Treatment response to bulevirtide is linked to amelioration of portal hypertension in patients with chronic hepatitis D
Lisa Sandmann, Mathias Jachs, Tammo L. Tergast, Lukas Hartl, Birgit Bremer, Martin A. Kabelitz, Michael Schwarz, Julius F.M. Egge, Lorenz Balcar, Benedikt Silvester Hofer, Christine S. Falk, Albert Friedrich Stättermayer, Markus Cornberg, Michael Trauner, Katja Deterding
TL;DR
Treatment with bulevirtide reduces portal hypertension in chronic hepatitis D patients who respond to the therapy.
Contribution
Shows that bulevirtide treatment reduces portal hypertension only in patients meeting specific treatment response criteria.
Findings
Bulevirtide significantly decreased hepatic venous pressure gradient in responders but not in non-responders.
Combined response patients showed complete HVPG response and improved biomarkers of inflammation and endothelial dysfunction.
Bulevirtide treatment improved clinical and biological markers only in patients meeting defined response criteria.
Abstract
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. 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. Of 34 patients receiving BL HVPG measurement, 20 patients with paired HVPG measurement…
Genes, proteins, chemicals, diseases, species, mutations and cell lines named across the full text — each resolved to its canonical identifier and authoritative record.
Click any figure to enlarge with its caption.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5Peer Reviews
No public reviews on file for this paper yet. If you reviewed it on a platform where reviews are public (OpenReview, ICLR, NeurIPS, ICML), you can paste yours below so the community can read it here.
Videos
No videos yet. Explain this paper in a talk, walkthrough, or lecture? Add one.
Taxonomy
TopicsLiver Disease and Transplantation · Liver Disease Diagnosis and Treatment · Hepatitis C virus research
Introduction
Portal hypertension (PH) is a major cause of morbidity and mortality in patients with advanced chronic liver disease.1 PH is the key driver and consequence of bacterial translocation, systemic inflammation, and immune dysfunction leading to hepatic decompensation and liver failure. In particular, patients with clinically significant portal hypertension (CSPH) are at risk of developing liver-related complications regardless of the etiology of the underlying liver disease.2 Thus, also in rare diseases such as chronic hepatitis D (CHD), CSPH is associated with the occurrence of liver-related complications.3 Importantly, successful treatment of the underlying liver disease is associated with improvement in PH, which translates into favorable clinical outcome.4^,^5 For chronic HCV infection, antiviral treatment has been shown to significantly reduce or even normalize PH6^,^7 and changes in the underlying mechanisms of PH were linked to treatment response.8^,^9 With the recent approval of the entry inhibitor bulevirtide (BLV), safe and effective HDV-specific antiviral treatment for patients with advanced CHD and PH has become available for the first time.10^,^11 Results from the phase III MYR-301 study show virological response (VR), biochemical response (BR), and combined response (CR) rates of 71%, 51%, and 45%, respectively, after 48 weeks of treatment.12 Importantly, response rates increase with longer treatment duration.13 However, the relevance of the applied response criteria on liver-related outcomes has not been investigated, so far.
Because of their advanced stage of liver disease at the time of diagnosis, patients with HDV and PH represent a subgroup of patients with a strong indication for antiviral treatment. Real-world studies showed that BLV is well tolerated in patients with advanced liver disease and non-invasively diagnosed CSPH.10 Dynamics in hepatic venous pressure gradient (HVPG) are a well-established surrogate of long-term outcome in patients with liver cirrhosis.4^,^14 So far, the course of PH during successful HDV suppression is insufficiently investigated. Specifically, it remains unclear if achieving response to BLV treatment leads to a reduction in HVPG or ameliorates pathophysiological mechanisms implicated in PH. In particular, the clinical relevance of achieving the currently proposed response criteria of maintenance therapy remains to be demonstrated.
The aim of this prospective, multicenter, observational study was to investigate the course of PH, assessed via paired HVPG measurements, in patients with HDV infection with cirrhosis receiving antiviral treatment with BLV.
