Abstract
Nucleo(s)tide analogue (NUC) withdrawal may result in HBsAg clearance in a subset of patients. However, predictors of HBsAg loss after NUC withdrawal remain ill-defined. We studied predictors of HBsAg loss in a global cohort of HBeAg-negative patients with undetectable HBV DNA who discontinued long-term NUC therapy. Patients requiring retreatment after treatment cessation were considered non-responders. We enrolled 1,216 patients (991 with genotype data); 98 (8.1%) achieved HBsAg loss. The probability of HBsAg loss was higher in non-Asian patients (adjusted hazard ratio [aHR] 8.26, p <0.001), and in patients with lower HBsAg (aHR 0.243, p <0.001) and HBV core-related antigen (HBcrAg) (aHR 0.718, p= 0.001) levels. Combining HBsAg (<10, 10-100 or >100 IU/ml) and HBcrAg (<2log vs. ≥2 log) levels improved prediction of HBsAg loss, with extremely low rates observed in patients with HBsAg >100 IU/ml with detectable HBcrAg. HBsAg loss rates also varied with HBV genotype; the highest rates were observed for genotypes A and D, and none of the patients with HBV genotype E experienced HBsAg loss (p <0.001 for the overall comparison across genotypes; p <0.001 for genotypes A/D vs. genotypes B/C). HBV genotype C was independently associated with a higher probability of HBsAg loss when compared to genotype B among Asian patients (aHR 2.494; 95% CI 1.490-4.174, p= 0.001). The probability of HBsAg loss after NUC cessation varies according to patient ethnicity, HBV genotype and end-of-treatment viral antigen levels. Patients with low HBsAg (<100 IU/ml) and/or undetectable HBcrAg levels, particularly if non-Asian or infected with HBV genotype C, appear to be the best candidates for treatment withdrawal. A subset of patients may achieve clearance of hepatitis B surface antigen (HBsAg) - so-called functional cure - after withdrawal of nucleo(s)tide analogue therapy. In this multicentre study of 1,216 patients who discontinued antiviral therapy, we identified non-Asian ethnicity, HBV genotype C, and low hepatitis B surface antigen and hepatitis B core-related antigen levels as factors associated with an increased chance of HBsAg loss.
Highlights
Recommended nucleo(s)tide analogues (NUC) effectively achieve HBV DNA suppression in almost all patients with hepatitis B virus (HBV) infection
Undetectable HBcrAg levels were associated with higher rates of HBsAg loss among both Asians and non-Asians
After adjusting for the differences in HBsAg and HBcrAg levels at treatment cessation in multivariable Cox regression analysis, HBV genotype C was independently associated with a higher probability of HBsAg loss when compared to genotype B
Summary
Recommended nucleo(s)tide analogues (NUC) effectively achieve HBV DNA suppression in almost all patients with hepatitis B virus (HBV) infection. HBV DNA suppression is associated with significant decrease of liver related complications but does not completely eliminate the risk of hepatocellular carcinoma (HCC). Focus has recently shifted towards achieving functional cure, defined as sustained loss of HBsAg from serum. Rates of HBsAg loss are low even after long-term NUC therapy[1]. Since early experiences with addition of pegylated interferon have been disappointing[2], alternative strategies involving therapy cessation are being explored. Recent studies have shown that a proportion of HBeAg negative patients may experience HBsAg loss after NUC withdrawal.[3]. Nucleo(s)tide analogue (NUC) withdrawal may result in HBsAg clearance in a subset of patients, but predictors remain ill-defined
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