Editorial on ‘Early HBcrAg and Anti-HBc Levels Identify Patients at High Risk for Severe Flares After Nucleos(t)ide Analogue Cessation: A Pooled Analysis of Two Clinical Trials’

Abstract

Cessation of nucleos(t)ide analogue (NA) can lead to the restoration of the immune system and ultimately result in higher rates of functional cure in a selected group of patients with chronic hepatitis B (CHB). However, off-treatment viral relapse is common and may lead to hepatic flares, hepatic decompensation or even death [1-3]. Consequently, identifying biomarkers and high-risk patient characteristics is important.

The manuscript by Dongelmans et al. highlights that higher HBcrAg levels, lower anti-HBc levels and a higher hepatitis B core-related antigen (HBcrAg) over hepatitis B core antibody (anti-HBc) ratio at the end of treatment (EOT) can predict severe flares (alanine aminotransferase [ALT] ≥ 10× upper limit of normal [ULN]) following NA cessation [4]. Most previous studies on relapse after treatment cessation have been retrospective, focusing primarily on hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA analysis [1]. Even though recent studies have examined HBcrAg and anti-HBc, these markers have generally been studied separately and rarely analysed together [5, 6]. Additionally, most studies have focused only on EOT as the primary analysis point. This study is the first to simultaneously analyse HBsAg, HBV DNA, HBcrAg and anti-HBc to investigate severe flares after treatment cessation. Pooling data from two prospective studies [7, 8] showed that higher HBcrAg, lower anti-HBc and a higher HBcrAg/anti-HBc ratio at EOT and at 6 weeks off-treatment are associated with severe flares after NA withdrawal. As HBcrAg provides more direct evidence of HBV replication and can be detected in clinical cases, where serum HBV DNA is undetectable during NA therapy, and as anti-HBc reflects certain aspects of the host's antiviral immune response [9], the combination of these two markers offers a more accurate reflection of the host–virus interaction. Importantly, the main reason why authors have chosen the Weeks 6–8 time point was because most flares occurred early after NA withdrawal (median time of 12 weeks) [1-3]. Early risk stratification is therefore essential. Based on the HBV kinetics they reported, significant changes from EOT were observed beyond off-treatment Week 4, which is why the first subsequent assessment was used for outcome prediction.

Nevertheless, some points merit further attention. In the present study, severe flares were observed in 28% of patients, which is unusually higher than the prior studies [1-3, 5, 6]. The study by Dongelmans et al. combines data from two prospective studies, reflecting more realistic clinical significance, as retrospective studies may underestimate the exact figures. However, nearly 70% of patients were treated with tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide fumarate (TAF) in this study. As TDF is associated with faster and more pronounced post-cessation flares compared to entecavir (ETV) treatment [10], this could potentially explain the higher proportion of severe flares observed in this study. As the authors also mentioned in the article, the post-cessation kinetics of HBcrAg and anti-HBc differed between TDF and ETV treatments. Therefore, a large scale of studies is mandatory to elucidate the drugs' effect in the future.

In conclusion, the study by Dongelmans et al. introduces a novel index combining HBcrAg and anti-HBc to assess the risk of severe flares following NA cessation. These results are promising, however, due to the relatively small sample size, and validation in larger cohorts is necessary in the future.

Ming Chao Tsai: writing – original draft. Tsung Hui Hu: writing – review and editing, conceptualization.

The authors declare no conflicts of interest.

This article is linked to Dongelmans et al paper. To view this article, visit https://doi.org/10.1111/apt.18416.