​Hung Van Le*
Biologics & Drug Targets, ProSci LLC, Rockaway, The United States
ORCID
https://orcid.org/0000-0002-6913-2373 (Hung Van Le)

Abstract
 
Immunotherapy has reshaped first-line systemic treatment for unresectable hepatocellular carcinoma (HCC), with immune-based combinations increasingly preferred over tyrosine kinase inhibitors for appropriately selected patients. This essay reviews key first-line immunotherapy regimens, including atezolizumab/bevacizumab, durvalumab/tremelimumab (STRIDE), and nivolumab/ipilimumab, emphasizing survival benefit, distinct adverse-event profiles, and practical safety considerations. Since immunotherapy entered routine HCC care around 2020, recognition and management of immune-related and VEGF-related toxicities have improved, providing better opportunities to detect and treat potentially serious adverse events before they become irreversible. Safe and effective use requires thoughtful patient selection based on physiologic reserve, frailty, liver function, bleeding risk, comorbidities, tumor burden, and goals of care. The essay also provides patient- and family-oriented guidance on expectations, red-flag symptoms, laboratory monitoring, treatment holds, discontinuation criteria, and escalation pathways to support shared decision-making and safer treatment navigation.

Highlights
 

• First-line systemic therapy for unresectable HCC is increasingly favoring immunotherapy-based combinations over tyrosine kinase inhibitors in appropriate patients.
• Atezolizumab/bevacizumab, durvalumab/tremelimumab (STRIDE), and nivolumab/ipilimumab offer survival benefit but have distinct safety profiles that require regimen-specific monitoring.
• Optimal outcomes depend on careful patient selection, including physiologic reserve, liver function, bleeding risk, comorbidities, and disease characteristics.
• Patient and family education, symptom-reporting checklists, laboratory surveillance, treatment-hold rules, and escalation plans are essential guardrails for safe immunotherapy.

Introduction
 
Hepatocellular carcinoma (HCC) accounts for approximately 90% of all primary liver cancers and often develops in the setting of cirrhosis caused by one or more underlying conditions, including hepatitis B, hepatitis C, alcohol-associated liver disease, or metabolic dysfunction-associated fatty liver disease [1]. Along with pancreatic cancer, HCC is among the most aggressive and difficult cancers to treat. Worldwide, it ranks as the sixth most common cancer and the third leading cause of cancer-related death [2]. Several treatment options are available, ranging from potentially curative approaches—such as surgical resection, liver transplantation, and radiofrequency or microwave ablation—to locoregional therapies, including transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and stereotactic body radiation therapy (SBRT). Depending on the clinical presentation, systemic therapy may be recommended as adjunctive treatment or as the main treatment for unresectable disease. Systemic therapy includes immunotherapy and targeted therapy; in current practice, immunotherapy-based combinations are now established first-line options for appropriately selected patients with unresectable HCC. This essay focuses on immunotherapy for HCC, particularly the practical information patients and families need when this treatment is offered by clinicians.

Immunotherapy versus targeted systemic therapy
 
Current first-line systemic therapies for HCC include both immunotherapy-based regimens and targeted therapies with tyrosine kinase inhibitors (TKIs). Immunotherapy regimens may combine a checkpoint inhibitor with an anti-angiogenic agent or, alternatively, use two checkpoint inhibitors together. Unlike TKIs, these agents are biologics. Checkpoint inhibitors are monoclonal antibodies directed against PD-L1, PD-1, or CTLA-4. Anti-angiogenic monoclonal antibodies target VEGF-A or members of the VEGF receptor (VEGFR) family. In practice, patients may encounter the checkpoint inhibitor plus anti-angiogenic combination summarized in Table 1.

​Alternatively, patients may receive one of the dual-checkpoint inhibitor combinations summarized in Tables 2 and 3.

​Overall survival advantage
 
All three immunotherapy combinations discussed here have demonstrated superior overall survival compared with their respective first-line control regimens—sorafenib or lenvatinib—in randomized phase III trials. In contrast to immunotherapies, sorafenib and lenvatinib are not biologics; they are small-molecule inhibitors that target a broad range of receptor tyrosine kinases, particularly vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs), and RAF kinases. Table 4 summarizes the reported gains in overall survival (OS).

​Atezolizumab/bevacizumab produced the largest median OS advantage versus sorafenib in IMbrave150. The updated analysis showed median OS of 19.2 months versus 13.4 months, an absolute difference of 5.8 months and a 34% relative reduction in the hazard of death [6]. STRIDE, the durvalumab/tremelimumab combination, produced a smaller median OS difference, but its long-term survival curve was clinically notable: median OS was 16.4 versus 13.8 months, yet approximately 31% of patients receiving STRIDE were alive at 3 years compared with 20% of those receiving sorafenib [7]. Nivolumab/ipilimumab currently has the longest reported median OS among these trials. CheckMate 9DW reported 23.7 versus 20.6 months; however, this should not be interpreted as evidence that nivolumab/ipilimumab is superior to atezolizumab/bevacizumab or STRIDE, because the trials differed in design, patient populations, comparator treatments, and follow-up [5]. The 2026 four-year follow-up is also notable: the OS hazard ratio remained 0.78, with 31% versus 18% of patients alive at 48 months [8].
 
The hazard ratios (HRs) from the three trials further support the effectiveness of these immunotherapy regimens compared with their respective control treatments: HR 0.66 for atezolizumab/bevacizumab, HR 0.78 for STRIDE, and HR 0.79 for nivolumab/ipilimumab. These values correspond approximately to 34%, 22%, and 21% lower relative hazards of death, respectively, versus the corresponding control arms. However, these results should not be used to rank the regimens against one another, because such ranking would rely on indirect cross-trial comparisons and would therefore be scientifically inappropriate.

 Comparable but distinct adverse-event profiles
 
The phase III trials not only established an overall survival advantage for immunotherapy-based regimens over first-line control treatments but also characterized their treatment-related adverse-event (TRAE) profiles. Tables 5–7 compare the reported incidence of Grade 1–5 TRAEs.

