ABSTRACT
Data Availability Statement
The data of this study can be available from the corresponding author upon reasonable request.
Background & Aims
There is still limited real‐life data for bulevirtide (BLV) therapy in chronic hepatitis D (CHD). We assessed the efficacy and safety of up to 2‐year BLV therapy in CHD patients treated at Greek centres.
Methods
All patients with CHD starting BLV 2 mg before the approvals of the HERACLIS_BLV_D study were included. All patients were followed according to standard clinical practice. Serum HDV RNA was determined by a polymerase chain reaction assay at a central lab. Virological response (VR) was defined as HDV RNA undetectable or decline > 2 log10 compared to baseline. Biochemical response (BR) was defined as normal ALT.
Results
Seventy‐six patients were included (45 with cirrhosis). At 12 and 24 months, rates of VR were 73% and 93%, HDV DNA undetectability 57% and 80.4%, BR 71% and 74%, and combined response (VR + BR) 51% and 74%, respectively. VR response at month 24 was associated with no baseline characteristic, while 24‐month HDV RNA undetectability was independently associated with lower baseline HDV RNA (p = 0.019) and platelets (p = 0.045). Both 24‐month BR and combined responses were independently associated with lower baseline gamma‐glutamyl transpeptidase (p = 0.004) and haemoglobin levels (p = 0.006). There was no drug‐related serious adverse event and no patient discontinued BLV due to an adverse event.
Conclusions
BLV monotherapy is safe and effective for the treatment of CHD patients followed at Greek tertiary liver centres offering increasing rates of VRHDV RNA undetectability and BR or combined response exceeding 90%, 80% and 70%, respectively, at 2 years of therapy.
Keywords: biochemical response, bulevirtide, hepatitis D, virological response
Summary.
Bulevirtide monotherapy is safe and effective for the real‐life treatment of chronic hepatitis D patients, even at advanced stages of liver disease.
Virological and biochemical response rates increase over time, exceeding 90% and 70% at 2 years of bulevirtide therapy in chronic hepatitis D.
1. Introduction
The global prevalence of chronic infection with hepatitis D virus (HDV) has been debatable and remains uncertain [1, 2], but there is no doubt that chronic HDV infection usually presents an aggressive course resulting in increased morbidity and mortality [3, 4, 5]. In particular, chronic hepatitis D (CHD) is frequently associated with rapid progression to advanced stages of liver disease including cirrhosis as well as with increased risk of hepatocellular carcinoma (HCC) [3, 4, 6, 7]. Hence, the prompt diagnosis of chronic HDV infection combined with early therapeutic intervention in patients with CHD has great clinical relevance for the optimization of management and eventually for improved outcomes [4, 5].
Key factors for the potential impact of any therapeutic intervention include the applicability and the effectiveness of therapy in the population with the disease. Until a few years ago, pegylated interferon‐alpha (pegIFNa) given as weekly subcutaneous injections for at least 48 weeks was the only recommended treatment for CHD, even though it has been officially approved only for the treatment of chronic hepatitis B but not D [4, 5, 8]. Given its limited applicability due to frequent contraindications and unfavourable safety and tolerability profile as well as its limited effectiveness, treatment with pegIFNa had an insufficient impact in patients with CHD [4, 5, 8].
Bulevirtide (BLV), an agent that inhibits the entry of hepatitis B virus (HBV) and consequently HDV in the hepatocytes by binding to and inactivating sodium/bile acid cotransporter, received conditional approval in July 2020 and full approval in July 2023 by the European Medicines Agency for the treatment of compensated CHD [8, 9]. Since 2020–2021, BLV has been increasingly used in European countries including Greece, but there is limited real‐life, especially long‐term relevant data to date [10]. Therefore, the aim of this study was to assess the efficacy and safety of up to 2 years of BLV therapy in CHD patients treated at Greek liver centers.
