What are the new drugs for Hepatitis B Virus (HBV) Infection?

Overview of Hepatitis B Virus (HBV) Infection
Hepatitis B virus (HBV) remains one of the most serious infectious agents worldwide. Despite the availability of effective vaccines, chronic HBV infection affects hundreds of millions of people and is responsible for a significant burden of cirrhosis, hepatocellular carcinoma, and liver-related mortality. The virus is transmitted predominantly via contact with infectious blood or bodily fluids, perinatally from mother‐to‐child, and through unsafe injection practices, sexual contact, or via direct exposure in healthcare settings. Research over the past decades has elucidated many aspects of its replication cycle, persistence in hepatocytes, and the associated immune dysregulation that leads to chronic infection. This knowledge has driven the pursuit of therapies that not only suppress viral replication but also aim to achieve what is being defined as a “functional cure” (sustained loss of HBsAg with restoration of immune control).

Pathophysiology and Transmission
HBV is a small, enveloped DNA virus belonging to the Hepadnaviridae family. After entering a susceptible individual, the virus travels to the liver where it infects hepatocytes, and its partially double‐stranded relaxed circular DNA is converted into covalently closed circular DNA (cccDNA) in the nucleus. This cccDNA serves as a stable template for continuous viral replication and is largely responsible for the persistence of the virus even under antiviral therapy. HBV is transmitted vertically during childbirth, horizontally among family members, and through exposure to infected blood and body fluids in high-risk populations. The interplay between viral replication and the host’s immune response determines the course of infection—from an acute self-limited episode resulting in viral clearance to the development of chronic infection where the immune system is unable to eradicate the virus due to functional exhaustion of HBV-specific T cells. This chronic infection, maintained by cccDNA and viral integration events, fuels progressive liver inflammation and fibrotic changes, ultimately increasing the risk of cirrhosis and hepatocellular carcinoma.

Current Treatment Landscape
For many years, the frontline treatment for chronic HBV has been based on two classes of antiviral agents: the interferons (particularly pegylated interferon α) and nucleos(t)ide analogues (NAs) such as lamivudine, adefovir, entecavir, tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF). These agents work primarily by suppressing viral replication, reducing serum HBV DNA levels, and achieving biochemical and histological improvements in the liver. However, while these therapies are effective at controlling viral replication during treatment, they rarely clear cccDNA, meaning that treatment is often lifelong, and only a small percentage of patients eventually achieve HBsAg loss, which is considered a “functional cure”. Furthermore, long‐term use of these drugs may lead to issues such as antiviral resistance, side effects, and high economic and psychosocial burdens for the patient. This limitation in achieving a durable cure has served as a major impetus for the ongoing research and development of next‐generation agents that target different steps in the HBV lifecycle and modulate host immunity.

Recent Advancements in HBV Treatment
Fueled by an enhanced understanding of HBV biology, its interplay with the immune system, and the limitations of current therapy, significant efforts have been directed toward the development of new drugs with alternative mechanisms of action. These novel therapies aim not only to suppress viral replication but also to target the persistent cccDNA reservoir, boost host immune responses, and ultimately offer a finite treatment duration with a higher likelihood of functional cure.

Newly Approved Drugs
In recent years, regulatory agencies in certain regions have approved a handful of new drugs that have expanded the treatment options available to patients with HBV infection. For instance, in China and other countries, several products have received attention as “new drugs” for HBV treatment:

• "恩维达" – An injectable formulation approved by the NMPA as indicated by the drug application number S20210046 for HBV treatment. This product represents an evolution of the nucleos(t)ide analogue platform that aims to provide effective viral suppression with improved safety and convenience.

• "恒沐" – A tablet formulation approved by the NMPA under drug application number H20210029. This is another example of the new generation of oral agents approved within China that potentially offer improved pharmacokinetic profiles and ease of administration for long-term therapy.

In addition to these localized approvals, a related product has also been noted:

• Products targeting hepatitis D virus (HDV) such as "Hepcludex" (trade name for bulevirtide) have received approvals by European regulatory agencies for treating HDV infection; while their primary indication is HDV, these agents also influence HBV biology because HDV replication depends on HBV surface antigen expression. Although not directly indicated for HBV monoinfection, their development underscores the broader therapeutic potential in targeting viral entry processes, which could be adapted for HBV treatment in the future.