The key finding for atezolizumab + bevacizumab versus sorafenib is that the overall incidence of severe toxicity was broadly similar: Grade 3–4 TRAEs occurred in 43% versus 46% of patients. The more important distinction lies in the type of toxicity. Atezolizumab/bevacizumab was associated with more hypertension and bleeding-related concerns, whereas sorafenib produced the familiar TKI pattern of hand-foot syndrome, diarrhea, fatigue, and related events [6]. Notably, the six treatment-related deaths (2%) reported with atezolizumab + bevacizumab were attributed to gastrointestinal hemorrhage, gastric-ulcer perforation, subarachnoid hemorrhage, pneumonia, abnormal hepatic function, and liver injury [6].

​Compared with atezolizumab + bevacizumab, tremelimumab + durvalumab (STRIDE) showed a different safety pattern. STRIDE produced substantially fewer Grade 3–4 TRAEs than sorafenib (25.8% vs 36.9%), although treatment-related fatal events were somewhat more frequent (2.3% vs 0.8%) [9]. Consistent with its mechanism of action, STRIDE produced more immune-mediated toxicity than sorafenib (Grade 3–4 immune-mediated TRAEs: 12.6% vs 2.4%) and required high-dose corticosteroids more often (20.1% vs 1.9%). Immune-mediated AEs leading to discontinuation were also more common (5.7% vs 1.6%) [9]. The nine treatment-related deaths in the STRIDE arm included immune-mediated hepatitis, myocarditis, pneumonitis, myasthenia gravis, hepatic failure, and other serious events [9]. Importantly, a lower overall Grade 3–4 rate does not necessarily mean that STRIDE’s serious toxicities are less consequential. Immune-mediated events may be uncommon, but they can be catastrophic if recognition and treatment are delayed.

​Nivolumab + ipilimumab shows a safety pattern distinct from STRIDE. The Grade 3–4 TRAE rate was almost identical between nivolumab/ipilimumab and the control regimens (41% vs 42%), but treatment-related deaths were more frequent with nivolumab/ipilimumab: 12 versus 3 patients [10]. The causes of those 12 deaths are clinically important: immune-mediated hepatitis accounted for four deaths, hepatic failure for three, and one death each was attributed to hepatic insufficiency, decompensated cirrhosis, diarrhea/colitis, autoimmune hemolytic anemia, and dysautonomia [10]. In addition, 29% of patients required high-dose corticosteroids for immune-mediated adverse events [5].
 
Although direct adverse-event comparisons across the three trials are not appropriate because of differences in trial design, patient populations, treatment exposure, duration of follow-up, and comparator regimens, viewing the results side by side, as in Table 8, highlights three useful safety insights.

​By conventional toxicity metrics, STRIDE appears favorable because it had the lowest Grade 3–4 TRAE rate (25.8%) and the lowest discontinuation rate (8.2%) [9]. However, it should not automatically be considered safer in every clinically meaningful sense, given the nine treatment-related deaths (2.3%) and the need for high-dose corticosteroids in 20.1% of patients with immune-mediated toxicity [9].
 
Nivolumab + ipilimumab deserves particular attention. Although its Grade 3–4 TRAE rate was not higher than that of the control regimens (41% vs 42%), fatal treatment-related events occurred more often (4% vs <1%). This illustrates why the percentage of Grade 3–4 events alone does not adequately describe the safety of an immunotherapy regimen [10].
 
Atezolizumab + bevacizumab presents a different toxicity profile. Its Grade 3–4 TRAE rate was also substantial (43%), but the combination adds VEGF-inhibition risks—including hypertension, proteinuria, bleeding, impaired wound healing, and gastrointestinal perforation—to the immune-related toxicity associated with atezolizumab [6].
 
Taken together, these data show that counting adverse events is not enough. Fatal treatment-related events occurred in all three immunotherapy trials, underscoring that serious toxicity, although uncommon, remains possible and requires appropriate preventive measures, early recognition, and prompt management. Safe use of immunotherapy in HCC therefore requires careful patient selection and practical guardrails designed to prevent immune-related or VEGF-related toxicities from progressing to fatal outcomes.

Selecting HCC patients for immunotherapy
 
Clinical trial data provide the foundation for an informed first-line systemic treatment decision in unresectable HCC: whether to use an immunotherapy-based regimen or a targeted therapy with a tyrosine kinase inhibitor (TKI). Although the survival advantages of immunotherapy are compelling, the decision should also depend on whether the patient has enough physiologic and hepatic reserve to tolerate treatment safely and remain on therapy long enough to benefit. In general, the best candidates are patients with preserved liver function, typically Child-Pugh class A, and good functional status, typically ECOG performance status 0–1. Disease characteristics may also influence the decision. Patients with high tumor burden, macrovascular invasion, extrahepatic spread, or a strong need for durable disease control may be more likely to benefit from immunotherapy, because these features are associated with a poor prognosis with conventional therapy.
 
Other factors may inform, but do not necessarily determine, treatment selection. These include the presence of hepatitis B or hepatitis C infection, biomarker status such as alpha-fetoprotein (AFP) and PD-L1 expression, and the immune context of the tumor microenvironment. In principle, a more immune-active tumor microenvironment might support the use of immunotherapy, whereas a strongly immunosuppressive microenvironment could reduce the likelihood of response. In routine practice, however, oncologists do not yet have a widely available, validated clinical test that can quickly and reliably classify the tumor immune microenvironment for treatment selection.
 
There are also situations in which immunotherapy, or a specific immunotherapy combination, may be inappropriate. Serious active autoimmune disease, a history of severe immune-mediated toxicity, or the need for ongoing immunosuppression may make an immune checkpoint inhibitor–based regimen unsafe. A high bleeding risk is particularly relevant for atezolizumab + bevacizumab, because bevacizumab can increase the risk of bleeding and may be unsuitable in patients with untreated or high-risk varices or other major bleeding concerns.
 
Choosing among immunotherapy regimens for an individual patient is even more complex and is best guided by an experienced liver oncology team. Still, the broad clinical considerations can be summarized as shown in Table 9.

