Nucleos(t)ide Analog Withdrawal in Patients With Chronic Hepatitis B

hepatitis b
hepatitis b
Investigators assessed virological, biochemical, and clinical outcomes following cessation of nucleos(t)ide analog therapy in patients with chronic hepatitis B.

Off-therapy outcomes following the cessation of nucleos(t)ide analog (NA) therapy in patients with chronic hepatitis B (CHB) are dependent on hepatitis B surface antigen (HBsAg) levels at the time of discontinuation and patient race, according to the results of a study published in Gastroenterology.

Over 1500 patients with CHB who were positive for HBsAg, negative for Hepatitis B e antigen (HBeAg), and virally suppressed at the time of NA discontinuation were included. The international, multi-center cohort study excluded patients with hepatocellular carcinoma, coinfections such as Hepatitis C and/or HIV, and patients who had received treatment with pegylated- (PEG-) interferon within the previous 12 months.

The primary outcome was HBsAg loss, considered a functional cure of CHB. Secondary outcomes included virological relapse, defined as a single elevation of Hepatitis B DNA of at least 2000 IU/mL, retreatment, and liver-related concerns like hepatic decompensation.

In total, 1552 patients were included in the study. The mean age at the cessation of therapy was 52.9±11.3 years, 72.3% were men, 86.7% were Asian, and 11.3% were White. Most patients were treated with entecavir (63.2%) or tenofovir disoproxil fumarate (27.1%) prior to discontinuation of therapy.

White patients had a significantly higher cumulative probability of HBsAg loss compared with Asian patients (36.5% vs 10.9%; P <.001). Patients with HBsAg <100 IU/mL had the most favorable outcomes, independent of race. However, the HBsAg threshold needed at NA withdrawal to obtain a 30% cumulative probability of HBsAg loss was much higher for White compared with Asian patients, at <1000 IU/mL and <100 IU/mL, respectively.

Virologic relapse occurred in over 80% of patients by 48-months, with over half of patients requiring retreatment. Hepatic decompensation was rare, only occurring in 19/1552 patients, though the fatality rate of decompensation was over 35%.

Investigators note their study is limited by variations in follow-up visit length and frequency. Additionally, misclassification bias for cirrhosis and hepatocellular carcinoma may have been present. Finally, hepatitis B virus genotyping was unable to be performed.

Researchers concluded, “While we may be able to discern which patient is more likely to achieve functional cure based on end of therapy profiles, it is still unclear what, and when, preemptive measures need to be taken to prevent severe hepatic flares which often lead to severe or even fatal outcomes.”

Disclosure: The authors declared affiliations with biotech, pharmaceutical, and/or device companies. Pleases see the original reference for a full list of author disclosures.


Hirode G, Choi HS, Chen C-H, et al. Off-therapy response after nucleos(t)ide analogue withdrawal in patients with chronic hepatitis B: an international, multi-center, multi-ethnic cohort (RETRACT-B study). Gastroenterol. Published online November 9, 2021. doi: 10.1053/j.gastro.2021.11.002