Editorial: Bile Acids Under Bulevirtide: A Pharmacodynamic Signature, Not a Prognostic Biomarker

Chronic hepatitis D (CHD) remains the most severe form of viral hepatitis, with accelerated progression to cirrhosis and hepatocellular carcinoma [1, 2]. Its true prevalence is likely underestimated, owing to inconsistent HDV screening and limited uptake of HDV reflex testing in primary care [3]. Bulevirtide (BLV), the first approved therapy for CHD, blocks the sodium taurocholate co-transporting polypeptide (NTCP), thereby preventing hepatocyte entry of the hepatitis D virus (HDV) [4]. Because NTCP is also the principal uptake transporter for conjugated bile acids (BA), pharmacological blockade inevitably shifts BA from the hepatocyte into the circulation [5]. This asymptomatic elevation has become a recognised pharmacodynamic hallmark of BLV therapy. However, to what extent does this biochemically apparent shift translate into meaningful clinical outcomes? In this issue of Alimentary Pharmacology & Therapeutics, Hintersteininger and colleagues address this pragmatic question with a long-term, real-world analysis of 25 patients receiving BLV at a single tertiary centre, with follow-up extending to 120 weeks [6]. Their findings are clear and clinically important. First, baseline BA mirrored underlying liver disease severity, rising progressively from compensated advanced chronic liver disease without portal hypertension (4.7 μmol/L) to patients with portal hypertension or decompensation (≈15–19 μmol/L). However, from a therapeutic perspective, neither absolute on-treatment BA nor change from baseline (ΔBA) correlated with HDV-RNA decline at week 48 or any later time point. A virologic response rate of 68% at W48 consistent with a pivotal trial [4] and recent real-world data [7] were achieved irrespective of the magnitude of BA elevation. Additionally, although baseline BA was significantly higher in patients reporting on-treatment pruritus, on-treatment BA levels did not differ between patients with and without pruritus, nor did they correlate with self-reported compliance. Finally, BA promptly normalised after treatment discontinuation, dispelling lingering concerns about cumulative cholestatic injury. These data extend the shorter term observations of Deterding et al. [8] and reinforce a biologically coherent message: elevated serum BA during BLV therapy is a predictable consequence of drug–transporter interaction rather than a biomarker of antiviral potency, adherence, or toxicity. Monitoring BA to gauge NTCP saturation, treatment response, or compliance therefore cannot be recommended. Conversely, clinicians should not be alarmed by substantial BA rises, which remained dissociated from pruritus severity and from treatment discontinuation in this and earlier cohorts. Caveats remain. The rarity of HDV inherently limits sample size and statistical power, and only total BA were analysed; conjugated versus unconjugated fractions and individual BA species may carry information not captured here. Because BA composition varies across liver disease etiologies [9], future studies integrating targeted metabolomics with HDV kinetics and exploring BA-mediated immunomodulation through FXR and TGR5 [10] might refine our understanding of the gut–liver–virus axis under sustained NTCP inhibition. Ultimately, BA elevation should be viewed as a predictable pharmacodynamic effect rather than a clinical concern. In the absence of proven surrogate markers to replace current monitoring protocols, HDV-RNA and ALT remain the definitive standards for assessing treatment success in patients with HDV. Apichat Kaewdech: conceptualization, writing – original draft. Pimsiri Sripongpun: conceptualization, writing – review and editing, visualization, supervision. The authors have nothing to report. This article is linked to Hintersteininger et al. paper. To view this article, visit https://doi.org/10.1111/apt.70675. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.