Chronic Delta Research Articles

High Diagnostic Value of Transient Elastography for Advanced Fibrosis and Cirrhosis in Patients With Chronic Hepatitis Delta

Liver biopsy remains the gold standard for fibrosis staging in patients with chronic hepatitis delta (CHD). Here we comparatively evaluated the performance of transient elastography (TE) and biomarkers for the diagnosis of liver fibrosis in patients with CHD. 230 HDV-infected RNA-positive patients from various centers who underwent liver biopsy and liver stiffness measurements (LSM) using Fibroscan®, within a period of 6 months maximum, were investigated retrospectively. AUROC and Youden index were used to establish cut-off values of LSM. TE was compared with other noninvasive tests (NITs): APRI, Fibrosis-4 and Delta-4 fibrosis scores. Histologic fibrosis stage distribution was: 20.4% for F0-F1; 27.0% for F2; 18.7% for F3 and 33.9% for F4. TE demonstrated good diagnostic performance for detecting cirrhosis and advanced fibrosis with AUROC of 0.88 and 0.86, values, which were significantly higher than those obtained with the other NITs (P = .004 and P < .001). With a cutoff value >12 kPa for cirrhosis, sensitivity was 70.5%, specificity 86.2%, positive predictive value (PPV) 72.4% negative predictive value (NPV) 85.1% and accuracy 80.9%. Using 10.4 kPa as cut-off value for F3, sensitivity was 70.2%, specificity 83.5%, PPV 82.5%, NPV 71.7% and accuracy 76.5%. In 89% of patients with LSM ≤ 6.2 kPa, liver biopsy disclosed only absent or minimal fibrosis. TE demonstrated good diagnostic performance for advanced fibrosis and cirrhosis in CHD patients. Advanced fibrosis is highly probable for LSM values ≥10 kPa. LSM values < 6 kPa almost totally exclude significant fibrosis. Between 6 and 10 kPa, liver biopsy should be discussed.

Patient-reported outcomes in chronic hepatitis delta: An exploratory analysis of the phase III MYR301 trial of bulevirtide

Once-daily treatment of chronic hepatitis delta (CHD) with bulevirtide is well tolerated and associated with significant reductions in HDV RNA in the blood and in biochemical liver disease activity. This study explored the effects of 48-week bulevirtide treatment on health-related quality of life (HRQoL) in patients with CHD. In an open-label, randomised, Phase 3 trial, 150 patients with CHD and compensated liver disease were stratified by liver cirrhosis status and randomised 1:1:1 to no treatment (control), bulevirtide 2 mg/day, or bulevirtide 10 mg/day for 48 weeks. HRQoL was evaluated by the following patient-reported outcome (PRO) instruments at baseline, 24 weeks, and 48 weeks: EQ-5D-3L, Hepatitis Quality of Life Questionnaire (HQLQ), and Fatigue Severity Scale (FSS). Patient characteristics and HRQoL scores were balanced at baseline between the treatment (2 mg, n = 49; 10 mg, n = 50) and control (n = 51) groups. Patients receiving 2-mg bulevirtide reported significant improvements compared with controls on the HQLQ domains of role physical, hepatitis-specific limitations, and hepatitis-specific health distress. Numerically higher scores for general health, hepatitis-specific limitations, and hepatitis-specific health distress domains were reported by patients with cirrhosis who received bulevirtide vs control. FSS scores remained stable across treatment groups throughout. At week 48, patients in the 2-mg group showed greater mean improvement from baseline in health status compared with controls on the EQ-5D-3L visual analogue scale. PROs indicate that 48-week treatment with bulevirtide monotherapy may improve aspects of HRQoL in patients with CHD. Bulevirtide 2 mg is the only approved treatment for patients with chronic hepatitis delta (CHD) in the EU. Patients with CHD have worse quality of life scores than those with chronic hepatitis B. Bulevirtide treatment for 48 weeks reduced HDV RNA and alanine aminotransferase levels and was well tolerated among patients with CHD. For the first time, this study shows that patients who received bulevirtide therapy for 48 weeks reported improvements in physical and hepatitis-related quality of life domains compared to those who did not receive therapy (control group). ClinicalTrials.gov Identifier, NCT03852719.