2. Methods
2.1. Patient Population
All adult (> 16 years old) patients with CHD treated with BLV who were followed at any of the participating centers could be included in the non‐interventional HERACLIS_BLV_D study (NCT05928000). All patients had CHD before BLV therapy, defined by elevated alanine aminotransferase (ALT) and detectable serum HDV RNA. In addition, all patients should have started BLV therapy before the approval of the study protocol in each center, which was obtained between May and November 2023, depending on the center. Thus, the decision to use BLV was not affected by the patient enrollment in this study.
The study protocol was approved by the ethics committees of the participating hospitals, and all patients provided written informed consent for their participation in the study. The enrollment period was planned to last 6 months, and 60–80 patients were anticipated to be enrolled.
2.2. Treatment—Endpoints
All patients were treated with daily BLV subcutaneous injections of 2 mg, with or without concomitant use of a nucleos(t)ide analogue (NA). Patients with concomitant use of pegIFNa could be included.
Primary endpoint for this study was combined response at week 48, whereas secondary endpoints were combined response at week 96 and complete virological response at week 48 and 96.
2.3. Follow‐Up—Definitions of Response
Patients' monitoring was based on standard clinical practice according to the existing national recommendations for the treatment of patients with CHD. All patients were followed at least every 3–6 months. A predefined case report form was used for the collection of standard clinical and laboratory data at baseline and every 6 months during BLV therapy. Cirrhosis was considered to be present in patients with histological findings of stage 5–6 fibrosis according to Ishak's classification and/or liver stiffness of > 12 kPa in case of ALT≤ULN or > 15 kPa in case of ALT>ULN as well as in patients with established ultrasonographic and/or endoscopic findings.
The upper limit of normal for ALT was 40 IU/L. During this study, serum HDV RNA levels were determined by a polymerase chain reaction assay at a central lab with a lower limit of quantification of 150 IU/mL and a lower limit of detection of 57.5 IU/mL [QIAamp Viral RNA kit and AmpliSens HDV‐FRT PCR kit (Bratislava, Slovak Republic) at RotorGene 5Plex device, QIAgen (Ohio, USA)]. However, some of the HDV RNA determinations before the patients' entry into the study were performed at other labs using various HDV RNA assays with a lower limit of detection of < 100 IU/mL.
Virological response was defined as serum HDV RNA decline > 2 log10 compared to baseline levels or HDV RNA undetectable, whereas serum HDV RNA undetectability (below the lower limit of detection of 57.5 IU/mL) was also assessed. Biochemical response was defined as normal ALT, and combined response was defined as both virological and biochemical response.
2.4. Safety
Any serious adverse event was recorded and reported according to the national regulations and the international principles of good clinical practice.
2.5. Statistical Analysis
All data were entered into a specifically designed Excel form and then SPSS database. Statistical analyses were performed using the SPSS package (IBM SPSS Statistics 29.0, SPSS Inc., IBM, Chicago, IL, USA). Categorical variables were summarised as frequencies and percentages, and their associations were determined using corrected chi‐squared or two‐sided Fisher's exact test. All quantitative variables were presented as mean ± standard deviation (SD) or as median values [interquartile range (IQR)], if they followed normal or non‐normal distribution, respectively. Comparisons of quantitative variables between two groups were performed by the t‐test or non‐parametric Mann–Whitney test, and the changes of the same quantitative variables over time were assessed by paired t‐test or Wilcoxon matched pairs test, whenever appropriate. Multivariable logistic regression analysis was used to identify independent predictors of several types of response, and their results were presented as odds ratio (OR) with 95% confidence interval (CI). Only variables that had an association or a trend for association (p < 0.10) with the dependent variable were included in the multiple logistic regression models. Statistical significance was set at p‐value < 0.05.
3. Results
3.1. Patient Characteristics
In total, 76 patients were included within the 6‐month enrollment period. Their main baseline characteristics are presented in Table 1. Their mean age was 50 ± 12 years, whereas 37 (49%) patients were males. Their mean liver stiffness was 15.9 ± 9.5 kPa, with most patients (45/76 or 59%) having cirrhosis at baseline. In particular, early decompensated cirrhosis was present in 7 (15.5%) of the 45 patients with cirrhosis (Child score 6: n = 4, score 7: n = 3). A history of past pegIFNa therapy was documented in 32 (42%) cases. No patient had co‐infection with hepatitis C virus or human immunodeficiency virus.
