Bulevirtide Monotherapy or in Combination for Chronic Hepatitis Delta: 2025 Update

Chronic hepatitis Delta (CHD) represents the most aggressive form of viral hepatitis. In the latest estimates, published in 2024 by the Polaris Observatory, the overall prevalence of the hepatitis Delta virus (HDV) in Hepatitis B surface antigen (HBsAg) + patients was estimated to be 2% worldwide, a lower figure than what was previously estimated to be around 6%-11%. Prevalence figures vary greatly across the globe, with the highest anti-HDV+ prevalence in Mongolia, where it reaches 60% of HBsAg+ individuals. Its clinical manifestations include accelerated progression to cirrhosis, increased risk of hepatic decompensation and heightened incidence of hepatocellular carcinoma (HCC). Notwithstanding the close dependency of HDV on the Hepatitis B virus (HBV), requiring HBsAg for cellular entry and propagation, nucleos(t)ide analogue (NA) therapies do not affect CHD. Ideally, a therapy capable of achieving HBsAg loss would also translate into CHD cure. Monitoring viremia is pivotal in estimating the effectiveness of HDV treatments. Consequently, a "virological response" is defined as a reduction of at least 2 logs in HDV RNA or achieving HDV RNA negativity, compared to baseline. Despite the crucial role of HDV RNA monitoring in managing patients with CHD, significant variability still exists in nucleic acid quantification techniques for HDV RNA. Quantification assays differ in their sensitivity. As previously mentioned, antiviral therapy for CHD had been challenging for decades. Until recently, pegylated interferon-alpha (PegIFNα) stood as the sole available treatment, despite its suboptimal response rates and considerable adverse effects. Furthermore, the high frequency of post-treatment relapse necessitated long-term monitoring of viral load. The landscape of HDV treatment has evolved significantly with the introduction of bulevirtide (BLV), a novel entry inhibitor that targets the sodium taurocholate co-transporting polypeptide (NTCP) receptor, blocking viral entry into hepatocytes. The European Medicines Agency (EMA)'s conditional approval for BLV in July 2020, at a recommended dose of 2 mg daily as subcutaneous injections for adult patients with compensated CHD, marked a central progress in HDV therapeutics. This approval was supported by promising phase II and III trials results, demonstrating both efficacy and tolerability of the compound. Following these promising results, EMA granted full approval for BLV in May 2023. EMA recommends proceeding with BLV therapy until proven clinical benefit, without further details on this topic. This review synthesizes current evidence on BLV's efficacy effectiveness and safety profile, both as monotherapy and in combination with PegIFNα, drawing from clinical trials and real-world studies, with the aim to propose treatment strategies aligned with disease severity and patients' profile.