Sodium taurocholate cotransporting polypeptide (NTCP) polymorphisms may influence HDV RNA load and early response to bulevirtide

Genetic polymorphisms in the sodium taurocholate cotransporting peptide (NTCP encoded by SLC10A1) have been described, but their role in untreated and treated patients with chronic hepatitis delta (CHD) remains unknown. Virological response (VR) to the NTCP inhibitor bulevirtide (BLV) was achieved at week 48 by >70% of patients with CHD, but nearly 15% experienced virological non-response (VNR) or partial response (PR). This study aimed to evaluate whether NTCP genetic polymorphisms affect baseline HDV RNA load and response to BLV in patients with CHD. BLV-untreated and -treated patients were enrolled in a retrospective cross-sectional and longitudinal study. Clinical and virological characteristics were collected at baseline and up to 96 weeks in the BLV-treated patients. NTCP genetic polymorphisms were identified by Sanger sequencing. Of the six NTCP polymorphisms studied in 209 untreated patients with CHD, carriers of the rs17556915 TT/CC (n= 142) compared to CT (n= 67) genotype presented with higher median HDV RNA levels (5.39 vs. 4.75 log10IU/ml, p= 0.004). Of 209 patients receiving BLV monotherapy at 2mg/day, 76 were evaluated at week 24 and 40 up to week 96. Higher mean baseline HDV RNA levels were confirmed in TT/CC (n= 43) compared to CT (n= 33) carriers (5.38 vs. 4.72 log10IU/ml, p= 0.010). Although 24-week VR was comparable between TT/CC and CT carriers (25/43 vs. 17/33, p= 0.565), the former group presented VNR more often than PR (9/11 vs. 9/23, p= 0.02) at week 24. 7/9 TT/CC genotype carriers remained VNR at week 48 of BLV treatment. The NTCP rs17556915 C>T genetic polymorphisms may influence baseline HDV RNA load both in BLV-untreated and -treated patients with CHD and may contribute to identifying patients with different early virological responses to BLV. Although several sodium taurocholate cotransporting polypeptide (NTCP) genetic polymorphisms have been described, no data are available on their potential role in modifying HDV RNA load or treatment response to bulevirtide (BLV) in patients with chronic hepatitis delta (CHD). In this study, we demonstrated that patients with CHD, either treated or untreated, carrying NTCP rs17556915 TT/CC, presented higher baseline HDV RNA levels compared to those with the CT genotype. Higher HDV RNA levels in TT/CC carriers compared to CT carriers were also confirmed in patients with CHD treated with BLV monotherapy up to 96 weeks. Furthermore, carriers of TT/CC, compared to CT genotype, more frequently showed viral non-response (VNR) than partial response (PR) at week 24 of BLV treatment, and 7/9 TT/CC genotype carriers remained VNR at week 48 of BLV treatment. This is the first study demonstrating a potential role of NTCP genetic polymorphisms in influencing HDV viral load and early virological response to BLV monotherapy. Since no direct HDV resistance to BLV has been described so far, if confirmed in larger studies, the genetic polymorphisms in NTCP may help identify patients with different patterns of early virological response to BLV.

Long-term outcome of hepatitis delta in different regions world-wide: Results of the Hepatitis Delta International Network.

Chronic hepatitis delta represents a major global health burden. Clinical features of hepatitis D virus (HDV) infection vary largely between different regions worldwide. Treatment approaches are dependent on the approval status of distinct drugs and financial resources. The Hepatitis Delta International Network (HDIN) registry involves researchers from all continents (Wranke, Liver International 2018). We here report long-term follow-up data of 648 hepatitis D patients recruited by 14 centres in 11 countries. Liver-related clinical endpoints were defined as hepatic decompensation (ascites, encephalopathy and variceal bleeding), liver transplantation, hepatocellular carcinoma or liver-related death. Patient data were available from all continents but Africa: 22% from Eastern Mediterranean, 32% from Eastern Europe and Central Asia, 13% from Central and Southern Europe, 14% from South Asia (mainly Pakistan) and 19% from South America (mainly Brazil). The mean follow-up was 6.4 (.6-28) years. During follow-up, 195 patients (32%) developed a liver-related clinical event after 3.5 (±3.3) years. Liver cirrhosis at baseline and a detectable HDV RNA test during follow-up were associated with a worse clinical outcome in multivariate regression analysis while patients receiving interferon alfa-based therapies developed clinical endpoints less frequently. Patients from South Asia developed endpoints earlier and had the highest mortality. The HDIN registry confirms the severity of hepatitis D and provides further evidence for HDV viraemia as a main risk factor for disease progression. Hepatitis D seems to take a particularly severe course in patients born in Pakistan. There is an urgent need to extend access to antiviral therapies and to provide appropriate education about HDV infection.

