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. 2025 Oct 17;8(1):101643.
doi: 10.1016/j.jhepr.2025.101643. eCollection 2026 Jan.

Treatment response to bulevirtide is linked to amelioration of portal hypertension in patients with chronic hepatitis D

Lisa Sandmann  1   2   3   4 , Mathias Jachs  1   5   6 , Tammo L Tergast  1 , Lukas Hartl  5   6 , Birgit Bremer  1 , Martin A Kabelitz  1 , Michael Schwarz  5   6 , Julius F M Egge  1 , Lorenz Balcar  5   6 , Benedikt Silvester Hofer  5   6 , Christine S Falk  4   7 , Albert Friedrich Stättermayer  5   6 , Markus Cornberg  1   2   3   4   8 , Michael Trauner  6 , Katja Deterding  1 , Mattias Mandorfer  5   6 , Heiner Wedemeyer  1   2   3   4 , Thomas Reiberger  5   6 , Benjamin Maasoumy  1   3   4
Affiliations

Treatment response to bulevirtide is linked to amelioration of portal hypertension in patients with chronic hepatitis D

Lisa Sandmann et al. JHEP Rep. .

Abstract

Background & aims: Portal hypertension (PH) drives decompensation in patients with advanced chronic liver disease. Effects of antiviral treatment with bulevirtide (BLV) and achievement of suggested treatment endpoints on PH in patients with chronic hepatitis D (CHD) are unknown.

Methods: BLV-treated CHD patients with PH were prospectively enrolled in this observational, multicenter study. Hepatic venous pressure gradient (HVPG) was measured before (BL) and after ≥12 months of BLV treatment (M12). HVPG response (≥10% decline) rates were compared between virological (VR), biochemical (BR), and combined (CR) responders vs. non-responders as defined in the BLV phase III studies. Associated changes in biomarkers of bacterial translocation, (dys)angiogenesis/endothelial dysfunction, and systemic inflammation (SI) were investigated.

Results: Of 34 patients receiving BL HVPG measurement, 20 patients with paired HVPG measurement and a BL clinically significant portal hypertension (CSPH) (≥10 mmHg HVPG) prevalence of 85% were included. At M12, HVPG significantly decreased in patients with CR (n = 12; 15.5 [IQR 10.5-21.8] to 12 [IQR 7.3-15.8] mmHg; p <0.001), VR (n = 14; 14.5 [IQR 10-21.3] to 12 [IQR 7.8-16.5] mmHg, p = 0.003), and BR (n = 16; 12.5 [IQR 10-20.5] to 10.5 [IQR 8-15] mmHg, p = 0.002); but not in non-responders. All patients with CSPH with CR (n = 10/10) and most of VR (83%, n = 10/12) and BR (85%, n = 11/13) achieved HVPG response, but no BLV non-responder. CSPH resolved in three of 17 (17.6%) patients. Markers of bacterial translocation (sCD163; p = 0.001), (dys)angiogenesis/endothelial dysfunction (Ang2; p = 0.001) and SI (IFNγ, IL-1RA, sCD25/IL-2Rα, CCL3/MIP-1alpha, HGF; all p <0.05) decreased in responders but not in non-responders.

Conclusions: Significant HVPG decreases accompanied by improvement of bacterial translocation, (dys)angiogenesis/endothelial dysfunction and SI are observed in patients with CHD achieving BLV response. These findings provide evidence for the validity and clinical relevance of the currently recommended on-treatment response criteria.

Clinical trials registration: This study is registered at ClinicalTrials.gov (NCT04863703).

Impact and implications: Portal hypertension is the main mechanism driving clinical deterioration in patients with compensated advanced chronic liver disease, for which patients with chronic hepatitis D (CHD) are at particularly high risk. This study demonstrates that in patients with CHD with portal hypertension, achieving response to antiviral treatment with bulevirtide decreases the hepatic venous pressure gradient (HVPG). Importantly, a clinical meaningful reduction in HVPG was observed only in treatment responders as defined by endpoints used in clinical trials, in particular, in all patients achieving combined response. Biomarkers of important pathophysiological mechanisms were also improved. The finding of a clinical meaningful HVPG decline in patients with CHD responding to antiviral treatment strengthens the clinical significance of the suggested on-treatment response criteria, supporting a disease-modifying effect of BLV response, likely translating into decreased morbidity and mortality in patients with CHD.