TABLE 1.
Main characteristics of 76 patients at the onset of bulevirtide therapy.
| Age, years | 50 ± 12 |
| Male gender, n (%) | 37 (49) |
| Body mass index, kg/m2 | 25.4 ± 3.9 |
| Country of birth, n (%) Greece | 21 (27.6) |
| Albania | 31 (40.8) |
| Romania | 4 (5.3) |
| Former USSR countries | 18 (23.7) |
| Other (Bangladesh, Pakistan) | 2 (2.6) |
| Alanine aminotrasnferase, IU/L | 75.5 (85) |
| Aspartate aminotransferase, IU/L | 62 (54) |
| Alkaline phosphatase, U/L | 83 (52) |
| Gamma‐glutamyl transpeptidase, U/L | 48 (61) |
| Albumin, g/dL | 4.0 ± 0.6 |
| Haemoglobin, g/dL | 13.9 ± 1.8 |
| White blood cells, ×103/mm3 | 4.8 ± 1.6 |
| Platelets, ×103/mm3 | 136 ± 54 |
| Liver stiffness measurement, kPa | 15.9 ± 9.5 |
| Cirrhosis, n (%) | 45 (59) |
| Decompensated cirrhosis, n/N (%) | 7/45 (15.5) |
| (Pegylated‐)interferon‐alfa in the past, n (%) | 32 (42) |
| ΗΒeAg positive, n (%) | 5 (6.6) |
| HBV DNA serum levels, IU/mL | 0 (27) |
| HDV RNA serum levels, ΙU/mL | 64 100 (406000) |
Note: Quantitative variables are presented as mean ± SD or median (interquartile range).
Abbreviation: USSR, Union of Soviet Socialist Republics.
3.2. Treatment
BLV was used as daily subcutaneous injections of 2 mg either alone in 9 (12%) or in combination with a NA in 67 (88%) patients. In particular, entecavir was used by 29, tenofovir disoproxil fumarate by 35, and tenofovir alafenamide by 3 patients. During the period of this study, no patient received therapy with pegIFNa, while only one patient had started pegIFNa in combination with BLV, but pegIFNa was discontinued after 2 months due to side effects (fatigue and neutropenia) and before the patient's enrollment in the present study.
3.3. Efficacy
Up to October 2024, 73, 70, 55, and 46 of the 76 patients completed follow‐up of 6, 12, 18, and 24 months, respectively. The rates of all types of responses increased gradually over time (Figure 1A). In particular, at 6, 12, 18, and 24 months, rates of virological response were 67%, 73%, 87% and 93%, of HDV RNA undetectability 38%, 57%, 70.4% and 80.4%, of biochemical response 66%, 71%, 74% and 74%, and of combined response 49%, 51%, 62%, and 74%, respectively.
FIGURE 1.
Rates of responses during 24 months of bulevirtide (BLV) therapy in patients with chronic hepatitis D ((A) In all patients with available data, (B) In the 46 patients who have completed 24 months of follow‐up under BLV). BR, Biochemical response; CR, Combined response; CVR, Complete virological response or HDV RNA undetectability; VR, Virological response.