Patients and methods
Study design and cohort
Patients with viremic CHD (anti-HDV positive, HDV RNA positive), PH (HVPG ≥ 6 mmHg), and planned start of HDV-targeted antiviral treatment with BLV were prospectively enrolled in this multicenter, observational study at Hannover Medical School (Hannover, Germany) and Medical University of Vienna (Vienna, Austria) from February 2020 to June 2023. Inclusion criteria were chronic HBV/HDV infection with detectable HDV RNA, reliable measurement of the HVPG, and planned start of antiviral treatment with BLV. Patients were included at the date of HVPG measurement before the start of BLV treatment. A second HVPG measurement was conducted after a minimum of 12 months of BLV treatment (M12). The current analysis cohort consists of all patients who underwent both HVPG measurements (Fig. 1). Clinical and laboratory data as well as liver stiffness (vibration-controlled transient elastography by FibroScan®, Echosens, Paris, France) were assessed at start of BLV treatment (baseline, BL) and M12. Decisions regarding BLV management were at the discretion of the treating physicians and not part of the study protocol of this observational study. Three patients treated at the Vienna General Hospital received add-on therapy with pegylated interferon alfa-2a (PEG-IFN) according to a local treatment policy previously described elsewhere.15Fig. 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. 1
Measurement of HVPG and definition of HVPG response
HVPG measurements were performed according to international recommendations.14^,^16 Briefly, under local anesthesia, the right internal jugular vein was punctured and the free and wedged hepatic venous pressure was measured. The HVPG was calculated by subtracting the free hepatic venous pressure from the wedged hepatic pressure and the mean of three measurements represents the final value. In case of non-selective beta blocker treatment, the treatment was paused 5 days before HVPG measurement. Only technically reliable HVPG measurements were considered. PH was defined according to current guidelines with an HVPG of >5 mmHg defining PH and ≥10 mmHg defining CSPH.14 A clinical meaningful change in HVPG (‘HVPG response’) was defined by a ≥10% decline in HVPG at the on-treatment HVPG measurement (M12).[17], [18], [19] Dynamics in HVPG were also explored in patients with subclinical PH at BL, in whom resolution of PH, that is, regression of the HVPG to normal values, is the most desirable endpoint.4
Evaluation of treatment response
Treatment response was assessed according to established response criteria from clinical trials12 at the time point of the follow-up HVPG measurement (M12), with (i) VR being defined as ≥2 log_10_ HDV RNA decline or HDV RNA undetectable (TND), (ii) BR as alanine aminotransferase (ALT) normalization according to the local laboratory, and (iii) CR as the combination of VR and BR. HDV RNA was measured according to the local standards by using the RoboGene quantification assay (Robogene HDV RNA Quantification Kit 2.0, Roboscreen, Leipzig, Germany) (Hannover Medical School) or a validated in-house HDV RNA quantification assay (Medical University of Vienna). For quantitative analyses, HDV RNA levels quantified by the in-house assay were converted from cp/ml to IU/ml by applying the conversion factor of 37.15 Importantly, local HDV RNA quantification assays remained unchanged throughout the study and virological treatment response was determined based on the original value from the local standard.
Exploratory analysis of PH-related biomarkers and systemic inflammatory markers
To investigate changes in pathophysiological mechanisms related and/or contributing to PH, markers of bacterial translocation (lipopolysaccharide-binding protein), macrophage activation (sCD163), (dys)angiogenesis/endothelial dysfunction (angiopoietin-1 [Ang1] and -2 [Ang2], vascular endothelial growth factor) and fibrogenesis (transforming growth factor beta, platelet-derived growth factor) were measured in patient serum samples before and at M12 by ELISA or as part of the 48 cytokines and chemokines Luminex-based multiplex bead assay (additional information provided in the Supplementary data). Changes in systemic inflammation (SI) were assessed by analyzing serum concentrations of 48 cytokines and chemokines by using the Luminex-based multiplex bead assay (Bio-Plex Pro™ Human Cytokine 48-plex Screening Panel, catalogue no. 12007283, BioRad Laboratories, Hercules, CA, USA) following the manufacturer’s instructions. Patients with add-on PEG-IFN treatment (n = 3) were excluded for analyses of SI markers.