Furthermore, improved analogues such as tenofovir alibufenamide (TMF) have emerged, which promise similar or superior efficacy compared to TDF and even TAF, with better safety profiles—especially among populations with concerns regarding renal or bone toxicities. Early-phase studies reported in major Chinese journals have contributed substantial data on these agents, suggesting that they may become integral to the next wave of HBV treatment.

Drugs in Clinical Trials
Perhaps more promising than those already approved are the numerous novel candidates currently undergoing clinical trials. These drugs are being developed on entirely new mechanistic platforms that go beyond simple viral polymerase inhibition:

• Pradefovir Mesylate – A novel prodrug candidate that has emerged during phase 3 clinical trials. In head-to-head studies comparing pradefovir to tenofovir disoproxil fumarate, pradefovir has demonstrated comparable virological suppression with potential safety advantages such as a lower trend of bone mineral density loss and less impact on renal function. Recent randomized, double-blind trials have reported favorable efficacy outcomes in reducing HBV DNA levels as well as promising safety data.

• RNA Interference (RNAi) Therapeutics – One of the most exciting areas of development is RNAi-based therapy. The candidate AB-729, developed by Arbutus Biopharma, is currently in phase 2a clinical trials examining both its ability to reduce HBsAg levels and its potential to restore innate and adaptive immune responses. Early data suggest that AB-729 achieves robust declines in HBsAg along with significant reductions in HBV DNA, making it a cornerstone in potential combination regimens aimed at a functional cure.

• siRNA Agents such as VIR-2218 – Developed by Vir Biotechnology, VIR-2218 is a subcutaneously administered siRNA targeting HBV transcripts. In early phase trials, VIR-2218 has shown dose-dependent reductions in HBsAg levels, with some regimens demonstrating sustained effects. VIR-2218 is being evaluated both as monotherapy and in combination with other agents to harness synergistic effects that may ultimately lower HBsAg further and boost immune control.

• Monoclonal Antibodies and Combination Immunotherapies – VIR-3434, an investigational monoclonal antibody targeting HBsAg, is being studied in combination with VIR-2218 and nucleos(t)ide analogues. The rationale behind this combination is that while siRNAs lower HBsAg levels, the monoclonal antibody can potentially enhance the clearance of residual antigens, thereby promoting a more robust T cell response to infected hepatocytes.

• TLR-8 Agonists – Selgantolimod is another promising candidate being evaluated as a toll-like receptor 8 (TLR-8) agonist. By stimulating innate immune pathways, selgantolimod may help overcome the immune tolerance seen in chronic HBV infection. Early-phase studies are exploring its role both as a stand-alone immunomodulator and as part of a combination regimen with RNAi therapeutics or other direct-acting antivirals.

• Therapeutic Vaccines and Immune Modulators – Although not traditional “drugs,” various therapeutic vaccines (for example, those incorporating recombinant proteins or DNA vaccine platforms) are in early clinical phases. These vaccines aim to stimulate HBV-specific T cell responses to facilitate the clearance of infected hepatocytes. In parallel, adoptive cellular therapies and checkpoint inhibitors have been explored to reverse T cell exhaustion, albeit with safety challenges to be overcome in large-scale trials.

• Capsid Assembly Modulators and Core Inhibitors – Some novel compounds targeting the HBV core protein and interfering with capsid assembly are in early development stages. Although details regarding specific drug names are still emerging in the literature, these molecules aim to disrupt the formation of the nucleocapsid, thereby attenuating viral replication at a critical step in the HBV life cycle.

• Nucleic Acid Polymers (NAPs) and HBsAg Release Inhibitors – There is ongoing work to develop inhibitors that directly block the release of subviral particles and HBsAg. By lowering circulating HBsAg levels, these agents may facilitate immune recognition and clearance. Early clinical studies have shown that when these agents are combined with other antivirals (such as nucleos(t)ide analogues), improvements in serologic markers may be observed.

Collectively, the pipeline includes a diverse range of agents targeting various steps of the viral life cycle, from entry inhibition and cccDNA targeting to RNA interference and immune modulation. This multi-pronged approach is seen as essential in achieving a functional or virological cure for chronic HBV infection.

Efficacy and Safety of New Drugs
Evaluating the efficacy and safety of new drugs for HBV infection is critical not only for regulatory approval but also for ensuring that these therapies provide meaningful improvements over current treatments. Clinical trials and real-world studies increasingly use endpoints such as reduction in HBsAg levels, undetectable HBV DNA, and biochemical and histological improvements to measure success.

