Clinical bottom line
Hepatitis Delta Virus (HDV) infection remains a challenging co-infection in patients with Hepatitis B Virus (HBV), associated with more aggressive liver disease and higher risk of cirrhosis and hepatocellular carcinoma. Recent advances in antiviral therapies, including novel entry inhibitors and prenylation blockers, offer promising options beyond pegylated interferon, which has limited efficacy and tolerability. However, optimal management requires comprehensive patient evaluation and individualized treatment strategies. These emerging therapies warrant further validation in diverse populations to clarify long-term benefits and safety.
What the evidence shows
HDV infection occurs only in the presence of HBV and significantly worsens the clinical course of chronic hepatitis B, accelerating progression to cirrhosis and liver failure (Kondili et al., 2024; Brillanti et al., 2022). The global burden remains substantial, with heterogeneous prevalence influenced by geographic and demographic factors, including migration patterns (Caviglia et al., 2025).
Diagnosis of HDV requires serologic and molecular testing to detect anti-HDV antibodies and HDV RNA, respectively, but remains underutilized in clinical practice (Wu et al., 2007). Kondili et al. (2024) emphasize a holistic evaluation approach integrating virologic, biochemical, and histologic parameters to stratify disease severity and guide management.
Historically, pegylated interferon alfa has been the mainstay treatment but achieves sustained virologic response in fewer than 30% of patients and is limited by adverse effects (Brillanti et al., 2022). Recent investigational agents target specific steps in the HDV life cycle. For example, bulevirtide, an entry inhibitor blocking the sodium taurocholate co-transporting polypeptide (NTCP) receptor, has shown efficacy in reducing HDV RNA levels and improving liver enzymes in phase 2 and 3 trials (Park et al., 2025). Similarly, lonafarnib, a prenylation inhibitor, disrupts viral assembly and secretion, demonstrating antiviral activity with manageable side effects when combined with ritonavir boosting (Park et al., 2025).
Combination therapies, including bulevirtide with pegylated interferon or lonafarnib, are under active investigation to enhance response rates and durability (Park et al., 2025). Kondili et al. (2024) highlight the importance of monitoring viral kinetics and liver fibrosis progression during treatment to tailor therapy duration and assess efficacy.
Caveats and uncertainty
Despite promising early results, long-term data on clinical outcomes such as prevention of cirrhosis, hepatocellular carcinoma, and liver transplantation remain limited. Most clinical trials have enrolled relatively small cohorts, often with heterogeneous inclusion criteria, limiting generalizability (Park et al., 2025). The impact of HDV genotype variability on treatment response is not fully elucidated, though some genotypes may influence disease severity and antiviral susceptibility (Wu et al., 2007).
Access to novel therapies like bulevirtide varies globally, and cost-effectiveness analyses are pending. Additionally, the optimal timing for initiation of therapy, especially in patients with compensated versus decompensated liver disease, has not been definitively established (Brillanti et al., 2022). The role of nucleos(t)ide analogues targeting HBV in combination with HDV-specific agents also requires further clarification.
How this may change practice
Clinicians should maintain a high index of suspicion for HDV co-infection in patients with chronic HBV, particularly those with unexplained liver disease progression or high transaminases despite HBV suppression. Routine screening using serologic and molecular assays is advisable in at-risk populations, including immigrants from endemic regions (Caviglia et al., 2025).
The availability of targeted therapies such as bulevirtide introduces new treatment paradigms, shifting from interferon monotherapy to combination regimens with improved tolerability and efficacy. Incorporating these agents into clinical practice will require multidisciplinary collaboration, patient education, and careful monitoring for adverse effects and viral resistance.
Future management will likely emphasize personalized approaches based on viral genotype, liver disease stage, and patient comorbidities. Integration of noninvasive fibrosis assessment and quantitative HDV RNA monitoring can guide treatment decisions and follow-up strategies (Kondili et al., 2024).