Statistical analysis
Categorical variables are presented as numbers and proportions and were analyzed with χ^2^, Fisher’s exact, or McNemar test. Continuous variables are reported as median with IQR or mean with standard deviation as indicated. Parameters were tested for normal distribution with Shapiro–Wilk test and analyzed using Mann–Whitney U or Wilcoxon rank statistics, or paired or unpaired t test as required. Values of p <0.05 were considered statistically significant. All statistical analyses were conducted using IBM SPSS Statistics (Version 28, IBM Corp., Armonk, NY, USA), GraphPad Prism version 10.2.1 for Windows (GraphPad Software, Boston, MA, USA) and R (version 4.2.0, R Foundation for Statistical Computing, Vienna, Austria)20 with the package “ggplot2”.21
Ethics
The study and its protocol were approved by the ethics committee of Hannover Medical School (No. 9644_BO_S_2021, NCT04863703). The Viennese patients participated in two prospective registry studies (No. 1262/2017 [NCT03267615] and 2139/2021). All patients provided written informed consent before their inclusion. The study was conducted in accordance with both the Declaration of Helsinki and Istanbul.
Results
Study cohort and treatment management
A total of 20 patients underwent paired HVPG measurement after a minimum of 12 months of BLV treatment and comprise the study cohort for this analysis (Fig. 1). At BL, patients had a median model for end-stage liver disease (MELD) of 10 points (IQR 9–12 points) and the majority was classified with Child-Pugh A cirrhosis. PH was diagnosed in all patients and 17/20 patients had CPSH (85%) (Table 1). Median time between HVPG measurement and BLV start was 59 days (IQR 20–85 days). BLV was administered at a daily dose of 2 mg and all patients received concomitant nucleos(t)ide analog treatment. PEG-IFN was added in three patients after a median treatment duration of 11 months BLV monotherapy. All of the three patients received PEG-IFN at a dose of 90 μg/week.Table 1. Baseline and on-treatment characteristics of the study cohort.Table 1. BaselineM12p valuePatients20Male13 (65)Age (years)48 (41.3–57.0)BMI (kg/m^2^)25.8 (22.3–29.0)HDV RNA (log_10_ IU/ml)4.45 (3.35–5.57)1.21 (0.21–2.21)<0.001HBV DNA (IU/ml)10 (2.5–20)0 (0–10)0.015HBsAg (log_10_ IU/ml)4.14 (3.67–4.33)4.0 (3.57–4.19)0.004AST (U/L)70 (47–148)41 (30–62)0.001ALT (U/L)72 (62–117)33 (23–45)<0.001Bilirubin (μmol/L)16 (13–23)16 (9–28)0.896Creatinine (μmol/L)66 (54–82)71 (51–85)0.401Albumin (g/L)36.9 (33–40)37.5 (34.8–42)0.064gGT (U/L)55 (34–91)34 (19–51)<0.001Platelets (G/L)80 (39-109)62 (39-125)1.0INR1.3 (1.2-1.4)1.3 (1.2-1.5)0.900Bile acids (μmol/L)22 (6-46)36 (20-61)0.001MELD10 (9-12)10 (9-13)0.524Child-Pugh stage1.0 A17 (85)17 (85) B3 (15)3 (15) C0 (0)0 (0)Previous hepatic decompensation2† (10)LSM (kPa)24 (13.5-28.5)13.5 (9.0-22.7)<0.001HVPG (mmHg)12.5 (10-18.8)10.5 (8-15.8)0.013PH20 (100)19 (95)1.0CSPH17 (85)14 (70)0.250Median with interquartile range for continuous parameters and numbers with percentages for categorical variables are depicted. Wilcoxon signed rank test and McNemar test were used to compare paired variables.ALT, alanine aminotransferase; AST, aspartate aminotransferase; CSPH, clinically significant portal hypertension; HVPG, hepatic venous pressure gradient; gGT, gamma-glutamyltransferase; INR, international normalized ratio; LSM, liver stiffness measurement; MELD, model for end-stage liver disease; M12, minimum of 12 months of antiviral treatment; NA, nucleos(t)ide analog; PH, portal hypertension; TND, target not detected.†Two patients experienced one single decompensating event (ascites: n = 1, esophageal bleeding: n = 1) 5 and 3 years before BL. Values in bold denote statistical significance.