Managing expectations
 
Patients receiving immunotherapy for unresectable HCC should have realistic expectations about the goals of treatment. A complete cure is usually not a realistic expectation in this setting. Instead, treatment generally aims to shrink tumors when possible, slow disease progression, prolong survival, relieve symptoms, preserve liver function, and maintain quality of life. Complete responses can occur, but they remain uncommon. For many patients, durable disease control or meaningful tumor stabilization is already an important treatment success.

Side effects and their management
 
Managing side effects during immunotherapy is critical to treatment success, and patients can play an important role by reporting concerning symptoms early. The oncology team should be notified within 24 hours for symptoms such as increasing diarrhea, persistent fever, worsening fatigue, new cough, jaundice, or severe headache. Patients should seek emergency care immediately for chest pain, difficulty breathing, large-volume bleeding, confusion, inability to keep fluids down, or signs of severe dehydration. This list is not comprehensive; the larger point is that new, worsening, or unusual symptoms during immunotherapy should not be ignored. Clear communication with the oncology team—and, when needed, emergency clinicians—is an essential part of safe treatment.

The safety net around immunotherapy
 
Immunotherapy is not inherently unsafe, but it does require a structured safety system. A major part of safe treatment is collaboration between the care team, the patient, and the family to recognize potentially manageable toxicity early—before it becomes serious. Equally important is establishing a safety net before treatment begins, maintaining it throughout therapy, and activating it quickly when toxicity occurs.
 
Before treatment, the care team should confirm that the selected immunotherapy regimen is appropriate for the individual patient. Baseline liver function, physiologic reserve, laboratory values, and organ function should be documented before the first infusion. Treatment-specific risks should also be identified in advance. Patients and families should be educated about these risks and given a clear symptom-reporting checklist, so they know when to call the oncology team and when to seek urgent or emergency care.
 
During treatment, laboratory tests and regimen-specific parameters should be monitored at appropriate intervals, and new symptoms should be investigated promptly rather than deferred until the next scheduled infusion. If toxicity develops, the care team should grade its severity and determine whether it is treatment-related or instead reflects another complication of HCC or cirrhosis. When indicated, treatment should be held and toxicity treated promptly, often with corticosteroids for clinically significant immune-mediated events. Escalation to appropriate specialists or hospital care should occur when necessary. Treatment should be resumed only after the toxicity has adequately resolved and the benefit-risk balance remains favorable.
 
Finally, treatment should be permanently discontinued when established criteria are met. Stopping immunotherapy in that setting should not be viewed as failure; it may be the safest and most appropriate outcome of good toxicity management.
 
For readers who want more practical detail, Appendix A describes the essential components of a safety net for HCC immunotherapies. Appendix B provides a red-flag symptom table to help patients and families recognize when adverse events require prompt action. Appendix C offers a companion table of commonly encountered treatment toxicities and typical action steps.

Conclusion
 
In conclusion, the treatment landscape for unresectable hepatocellular carcinoma has changed substantially since immunotherapy entered first-line systemic treatment around 2020. For appropriately selected patients, immunotherapy-based combinations have become the principal first-line systemic treatment options because these regimens have demonstrated meaningful survival advantages and the possibility of durable disease control. However, the same evidence also makes clear that the benefit of immunotherapy depends not only on choosing an active regimen, but also on choosing the right patient and surrounding treatment with a disciplined safety system.
 
Much has been learned since these therapies were introduced. Immune-related and VEGF-related adverse effects are now better recognized, graded, monitored and treated than they were early in the immunotherapy era. Fatal events remain possible, especially in patients with limited hepatic reserve or delayed recognition of toxicity, but better baseline assessment, earlier reporting, treatment holds, corticosteroids or other immunosuppression when indicated, and timely specialist or hospital care have all improved the ability to prevent manageable complications from becoming irreversible.
 
Patient selection is therefore central. The best outcomes are most likely when treatment decisions account for physiologic reserve or frailty, ECOG performance status, Child-Pugh liver function, portal hypertension and bleeding risk, autoimmune history, comorbid illness, tumor burden, macrovascular invasion, extrahepatic spread and the patient’s goals of care. In this sense, immunotherapy should not be viewed as a single default option for all patients with unresectable HCC, but as a powerful treatment strategy whose value is maximized when matched carefully to the patient’s clinical condition and disease characteristics.
 
Equally important is patient and family education. Patients should know before the first infusion which symptoms require a prompt call, which require same-day assessment, and which require emergency care. Families should also be prepared to recognize changes the patient may minimize or fail to notice, such as confusion, worsening weakness, jaundice, bleeding, dehydration or shortness of breath. These practical guardrails—baseline evaluation, symptom checklists, routine laboratory surveillance, regimen-specific monitoring, clear rules for holding or stopping treatment and an escalation plan for serious toxicity—are not optional details; they are part of safe immunotherapy.
 
The purpose of this essay has been to translate the evidence and safety considerations into information that patients and families can use when immunotherapy is offered for HCC. It does not replace the judgment of an experienced liver oncology team, but it can help patients ask better questions, understand the rationale for regimen selection, recognize warning signs earlier, and participate more effectively in shared decision-making. In the modern management of unresectable HCC, survival benefit and safety are inseparable: immunotherapy offers real promise, but the best outcomes come when treatment is individualized, monitored closely and supported by an informed patient-family-care team partnership.

