Current challenges in the management of chronic HBV infection

Despite the tremendous progress that has been made in the prevention, diagnosis, and management of patients with chronic HBV infection over the past 5 decades, chronic hepatitis B (CHB) still remains a major public health threat worldwide. Challenges exist among various populations and countries.

REVISITING THE NATURAL HISTORY OF CHRONIC HBV INFECTION

Traditionally, the natural history of CHB resulting from infection in early life can be categorized into 4 distinct phases based on HBeAg status, serum alanine transaminase levels, serum HBV DNA levels, and histological findings: immune tolerance, immune clearance, inactive carrier, and reactivation phases. Novel biomarkers, in conjunction with traditional ones, help distinguish the disease phases of chronic HBV infection.¹ Three new quantitative viral biomarkers including serum HBsAg, hepatitis B core-related antigen, and HBV RNA have been actively investigated. By combining these virological and serological biomarkers, we can now characterize the clinical phases of CHB and predict the outcomes in a more precise and sophisticated manner.

UPDATES AND APPLICATIONS OF NEW HBV BIOMARKERS

Precision medicine and risk stratification are important clinical issues for any human disease. As for chronic HBV infection, the most commonly asked questions include the following: What are the natural outcomes and treatment responses? Regarding these questions, again, serum HBV DNA, quantitative serum HBsAg, and quantitative serum hepatitis B core-related Ag provide some answers. In this supplement, the meaning and value of these new biomarkers in the personalized management of patients with chronic HBV infection are introduced.² Particularly, their applications in terms of HBV infection, HCC risk stratification, anti-HBV treatment decisions, and follow-up strategies are demonstrated.

ROLE OF AI IN CLINICAL PREDICTION

Clinical manifestations of chronic HBV infection can be influenced by various host, viral, and environmental factors. The contribution of each factor can only be analyzed by artificial intelligence (AI)-based big data analysis of a large clinical cohort at the same time.³ AI modeling consideration and development are introduced, and the value of AI in the management of liver diseases is demonstrated in certain clinical settings.

IMPACT OF METABOLIC DYSFUNCTION IN PATIENTS WITH HBV INFECTION

Clinically, the prevalence of metabolic dysfunction is common in patients with HBV infection.⁴ The negative impact of metabolic dysfunction has been demonstrated in recent retrospective cohort studies. Furthermore, the more the number of metabolic derangements, the higher the risk of developing HCC. Thus, in addition to the control of active HBV infection, correction of metabolic derangement should also be considered to improve the outcomes of these subjects with HBV infection and co-existing metabolic syndrome. Interestingly, patients with simple hepatic steatosis but without metabolic derangement are not at a higher risk of developing HCC and beneficially have a higher chance of HBsAg seroclearance. Scientifically, the mechanisms involved should be deciphered to develop effective strategies toward the goal of HBV functional cure.

PROS AND CONS OF EXPANDING TREATMENT INDICATIONS IN PATIENTS WITH CHRONIC HBV INFECTION

Controversial issues regarding the treatment of chronic HBV infection include when to start anti-HBV therapy.^5,6 Solid evidence supports that patients with high serum HBV DNA liver (≥ 20,000 IU/mL for HBeAg-positive subjects and ≥ 2000 IU/mL for HBeAg-negative subjects) and active necroinflammatory activity of the liver (indicated by elevated serum alanine transaminase level ≥ 2 times upper limit of normal) should be considered for anti-HBV therapy. Patients with advanced fibrosis or established cirrhosis should also be given long-term anti-HBV therapy when their serum HBV DNA is detectable. However, there are so-called “indeterminate phases” of HBV infection, and “grey zone” exists regarding the administration of anti-HBV therapy among these phases. Points favoring the expansion of treatment criteria include patients with CHB in the indeterminate phase still bearing the risk of fibrosis progression and HCC development; antiviral therapies can reverse hepatic fibrosis in patients with CHB with advanced fibrosis or cirrhosis; and the latest research showed that antiviral drugs reduce the risk of HCC among patients in the indeterminate phase. Considerations against the expansion of criteria include an extremely low risk of HCC development in patients with HBV in the immune-tolerant phase; the clinical outcomes of patients in the indeterminate phase remain dubious; and the rate of HBsAg seroclearance is low using current oral anti-HBV agents.

