Letter: Should HBV Therapy Be Stopped Based on HBsAg Level Alone?

We read with interest the article 'An open-label, randomized trial of different re-start strategies after treatment withdrawal in HBeAg-negative chronic hepatitis B' by Asgeir et al. [1] The study explored the hypothesis of delaying antiviral therapy restart after stopping treatment to allow for immune reconstitution leading to a higher rate of HBsAg loss. While this is a novel concept, we have questions about the patient selection and the feasibility of the study. The RETRACT-B study published in 2022 provided convincing evidence that patients with qHBsAg >1000 IU/mL at end-of-therapy had significant relapse rates regardless of their ethnic background [2]. In the study by Asgeir et al., 67.7% of the patients had qHBsAg levels above 1000 IU/mL. None of the patients with qHBsAg >1000 IU/mL achieved HBsAg loss regardless of their assigned treatment restarting arms. These results were consistent with the observations in the RETRACT-B study. With this predictable universal relapse rate associated with high HBsAg titers prior to stopping treatment, the study could not address the hypothesis adequately. We do understand that the study was likely conceived and carried out prior to the knowledge of the more recent publications. Stopping antiviral therapy on patients who were previously stable on medication was not without risks. As the authors noted, 25.4% and 14.1% of the patients in the high- and low-threshold groups, respectively, experienced severe medical events upon treatment withdrawal. It is known that integrated HBV DNA (iDNA), in addition to cccDNA, can generate HBsAg. The proportion of iDNA-produced HBsAg is particularly high among patients with HBeAg-negative chronic hepatitis B [3]. Our current qHBsAg assay cannot distinguish the sources of the serum HBsAg. Patients with functional cure by definition have transcriptionally silent cccDNA. It would be ideal if we could apply biomarkers other than qHBsAg alone to determine treatment withdrawal to prevent potential significant morbidities. Serum HBV RNA and hepatitis B core-related antigen (HBcrAg) are surrogate markers of cccDNA. Recent report suggested that serum HBV RNA levels, along with qHBsAg, could be utilised in selecting patients for treatment withdrawal studies to maximise the benefits [4]. The study observed that those with detectable HBV RNA and HBsAg >100 IU/mL prior to treatment withdrawal had significantly higher virological, biochemical relapses and hepatitis flare compared to those with undetectable HBV RNA and HBsAg <100 IU/mL. Similarly, using HBcrAg cut-off value with a low end-of-therapy HBsAg level was reported to better predict HBsAg loss and prevent HBV relapse [5]. The application of a combination of novel virological markers, therefore, may enhance our ability to select patients with high probability of HBsAg loss after antiviral therapy cessation. Stopping therapy, however, should be considered a temporary solution until the availability of new therapeutic modalities that can offer durable cure with definite treatment duration. Naeem A. Khan: conceptualization, writing – original draft, writing – review and editing, visualization. Syed B. Shah: conceptualization, writing – original draft, writing – review and editing, visualization. Umar I. J. Choudhary: writing – review and editing, conceptualization. A. Ullah: conceptualization, writing – review and editing. Saeed Ahmad: conceptualization, writing – review and editing. V. Patwardhan: conceptualization, writing – original draft, writing – review and editing, supervision, validation. The authors declare no conflicts of interest. This article is linked to Johannessen et al papers. To view these articles, visit https://doi.org/10.1111/apt.18147 and https://doi.org/10.1111/apt.18439. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.