Response to treatment
Median MELD and Child-Pugh score did not change during treatment, whereas median levels of HDV RNA, ALT, aspartate aminotransferase (AST), and gamma-glutamyltransferase (gGT) declined significantly (Table 1). At M12, median liver stiffness measurement (LSM) values showed a substantial decline (24 kPa [IQR 13.5–28.5 kPa] vs. 13.5 kPa [IQR 9.0–22.7 kPa], p <0.001) and also median HVPG values significantly decreased from BL to M12 (12.5 mmHg [IQR 10–18.8 mmHg] vs. 10.5 mmHg [IQR 8–15.8 mmHg], p = 0.013) (Table 1). The second HVPG measurement was performed after a median of 13 months (IQR 12–17 months) of antiviral treatment. At this time point (M12), 60% (12/20), 70% (14/20), and 80% (16/20) of patients achieved CR, VR, and BR, respectively. In five of the 14 virological responders HDV RNA became undetectable. At M12, 65% (11/17) of the patients with CSPH at BL showed a clinical meaningful HVPG decline ≥10% (Table 2). Two of the three patients with subclinical PH at BL showed a numerical HVPG decline at M12, with PH fully resolving in one patient.Table 2. Treatment overview and on-treatment response rates.Table 2. Treatment overviewTreatment duration (months)13 (12–17)Combination with PEG-IFN3 (15)Combined response12 (60)Biochemical response16 (80)Virological response14 (70) HDV RNA TND5 (25) HDV RNA < LLOQ6 (30) HDV RNA decline ≥2 log_10_13 (65)HVPG response (mmHg)-2.5 (-4.0–0)HVPG decline ≥10%†11 (65)Median with interquartile range for continuous parameters and numbers with percentages for categorical variables are depicted.HVPG, hepatic venous pressure gradient; LLOQ, lower limit of quantification; PEG-IFN, pegylated interferon alfa-2a; TND, target not detected.†Patients with CPSH at baseline only (n = 17).
Significant improvement of portal hypertension in patients with treatment response
Significant improvement of PH from BL to M12 was present in the 12 patients with CR (15.5 mmHg [IQR 10.5–21.8 mmHg] to 12 mmHg [IQR 7.3–15.8 mmHg], p <0.001) whereas HVPG remained unchanged in the eight patients without CR (11 mmHg [IQR 10–14 mmHg] to 10 mmHg [8.5–17 mmHg], p = 0.5) (Fig. 2A and B). Similarly, significant HVPG improvement was only detected in the 14 patients with VR (14.5 mmHg [IQR 10–21.3 mmHg] to 12 mmHg [IQR 7.8–16.5 mmHg], p = 0.003) and in the 16 patients with BR (12.5 mmHg [IQR 10–20.5 mmHg] to 10.5 [IQR 8–15 mmHg], p = 0.002), but not in patients failing to meet these response criteria (Fig. 2C–F). Only two patients showed neither VR nor BR. In both patients, HDV RNA declined <2 log_10_ IU/ml and ALT levels increased from BL to M12. HVPG remained almost unchanged (from 11 mmHg to 10 mmHg) or increased (from 18 mmHg to 21 mmHg) from BL to M12 in these two patients.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. 2
Median HVPG change from BL to M12 was significantly higher in responders compared to non-responders (Table S1). When comparing patients with CR to patients only showing VR or BR, the median HVPG decline was significantly higher in patients with CR (-3.5 [IQR -5.75 to -2.25 mmHg] vs. 0.5 [IQR -0.75 to 3.0 mmHg]; p = 0.002) (Fig. S1). Importantly, median HVPG levels at BL did not differ significantly between future CR, VR, or BR responders and non-responders (Table S1). Among the patients with CSPH at BL, HVPG response was achieved by all patients who showed CR (n = 10/10), and most of virological (83%, n = 10/12) and biochemical responders (85%, n = 11/13). The proportion of CSPH patients showing a clinical meaningful HVPG response was significantly higher in patients with CR (100%, n = 10/10) compared with patients showing VR or BR only (20%, n = 1/5; p = 0.004). Meanwhile, none of the CSPH patients without any treatment response (CR/VR/BR) achieved HVPG response at M12. CSPH resolved in 18% (3/17) of patients with CSPH at BL.