PROS AND CONS OF FINITE THERAPY FOR CHRONIC HEPATITIS B

Once anti-HBV therapy has been initiated, the next important question goes to when to stop anti-HBV therapy. Points favoring finite anti-HBV therapy include increasing rates of HBsAg seroclearance, probability of transitioning into chronic HBV infection without any anti-HBV treatment, no need for long-term adherence, and lower medical cost.⁷ Cons for finite anti-HBV therapy include high rates of virologic and clinical relapse, risk of severe hepatitis flare and associated liver decompensation, and risk of insidious liver disease progression.⁸

DREAMS AND FUTURE STRATEGIES ABOUT FUNCTIONAL CURE OF HBV INFECTION

Cohort studies support that the clinical outcomes are usually good once patients obtain seroclearance of HBsAg. Thus, for any therapeutic intervention, the holistic goal is to achieve HBsAg seroclearance, the so-called “functional cure.” By adopting current anti-HBV agents, either interferon-based therapy or nucleos(t)ide analog, the rate of HBsAg seroclearance is low. Promising agents/strategies with a higher rate of HBsAg seroclearance include siRNA and antisense oligonucleotide and the addition of pegylated interferon or immune modulatory therapy after HBV DNA suppression.⁹ Other emerging strategies under development have also been reviewed in this supplement.

MANAGEMENT OF PATIENTS WITH DUAL HBV AND HDV INFECTION

Patients with HBV infection may acquire HDV infection simultaneously (HBV and HDV co-infection) or later on during chronic HBV infection (HDV super-infection). These patients are at a higher risk of developing acute liver failure or progressing into end-stage liver diseases. In the past, off-label interferon is the only agent being shown to be effective in the control of HDV replication. Recent trial findings support that bulivertide (NTCP entry inhibitor) can be used to decrease hepatitis D viremia. Updated epidemiology and emerging anti-HDV therapies are reviewed in this supplement.¹⁰

PREVENTION AND MANAGEMENT OF HBV INFECTION IN PEDIATRIC POPULATIONS

How to increase the rate of HBV vaccination to prevent mother-to-child transmission of HBV infection and increase the immunity in populations at risk of HBV infection are priority public health issues. Management of active HBV infection and surveillance of HCC development in the pediatric population are also important clinical topics. In this supplement, strategies toward further reduction of new HBV infections are introduced.¹¹ Monitoring and antiviral treatment for chronic HBV infection (CHB) in children are discussed. Unmet needs include risk-beneficial expansion of treatment criteria and the development of safe curative regimens.

MANAGEMENT OF HBV REACTIVATION IN SPECIAL POPULATIONS

For any subject with HBsAg carriage, the risk of HBV reactivation (HBVr) should be considered when any cancer chemotherapy or immunosuppressive therapy is to be delivered. Also, a prophylactic anti-HBV agent should be given to prevent the development of HBVr.¹² Currently, most guidelines have clear recommendation about screening and prophylaxis of HBV reactivation in this disease setting and are summarized in this supplement. Among subjects with apparent resolved HBV infection, the minimal amount of HBV exists in the liver. Serologically, these subjects are negative for serum HBsAg and positive or negative for serum anti-HBs and anti-HBc. Long-term cohort studies suggested that the clinical outcomes of these subjects with resolved HBV infection are usually well, with minimal or no risk of developing liver complications, including the development of liver cirrhosis or HCC. However, when these subjects receive intense immunosuppression, they may be at risk of developing HBVr. Clinical observations revealed that the risk could be high (> 10%) when B cell-depleting agent is administered. Although knowledge gaps about HBVr remain in new treatment areas, applying HBV screening guidelines in practice can risk stratify patients as high, moderate, or low risk of HBVr to inform recommendations for prophylactic treatment. The role of HBsAb in risk stratification and duration of prophylactic treatment deserve further studies.

CONCLUSIONS

Through the succinct yet insightful review of these challenging topics, more investigations are encouraging in tackling these challenges with opportunities in the future, and more consensus regarding the management of patients with chronic HBV infection in different clinical scenarios is eagerly awaited.

CONFLICTS OF INTEREST

The authors have no conflicts to report.