Rebound of HBV DNA after cessation of nucleos/tide analogues in chronic hepatitis B patients with undetectable covalently closed circular DNA

Abstract

Background and Aims: Nucleos/tide analogues (nucs) effectively suppresses serum hepatitis B virus (HBV) DNA. Previously, we have identified 21 patients with undetectable covalently closed circular DNA (cccDNA) upon long term nucs therapy. This study investigated the effect of nucleos/tide analogues (nucs) withdrawal in patients with undetectable cccDNA levels.

Methods: Nineteen patients on long term nucs (median 13.4 years) were recruited: 13 were randomized to discontinue nucs; six to continue taking nucs. All had undetectable cccDNA at the time of last liver biopsy (median time 2.9 years prior to randomization). Serum HBV DNA, hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg), liver biochemistry, and serum HBV RNA were monitored.

Results: At the time of randomization, all patients had undetectable serum HBV DNA and HBV RNA. Twelve of the 13 patients had HBV DNA rebound to 100 IU/mL within 20 weeks of nucs discontinuation. The thirteenth patient had HBV DNA rebound at week 70. Three patients experienced biochemical flares after re-treatment which subsequently resolved. There was no significant association between the time of HBV DNA rebound and baseline HBsAg, HBcrAg and alanine transaminase, duration of treatment, and age at which treatment was stopped (all p > 0.05). At the time of HBV DNA rebound, HBV DNA levels correlated with HBcrAg levels (p=0.003), but not with HBsAg levels (p=0.262).

Conclusions: In patients with undetectable intrahepatic cccDNA, virologic rebound still occurred after nuc cessation. At the rebound of HBV DNA, the kinetics of HBsAg production were independent of that of viral DNA replication. Additional studies are required to determine the factors that may predict virologic rebound and when nucs can be discontinued in HBsAg-positive CHB patients.