Similar rates and trends of all types of responses were observed in the 46 who have completed 24 months of follow‐up under BLV (Figure 1B). At 24 months of BLV therapy, the same 34 (74%) of the 46 patients achieved both biochemical and combined response. Of those 34 patients, 29 (85%) also achieved HDV RNA undetectability. Virological response at 24 months was achieved in 43 (94%) of the 46 patients; 35/37 (95%) patients with and 8/9 (89%) patients without virological response at 12 months, whereas it was lost in 2 (5%) of 37 patients with virological response at 12 months. Of the 3 patients without virological response at 24 months, one achieved HDV RNA decline of 1–2 log10 and two had no HDV RNA decline > 1 log10; one of the latter two patients had 24‐month ALT decline > 50% of pretreatment values and the other two cases had increased 24‐month ALT levels. Moreover, HDV RNA undetectability at 24 months was achieved in 37/46 (80%) patients; 9/17 (53%) patients with detectable HDV RNA and 28/29 (97%) patients with undetectable HDV RNA at 12 months, whereas it was lost in 1/29 (3%) patients with undetectable HDV RNA at 12 months. Finally, biochemical response at 24 months was achieved in 3 (28%) of 13 patients without biochemical response at 12 months and was lost in 2 (6%) of 33 patients with biochemical response at 12 months. The only patient who lost HDV RNA undetectability from 12 to 24 months (one of the two patients who also lost virological and biochemical response from 12 to 24 months) was diagnosed to develop HCC at month 23, while the other patient who lost virological and biochemical response from 12 to 24 months was reported to have suboptimal adherence to BLV injection during the second year.
3.4. Predictors of Response
Virological response, which was achieved in all but 3 of the 46 patients assessed at 24 months, was not associated with any baseline characteristic (Table 2). HDV RNA undetectability at 24 months was found to be associated with lower platelet counts and lower baseline HDV RNA levels (Table 2). The addition of NA to BLV therapy did not affect HDV RNA or HBV DNA responses, whereas two patients with detectable low HBV DNA levels (< 50 IU/mL) at 24 months were both receiving BLV plus NA therapy. In multivariable analysis, lower baseline HDV RNA levels were independently associated with 24‐month HDV RNA undetectability (OR per log IU/mL: 0.420, 95% CI: 0.195–0.905; p = 0.027), which showed only a trend for independent association with lower platelets (OR per 103/mm3: 0.986, 95% CI: 0.971–1.001; p = 0.063).
TABLE 2.
Main baseline characteristics in chronic hepatitis D patients with and without virological response or with and without detectable serum HDV RNA at 24 months of bulevirtide (BLV) therapy.
| Virological response (Ν = 43) | No virological response (Ν = 3) | p | HDV RNA undetectable (Ν = 37) | HDV RNA detectable (Ν = 9) | p | |
|---|---|---|---|---|---|---|
| Age, years | 49 ± 11 | 58 ± 18 | 0.185 | 49 ± 10 | 51 ± 15 | 0.692 |
| Male gender, n (%) | 17 (39.5) | 3 (100) | 0.075 | 15 (40.5) | 5 (56) | 0.660 |
| Body mass index, kg/m2 | 25.5 ± 4.3 | 26.8 ± 3.2 | 0.605 | 25.7 ± 4.5 | 25.2 ± 2.8 | 0.732 |
| Alanine aminotransferase, IU/L | 69 (71) | 221 (−) | 0.192 | 77 (74) | 48 (133) | 0.353 |
| Aspartate aminotransferase, IU/L | 55 (58) | 141 (−) | 0.103 | 71 (61) | 41 (67) | 0.160 |
| Alkaline phosphatase, U/L | 83 (52) | 72 (−) | 0.834 | 83 (52) | 69 (50) | 0.513 |
| GGT, U/L | 45 (62) | 93 (−) | 0.243 | 48 (67) | 40 (69) | 0.663 |
| Albumin, g/dL | 4.0 ± 0.5 | 3.7 ± 1.4 | 0.345 | 4.0 ± 0.5 | 3.9 ± 0.8 | 0.564 |
| Haemoglobin, g/dL | 13.6 ± 1.6 | 14.2 ± 2.1 | 0.526 | 13.6 ± 1.4 | 13.8 ± 2.3 | 0.771 |