Clinical outcome during follow-up
Clinical follow-up data was available for all patients with a median follow-up time of 22 (IQR 14.1–32.8) months after M12. During follow-up, only one patient developed a decompensating event (ascites) after M12. This patient did not show any treatment response (neither VR nor BR) and HVPG was increasing from BL to M12. The patient developed further decompensation and received liver transplantation 9 months after the initial decompensating event. None of the other patients showed any decompensating event during follow-up. Hepatocellular carcinoma was diagnosed in four patients after a median treatment duration of BLV of 18.8 (IQR 16–24.9) months.
Concordance of HVPG measurement and non-invasive test assessment before and during treatment with BLV
Non-invasive tests (NITs) can be applied to detect or exclude CSPH in patients with CHD.3 Whether on-treatment NIT assessment reliably detects PH amelioration during antiviral treatment of CHD is unclear. From BL to M12, median LSM values declined significantly in patients with treatment response (Table S2). They remained unchanged in patients without VR or BR, but also decreased in patients without CR (20.8 kPa [IQR 11–26 kPa] to 14.4 kPa [IQR 7.3–25 kPa], p = 0.039). The two patients without any treatment response showed divergent LSM, with one showing an increase and the other a decline. No significant differences were detected when comparing LSM results of responders and non-responders at BL and M12. However, the difference in median LSM between BR and non-responders at M12 almost reached statistical significance (Table S3).
When applying the widely used non-invasive Baveno VII criteria for CSPH ruling-in (LSM ≥25 kPa) and ruling-out (LSM ≤15 kPa and platelet count ≥150 G/L)14 to the cohort, the specificity and positive predictive values for the ‘ruled-in’ of CSPH were 100% at BL and M12. Similarly, a reliable exclusion based on the ‘ruled-out’ criteria was observed at BL and M12 (Table S4). However, the proportion of patients in the gray zone increased from 55% at BL to 75% at M12. None of the three patients with CPSH resolution at M12 would have been classifiable by NIT assessment, as all were in the gray zone.
Treatment-induced changes of PH-related biomarkers
To investigate changes in pathophysiological mechanism contributing to PH, biomarkers reflecting bacterial translocation, macrophage activation, (dys)angiogenesis, endothelial dysfunction, and fibrogenesis were analyzed. With ongoing antiviral treatment, median levels of sCD163, a marker reflecting macrophage activation, declined significantly. Interestingly, this effect was only observed in patients with treatment response and irrespective of the classification of response (Fig. 3A). Furthermore, median levels of the (dys)angiogenesis and endothelial dysfunction marker Ang2 declined significantly from BL to M12. This decline was only observed in the subgroups of patients with treatment response and not in those without (Fig. 3B). No significant differences were observed when comparing BL and M12 levels of LBP, TGFb, PDGF, VEGF, Ang1, or the Ang2/Ang1 ratio (Table S5). Median cytokine levels at BL did not differ between future combined, virological, or biochemical responders and non-responders (Table S6). Similar results were obtained when stratifying according to clinical meaningful HVPG response (Table S7).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. 3
Changes of systemic inflammation in patients with treatment response
No significant differences were detected for levels of C-reactive protein or white blood cell count when comparing BL and M12 results of treatment responders and non-responders (Table S8). However, when comparing the comprehensive panel of SI markers during antiviral treatment, CR and non-responders showed different patterns of SI changes (Fig. 4A and B). In patients with CR, significant declines of interleukin-1 receptor antagonist (IL-1RA), interleukin-2 receptor alpha (sCD25), interferon gamma (IFNγ), hepatocyte growth factor (HGF), and macrophage inflammatory protein-1 alpha (CCL3/MIP-1a) were detected from BL to M12, while no significant differences were present in patients without CR. Comparable patterns of SI changes were present in patients with VR and BR (Fig. 4C and E). By contrast, patients without treatment response showed a strong numerical increase of IL-6 levels from BL to M12. This increase was highest in patients without BR.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.Fig. 4
Discussion
In this prospective, observational study of CHD patients with PH treated with BLV for a minimum of 12 months, response to treatment according to endpoints applied in clinical studies on BLV treatment was associated with clinically meaningful HVPG decreases in all or most of the patients who achieved CR or VR/BR, respectively. Meanwhile, none of the non-responders achieved HVPG response.