Abbreviations
 
AFP: Alpha-fetoprotein
AE: Adverse event
ECOG: Eastern Cooperative Oncology Group
HCC: Hepatocellular Carcinoma
HR: Hazard Ratio
OS: Overall Survival
PD-1: Programmed Cell Death Protein 1
PD-L1: Programmed Death-Ligand 1
RAF: Rapidly Accelerated Fibrosarcoma
SBRT: Stereotactic Body Radiation Therapy
TACE: Transarterial Chemoembolization
TARE: Transarterial Radioembolization
TKI: Tyrosine kinase Inhibitor
TRAE: Treatment Related Adverse Event
VEGF-A: Vascular Endothelial Growth Factor A
VEGFR: Vascular Endothelial Growth Factor Receptor

Appendix A
 
Safety net for HCC immunotherapies
 
Nine essential components
 
1. Establish a baseline before treatment
Before the first infusion, the care team should document a detailed baseline health profile for the patient with HCC.
At minimum, this baseline assessment should include:

• ECOG performance status/frailty
• Child-Pugh/liver function
• CBC
• bilirubin, AST/ALT, alkaline phosphatase
• creatinine/electrolytes
• thyroid function
• blood pressure
• medications and supplements
• autoimmune history
• cardiovascular history

For atezolizumab + bevacizumab, the baseline assessment should also include careful evaluation of portal hypertension and variceal bleeding risk. Because bevacizumab can increase bleeding risk, ASCO recommends that esophageal varices be managed before atezolizumab/bevacizumab is started [11].
This is a preventive guardrail: the goal is to reduce avoidable bleeding risk before a complication occurs.
 
2. Establish a treatment-specific risk profile
The three regimens do not have identical safety profiles.
Atezolizumab + bevacizumab: bleeding risk, hypertension, proteinuria, wound-healing complications, and immune-related toxicity.
Durvalumab + tremelimumab (STRIDE): immune-mediated toxicity, particularly hepatitis, colitis, endocrinopathies, pneumonitis, and other inflammatory complications.
Nivolumab + ipilimumab: potentially more intense immune-mediated toxicity because of repeated CTLA-4 blockade.
The safety plan should therefore be tailored to the selected regimen rather than treating immunotherapy as one uniform category.
 
3. Give the patient and family a symptom-reporting checklist
This may be the most important guardrail for preventing catastrophic outcomes. Before the first infusion, patients and family members should know which symptoms require a prompt call to the oncology team and which symptoms require urgent or emergency care.
For example:
GI

• new or increasing diarrhea
• abdominal pain
• blood/mucus in stool
• persistent vomiting
• inability to maintain hydration

Liver

• jaundice
• dark urine
• unusual bruising/bleeding
• severe nausea/anorexia
• right-upper-quadrant pain

Respiratory

• new cough
• shortness of breath
• chest pain

Neurologic

• new weakness
• confusion
• severe headache
• visual changes
• difficulty speaking/swallowing

Endocrine

• extreme fatigue
• dizziness
• unusual thirst/urination
• unexplained weight change
• persistent headache

ASCO specifically recommends educating patients and caregivers and maintaining a high level of suspicion that new symptoms may be treatment-related [12].
 
4. Do not wait for symptoms: perform routine laboratory surveillance
For checkpoint inhibitors this includes, at appropriate intervals:

• CBC
• liver enzymes and bilirubin
• creatinine
• electrolytes
• thyroid function
• glucose

The durvalumab prescribing information, for example, specifically calls for monitoring liver enzymes, creatinine and thyroid function at baseline and periodically during treatment [13].
In HCC, liver-test abnormalities are particularly difficult to interpret because many patients already have underlying liver disease.
A rise in AST or ALT is not automatically immune-mediated hepatitis.
The clinician should consider other possible causes, including:

• tumor progression
• viral hepatitis
• biliary obstruction
• ischemia
• infection
• other hepatotoxic drugs
• underlying cirrhosis
• immune-mediated hepatitis.

This differential diagnosis is essential because management can differ substantially depending on the cause.
 
5. Add regimen-specific surveillance
For atezolizumab + bevacizumab, blood pressure and urine protein deserve special attention. The current Tecentriq label reports hypertension in 30% of HCC patients receiving atezolizumab + bevacizumab, with Grade 3–4 hypertension in 15%, and proteinuria in 20%, with Grade 3–4 proteinuria in 3% [14]. These are not theoretical risks. Before treatment begins, the team should also assess varices and overall bleeding risk.
For dual immunotherapy regimens, the emphasis shifts toward:

• liver tests
• GI symptoms
• thyroid/adrenal function
• glucose
• pulmonary symptoms
• neurologic symptoms
• cardiac symptoms when clinically indicated.

 
6. Have explicit "hold treatment" rules
Patients should understand that an infusion does not have to be given simply because it is scheduled. If a concerning toxicity appears, the appropriate sequence may be to assess the symptom, investigate the cause, treat the toxicity, and then decide whether to hold, resume, or discontinue treatment. ASCO's general framework recommends continuing immunotherapy with monitoring for most Grade 1 toxicities, holding for most Grade 2 toxicities, and holding for Grade 3 toxicity while initiating high-dose corticosteroids [15]. These are general principles; management is organ-specific and should follow the relevant prescribing information and immune-related toxicity guidelines.
 
7. Have explicit "never give another dose" rules
This is the other half of the safety system. Patients should not have to wonder how severe a toxicity must become before treatment is stopped. Prescribing information and immune-toxicity guidelines provide criteria for permanent discontinuation in specific severe or life-threatening toxicities. Importantly, permanent discontinuation is not necessarily a treatment failure. In some situations, stopping the drug is what successful toxicity management looks like.
 
8. Have a rescue plan when toxicity does not respond
Corticosteroids are often appropriate when clinically significant immune-related toxicity is suspected, but that statement is incomplete by itself.
The safety algorithm needs an escalation pathway:
Recognize → hold treatment → evaluate → corticosteroids when indicated → reassess → escalate immunosuppression if steroid-refractory → specialist/hospital care when appropriate.
For example, ASCO recommends high-dose corticosteroids for many Grade 3 immune-mediated toxicities [15]. When toxicity is steroid-refractory, additional immunosuppressive therapy may be required depending on the affected organ. Immune-mediated hepatitis, for example, may require mycophenolate mofetil if corticosteroids fail [16]. This matters because “give steroids” is not the whole story; reassessment and escalation must be built into the plan.
 
9. Do not assume every symptom is an immune adverse event
This point may sound counterintuitive, but it is especially important in HCC. A patient with cirrhosis and advanced HCC can develop several complications independently of immunotherapy, including:

• infection
• spontaneous bacterial peritonitis
• GI bleeding
• hepatic encephalopathy
• portal hypertension
• biliary obstruction
• thromboembolism
• renal dysfunction
• tumor progression

These problems can occur independently of immunotherapy. Therefore, new symptoms require evaluation, not automatic attribution to immunotherapy. This is especially important for liver-test abnormalities, where clinicians should investigate alternative causes before labeling an abnormality immune-mediated [16].

