Editorial: Bile Acids Under Bulevirtide—A Pharmacodynamic Signature, Not a Prognostic Biomarker. Authors' Reply

We sincerely thank Kaewdech and Sripongpun [1] for their insightful editorial and discussion of our study [2] concerning bile acid (BA) dynamics during and after BLV treatment in patients with chronic hepatis D (CHD). We fully agree with their interpretation that BA elevations under bulevirtide therapy primarily reflect on-target NTCP inhibition (i.e., pharmacodynamics) rather than antiviral efficacy. One finding that particularly surprised us was that even virological non-responders exhibited marked NTCP mediated increases in circulating BA levels throughout the entire follow-up period of 120 weeks. This further supports the concept that pharmacodynamic target engagement can occur independently of antiviral response and suggests a mechanistic dissociation between NTCP blockade and effects on HDV replication. Moreover, BA dynamics did not predict adverse events, nor did they reflect compliance with therapy. Consequently, monitoring BA levels during or after bulevirtide treatment is not recommended in routine clinical practice. To date, no standardised criteria for discontinuation of BLV treatment have been established. W240 data from the MYR301 study [3] suggest that a prolonged duration of HDV-RNA suppression (i.e., ≥ 96 weeks) prior to treatment cessation associate with low relapse rates. In addition, emerging real-world evidence indicates that discontinuation of BLV following sustained long-term HDV-RNA suppression appears to be safe [4, 5]. In this context, our finding on the complete reversibility of BA elevations observed after treatment discontinuation [2] is reassuring, as it indicates lack of any persisting impact on BA homeostasis despite substantial increases in serum BA concentrations during therapy. We agree that more detailed characterisation of BA composition may be highly informative. Beyond a potential role for treatment monitoring, BA profiling could eventually provide prognostic insights and may help identify distinct biological response patterns during chronic NTCP inhibition. CHD remains the most severe form of viral hepatitis and is associated with rapid progression to cirrhosis, hepatic decompensation and hepatocellular carcinoma [6-8]. Despite the important therapeutic advances facilitates by bulevirtide [5, 9, 10], there remains a substantial need for novel and more effective treatment strategies for CHD. In this context, emerging therapeutic approaches have reportedly achieved highly promising results. Combination therapy with tobevibart and elebsiran is currently being evaluated in clinical trials and may represent an important next-generation strategy to further improve antiviral efficacy, tolerability and potentially achieve functional cure in patients with CHD and thereby reduce their risk of developing cirrhosis and hepatocellular carcinoma. Marlene Hintersteininger: conceptualization, writing – original draft. Thomas Reiberger: writing – review and editing, supervision, conceptualization. Mathias Jachs: conceptualization, writing – review and editing, supervision. The authors have nothing to report. The authors did not receive any financial support for this letter. M.H. served as a speaker for Gilead and received travel support from Roche, AbbVie and Gilead. T.R. served as a speaker and/or consultant and/or advisory board member for AbbVie, Bayer, Boehringer Ingelheim, Gilead, Intercept, MSD, Siemens and W. L. Gore & Associates and received grants/research support from AbbVie, Boehringer Ingelheim, Gilead, Intercept, MSD, Myr Pharmaceuticals, Pliant, Philips, Siemens and W. L. Gore & Associates as well as travel support from AbbVie, Boehringer Ingelheim, Gilead and Roche. M.J. served as speaker and/or consultant for Gilead and Echosens and has received grant support from Gilead. This article is linked to Hintersteininger et al. papers. To view these articles, visit https://doi.org/10.1111/apt.70675 and https://doi.org/10.1111/apt.70707. The data that support the findings of this study are available from the corresponding author upon reasonable request.