Efficacy of Pegylated Interferon-alpha-2a in Chronic Hepatitis Delta: Experience from a Tertiary Care Hospital in Karachi.

Chronic hepatitis D (CHD) along with chronic hepatitis B (CHB) is an important cause of morbidity and mortality in patients with cirrhosis. It is a potentially curable infection that has long awaited a good treatment option. To ascertain the efficacy of pegylated interferon (PEG-IFN)-alpha-2a in patients suffering from CHD. A tertiary care hospital experience from Pakistan. The study included 207 CHD polymerase chain reaction (PCR)-positive patients treated with PEG-IFN-alpha-2a between July 2020 and October 2022. Virological response rate (PCR negative) at weeks 24 and 48 was the primary endpoint. Secondary outcomes included partial response (>2 log reduction in PCR) and treatment failure rate (<2 log reduction in PCR). A total of 187 patients started PEG-IFN therapy, and 148 patients completed the assigned 48 weeks of therapy. Patients' mean age was 25.7 years with 65% being males. The virological response rate was 40.5% at week 24 and 32.4% at week 48. The partial response rate was 24% at both weeks 24 and 48. The treatment failure rate was 36% at week 24 and 44% at week 48. Hemoglobin, white blood cell (WBC) count, and total bilirubin were found to be predictive of treatment response. Side effects led to treatment discontinuation among eighteen patients and one patient died due to hepatic failure. Therapy with PEG-IFN-alpha-2a shows suboptimal outcomes in patients with CHD. There is a strong need for more effective alternate therapies for CHD patients. Butt N, Usmani MT, Hussain R, et al. Efficacy of Pegylated Interferon-alpha-2a in Chronic Hepatitis Delta: Experience from a Tertiary Care Hospital in Karachi. Euroasian J Hepato-Gastroenterol 2024;14(1):51-55.

GS-002 48-week off-therapy efficacy and safety of bulevirtide in combination with pegylated interferon alfa-2a in patients with chronic hepatitis delta: final results from the phase 2b, open-label, randomised, multicentre study MYR204

GS-002 48-week off-therapy efficacy and safety of bulevirtide in combination with pegylated interferon alfa-2a in patients with chronic hepatitis delta: final results from the phase 2b, open-label, randomised, multicentre study MYR204

Bulevirtide monotherapy in patients with chronic HDV: Efficacy and safety results through week 96 from a phase III randomized trial