Appendix B
 
Red-flag symptoms

​When should a patient call?
Do not wait for the next scheduled infusion if a new or rapidly worsening symptom develops. Call the oncology team. If the symptom is severe—especially difficulty breathing, chest pain, fainting, confusion, severe abdominal pain, significant bleeding, or inability to stay hydrated—seek emergency care.
 
A critical role for the patient's family
Because the patient may become too sick to recognize the significance of symptoms.
Family members should call immediately if they notice:

• sudden confusion or unusual behavior
• extreme sleepiness or difficulty waking
• new difficulty breathing
• fainting
• new weakness or inability to walk
• vomiting blood or black stools
• jaundice
• severe dehydration
• rapidly deteriorating general condition

Appendix C
 
Toxicity commonly encountered during imunotherapy and corresponding action steps

​Hung Van Le*
Biologics & Drug Targets, ProSci LLC, Rockaway, NJ, United States
ORCID
https://orcid.org/0000-0002-6913-2373 (Hung Van Le)

Abstract
 
Chronic hepatitis B remains a major global health challenge despite the success of universal vaccination and the availability of effective nucleos(t)ide analogue therapy. Current standard-of-care treatments suppress viral replication and reduce liver-related complications but rarely achieve functional cure, largely because cccDNA, integrated HBV DNA, and immune exhaustion persist. Recent therapeutic advances have begun to change this outlook. Bulevirtide has introduced a targeted entry-inhibition strategy for patients with HBV/HDV co-infection, while bepirovirsen may provide a broader finite-duration approach capable of increasing HBsAg loss beyond that achieved with standard therapy alone. In parallel, late-stage agents including siRNAs, capsid assembly modulators, neutralizing antibodies, therapeutic vaccines, and checkpoint inhibitors are advancing through Phase 2 and Phase 3 trials. These candidates support a shift toward rational combination regimens that reduce antigen burden, suppress replication, and restore antiviral immunity. Although disease severity and host immune status may limit response, the integration of vaccination, expanded access to care, and improved therapeutics could substantially advance HBV elimination efforts.

Clinical bottom line
 

• Current standard therapy effectively suppresses HBV but rarely cures it.
• Bulevirtide and bepirovirsen represent the first meaningful therapeutic advances beyond standard care.
• The future of HBV treatment lies in rational combination therapy rather than single agents.
• Not all patients are equally likely to achieve functional cure.
• HBV elimination will require both better therapeutics and stronger prevention.

 

Introduction
 
The introduction of the hepatitis B virus (HBV) vaccine more than four decades ago ranks among the greatest achievements in preventive medicine. According to the World Health Organization (WHO) Global Hepatitis Report 2026 [1], the global prevalence of chronic HBV infection among children younger than five years has declined from approximately 5% in the pre-vaccine era to just 0.6% today. More than 80 countries have already met the WHO's 2030 elimination target of reducing childhood HBV prevalence to below 0.1%. Worldwide, the annual incidence of acute HBV infection has fallen by more than 32% since 2015. In countries with longstanding universal infant vaccination programs, including Taiwan, the United States, and many European nations, childhood-acquired chronic HBV infection and its associated pediatric hepatocellular carcinoma have become exceedingly rare.
 
 
Despite this remarkable public health success, hepatitis B remains a major global health challenge, causing more than 1.1 million deaths annually. Approximately 240 million people worldwide continue to live with chronic HBV infection. Most were born before universal infant vaccination was implemented or reside in regions where vaccine coverage remains inadequate. Although completion of the three-dose infant vaccination series is relatively high worldwide, timely administration of the birth-dose vaccine within 24 hours of delivery continues to lag, particularly in low-income countries. In the WHO African Region, only 17% of newborns receive the recommended birth dose, allowing mother-to-child transmission to remain a major driver of the epidemic. Because vaccination prevents new infections but does not eradicate established ones, millions of chronically infected adults remain at risk of progressive liver disease, cirrhosis, and hepatocellular carcinoma. Compounding this problem, fewer than 5% of individuals with chronic HBV infection currently receive antiviral treatment [2,3].
 
Current therapy for chronic hepatitis B (CHB) relies primarily on long-term oral nucleos(t)ide analogues (NAs) and, in selected patients, subcutaneous pegylated interferon-α (PegIFN-α). Although NAs effectively suppress viral replication and markedly reduce the risk of liver disease progression, they rarely achieve a functional cure because they neither eliminate the stable covalently closed circular DNA (cccDNA) reservoir within hepatocyte nuclei nor prevent viral protein expression from integrated HBV DNA. Consequently, functional cure—defined as sustained loss of hepatitis B surface antigen (HBsAg) with undetectable serum HBV DNA for at least 24 weeks after treatment cessation—is achieved only infrequently with NA monotherapy. In most patients, discontinuation of therapy results in virological relapse, necessitating lifelong treatment [4,5].
 
PegIFN-α offers a finite-duration alternative but is limited by its parenteral administration, considerable adverse-effect profile, and suitability for only a carefully selected subset of patients. Functional cure rates following a standard course of PegIFN-α are modest, with cumulative HBsAg loss of approximately 8%–12% after 3–5 years of follow-up. Higher rates of HBsAg loss (15%–25%) have been reported when PegIFN-α is used as an add-on or switch strategy in carefully selected patients who have already achieved long-term viral suppression with NAs, particularly those with low baseline HBsAg levels (<1,000 IU/mL) [6,7]. Nevertheless, these outcomes remain unsatisfactory, underscoring the need for more effective therapeutic strategies capable of producing substantially higher rates of functional cure.
 
Recent advances in the understanding of the HBV life cycle and host immune responses [8] have stimulated the development of multiple novel antiviral and immunomodulatory agents [9]. Although none has yet achieved the long-sought goal of a sterilizing cure, these emerging therapies represent important incremental advances toward higher rates of functional cure. This review summarizes the current therapeutic landscape and highlights the progress, challenges, and future directions in HBV treatment.

