Early 2025 marks a pivotal shift toward expanded antiviral eligibility, novel direct-acting agents, and immunotherapies designed to achieve a functional cure of chronic hepatitis B virus (HBV) infection.

1. Expanded Treatment Eligibility

Both the European Association for the Study of the Liver (EASL) and World Health Organization (WHO) guidelines now recommend treating a broader patient population by simplifying algorithms based on ALT levels, HBV DNA, and noninvasive fibrosis assessment (Fibrosis-4, FibroTest, elastography). This update enables more patients—including those with milder liver injury—to initiate antiviral therapy earlier, reducing progression to cirrhosis and hepatocellular carcinoma.

2. Novel Direct-Acting Antivirals

  • AHB-137 (antisense oligonucleotide): Demonstrated favorable safety and significant HBsAg reduction in Phase II patients with baseline antigen 100–3,000 IU/mL.

  • ALG-000184 (capsid assembly modulator): Exhibited potent viral suppression and encouraging HBeAg seroconversion as monotherapy and combined with entecavir in treatment-naïve patients.

  • Imdusiran + VTP-300 (siRNA + chimpanzee-adenovirus/MVA therapeutic vaccine): Combination delivered greater HBsAg loss than either agent alone, highlighting the benefit of multi-modal antigen reduction.

  • Antisense bepirovirsen and other siRNA molecules (e.g., VIR-2218) are advancing in Phase III, aiming to lower antigen load before immunomodulatory add-ons.

3. Therapeutic Vaccines

  • TherVacB: A first-in-class, prime-boost vaccine regimen entering clinical trials in Europe and Africa from June 2025. Designed to restore HBV-specific B and T cell immunity, TherVacB is funded under Horizon 2020 and seeks to achieve durable functional cure in chronically infected patients.

  • Additional candidates (TG1050, GS-4774, BRII-179) are in Phase II evaluation, often in combination with antigen-reducing agents to enhance seroclearance rates.

Hepatitis liver. Symptoms of hepatitis B in the form of color icons with corresponding marks. Vector illustration in flat style isolated on white background.

4. Hepatitis D Co-Infection Advances

  • Bulevirtide: EMA-approved entry inhibitor for HDV, showing durable RNA suppression in real-world cohorts.

  • Tobevibart (VIR-3434) + Elebsiran (VIR-2218): Monoclonal antibody and siRNA combo achieved rapid HDV RNA and ALT reductions at 48 weeks, indicating promise for HDV cure strategies.

5. Future Directions

  • Combination Regimens: Integrating nucleos(t)ide analogues, direct-acting antivirals, therapeutic vaccines, and immunomodulators (pegIFN) is critical to tackle persistent cccDNA and achieve HBsAg seroclearance.

  • Biomarker-Driven Personalization: Utilizing quantitative HBsAg and novel host/viral markers to tailor therapy duration and maximize functional cure rates.

  • Global Access & Implementation: Emphasis on scalable, cost-effective viral load and antigen testing, particularly in low-resource settings, to broaden treatment uptake.

Continued clinical trial readouts in late 2025 will further define optimal combinations and solidify the first curative regimens for chronic HBV infection.

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