PH is the driving mechanism of clinical deterioration in patients with advanced chronic liver disease. Particularly, patients with CSPH are at risk of developing decompensating events thereby leading to increased morbidity and mortality.2 Also, in patients with CHD, CSPH is associated with the occurrence of decompensating events and worse outcome.3 With the availability of BLV the treatment landscape of CHD has changed significantly.22^,^23 The treatment is well tolerated and response rates increase with longer treatment duration even in patients with CSPH in whom previous treatment options, that is, PEG-IFN, were often poorly tolerated.13 Still, treatment duration is unclear and treatment response is evaluated based on the surrogate endpoints HDV RNA response (VR), ALT normalization (BR), or their combination (CR).24 Notably, particularly the decrease in HDV RNA by ≥2 log_10_ units was arbitrarily defined owing to post-hoc analyses of the first landmark study evaluating interferon treatment in CHD.25^,^26 Interestingly, interferon treatment per se has previously been associated with clinical benefit irrespective of treatment response.27 Meanwhile, long-term follow-up studies investigating hard clinical endpoints such as improvement of patient survival by the achievement of response to treatment are lacking. HVPG response is a well-established surrogate for clinical benefit and is recommended for clinical studies on PH according to international consensus.14 Intriguingly, all patients who achieved CR in our cohort also achieved HVPG response. Our findings corroborate the previously demonstrated findings for chronic HCV infection, where several studies investigated the effect of antiviral treatment on PH either evaluated by HVPG measurement4^,^7^,^28 or NITs.29^,^30 Interestingly, the achievement of HVPG response protected patients from future hepatic decompensation,4 which is also demonstrated by the clinical follow-up data of our cohort.
Importantly, recent data have shown that also in CHD, the absence of CSPH identifies a subgroup of patients with no or only very low risk of developing decompensating events.3 Therefore, the high rate of clinical meaningful HVPG decline in patients responding to antiviral treatment, as shown in the present study, strengthens the clinical relevance of the suggested on-treatment response criteria. Meanwhile, we observed ubiquitous decreases in LSM, the most relevant CSPH-NIT, in all patients, including those without CR. Notably, early LSM decline during antiviral treatment is most likely linked to the regression of hepatic inflammation, for which ALT decline or ALT normalization is a surrogate marker.31^,^32 Patients without CR can still show BR, which explains the previously mentioned findings. The extent to which and at what point during antiviral treatment the decline in LSM actually reflects regression of fibrosis would need to be investigated in future studies. Along this, future studies comprising larger cohorts may focus on the diagnostic value of LSM in predicting events during or following BLV treatment in CHD, similar to the studies conducted for chronic HCV infection and antiviral treatment.4^,^6^,^28^,^29
Little is known about the impact of antiviral treatment in CHD on the pathophysiological mechanisms of PH. In our study, markers of macrophage activation (sCD163) and (dys)angiogenesis (Ang2) declined significantly during treatment in patients with treatment response. Both parameters have been investigated in the context of chronic HCV infection and antiviral treatment with declining levels being associated with treatment response.8^,^33 Furthermore, levels of sCD163 positively correlated with the severity of PH in patients with cirrhosis.34^,^35 Circulating Ang2 levels decreased in patients achieving HCV cure and were linked to an improvement in PH in patients with CSPH before antiviral treatment.8 Accordingly, higher Ang2 levels after antiviral treatment were associated with post-treatment hepatic decompensation. Our results are consistent with published data on chronic HCV and HBV infection. However, it is not possible at present to distinguish whether the changes are due to the resolution of hepatic inflammation as a result of antiviral treatment or to a regression of fibrosis. Interestingly, analyses of SI biomarkers revealed different patterns of change in treatment responders and non-responders. By reducing the viral load, antiviral treatment leads to pathogen reduction and regression of liver