Editor's Note: Hepatitis D virus (HDV) is a defective virus that requires the hepatitis B surface antigen (HBsAg) to replicate. Co-infection with HBV and HDV is considered the most severe form of chronic viral hepatitis, accelerating liver-related mortality and the development of hepatocellular carcinoma (HCC). At the 2024 European Association for the Study of the Liver (EASL) annual meeting held in Milan, Italy from June 5-8, the latest research on the treatment of chronic hepatitis D (CHD) with Bulevirtide (BLV) drew significant attention. These studies not only provide new strategies and evidence-based medicine for CHD treatment but also lay the foundation for future research. This article compiles and organizes three key studies presented at the conference for our readers.Abstract GS-002
Efficacy and Safety of Bulevirtide Combined with Pegylated Interferon-α2a in Treating Chronic Hepatitis D: Final Results of a Randomized, Multicenter, Open-label Phase IIb Study (MYR204)
Background Bulevirtide (BLV) is the first entry inhibitor approved in the EU for treating CHD. This Phase IIb study (MYR204, NCT03852433) evaluated the safety and efficacy of BLV (2 mg and 10 mg) with or without Pegylated Interferon-α2a (PegIFNα) in treating compensated CHD patients. The report presents the final results 48 weeks after the end of treatment (EOT).
Methods The study included 174 CHD patients randomized into four groups (1:2:2:2): (A) PegIFNα monotherapy for 48 weeks; (B) BLV 2 mg + PegIFNα for 48 weeks; (C) BLV 10 mg + PegIFNα for 48 weeks, followed by BLV 2 mg or 10 mg monotherapy for 48 weeks; (D) BLV 10 mg monotherapy for 96 weeks. All patients were followed for 48 weeks post-EOT (FU-48). The primary endpoint was undetectable HDV RNA at week 24 post-EOT (FU-24) [< lower limit of quantification (LLOQ) 50 IU/mL, detection limit 6 IU/mL], comparing groups C and D. Combined response endpoint included undetectable HDV RNA and normalization of alanine aminotransferase (ALT). Other endpoints included ALT normalization, liver stiffness changes by transient elastography, and HBsAg loss.
Results Baseline characteristics were similar across groups: mean age 41 (SD=8.7) years, 71% male, 87% white. Overall, 34% of patients had compensated cirrhosis, mean liver stiffness was 13.1 (SD=7.7) kPa, HDV RNA was 5.3 (SD=1.2) log10 IU/mL, ALT was 114 (SD=94.8) U/L, 48% received nucleos(t)ide analogs, and 48% received interferon therapy. At FU-48, undetectable HDV RNA was observed in 25% (6/24) of group A, 26% (13/50) of group B, 46% (23/50) of group C, and 12% (6/50) of group D (C vs. D, P=0.0003). At FU-24, undetectable HDV RNA was observed in 17% (4/24) of group A, 32% (16/50) of group B, 46% (23/50) of group C, and 12% (6/50) of group D (C vs. D, P=0.0003; C vs. A, P=0.0197; B vs. D, P=0.0283). At FU-48, ALT normalization and combined response rates were 42% and 25% for group A; 38% and 22% for group B; 46% and 40% for group C; 22% and 8% for group D (C vs. D, P<0.05). At FU-48, HBsAg decline was observed only in BLV treatment groups: 0% in group A, 10% (5/50) in group B, 4% (2/50) in group C, and 2% (1/50) in group D. BLV was well tolerated, with one participant discontinuing BLV due to an adverse event and three experiencing serious adverse events.
Conclusion BLV 10 mg combined with PegIFNα had the highest rate of undetectable HDV RNA at EOT and FU-24, sustained to FU-48, providing a viable treatment option for compensated CHD patients.
Abstract OS-120
Bulevirtide Monotherapy Prevents Liver Decompensation and Reduces Mortality in HDV-Related Cirrhosis: A Propensity Score-Weighted Case-Control Study
Background BLV monotherapy shows high virological and biochemical response rates in HDV-related cirrhosis but limited clinical efficacy.
Methods In a European retrospective multicenter study (SAVED), researchers compared HDV-related cirrhosis patients treated with BLV monotherapy to untreated HDV cirrhosis patients from a previous cohort study (Romeo, Gastroenterology 2009) using inverse probability of treatment weighting (IPTW) to compare liver-related events (LRE: HCC, decompensation) and overall mortality.