Bulevirtide (BLV), a first-in-class entry inhibitor, is approved in Europe for the treatment of chronic hepatitis delta (CHD). BLV monotherapy was superior to delayed treatment at week (W) 48, the primary efficacy endpoint, in the MYR301 study (NCT03852719). Here, we assessed if continued BLV therapy until W96 would improve virologic and biochemical response rates, particularly among patients who did not achieve virologic response at W24. In this ongoing, open-label, randomized phase III study, patients with CHD (N= 150) were randomized (1:1:1) to treatment with BLV 2mg/day (n= 49) or 10mg/day (n= 50), each for 144 weeks, or to delayed treatment for 48 weeks followed by BLV 10mg/day for 96 weeks (n= 51). Combined response was defined as undetectable hepatitis delta virus (HDV) RNA or a decrease in HDV RNA by ≥2 log10 IU/ml from baseline and alanine aminotransferase (ALT) normalization. Other endpoints included virologic response, ALT normalization, and change in HDV RNA. Of 150 patients, 143 (95%) completed 96 weeks of the study. Efficacy responses were maintained and/or improved between W48 and W96, with similar combined, virologic, and biochemical response rates between BLV 2 and 10mg. Of the patients with a suboptimal early virologic response at W24, 43% of non-responders and 82% of partial responders achieved virologic response at W96. Biochemical improvement often occurred independently of virologic response. Adverse events were mostly mild, with no serious adverse events related to BLV. Virologic and biochemical responses were maintained and/or increased with longer term BLV therapy, including in those with suboptimal early virologic response. BLV monotherapy for CHD was safe and well tolerated through W96. In July 2023, bulevirtide was fully approved for the treatment of chronic hepatitis delta (CHD) in Europe based on clinical study results from up to 48 weeks of treatment. Understanding the efficacy and safety of bulevirtide over the longer term is important for healthcare providers. In this analysis, we demonstrate that bulevirtide monotherapy for 96 weeks in patients with CHD was associated with continued improvements in combined, virologic, and biochemical responses as well as liver stiffness from week 48at both the 2mg and 10mg doses. Patients with suboptimal virologic responses to bulevirtide at week 24 also benefited from continued therapy, with the majority achieving virologic response or biochemical improvement by week96. NCT03852719.

Quantification of serum HDV RNA by Robogene 2.0 in HDV patients is significantly influenced by the extraction methods.

Management of chronic hepatitis delta (CHD) requires reliable tests for HDV RNA quantification. The aim of the study was to compare two extraction methods for the quantification of HDV RNA in untreated and bulevirtide (BLV)-treated CHD patients. Frozen sera from untreated and BLV-treated CHD patients were tested in a single-centre study for HDV RNA levels (Robogene 2.0, Roboscreen GmbH, Leipzig, Germany; LOD 6 IU/mL) with two extraction methods: manual (INSTANT Virus RNA/DNA kit; Roboscreen GmbH, Leipzig, Germany) versus automated (EZ1 DSP Virus Kit; Qiagen, Hilden, Germany). BLV-treated patients were sampled at baseline and during therapy. Two hundred sixty-four sera collected from 157 CHD (139 untreated, 18 BLV-treated) patients were analysed: age 51 (28-78), 59% males, 90% of European origin, 60% cirrhotics, ALT 85 (17-889) U/L, HBsAg 3.8 (1.7-4.6) Log IU/mL, 81% HBV DNA undetectable, 98% HDV genotype 1. Median HDV RNA was 4.53 (.70-8.10) versus 3.77 (.70-6.93) Log IU/mL by manual versus automated extraction (p < .0001). Manual extraction reported similar HDV RNA levels in 31 (20%) patients, higher in 119 (76%) [+.5 and +1 log10 in 60; > +1 log10 in 59] and lower in 7 (4%). Among 18 BLV-treated patients, rates of HDV RNA < LOD significantly differed between the two assays at Weeks 16 and 24 (0% vs. 22%, p = .02; 11% vs. 44%, p = .03), but not at later timepoints. By contrast, virological response rates were similar. Quantification of HDV RNA by Robogene 2.0 is influenced by the extraction method, the manual extraction being 1 Log more sensitive.

Results of HDV RNA detection in male seminal fluid and female cervical swab samples using RT-PCR

Mongolia has an extremely high prevalence of hepatitis D virus (HDV), which leads to increased morbidity and mortality from hepatocellular carcinoma (HCC). HDV is the most severe form of chronic viral hepatitis (CVH). A recent study estimated that the prevalence of anti-HDV was 67.5% among hepatitis B surface antigen-positive cases in Mongolia. HDV infection is particularly prevalent in sexually active young people. The virus may be transmitted through sexual intercourse, and it is crucial to confirm this by detecting HDV RNA in semen and cervical swabs of patients with chronic hepatitis delta. This pilot study was conducted with 16 participants, including eight males and eight females. Viral RNA was isolated from the blood, male seminal fluid, and female cervical swab samples of all participants in the study. HDV RNA was quantified using RT-PCR in samples from blood, seminal fluid, and cervical swabs. This study found that the detection rate of HDV RNA differed between male and female samples, with 62.5% of seminal fluid samples in the male cohort being positive compared with 87.5% in the female cohort. The data shows a statistically significant difference between genders for the presence of HDVRNA in seminal fluid and cervical swabs (OR 0.238, 95% CI= 0.02-3.01). A significant correlation was found between blood HDV RNA quantity and HDV RNA presence status in seminal fluid and cervical swab samples, indicating a potential risk of sexual HDV transmission. The R2 values for semen and cervical swab samples were 0.1095 and 0.9755, respectively.

