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INTRODUCTION: Pegylated interferon alpha-2a (PEG-IFN) has been used off-label as chronic hepatitis delta (CHD) treatment since the 1990s. However, it has not received formal approval for this indication. Bulevirtide (BLV), a first-in-class entry inhibitor, is the first drug approved for the treatment of compensated CHD. Since its conditional approval in 2020, data from clinical trials and real-world studies have emerged. Literature search included PubMed (last accessed July 2025), European Medicines Agency official reports, and international conference abstract books. AREAS COVERED: Several evidence gaps remain unmet, including the definition of treatment endpoints, the impact of therapy on clinical outcomes, optimal therapy duration, and the potential benefits of combination with PEG-IFN. This review aims to provide a comprehensive overview of the current evidence regarding the use of BLV, both as monotherapy and in combination with PEG-IFN. EXPERT OPINION: Bulevirtide 2 mg is an effective treatment for CHD in patients with and without advanced chronic liver disease, as demonstrated in clinical trials and real-world cohorts. In addition, long-term therapy appears to enhance response rates and may even promote the loss of HDV-infected hepatocytes, potentially leading to a sustained off-therapy response. However, new therapeutic strategies are needed for patients who do not respond.
Cobo et al. (2025) studied this question.