Results The BLV treatment cohort included 176 patients [median follow-up: 15 (2-46) months]: median age at BLV initiation was 50 years (19-82), 59% male, ALT 77 U/L (23-1074), albumin 3.9 g/dL (2.8-4.9), 100% CPT score A, 55% had varices. The untreated cohort included 140 patients [median follow-up: 91 months (3-359)]: median age 40 years (18-66), 78% male, ALT 102 U/L (11-3054), albumin 4.0 g/dL (2.0-5.2), 94% CPT score A, 46% had varices. The 2-year cumulative LRE probability was 6.9% (95%CI: 3-11%) in the BLV group versus 15.7% (95%CI: 9-22%) in the untreated group (P=0.02); new HCC was 4.9% vs. 6.7% (P=0.45), decompensation was 2.0% vs. 9.1% (P=0.01). The 2-year overall mortality was 1.2% (95%CI: 0.3-3%) in the BLV group and 3% (95%CI: 0.5-6%) in the untreated group (P=0.13). After IPTW adjustment for baseline confounders and competing risks, BLV treatment significantly reduced the risk of all liver-related events (HR: 0.38, 95%CI: 0.24-0.60, P<0.0001), decompensation (HR: 0.15, 95%CI: 0.06-0.36, P<0.0001), and mortality (HR: 0.27, 95%CI: 0.08-0.93, P=0.04) compared to the untreated group. HCC risk was similar (HR: 0.76, 95%CI: 0.42-1.40, P=0.38).
Conclusion Two years of BLV monotherapy significantly reduces the risk of decompensation and mortality in HDV-related compensated cirrhosis patients compared to untreated patients but does not reduce the risk of HCC.
Abstract OS-122
Sustained Intrahepatic Response after Discontinuation of Bulevirtide Combined with Pegylated Interferon-α2a
Background Bulevirtide (BLV) is the first entry inhibitor approved in the EU for treating CHD. A multicenter, open-label, randomized Phase IIb study (MYR204, NCT03852433) evaluated the safety and efficacy of BLV (2 mg/d and 10 mg/d) combined with or without Pegylated Interferon-α2a (PegIFNα) in treating CHD and compensated liver disease. This subgroup analysis aimed to assess virological changes at 24 weeks post-EOT compared to baseline. Researchers also evaluated the relationship between intrahepatic prognosis and peripheral parameters, including intrahepatic innate and inflammatory gene expression profiles, to further understand the treatment effects.
Methods 174 CHD patients were randomized into four groups (1:2:2:2): (A) PegIFNα monotherapy for 48 weeks; (B) BLV 2 mg + PegIFNα for 48 weeks; (C) BLV 10 mg + PegIFNα for 48 weeks, followed by BLV 2 mg or 10 mg monotherapy for 48 weeks; (D) BLV 10 mg monotherapy for 96 weeks. Some patients had paired liver biopsy results at baseline and 24 weeks post-EOT (molecular analysis n=42, histological analysis n=44). HDV parameters and infection-related host genes were evaluated by qPCR and HDAg immunohistochemistry.
Results At 24 weeks post-EOT, the median decline in intrahepatic HDV RNA compared to baseline was 1.9 log10 in group A (n=5), 2.0 log10 in group B (n=14), 3.2 log10 in group C (n=11), and 0.8 log10 in group D (n=12). Intrahepatic HDV RNA levels correlated with the number of HDAg-positive cells (r=0.85, P<0.0001), with a median decline of 1.9 log10 in group A (n=6), 1.0 log10 in group B (n=14), 1.9 log10 in group C (n=11), and 0.8 log10 in group D (n=13). In groups B and C, 57% (8/14) and 73% (8/11) of patients had undetectable HDV RNA at follow-up, while in groups A and D, 60% (3/5) and 8% (1/12) had undetectable intrahepatic HDV RNA. Changes in intrahepatic HDV RNA mirrored serum HDV RNA changes (r=0.82, P<0.0001). In the combination therapy groups, inflammatory chemokine and infection-related gene transcription levels decreased at follow-up. Notably, the reduction in chemokines (e.g., CXCL10) correlated strongly with the decrease in intrahepatic HDV RNA (r=0.67, P<0.0001) and changes in peripheral ALT levels (r=0.75, P<0.0001), indicating improved liver inflammation.
Conclusion Paired analysis of liver biopsy results before and after treatment showed a strong correlation between reduced intrahepatic HDV RNA expression and decreased serum levels. As HDV parameters decreased, the expression of innate immune genes also declined. The highest intrahepatic virological response rates post-treatment discontinuation were observed in the BLV 10 mg + PegIFNα combination therapy group.
