The times they are a-changing – A refined proposal for finite HBV nucleos(t)ide analogue therapy

Although discontinuation of nucleos(t)ide analogue (NA) treatment before HBsAg loss is part of all current hepatitis B virus (HBV) treatment guidelines for HBeAg-positive patients who achieved HBeAg seroconversion, a treatment endpoint known to be associated with silencing of HBV transcriptional activity and restoration of HBV-specific immune control, it is still highly controversial whether it is even appropriate to consider NA discontinuation before HBsAg loss in the HBeAg-negative phase. Despite the growing evidence that a relevant, albeit small, proportion of patients with HBeAg-negative disease can be cured by stopping NA treatment, the fear of discontinuation-associated relapse and the uncertainty of how to predict off-therapy response and monitor patients after discontinuation have generated scepticism and subsequently led to low implementation of this concept in the clinic. In this article, we propose a concept in which NA discontinuation-associated relapse is an integral part of the stop-to-cure approach and ultimately the trigger for achieving HBsAg loss. However, the relapse in this sense only becomes functionally effective if HBV-specific immune reinvigoration and silencing of HBV transcriptional activity have been achieved previously under the NA treatment period. The probability with which a functional cure can be achieved but also the severity of post-discontinuation flares depends on the underlying baseline HBV transcriptional activity when NA was started as well as the duration of NA treatment, both factors that we should consider as we move towards individualised cure approaches in the future.