Keywords: CSPH; HDV; HVPG; Viral hepatitis.

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Conflict of interest statement

The authors declare no conflict of interest regarding this study. Outside the submitted work, the authors declare the following potential conflicts of interest: LS reports lecture honoraria and personal fees from Falk Pharma e.V., Gilead and Roche, and travel support from AbbVie and Gilead. MJ served as a speaker and consultant for Gilead. TLT served as speaker for Falk Pharma GmbH. MSch received travel support from MSD, Sandoz, BMS, AbbVie, and Gilead; received speaking honoraria from BMS and Gilead; and served as a consultant for Gilead. BSH reports travel support by Ipsen. MC reports personal fees from AbbVie, Falk Foundation, Gilead, Janssen-Cilag, GSK, MSD, Spring Bank, and SOBI. MT served as a speaker and/or consultant and/or advisory board member for Agomab, Albireo, BiomX, Falk, Boehringer Ingelheim, Bristol-Myers Squibb, Chemomab, Falk, Genfit, Gilead, Intercept, Janssen, MSD, Madrigal, Novartis, Phenex, Pliant, Regulus, and Shire, and received travel support from AbbVie, Falk, Gilead, and Intercept, as well as grants/research support from Albireo, Alnylam, Cymabay, Falk, Gilead, Intercept, MSD, Takeda, and UltraGenyx. He is also co-inventor of patents on the medical use of 24-norursodeoxycholic acid filed by the Medical Universities of Graz and Vienna. KD received lecture and personal fees from Gilead, Falk Pharma e.V., AbbVie, MSD/Merck, and Alnylam. MM served as a speaker and/or consultant and/or advisory board member for AbbVie, AstraZeneca, Echosens, Eli Lilly, Falk, Gilead, Ipsen, Takeda, and W.L. Gore & Associates and received travel support from AbbVie and Gilead as well as grants/research support from Echosens. HW has received fees for lectures and/or consultations from AbbVie, Aligos, Altimmune, Biotest, BMS, BTG, Dicerna, Enanta, Gilead, Janssen, Merck/MSD, MYR GmbH, Roche, and Vir Biotechnology. TR 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. BM served as a speaker and/or advisory board member for AbbVie, AstraZeneca, Fujirebio, Gilead, Luvos, MSD, Norgine, Roche, W.L. Gore & Associates and received research support from Altona, EWIMED, Fujirebio, and Roche. The remaining authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details.

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
Patient flow chart. BLV, bulevirtide; CSPH, clinically significant portal hypertension; HDV, hepatitis D virus; HVPG, hepatic venous pressure gradient; M12, minimum of 12 months of antiviral treatment.
Fig. 2
Fig. 2
Course of portal hypertension according to bulevirtide response status. Comparison of HVPG at baseline and M12 of patients with (A) or without (B) combined response, with (C) or without (D) virological response, and with (E) or without (F) biochemical response. Medians with interquartile range and individual values are depicted. Wilcoxon signed rank test was used to compare baseline and M12 results. ∗∗p <0.01; ∗∗∗p <0.001; n.s., not significant.
Fig. 3
Fig. 3
Comparison of PH-related biomarkers reflecting macrophage activation and (dys)angiogenesis. Comparison of baseline and M12 levels of sCD163 (A) and Ang2 (B) of all patients, and grouped according to treatment response. Medians with interquartile range are depicted. Wilcoxon signed rank test was used to compare baseline and M12 parameters. ∗p <0.05; ∗∗p <0.01; ∗∗∗p <0.001. Ang2, angiopoietin-2; M12, minimum of 12 months of antiviral treatment; sCD163, soluble cluster of differentiation 163.
Fig. 4
Fig. 4
Changes in circulating systemic inflammation profile according to bulevirtide response status. Relative mean change of systemic inflammation markers is depicted for patients with (A) and without (B) combined response, with (C) and without (D) virological response, and with (E) and without (F) biochemical response. Wilcoxon signed rank test was used to compare baseline and M12 results. ∗p <0.05; ∗∗p <0.01. BL, baseline; M12, minimum of 12 months of antiviral treatment.
See this image and copyright information in PMC

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