Comparative Efficacy Studies
Recent clinical studies have provided insights into how novel agents compare with existing standard-of-care therapies. For instance, phase 3 randomized trials comparing pradefovir mesylate with TDF have demonstrated that pradefovir is non-inferior to TDF in achieving virological suppression. Notably, pradefovir has been associated with trends toward better safety outcomes with regard to bone mineral density and renal biomarkers, which is particularly important given the long-term nature of HBV treatment.

Similarly, RNAi-based therapies such as AB-729 have shown impressive efficacy signals in reducing serum HBsAg. Early-phase trials indicate that AB-729 can produce robust declines in HBsAg in a significant proportion of participants, potentially paving the way for combination approaches that could increase the rate of functional cure. Comparative data from studies on VIR-2218 have revealed that a longer treatment duration and multiple dosing regimens result in deeper, more sustained reductions in HBsAg levels. These studies typically measure endpoints such as ≥1 log10 reduction in HBsAg as a marker of efficacy.

In addition, combination regimens that incorporate both RNAi agents (e.g., VIR-2218) and monoclonal antibodies (e.g., VIR-3434) have shown promising results in early trials, with synergistic effects observed in the reduction of viral antigenemia and improved virologic control. These comparative studies underscore the potential for these new agents to achieve outcomes that rival or exceed those of traditional nucleos(t)ide analogues while offering the possibility of finite treatment durations.

Safety Profiles and Side Effects
Safety is one of the most important considerations in the development of new HBV drugs, particularly because current therapies are known for their favorable long-term tolerability despite their chronic use. The new agents are being scrutinized for both their short-term adverse events and long-term risk profiles.

For example, pradefovir mesylate has been associated with a lower incidence of adverse events related to bone mineral density loss and renal toxicity than TDF in long-term studies. This is a significant consideration because many patients on current NAs require lifelong therapy, which exposes them to cumulative side effects over time.

RNAi therapeutics such as AB-729 and VIR-2218 have undergone extensive safety evaluations in early-phase trials, and results to date indicate a favorable safety profile with minimal serious adverse events. Injection site reactions and transient laboratory abnormalities have been reported in some studies, but these events are generally well-tolerated and reversible upon treatment discontinuation.

Furthermore, immunomodulatory agents like TLR-8 agonists (selgantolimod) are under close observation for their potential to induce cytokine-mediated adverse effects. Early-phase studies suggest that while immune activation does occur, the adverse events remain within acceptable limits and are manageable with appropriate dose adjustments.

More complex regimens that combine different classes of agents are carefully designed with detailed monitoring protocols in clinical trials. These combination therapies aim to strike a balance between enhanced antiviral efficacy and acceptable tolerability, with multiple studies providing early evidence that the adverse effect profiles of these novel regimens do not significantly exceed those observed with existing therapy. Still, long-term data are required to fully establish the safety profiles of these promising new treatments.

Future Directions in HBV Treatment
The future of HBV management is poised to change significantly as novel agents continue to progress through clinical development. Future therapy strategies are expected to move away from indefinite suppressive therapy and toward finite-duration regimens that achieve sustained virological remission or functional cure.

Emerging Therapies
The therapeutic landscape is evolving toward combination approaches that integrate several mechanisms of action. Emerging therapies include:

• Next-Generation RNAi and siRNA Therapeutics – The continued development of RNAi agents such as AB-729 and VIR-2218 in combination with HBsAg-targeting monoclonal antibodies (VIR-3434) represents a promising strategy to lower viral antigen load and restore immune control. These agents might be particularly advantageous when combined with immunomodulators, as the reduction in HBsAg levels may relieve the immunosuppressive milieu created by chronic HBV, thus enabling a more effective immune clearance.

• Capsid Assembly Modulators and Core Inhibitors – As mentioned earlier, drugs targeting the nucleocapsid formation represent an emerging class that interferes with a critical step in the viral replication cycle. Although many of these molecules remain in early phases of development, they hold promise for disrupting the viral life cycle at a stage that historical NAs have not addressed. These agents may also help target newly formed cccDNA indirectly by inhibiting the recycling of viral genomes.

• Entry Inhibitors and cccDNA Targeting Agents – Efforts are ongoing to develop inhibitors that prevent the virus from entering hepatocytes, thereby blocking the initiation of infection. In addition, therapies that directly target the stability or transcriptional activity of cccDNA are under investigation. Although these approaches are challenging given the stable nature of cccDNA, advances in molecular medicine and gene editing technology (such as CRISPR/Cas systems) have opened new avenues for targeting cccDNA directly.