inflammation, which could also be reflected in changes of SI biomarker. In addition, improvement of PH could also lead to a reduction of systemic inflammation. PH is associated with systemic inflammation,36 and effective treatment of PH has been shown to reduce systemic inflammation.35 In our cohort, the most striking differences appear to be present in declining levels of IL-1RA, sCD25/interleukin-2 receptor alpha, IFNγ, HGF, and CCL3/MIP-1a in responders and increasing levels of IL-6 in non-responders. Data on dynamics in SI during antiviral treatment in CHD are scarce. Three studies investigated selected cytokines during PEG-IFN treatment37^,^38 of which only one included off-treatment data.39 In the latter, mean levels of IFNγ did not change significantly between BL and 6 months off-treatment in patients with VR. However, comparability to our study is questionable, as treatment regimen and response criteria differed. Other markers have been investigated in the context of chronic HCV infection and antiviral treatment. Higher levels of IL-1RA were present in patients with ongoing HCV infection, while declining levels were observed after HCV cure.40^,^41 Similarly, declining levels of CCL3/MIP-1a were observed in patients with HCV receiving antiviral treatment,42^,^43 whereas higher levels of HGF were detected in patients with more advanced liver disease irrespective of the etiology of liver disease.44 Overall, relative decrease of SI was present in patients with treatment response in our cohort. By contrast, non-responders showed a relative increase in IL-6, a pro-inflammatory cytokine that has been shown to be elevated in patients with advanced liver disease and thus serves as a predictor of decompensating events.45
Our study has limitations. First, we could only include a relatively small number of patients. It is possible that a larger cohort would have led to different results in the analysis of exploratory endpoints such as LSM or markers of systemic inflammation. However, CHD is an orphan disease and HVPG measurements are only performed in specialized centers. Importantly, the observed results regarding the HVPG response were striking, clearly linking the achievement of surrogate treatment endpoints to HVPG response even in a limited number of patients. Second, the treatment decision was based on the treating physician's decision and was not part of the study protocol of this observational study. Therefore, three patients received add-on treatment with PEG-IFN after a median of 11 months of BLV monotherapy. As the main objective of this study was to investigate the impact of treatment response on HVPG regardless of treatment regimen, we do not see any relevant impact on the main findings of this study. Two of the three patients receiving add-on PEG-IFN showed VR, BR, and CR whereas one patient was classified as a non-responder (virological and biochemical non-response). Importantly, patients receiving add-on PEG-IFN treatment were excluded from analyses of SI markers, as a considerable confounding effect of PEG-IFN is expected. Additionally, BR and CR rates in our study were higher than those reported in the phase III clinical study. These differences are most likely explained by the differences between the cohorts. Our study exclusively included patients with cirrhosis and PH, whereas only 47% of the patients in the clinical study had liver cirrhosis. Additionally, median ALT levels at baseline were lower in our cohort compared with the phase III clinical study, which can be explained by the higher rates of advanced liver disease. Overall lower ALT levels at baseline are likely to result in higher rates of normalized ALT levels at follow-up, which explains the higher rate of BR and CR in our study cohort. When comparing our results with those of other real-life cohorts including patients with advanced liver disease, the VR and BR rates were comparable.46
In conclusion, this prospective observational study demonstrates that response to antiviral treatment with BLV in patients with CHD and PH is associated with a clinically meaningful decrease in HVPG and improvement of biomarkers reflecting liver disease activity and progression. The findings of our study provide for the first time strong evidence for the validity and clinical relevance of the currently suggested response criteria for antiviral therapy in advanced CHD, as their achievement is linked to a HVPG response as a key surrogate for clinical benefit in regard to favorable long-term outcomes.