The cascade of care for patients with chronic hepatitis delta in Southern Stockholm, Sweden for the past 30 years.

Previous studies have shown suboptimal screening for hepatitis D virus (HDV) among patients with chronic hepatitis B (CHB). This study presents the cascade of care for HDV infection in a major secondary referral centre in Southern Stockholm, Sweden. HBsAg+ve patients attending Karolinska University Hospital (KUH) from 1992 to 2022 were identified. The prevalence of anti-HDV and/or HDV RNA positivity, interferon (IFN) therapy and maintained virological responses (MVR) after HDV treatment were assessed. Also, time to anti-HDV testing was analysed in relation to liver-related outcomes with logistic regression. Among 4095 HBsAg+ve persons, 3703 (90.4%) underwent an anti-HDV screening; within a median of 1.8 months (range 0.0-57.1) after CHB diagnosis. This screening rate increased over time, to 97.9% in the last decade. Overall, 310 (8.4%) were anti-HDV+ve, of which 202 (65.2%) were HDV RNA+ve. Eighty-five (42%) received IFN, and 9 (10.6%) achieved MVR at the last follow-up. The predictive factors for anti-HDV screening were Asian origin, diagnosis after the year 2012, HIV co-infection (negative factor) and HBV DNA level < 2000 IU/mL in univariable analysis, while HIV co-infection was the only remaining factor in multivariable analysis. Delayed anti-HDV test >5 years was independently associated with worsened liver-related outcomes (adjusted odds ratio = 7.6, 95% CI 1.8-31.6). Higher frequency of HDV screening than previously published data could be seen among CHB patients at KUH in a low-endemic setting. Receiving a delayed screening test seems to be associated with worse outcomes, stressing the need of a strategy for timely HDV diagnosis.

Pegylated interferon in the treatment of chronic delta hepatitis: the experience from real-world clinical practice

Rationale: The high prevalence of hepatitis D virus (HDV) infection in the Republic of Dagestan, significantly exceeding that in the European part of the Russian Federation, as well as the limited choice of therapeutic options, have led to the need to analyze the accumulated experience of interferon therapy in the real clinical practice to further select possible treatment regimens.&#x0D; Aim: To evaluate the efficacy of pegylated interferon alpha (Peg-IFN-) in patients with chronic hepatitis D (CHD) in real world clinical practice.&#x0D; Materials and methods: In a retrospective study, the efficacy, safety and tolerability of Peg-IFN- were analyzed in 34 patients with CHD living in the Republic of Dagestan. Main virological parameters (anti-HDV antibodies (anti-HDV), HDV RNA and HBV DNA), alanine aminotransferase levels, changes over time in liver density by elastometry, and clinical parameters (hematology and urine tests, clinical chemistry, thyroid function tests) were assessed at 24 and 48 weeks of therapy, as well as at 48 weeks after its completion.&#x0D; Results: The treatment with Peg-IFN- for 48 weeks resulted in a virological response, defined as a HDV RNA decrease by more than 2 lg copies/mL, in 32% (11/34) of the patients. A sustained virological response, defined as undetectable HDV RNA at 48 weeks after the end of therapy, was not observed in any case. Treatment with interferon was associated with a decrease in liver density by average 4.1 kPa by week 48 on therapy. Normalization of alanine aminotransferase levels after 48 weeks of treatment was observed in 59% (20/34) of the patients; however, sustained biochemical response was achieved in none of them. Serious adverse events of high or moderate severity that resulted in the discontinuation of therapy were observed in 12% (4/34) of the cases.&#x0D; Conclusion: The results obtained indicate low efficacy of Peg-IFN- in the treatment of CHD in the Dagestan patients. Further research is needed to refine optimal interferon therapy regimens, to search for predictors of treatment response, and to evaluate the impact of interferon treatment regimens on the risk of hepatic complications, clinical outcomes, and patient survival. However, the most obvious solution to the problem of CHD therapy is the development and implementation of interferon-free treatment regimens.