• Therapeutic Vaccines and Immunomodulatory Strategies – There is renewed interest in therapeutic vaccines that can re-stimulate HBV-specific T cell responses. Early-phase trials of protein- or DNA-based vaccines are exploring their potential as adjuncts to antiviral therapy. In parallel, adoptive cell transfer therapies and checkpoint inhibitors are under investigation to reverse the exhausted T cell phenotype frequently observed in HBV-infected patients.

Research and Development Trends
The research pipeline for HBV treatment is marked by a multi-disciplinary approach that integrates virology, immunology, and novel drug delivery technologies. Key trends include:

• Combination Therapies – Future regimens are likely to be composed of a combination of direct-acting antivirals and immune modulators. This approach may optimize antiviral potency while simultaneously restoring effective immune surveillance, offering the potential for finite treatment durations compared to lifelong suppressive therapy.

• Biomarker Development and Treatment Endpoints – As new drugs emerge, there is a critical need to develop sensitive and specific biomarkers that can monitor intrahepatic viral activity, cccDNA levels, and immune restoration. New endpoints, such as the quantitative assessment of HBV RNA, HBcrAg, and other emerging markers, are being integrated into clinical trials to evaluate the achievement of functional cure more accurately.

• Enhanced Drug Delivery Platforms – Nanotechnology and other advanced drug delivery strategies are being deployed to target drugs specifically to liver cells, thereby increasing efficacy while minimizing systemic side effects. These novel carriers are being optimized for both oral and parenteral formulations, ensuring that patients receive medication in the most efficient and tolerable manner possible.

• Global Collaboration and Regulatory Innovation – With HBV affecting diverse populations worldwide, there is a growing trend towards international collaboration among academia, industry, and regulatory bodies. This is essential to harmonize clinical trial designs, treatment endpoints, and approval pathways, thereby expediting the availability of new therapies to populations in need. Recent data sharing initiatives and expert guideline updates illustrate the commitment to a unified approach in the fight against HBV infection.

In addition, attention is increasingly focused on personalized medicine approaches, where treatment regimens might be tailored based on HBV genotype, baseline viral load, and host immune status. This stratified strategy aims to maximize therapeutic efficacy while minimizing overtreatment and adverse effects.

Conclusion
In summary, the landscape of HBV treatment is witnessing dynamic changes driven by new drugs designed to overcome the limitations of conventional therapies. The traditional nucleos(t)ide analogues and interferon therapies, while effective at suppressing viral replication, do not eradicate cccDNA and seldom achieve functional cure. Recent advancements include the approval of new drugs like "恩维达" and "恒沐" in certain jurisdictions, as well as the advent of innovative candidates such as pradefovir mesylate, RNAi therapeutics (e.g., AB-729), siRNA agents (VIR-2218), and promising combination strategies integrating monoclonal antibodies (VIR-3434) and TLR-8 agonists (selgantolimod). Comparative studies have indicated that these new agents offer comparable—if not superior—antiviral efficacy with improved safety profiles, particularly in terms of renal function and bone health.

Emerging therapies which target core assembly, inhibit viral entry, combat subviral particle release, and directly target cccDNA are paving the way for finite, curative treatment regimens. In parallel, research is now oriented toward the development of robust biomarkers and personalized treatment strategies that will enable clinicians to monitor treatment response more accurately and adjust regimens accordingly. Furthermore, enhanced drug delivery systems promise targeted therapy with reduced systemic toxicity.

The future of HBV treatment resides in a multi-pronged approach that combines potent direct-acting antivirals with strategies to reinvigorate the host immune response. While many promising novel agents are still under clinical evaluation, early clinical trial data and preclinical studies indicate significant potential to revolutionize the management of chronic HBV infection. Over coming years, these advances are expected to translate into finite-duration therapies that offer the possibility of a functional cure, thereby diminishing the global burden of HBV-related liver disease.

Overall, from a general perspective, the transition from lifelong suppression to finite curative regimens represents a paradigm shift in HBV management. With detailed evaluation from multiple angles—ranging from efficacy, safety, and immunomodulation to advanced drug delivery and biomarker-guided treatment—the future of HBV therapy is more promising than ever. Continued collaboration among researchers, clinicians, industry partners, and regulatory bodies is essential to fully realize the potential of these new drugs and ensure that they reach the patients who need them most.