PEG-IFN plus novel agents may boost functional cure in chronic hepatitis B

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Frontiers in Medicine Published June 6, 2026 Medically reviewed June 6, 2026 DOI ↗ By Dr. Amelia Tan, PhD · Internal Medicine & Chronic Disease

Key Takeaway

Consider that PEG-IFN plus novel immunotherapies may improve functional cure rates, but evidence is preliminary.

This is a narrative review that explores the potential of combining pegylated interferon-α (PEG-IFN-α) with novel immunotherapies to achieve functional cure in patients with chronic hepatitis B. The review covers antigen-reduction strategies (e.g., siRNA, antisense oligonucleotides, HBsAg-targeting monoclonal antibodies), therapeutic vaccines, and immune-modulatory approaches. The authors synthesize qualitative findings from the literature, suggesting that these combination regimens may enhance functional cure rates compared to nucleos(t)ide analogues or PEG-IFN-α alone.

No pooled effect sizes, sample sizes, or comparative data are reported, as the review is narrative in nature. The authors do not explicitly discuss limitations, but the lack of quantitative synthesis and reliance on early-phase or heterogeneous studies limits the strength of conclusions. Safety data, including adverse events and tolerability, are not reported.

For clinicians, the review highlights an evolving therapeutic landscape but underscores that functional cure with these combinations remains investigational. Practice relevance is not directly addressed, and no specific recommendations are provided. Further high-quality trials are needed before clinical adoption.

Study Details

Study typeSystematic review

EvidenceLevel 1

PublishedJun 2026

View Original Abstract ↓

Chronic hepatitis B (CHB) affects approximately 250 million people worldwide. The major barrier to cure lies in the persistent presence of covalently closed circular DNA (cccDNA) and integrated HBV DNA within hepatocytes, which continuously drive hepatitis B surface antigen (HBsAg) expression and maintain immune tolerance, thereby leading to functional exhaustion of antiviral effector cells. Although nucleos(t)ide analogues (NAs) effectively suppress viral replication, they have limited impact on cccDNA activity and antigen production. In contrast, pegylated interferon-α (PEG-IFN-α) enhances antigen presentation, activates innate immunity, and partially restores HBV-specific T cell function, thereby contributing to the disruption of immune tolerance to some extent. However, its therapeutic efficacy remains influenced by host immune status and antigen burden. With the development of antigen-reduction strategies (such as siRNA/antisense oligonucleotides [ASO] and HBsAg-targeting monoclonal antibodies), therapeutic vaccines, and immune-modulatory approaches, PEG-IFN-α is increasingly being incorporated into combination therapies. This review summarizes its immunological basis and clinical advances, and further discusses biomarker-driven patient stratification strategies, with the aim of improving functional cure rates in CHB.