Abbreviations
ALT, alanine aminotransferase; Ang1, angiopoietin-1; Ang2, angiopoietin-2; AST, aspartate aminotransferase; BL, baseline; BLV, bulevirtide; BR, biochemical response; CHD, chronic hepatitis delta; CR, combined response; CSPH, clinically significant portal hypertension; gGT, gamma-glutamyltransferase; HGF, hepatocyte growth factor; HVPG, hepatic venous pressure gradient; IFNγ, interferon gamma; IL-1RA, interleukin-1 receptor antagonist; INR, international normalized ratio; LSM, liver stiffness measurement; M12, treatment month 12; MELD, model for end-stage liver disease; MIP-1a, macrophage inflammatory protein-1 alpha; NITs, non-invasive tests; PEG-IFN, pegylated interferon alfa-2a; PH, portal hypertension; SI, systemic inflammation; TND, target not detected; VR, virological response.
Financial support
LS was partially funded by the Advanced Clinician Scientist program of the German Center for Infection Research (DZIF). The study was partially funded by HiLF I of Hannover Medical School.
Authors’ contributions
Conception and design of the study: LS, MJ, TLT, TR, BM. Funding acquisition: LS, BM. Acquisition of data: LS, MJ, M S, LB, BSH, AFS, JFME, BB, CSF, KD, MM, BM. Data analysis: LS, MJ, MAK. Interpretation of data: LS, MJ, HW, TR, BM. Drafting of the manuscript: LS, MJ. Reviewing and editing: all authors. Final approval of the manuscript: all authors.
Data availability
Data are available upon reasonable request.
Conflicts of interest
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.
The reference list from the paper itself. Each links out to its DOI / PubMed record.
- 1D'Amico G.Garcia-Tsao G.Pagliaro L.Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies J Hepatol 4420062172311629801410.1016/j.jhep.2005.10.013 · doi ↗ · pubmed ↗
- 2Ripoll C.Groszmann R.Garcia-Tsao G.Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis Gastroenterology 13320074814881768116910.1053/j.gastro.2007.05.024 · doi ↗ · pubmed ↗
- 3Jachs M.Sandmann L.Hartl L.Validation of Baveno VII criteria and other non-invasive diagnostic algorithms for clinically significant portal hypertension in hepatitis delta J Hepatol 8120242482573847961210.1016/j.jhep.2024.03.005 · doi ↗ · pubmed ↗
- 4Mandorfer M.Kozbial K.Schwabl P.Changes in hepatic venous pressure gradient predict hepatic decompensation in patients who achieved sustained virologic response to interferon-free therapy Hepatology 712020102310363136576410.1002/hep.30885 PMC 7155089 · doi ↗ · pubmed ↗
- 5Manolakopoulos S.Triantos C.Theodoropoulos J.Antiviral therapy reduces portal pressure in patients with cirrhosis due to H Be Ag-negative chronic hepatitis B and significant portal hypertension J Hepatol 5120094684741961633910.1016/j.jhep.2009.05.031 · doi ↗ · pubmed ↗
- 6Mandorfer M.Kozbial K.Schwabl P.Sustained virologic response to interferon-free therapies ameliorates HCV-induced portal hypertension J Hepatol 6520166926992724231610.1016/j.jhep.2016.05.027 · doi ↗ · pubmed ↗
- 7Lens S.Baiges A.Alvarado-Tapias E.Clinical outcome and hemodynamic changes following HCV eradication with oral antiviral therapy in patients with clinically significant portal hypertension J Hepatol 732020141514243253506010.1016/j.jhep.2020.05.050 · doi ↗ · pubmed ↗
- 8Bauer D.Kozbial K.Schwabl P.Angiopoietin 2 levels decrease after HCV-cure and reflect the evolution of portal hypertension Dig Liver Dis 542022122212293538297410.1016/j.dld.2022.02.013 · doi ↗ · pubmed ↗