| White blood cells, × 103/mm3 | 4.8 ± 1.8 | 5.2 ± 1.3 | 0.728 | 4.6 ± 1.8 | 5.6 ± 1.6 | 0.130 |
| Platelets, × 103/mm3 | 129 ± 56 | 163 ± 54 | 0.313 | 123 ± 55 | 167 ± 47 | 0.033 a |
| Liver stiffness measurement, kPa | 16.8 ± 8.3 | 35.9 ± 25.5 | 0.324 | 17.2 ± 7.8 | 21.6 ± 18.9 | 0.282 |
| Cirrhosis, n (%) | 27 (73) | 4 (44) | 0.215 | 21 (75) | 14 (70) | 0.956 |
| (Peg)IFNa in the past, n (%) | 20 (46.5) | 1 (33) | 1.000 | 16 (43) | 5 (56) | 0.770 |
| ΗΒeAg positive, n (%) | 3 (7) | 0 | 1.000 | 3 (8) | 0 | 1.000 |
| HBV DNA serum levels, IU/mL | 0 (20) | 0 (−) | 0.177 | 0 (17) | 0 (5111) | 0.273 |
| HDV RNA serum levels, IU/mL | 63 000 (378140) | 180 000 (−) | 0.674 | 39 000 (273250) | 420 000 (7921500) | 0.007 b |
| BLV + NA/BLV only, n/n | 40/3 | 2/1 | 0.244 | 34/3 | 8/1 | 1.000 |
Note: Quantitative variables are presented as mean ± SD or as median (interquartile range). Bold values are indicated by the significance of p values.
Abbreviations: GGT, gamma‐glutamyl transpeptidase; NA, nucleos(t)ide analogue.
This is the significance for the comparison of baseline platelets in patients with and without HDV RNA detectable at 24 months.
This is the significance for the comparison of baseline HDV RNA levels in patients with and without HDV RNA detectable at 24 months.
In univariable analyses, 24‐month biochemical or combined response was found to be significantly associated with female gender, lower baseline ALT, aspartate aminotransferase (AST), gamma‐glutamyl transpeptidase (GGT) and haemoglobin levels (Table 3). In the multivariable analysis, however, 24‐month biochemical or combined response was independently associated only with lower baseline GGT (OR per 10 IU/L: 0.853, 95% CI: 0.753–0.967; p = 0.013) and haemoglobin levels (OR per g/dl: 0.136, 95% CI: 0.024–0.769; p = 0.024).
TABLE 3.
Main baseline characteristics in chronic hepatitis D patients with and without biochemical or combined response at 24 months of bulevirtide (BLV) therapy (the same patients had biochemical and combined responses at 24 months).
| Combined or biochemical response (Ν = 34) | No combined or no biochemical response (Ν = 12) | p | Multivariable logistic regression analysis OR (95% CI), p | |
|---|---|---|---|---|
| Age, years | 50 ± 11 | 49 ± 12 | 0.710 | — |
| Male gender, n (%) | 11 (32) | 9 (75) | 0.026 a | 0.835 (0.065–10.744), 0.890 |
| Body mass index, kg/m2 | 25.4 ± 4.5 | 26.1 ± 3.4 | 0.615 | — |
| Alanine aminotransferase, IU/L | 56.5 (62) | 128 (87) | 0.005 b | 0.997 (0.968–1.027), 0.846 |
| Aspartate aminotransferase, IU/L | 48 (42) | 99.5 (32) | 0.007 c | 0.993 (0.965–1.022), 0.633 |
| Alkaline phosphatase, U/L | 79 (56) | 103.5 (69) | 0.082 | 1.001 (0.974–1.029), 0.931 |
| GGT, U/L | 41.5 (62) | 78 (230) | 0.017 d | 0.853 (0.753–0.967), 0.013 e |
| Albumin, g/dL | 4.1 ± 0.5 | 3.8 ± 0.7 | 0.240 | — |
| Haemoglobin, g/dL | 13.2 ± 1.3 | 15.0 ± 1.6 | 0.002 f | 0.136 (0.024–0.769), 0.024 g |
| White blood cells, × 103/mm3 | 4.6 ± 1.9 | 5.4 ± 1.3 | 0.121 | 1.000 (0.999–1.001), 0.676 |
| Platelets, × 103/mm3 | 130 ± 60 | 135 ± 42 | 0.752 | — |
| Liver stiffness measurement, kPa | 16.9 ± 8.9 | 21.3 ± 14.8 | 0.228 | — |
| Cirrhosis, n (%) | 21 (62) | 10 (83) | 0.311 | — |
| (Peg)IFNa in the past, n (%) | 17 (50) | 4 (33) | 0.510 | — |
| ΗΒeAg positive, n (%) | 2 (6.0) | 1 (8) | 1.000 | — |
| HBV DNA serum levels, IU/mL | 0 (17) | 0 (7950) | 0.145 | — |
| HDV RNA serum levels, IU/mL | 62 000 (1698115) | 117 609 (279825) | 0.910 | — |
| BLV + NA/BLV only, n/n | 32/2 | 10/2 | 0.276 | — |
Note: Quantitative variables are presented as mean ± SD or as median (interquartile range). Bold values are indicated by the significance of p values.