S1617 Elevations in Total Serum Bile Acids During Bulevirtide Treatment Show No Association With Adverse Events of Interest in Patients With Chronic Hepatitis Delta: An Integrated Safety Analysis of 48-Week Data

S1617 Elevations in Total Serum Bile Acids During Bulevirtide Treatment Show No Association With Adverse Events of Interest in Patients With Chronic Hepatitis Delta: An Integrated Safety Analysis of 48-Week Data

Interferon-Free Regimens and Direct-Acting Antiviral Agents for Delta Hepatitis: Are We There Yet?

Chronic delta hepatitis is a global health problem. Although a smaller percentage of chronic HBV-infected patients are coinfected with the hepatitis delta virus, these patients have a higher risk of an accelerated progression to fulminant "delta hepatitis", cirrhosis, hepatic decompensation, and hepatocellular carcinoma, putting a financial strain on the healthcare system and increasing the need for a liver transplant. Since its discovery, tremendous efforts have been directed toward understanding the intricate pathogenic mechanisms, discovering the complex viral replication process, the essential replicative intermediates, and cell division-mediated viral spread, which enables virion viability. The consideration of the interaction between HBV and HDV is crucial in the process of developing novel pharmaceuticals. Until just recently, interferon-based therapy was the only treatment available worldwide. This review aims to present the recent advancements in understanding the life cycle of HDV, which have consequently facilitated the development of innovative drug classes. Additionally, we will examine the antiviral strategies currently in phases II and III of development, including bulevirtide (an entry inhibitor), lonafarnib (a prenylation inhibitor), and REP 2139 (an HBsAg release inhibitor).

Current and Evolving Management of Chronic Hepatitis Delta Virus (HDV) Infection

Current and Evolving Management of Chronic Hepatitis Delta Virus (HDV) Infection

GS-012 - Week 48 results of the phase 3 D-LIVR study, a randomized double-blind, placebo-controlled trial evaluating the safety and efficacy of Lonafarnib-boosted with Ritonavir with or without Peginterferon Alfa in patients with chronic hepatitis delta

GS-012 - Week 48 results of the phase 3 D-LIVR study, a randomized double-blind, placebo-controlled trial evaluating the safety and efficacy of Lonafarnib-boosted with Ritonavir with or without Peginterferon Alfa in patients with chronic hepatitis delta

WED-166 - Characterizing chronic hepatitis delta in Spain and the gaps in its management

WED-166 - Characterizing chronic hepatitis delta in Spain and the gaps in its management

SAT-183 - Safety and efficacy of REP 2139-Mg in association with TDF in chronic hepatitis delta patients with decompensated cirrhosis

SAT-183 - Safety and efficacy of REP 2139-Mg in association with TDF in chronic hepatitis delta patients with decompensated cirrhosis

WED-130 - Patients with chronic hepatitis delta virus coinfections have higher risk of disease progression than chronic hepatitis B virus monoinfection-results from a Spanish national hospital database

WED-130 - Patients with chronic hepatitis delta virus coinfections have higher risk of disease progression than chronic hepatitis B virus monoinfection-results from a Spanish national hospital database

SAT-159 - Kinetics of HBsAg forms in chronic hepatitis delta patients treated with bulevirtide for 48 weeks: correlation with virological response

SAT-159 - Kinetics of HBsAg forms in chronic hepatitis delta patients treated with bulevirtide for 48 weeks: correlation with virological response

FRI-152 - Qualitative interviews to assess the impact of chronic hepatitis delta virus infection on health-related quality of life in untreated patients from the US, Italy, Spain, and Germany

FRI-152 - Qualitative interviews to assess the impact of chronic hepatitis delta virus infection on health-related quality of life in untreated patients from the US, Italy, Spain, and Germany