Two Promising Direct-Acting Antiviral Approaches: Bulevirtide and Bepirovirsen
 
Bulevirtide: Targeting Viral Entry in HBV/HDV Co-Infection
 
Bulevirtide, developed by Gilead Sciences and marketed as Hepcludex, is approved for chronic hepatitis delta virus (HDV) infection in adults who are serum HDV-RNA positive and have compensated liver disease. The European Medicines Agency approved the drug in July 2020, followed by approvals in Canada in May 2025 and the United States in May 2026 [10]. Because HDV infection occurs only in people with hepatitis B virus (HBV) infection, bulevirtide is most relevant to patients with HBV/HDV co-infection.
 
Bulevirtide is a first-in-class entry inhibitor that binds to and inactivates the sodium taurocholate co-transporting polypeptide (NTCP) receptor on hepatocytes. Both HBV and HDV use NTCP to enter liver cells, so blocking this receptor prevents newly produced viral particles from infecting uninfected hepatocytes. This mechanism is especially important because HDV is an incomplete satellite virus that requires hepatitis B surface antigen (HBsAg) to assemble its envelope and spread [11].
Clinically, this fills a major unmet need. HBV/HDV co-infection is among the most aggressive forms of chronic viral hepatitis and can progress rapidly to cirrhosis and liver failure. Before bulevirtide, treatment options were limited, and finite therapies such as pegylated interferon-α (PegIFN-α) were often ineffective, poorly tolerated, or suitable only for carefully selected patients [12].
 
Administration and combination with nucleos(t)ide analogues
 
Bulevirtide is a 47-amino-acid lipopeptide administered as a daily 2 or 8.5 mg subcutaneous injection depending on EU or US approval, respectively [13, 10]. Treatment is generally long term and continued while clinical benefit is maintained. This prolonged treatment requirement reflects its mechanism of action: as an entry inhibitor, bulevirtide prevents new infection of hepatocytes but does not directly eliminate intrahepatic viral genetic material.
Most clinical practice guidelines, including EASL guidance, and national regulatory bodies such as HAS in France recommend routine co-administration with a nucleos(t)ide analogue (NA), such as tenofovir (TDF/TAF) or entecavir [14]. This approach helps maintain suppression of HBV replication while bulevirtide targets HDV entry.
 
The rationale is based on the interaction between the two viruses. In co-infected patients, HDV can suppress HBV replication, keeping serum HBV DNA low. When bulevirtide reduces HDV RNA, this viral interference may be lifted, potentially allowing HBV replication to rebound. Co-administering an NA reduces that risk by keeping HBV replication suppressed.
 
Potential role with PegIFN-α
 
Bulevirtide has also been studied in combination with PegIFN-α. While bulevirtide plus NA can suppress HDV RNA during treatment, adding PegIFN-α may increase the likelihood of off-treatment sustained virological response (SVR) and HBsAg clearance in selected trial cohorts [12].
 
Bepirovirsen: Toward a Broader Functional-Cure Strategy
 
Bepirovirsen, developed by GSK, is under formal regulatory review by both the US FDA and the European Medicines Agency as a potential first-in-class functional-cure therapy for chronic hepatitis B (CHB). The submissions are supported by two large global Phase 3 registrational trials, B-Well 1 and B-Well 2 [15], which enrolled more than 1,800 patients across 29 countries. The FDA has set a target action date of October 26, 2026, and an EMA opinion is expected in late 2026 or early 2027.
 
In B-Well 1 and B-Well 2, a 24-week course of once-weekly subcutaneous bepirovirsen, given as an add-on to standard NA therapy, produced functional cure in 20% of patients with chronic HBV infection at the 72-week follow-up. This result is comparable to functional-cure rates reported with PegIFN-α add-on strategies in carefully selected patients who have already achieved long-term viral suppression with NAs.
The key advantage of bepirovirsen is its broader potential applicability. Its safety and adverse-event profile appears more localized, manageable, and tolerable than that of PegIFN-α, which could make a similar level of functional-cure efficacy available to a larger cross-section of patients with chronic HBV infection [16].
 
Bepirovirsen may also create new opportunities for combination or sequential approaches. Preliminary studies suggest that PegIFN-α given after a course of bepirovirsen may reduce relapse rates compared with bepirovirsen alone [17]. Further study will be needed to define which patients are most likely to benefit and how best to sequence these therapies.
 
In summary, bulevirtide and bepirovirsen expand the therapeutic landscape for chronic HBV-related disease in complementary ways. Bulevirtide addresses the major unmet need of HBV/HDV co-infection, while bepirovirsen may increase functional-cure rates across a broader population of patients with chronic HBV infection, including those who are not candidates for PegIFN-α. Future combination studies involving these agents, NAs, and PegIFN-α will be important to determine whether relapse can be delayed, sustained responses improved, or functional cure achieved in selected patient groups.

Other Significant Anti-HBV Therapeutics in Late-Stage Phase 2/3 Development
 
Direct-Acting Antivirals (DAAs)
 
Global clinical-development pipelines have shifted away from monotherapy toward combination strategies that pair complementary mechanisms of action to increase the likelihood of functional cure, defined as sustained HBsAg loss with undetectable HBV DNA after treatment cessation, in patients with chronic HBV infection. Based on clinical-trial momentum, robust Phase 2 efficacy data, and expedited regulatory designations, three drug candidates (Table 1) appear most likely to advance toward regulatory submission after bepirovirsen.
 
Elebsiran (VIR-2218) is a small interfering RNA (siRNA) developed by Vir Biotechnology in collaboration with Alnylam and is currently being evaluated in Phase 2b/3 clinical trials. It targets a conserved 3′ region of HBV RNA, promoting degradation of viral transcripts and reducing serum HBsAg levels. Elebsiran is positioned for further development on the basis of encouraging Phase 2 results from studies such as MARCH and SOLSTICE, in which combinations with the neutralizing monoclonal antibody tobevibart and/or pegylated interferon produced off-treatment functional cure rates of 17% to 21% in patients with low baseline HBsAg [18]. In addition, elebsiran is being evaluated with tobevibart in the pivotal Phase 3 ECLIPSE trial for HDV/HBV co-infection, a program that has received FDA Breakthrough Therapy and EMA PRIME designations [19].
 