Abbreviations: CI, confidence interval; GGT, gamma‐glutamyl transpeptidase; NA, nucleos(t)ide analogue; OR, Odds ratio.
This is the significance for the comparison of gender distribution in patients with and response at 24 months.
This is the significance for the comparison of baseline ALT levels in patients with and response at 24 months.
This is the significance for the comparison of baseline AST levels in patients with and response at 24 months.
This is the significance for the comparison of baseline GGT levels in patients with and response at 24 months.
This is the significance in multivariable analysis for the effect of baseline GGT levels on response at 24 months.
This is the significance for the comparison of baseline Hb levels in patients with and response at 24 months.
This is the significance in multivariable analysis for the effect of baseline Hb levels on response at 24 months.
3.5. Safety and Tolerability—Major Events
BLV therapy was generally safe and well tolerated. There was no drug‐related serious adverse event during this study and no patient discontinued BLV therapy due to an adverse event. HCC was diagnosed in two patients (male 59 years old and male 72 years old) at 23 and 30 months of BLV therapy; both patients who developed HCC had achieved HDV RNA undetectability at 12 months, but the first patient experienced HDV RNA breakthrough at HCC diagnosis. Cholangiocarcinoma was diagnosed in another patient (male 42 years old) at 3 months of BLV therapy, who achieved virological response at 6 months. All these 3 patients had cirrhosis at baseline (the second patient with HCC had decompensated cirrhosis). Lung cancer was also diagnosed in one patient (male 46 years old without cirrhosis at baseline) at 9 months of BLV therapy. Two patients have died so far; the patient with cholangiocarcinoma who died 10 months later and a 77‐year‐old patient with Child B cirrhosis at baseline (Child‐Pugh score: 7); the latter patient presented with liver decompensation (ascites) at 6 months when she still had low but detectable HDV RNA levels without virological response and died from complications of decompensated cirrhosis (variceal bleeding) at 10 months after the onset of BLV therapy. The other 6 patients with decompensated cirrhosis at baseline achieved reversion of liver decompensation by 12 months of BLV therapy (HDV RNA undetectability: 4, virological response: 1, no virological response: 1). Five (6.6%) patients without any report of adverse events were considered to have been lost to follow‐up at the time of the analysis, defined by no clinic visits for at least 12 months after their last visit.
