastography and serum enhanced liver fibrosis test

Abstract

Background and aim: We assessed the effect of hepatitis B surface antigen (HBsAg) seroclearance (HBsAg-loss) on liver fibrosis regression in patients with chronic hepatitis B (CHB) infection.

Method: CHB patients with recent documented HBsAg-loss were age- and gender-matched with treatment-naïve HBeAg-negative CHB infection. Paired assessment with transient elastography and enhanced liver fibrosis (ELF) measurements were performed and repeated at 3 years. Fibrosis regression was arbitrarily defined as decrease in ≥ 1 fibrosis stage by ELF, or combining with reduction > 30% in liver stiffness.

Results: A total of 142 HBsAg-loss and 142 CHB subjects were recruited (median age 58.1 years, 51.4% male). A total of 1.8% (1.4% HBsAg-loss vs 2.1% CHB) achieved combined endpoint of fibrosis regression at 3 years. When ELF-only definition of fibrosis regression was used, 14.5% HBsAg-loss and 16.9% CHB subjects achieved this endpoint, which was significantly associated with baseline ELF (hazard ratio (HR) 1.827, 95% confidence interval (CI) 1.085-3.075) and time since HBsAg-loss (HR 2.688, 95% CI 1.257-5.748). While increasing time since HBsAg-loss increased the proportion of ELF-defined fibrosis regression, increasing age was also associated with significant fibrosis. Age of achieving HBsAg-loss (ageSC) was independently associated with high baseline ELF values. Up to 52.3% and 63.8% subjects with ageSC > 50 had advanced fibrosis/cirrhosis at baseline and 3 years, respectively, compared with 5.9% and 20.6% in subjects with ageSC < 50.

Conclusion: Fibrosis regression occurred in a minority of subjects achieving HBsAg-loss, which was not significantly different compared with subjects with persistent overt CHB. Subjects after achieving HBsAg-loss, especially among those with ageSC > 50, should receive ongoing surveillance for liver-related complications.

Keywords: Age; Chronic viral hepatitis; Fibrosis regression; Functional cure; HBV.

Figure 1

Distribution of liver fibrosis stage at baseline and 3 years. (a) Left panel: ELF‐defined fibrosis stages. (b) Right panel: LS‐defined fibrosis stages. ELF, enhanced liver fibrosis; F0/F1, no or minimal fibrosis; F2, significant fibrosis; F3, advanced fibrosis; F4, cirrhosis; LS, liver stiffness. (a) , F0/F1; , F2.Gray zone; , F3; , F4. (b) , F0/F1; , F2/Gray zone; , F3; , F4.

Figure 2

(a) ELF and LS values at baseline and 3 years in CHB and HBsAg‐loss subjects. (b) ELF and LS change (absolute value and percentage) at 3 years in CHB and HBsAg‐loss subjects. (c) Proportion of subjects achieving fibrosis regression at 3 years using various definitions, stratified by HBsAg‐loss or CHB. CHB, chronic hepatitis; ELF, enhanced liver fibrosis; HBsAg, hepatitis B surface antigen; LS, liver stiffness; n.s., not significant; S‐loss, HBsAg seroclearance. (c) , CHB (n = 142); , HBsAg seroclearance.

Figure 3

(a) Proportion of subjects with HBsAg‐loss in different age groups (stratified by the quartile of age). (b) Proportion of subjects with ≥ F2 defined by ELF or LS at baseline and 3 years in different age groups (stratified by the quartile of age). ELF, enhanced liver fibrosis; ≥ F2, at least significant fibrosis; HBsAg, hepatitis B surface antigen; LS, liver stiffness. (b) , Age < 51.6; , Age 51.6–58.1; , Age 58.1–64.1; , Age > 64.1. n = 71 in each group.

Figure 4

Proportion of subjects with F3/F4 defined by ELF or LS at baseline and 3 years, stratified by ageSC (age of achieving HBsAg‐loss). ELF, enhanced liver fibrosis; F/F4, advanced fibrosis or cirrhosis; HBsAg, hepatitis B surface antigen; LS, liver stiffness. , Age at HBsAg seroclearance < 50 (n = 34); , Age at HBsAg seroclearance ≥ 50 (n = 108).