Another siRNA candidate, Imdusiran (AB-729), developed by Arbutus Biopharma, has reached Phase 2a/2b clinical development and is moving toward Phase 3 planning [20]. It is a subcutaneously delivered N-acetylgalactosamine (GalNAc)-conjugated siRNA designed to suppress HBV transcripts broadly, thereby reducing HBsAg expression and potentially relieving HBV-specific T-cell exhaustion. Clinical data presented at major hepatology conferences, including AASLD, from the IM-PROVE I trial showed that adding a short 24-week course of PegIFN-α to imdusiran plus NA therapy achieved a 25% overall functional cure rate, rising to 50% among patients with baseline HBsAg < 1,000 IU/mL [21]. Imdusiran has also shown strong synergy when paired with therapeutic vaccines, such as VTP-300, and low-dose checkpoint inhibitors, including anti-PD-1 therapy, positioning it as a potential backbone for future finite-duration cure regimens [22].
 
Pevifoscorvir Sodium (ALG-000184) is a capsid assembly modulator (CAM) developed by Aligos Therapeutics and is being evaluated in the Phase 2 B-SUPREME trial. It is a potent oral Class II CAM, or CAM-E, that disrupts capsid formation, blocks pregenomic RNA packaging, and may limit replenishment of intrahepatic cccDNA. Pevifoscorvir sodium is positioned for further development because of two notable advantages. First, it has demonstrated best-in-class potency: unlike earlier-generation CAMs, which showed only modest antiviral activity, ALG-000184 has produced profound multi-log reductions in HBV DNA, HBV RNA, and hepatitis B core-related antigen (HBcrAg) [23,24]. Second, it is orally active and is being directly compared with tenofovir disoproxil fumarate (TDF) in the Phase 2 B-SUPREME trial, offering a potential oral backbone that could replace lifelong NA therapy or be combined with injectable RNAi or antisense oligonucleotide therapies [25].
 
Immunomodulatory Agents and Host-Targeting Strategies
 
Several immunomodulatory and host-targeting agents are in active Phase 2 or Phase 2/3 clinical development. Historically, immunomodulators have faced a major hurdle: when circulating HBsAg levels remain very high, HBV-specific immune cells are profoundly exhausted, limiting the efficacy of therapeutic vaccines or checkpoint inhibitors when used alone. Now that direct-acting agents such as siRNAs and antisense oligonucleotides can reduce serum HBsAg by more than 99%, immunomodulatory therapies are emerging as essential components of combination cure regimens. Four prominent immunomodulatory and host-directed candidates (Table 2) are currently in Phase 2 or Phase 2/3 development.
 
Tobevibart (VIR-3434) is a neutralizing human monoclonal antibody developed by Vir Biotechnology and is being evaluated in Phase 2/3 clinical trials, including ECLIPSE and MARCH [26]. It is engineered to target the conserved S antigen of HBV and serves two complementary functions. First, it binds and neutralizes circulating HBsAg particles, promoting their rapid clearance from the bloodstream [27]. Second, because its Fc region is modified to engage Fc receptors on dendritic cells and promote antigen uptake, it may act as a passive-to-active immune stimulator with a vaccine-like effect [28]. As noted above, tobevibart combined with the siRNA elebsiran has achieved off-treatment HBsAg loss rates of approximately 20% in Phase 2 studies and is advancing toward registration.
 
VTP-300 is an antigen-specific therapeutic vaccine developed by Barinthus Biopharma, formerly Vaccitech, and is being evaluated in Phase 2b clinical trials, including HBV003 and IM-PROVE II. It uses a prime-boost vector strategy, with a ChAdOx1 prime followed by an MVA boost, to deliver HBV antigens, including core, polymerase, and surface proteins, directly to antigen-presenting cells [29]. When administered alone, therapeutic vaccines have limited efficacy in the setting of high viral-antigen burden. However, when VTP-300 is given after siRNA-mediated HBsAg reduction, such as with imdusiran [30], or combined with low-dose anti-PD-1 therapy [31], it can promote sustained T-cell responses and persistent HBsAg declines.
 
BRII-179 (VBI-2601) is a recombinant pre-S1/pre-S2/S therapeutic vaccine developed by Brii Biosciences and VBI Vaccines and is being evaluated in Phase 2b clinical trials. It is a virus-like particle (VLP) recombinant vaccine expressing all three HBV surface antigens—pre-S1, pre-S2, and S—designed to restore both B-cell antibody production and T-cell responses in virally suppressed patients. Phase 2 data suggest that adding BRII-179 to standard care, or to PegIFN-α, may increase the proportion of patients who achieve HBsAg loss and reduce viral rebound after therapy is stopped. It is also being studied as a biomarker tool to identify patients whose immune systems may be amenable to immune re-priming for functional cure [32].
 
Finally, ASC22 (envafolimab, also known as KN035) is a subcutaneous anti-PD-L1 checkpoint inhibitor licensed from Suzhou Alphamab by Ascletis Pharma for development and commercialization in viral diseases, primarily chronic hepatitis B and HIV [33]. The rationale is based on the observation that HBV can promote T-cell exhaustion through upregulation of the PD-1/PD-L1 immune-checkpoint pathway. Blocking PD-L1 is intended to reverse T-cell exhaustion and reactivate HBV-specific CD8+ cytotoxic T cells in the liver. Ascletis advanced ASC22 through a Phase 2b clinical trial [34], demonstrating functional cure rates of 21% to 42% in a subset of patients with very low baseline antigen levels, but limited meaningful HBsAg loss in patients with higher baseline viral loads [35]. Although these results were modest, they support immune checkpoint blockade as a potential pillar of combination cure strategies. They are also noteworthy because several anti-PD-1 and anti-PD-L1 monoclonal antibodies approved for oncology could, in principle, be evaluated in combination with HBV antivirals.