4. Discussion
In our real‐life cohort study, BLV therapy, with or without NA, was found to achieve high and increasing rates of all types of responses in patients with CHD treated at liver clinics of tertiary centres throughout Greece. In particular, virological response using a standard definition of at least 2 log10 decline of or undetectable HDV RNA and especially HDV RNA undetectability were achieved already at month 6 in 68% and 38% of our patients, respectively, gradually increasing to 93.5% and 80% at month 24. Similarly, combined virological and biochemical response was achieved at month 6 in 47% of patients increasing to 74% at month 24, whereas biochemical response rates were 66% at month 6% and 74% at month 24 (Figure 1A). Such response rates are relatively higher compared to the respective rates reported in most previously published studies [10, 11, 12], even in clinical trials [13, 14] in which patients' follow‐up is expected to be stricter and thus patients' adherence to therapy is expected to be better compared to real‐life patients' management in clinical practice across different centres. In addition, characteristics of patients with CHD included in real‐life cohorts like ours may be worse than those of carefully selected patients enrolled in randomised clinical trials [10, 11, 14]. In particular in our cohort, not only a great proportion (almost 60%) of patients had cirrhosis, but some of them (15% of cirrhotics or 9% of all patients) had already decompensated cirrhosis at baseline.
Whether virological and biochemical responses can improve the course of patients with CHD has not been completely clarified, but they are usually considered to represent useful surrogate end points and predictors of clinical outcomes [8]. In the short term, effects of any therapy on clinical outcomes may be more easily reflected in patients with very advanced stages of the disease and therefore at high risk for events [12, 15, 16]. In our study, we included only 7 patients with decompensated cirrhosis at baseline and 6 of them had excellent clinical courses not only without progression of liver impairment but with reversion of liver decompensation (recompensation) within the first year of therapy as well, even though HDV RNA undetectability was achieved in 4 of these 6 cases. Only one patient with decompensated cirrhosis at baseline and without virological response worsened during an episode of variceal bleeding and eventually died.
A reassuring finding was that most patients without responses during the first year are achieving responses in the second year of BLV therapy, while exceptionally rare patients (≤ 5%–6%) are losing responses in the same period. In fact, loss of response was associated with specific events such as HCC development or poor compliance to treatment. Similar findings of increasing response rates with prolongation of BLV therapy in CHD have also been reported in previous studies [10, 11, 12, 14] and can be explained by the high barrier to resistance of BLV as well as its mechanism of action as an entry inhibitor that prevents de novo infection of hepatocytes having no direct antiviral activity on viral replication [17].
Although most patients with CHD respond to BLV therapy, predictors of response are always important and have not been adequately determined in this setting [10]. Similarly to previous studies, most patients' characteristics, including the presence of cirrhosis at baseline, were not found to be associated with the probability of any type of response. According to our results, however, lower baseline HDV RNA levels were independently associated with a higher probability of HDV RNA undetectability at month 24, which can be considered a reasonable finding. On the other hand, lower GGT and haemoglobin levels were independently associated with a higher probability of both biochemical and combined response at month 24. An association of higher GGT levels with worse long‐term outcomes after pegIFNa therapy in patients with CHD has been previously reported [18], but the effects of GGT and haemoglobin levels on the probability of response to BLV therapy need further confirmation.
As previously reported [15, 19], we also observed that BLV therapy was safe and well tolerated. There was no serious drug‐related adverse event and none of our patients discontinued BLV therapy due to a drug‐related adverse event. There were, however, a few patients who were lost to follow‐up and a few patients with probably suboptimal adherence to treatment, a phenomenon that can be rather important for any long‐term therapy, especially in patients with advanced stages of liver disease.
Our study had several limitations. It was a real‐life cohort study, which was prospective after patients' enrollment, but the decision to start BLV therapy was based on the physicians' individual decisions. The HDV RNA assay used in our study was not as sensitive as the assays used in randomised controlled trials (lower limit of detection 57.5 instead of 6 IU/mL) [20] and therefore the rates of at least HDV RNA undetectability might have been slightly overestimated [21], although we cannot be sure about the clinical relevance of persistently low (e.g., < 100 IU/mL) HDV RNA levels in this setting. HDV and HBV genotypes were not determined, and most probably all HDV and HBV genotypes were not represented in our cohort. It should be noted, however, that BLV appears to be active against every HDV and HBV genotype [22], whereas most of our patients should have had infections with HBV genotype D and HDV genotype 1, which are by far the most common genotypes in our area [23, 24]. Finally, detailed adherence data have not been collected so far, even though they may affect the probability of responses under treatment and deserve further study.