Discussion
 
The therapeutic landscape for hepatitis B remains one of the most dynamic areas of antiviral research, spanning both preclinical discovery and late-stage clinical development. Although current nucleos(t)ide analogue therapy has transformed chronic HBV infection from a rapidly progressive disease into a manageable long-term condition, it rarely produces functional cure and usually requires indefinite treatment. The persistence of cccDNA, the contribution of integrated HBV DNA to HBsAg production, and the profound immune exhaustion associated with chronic antigen exposure continue to make HBV biologically difficult to cure. For this reason, the field has increasingly moved away from single-agent viral suppression and toward finite, mechanism-based combination regimens designed to reduce viral antigen burden, restore antiviral immunity, and prevent relapse after treatment cessation. This strategy is illustrated in Figure 1.
 
Against this background, the introduction of bulevirtide and the anticipated introduction of bepirovirsen represent important incremental advances. Bulevirtide addresses a particularly severe clinical niche: chronic HBV/HDV co-infection, in which therapeutic options have historically been limited and disease progression can be rapid. By blocking NTCP-mediated viral entry, bulevirtide provides a targeted approach for suppressing HDV spread when used with background HBV suppression. Bepirovirsen, by contrast, has broader relevance to chronic HBV infection because it directly reduces HBV RNA transcripts and HBsAg production. Its Phase 3 functional-cure rates of approximately 20% are well above those generally achieved with nucleos(t)ide analogue monotherapy and may offer a finite-treatment option for selected patients, particularly those with lower baseline HBsAg levels. Together, these agents are unlikely to represent a final cure strategy, but they mark a meaningful step beyond the current standard of care.
 
The next decade is likely to bring further progress as multiple agents with diverse mechanisms of action advance through Phase 2 and Phase 3 trials. RNA-targeting agents such as elebsiran and imdusiran can markedly reduce HBsAg levels; capsid assembly modulators such as pevifoscorvir sodium may provide more potent control of viral replication and cccDNA replenishment; neutralizing antibodies such as tobevibart can accelerate clearance of circulating antigen; and therapeutic vaccines or checkpoint inhibitors may help restore exhausted HBV-specific immune responses. The diversity of this pipeline is important because HBV persistence is unlikely to be reversed through a single mechanism. Instead, higher functional-cure rates will probably require rational combinations that pair antigen reduction with immune reactivation and durable suppression of viral replication. If current clinical momentum continues, several of these agents could emerge as approved components of finite combination regimens, raising the possibility that functional-cure rates will move substantially beyond those achieved by today’s therapies.
 
Nevertheless, the upper limit of functional cure may be constrained by disease severity and host factors. Patients with long-standing infection, advanced fibrosis or cirrhosis, high baseline HBsAg levels, impaired innate and adaptive immune responses, or HBV/HDV co-infection may respond less well than individuals with lower antigen burden and preserved immune function. Even when HBsAg loss is achieved, some patients may retain intrahepatic viral reservoirs or integrated HBV sequences that sustain relapse risk or contribute to hepatocarcinogenesis. Thus, future clinical strategies will need to identify the patients most likely to benefit from finite cure regimens, determine whether sequential or combination approaches can overcome poor-response features, and maintain surveillance for liver cancer in those with established advanced liver disease.
 
Ultimately, HBV eradication will require integration of prevention and treatment rather than reliance on therapeutics alone. Universal infant vaccination, timely birth-dose vaccination, maternal screening, antiviral prophylaxis during pregnancy when indicated, expanded testing, and linkage to care remain essential for interrupting transmission. At the same time, the emergence of more effective finite therapies could reduce the pool of chronically infected individuals capable of transmitting infection and progressing to cirrhosis or hepatocellular carcinoma. If highly effective vaccines are deployed equitably and the best emerging therapeutics become accessible beyond high-income settings, the long-term prospect of HBV elimination—and eventually eradication as a public health threat—becomes increasingly realistic. The central challenge will be ensuring that scientific progress is matched by global implementation, affordability, and sustained political commitment.

Conclusion
 
HBV therapy is entering a period of meaningful but still incremental progress. Long-term nucleos(t)ide analogue therapy remains highly effective for viral suppression, yet it rarely produces functional cure. The approval of bulevirtide for HBV/HDV co-infection and the anticipated availability of bepirovirsen for chronic HBV infection signal a transition toward more targeted, finite, and mechanism-based treatment strategies. Even greater gains may come from emerging agents now in Phase 2 and Phase 3 trials, especially when combined to lower antigen burden, intensify viral suppression, and restore exhausted immune responses. However, cure rates are unlikely to improve uniformly across all patients; advanced liver disease, high baseline HBsAg levels, viral reservoirs, and impaired host immunity may continue to constrain outcomes. The long-term goal should therefore be twofold: to develop safer and more effective cure regimens for those already infected, and to strengthen prevention through universal vaccination, timely birth-dose coverage, maternal screening, and equitable access to treatment. Together, these measures could move HBV control from lifelong management toward functional cure and eventual elimination as a public health threat.

Abbreviations
 
ASO: Antisense Oligonucleotide 
CAM: Capsid Assembly Modulator
CHB: Chronic Hepatitis B
cccDNA: covalently closed circular DNA
EMA: Europeam Medicines Agency
EASL: European Association for the Study of the Liver
FDA: Federal Drug Administration
HAS: Haute Autorité de Santé
HBV: Hepatitis B Virus
HDV: Hepatitis Delta Virus
HBcrAg: Hepatitis B core-related Antigen
HBsAg: Hepatitis B surface Antigen
GalNac: N-acetyl Galactosamine
NA: Nucleos(t)ide Analogue
NTCP: sodium taurocholate co-transporting polypeptide
SVR: Sustaine Virological Response
TDF: Tenofovir Disoproxyl Fumarate
TAF: Tenofovir alafenamide
VLP: Virus Like Particle
WHO: World Health Organization

​Table 1. Summary of Emerging Pipeline of Direct-Acting Antivirals

​Table 2. Summary of Emerging Pipeline of immunomodulatory and host-targeting agents