In conclusion, BLV therapy is safe and effective for the treatment of patients with CHD followed at Greek tertiary liver centers offering increasing rates of virological and biochemical responses exceeding 90% and 70%, respectively, at 2 years of therapy. BLV therapy can be beneficial even in patients with early decompensated cirrhosis and it is generally safe and well tolerated even in such advanced stages of liver disease. The assessment of predictors of response as well as the rates and risks of suboptimal treatment adherence in the long‐term requires further evaluation.
Author Contributions
M.P. participated in data collection, performed statistical analyses and prepared the first draft of the manuscript; V.S., K.Z., D.C., J.K., M.D., A.A., I.E., C.T., E.G., T.A., D.K., I.M., D.D., M.M., E.S., S.M., K.M., N.P., A.K., C.V., D.L., G.G., V.P., E.A., A.P., S.P., L.V., H.K., E.K., N.P., P.F., J.V., E.C., S.M., I.G. and G.D. contributed to data collection and data interpretation and made critical revisions of the manuscript; G.P. completed the study conception and study design, contributed to statistical analyses and data interpretation and made critical revisions of the manuscript. All authors have read and approved the final version of the manuscript.
Ethics Statement
The study protocol was approved by the ethics committees of the participating hospitals.
Consent
All patients provided written informed consent for their participation in the study.
Conflicts of Interest
The authors declare no conflicts of interest. J.K. has served as advisor and/or lecturer for Abbvie, Astra‐Zeneca, Bayer, Gilead, Integris, Ipsen, Merck Sharp & Dohme, Novartis and Roche and has received research grants from Bayer, Gilead, Merck Sharp & Dohme, Novartis and Roche. M.D. has served as lecturer for Gilead. I.E. has served as advisor and/or lecturer for Astra‐Zeneca, Gilead, Ipsen and Roche. E.S. has served as advisor and/or lecturer for Abbvie, Astra‐Zeneca, Genesis, Gilead, GlaxoSmithKline, Ipsen, Novo Nordisk, Roche and has received research grants from Astra‐Zeneca. K.M. has served as advisor for AbbVie, Gilead, Merck Sharp & Dohme and has received grants from Gilead, Vianex and Elpen. J.V. has served as advisor and/or lecturer for Abbvie, Astra‐Zeneca, Bayer, BioArs, Galenica, Gilead, Integris Pharma, Sobi and Viatris. S.M. has served as advisor and/or lecturer for Abbvie, Astra‐Zeneca, Bioars, Gilead, Integris, Ipsen and Roche. I.G. has served as advisor and/or lecturer for Astra‐Zeneca, Gilead, Ipsen and Roche. G.D. has received research grants from Gilead and Ipsen and has served as advisor and/or lecturer for Ipsen, Gilead, Genesis, Pfizer, Sanofi and Sobi as well as principal investigator in clinical trials of Amyndas Pharmaceuticals, Intercept Pharma, CymaBay Therapeutics, Genkyotex, Novo Nordisk, Pfizer, Regulus Therapeutics, Sobi and Tiziana Life Sciences. G.P. has served as advisor and/or lecturer for Abbvie, Albireo, Amgen, Astra‐Zeneca, BioArs, Elpen, Genesis, Gilead, GlaxoSmithKline, Ipsen, Janssen, Merck Sharp & Dohme, Novo Nordisk, Roche, Takeda and Vir Pharmaceuticals and has received research grants from Abbvie, Gilead, Takeda and Vianex.
Papatheodoridi M., Sevastianos V., Zachou K., et al., “HERACLIS_BLV_D: Increasing Response Rates During 2‐Year Bulevirtide Real‐Life Therapy in Chronic Hepatitis D,” Liver International 45, no. 7 (2025): e70151, 10.1111/liv.70151.
Funding: This work was supported by Gilead Sciences.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data of this study can be available from the corresponding author upon reasonable request.
The data that support the findings of this study are available from the corresponding author upon reasonable request.