We are grateful to Dr. Wong, Dr. Yu, Dr. Wang, and their respective colleagues for their insightful commentaries on our study recently published in Clinical and Molecultar Hepatology [1]. Their thoughtful remarks not only highlight the complexities of managing chronic hepatitis B (CHB) with currently available antiviral therapies but also put our findings into perspective regarding inequalities in the burden of hepatitis B virus (HBV) around the world. We firmly believe that such active dialogue is critical as we strive toward eliminating HBV as a global public health threat. Below, we address their comments in detail.

Dr. Wong highlights the momentum towards simplifying and broadening CHB treatment criteria, citing our study as part of this growing body of evidence [2]. We appreciate his emphasis on the clinical implications of our findings, especially the histological improvements observed when patients transitioned from placebo to tenofovir disoproxil fumarate. While we employed paired biopsies as endpoints, we agree with Dr. Wong that future investigations need to focus on long-term clinical outcomes—such as the incidence of hepatocellular carcinoma (HCC) and liver-related mortality—to strengthen the evidence for expanding treatment eligibility.

In his commentary, Dr. Wong pointed out that existing guidelines for CHB treatment eligibility are overly complex, incorporating multiple variables like age, comorbidities, liver disease severity, and viral load. Such complexity often delays or restricts access to treatment. With safe and effective antiviral options available, treatment expansion has the potential to reduce CHB-related morbidity and mortality substantially. He suggests treatment algorithms be simplified to reduce gaps in treatment access. We share his perspectives and believe that our findings support this direction. Current guidelines from major liver societies often rely on complex and restrictive criteria that inadvertently exclude patients with mild alanine aminotransferase (ALT) elevation, despite their risk of HCC [3]. In addition to the current study, other data from the TORCH-B trial has demonstrated that antiviral therapy can prevent liver fibrosis progression and reduce the occurrence of HBV DNA integrations in this “gray-zone” population [4,5]. These findings support the World Health Organization’s updated guidelines advocating broader treatment eligibility criteria [6].

Drs. Wang and Yu commend the use of histopathological endpoints in our study and emphasize the importance of further research to confirm effectiveness in clinical outcomes. They also draw attention to several limitations of currently available therapy for CHB, particularly the lack of hepatitis B surface antigen (HBsAg) clearance [7]. Although nucleos(t) ide analogue (NUC) treatments effectively suppress viral replication, integrated HBV DNA continues to drive the production of HBsAg [8], which can undermine immune responses [9]. We echo their comment that NUC therapy is ineffective to clear HBsAg and novel therapeutic strategies, such as combination regimens incorporating immune modulators [10], are required to improve the management of CHB.

They also discussed that some patients still experienced progression in liver fibrosis or inflammation despite treatment (13.8% and 29.3%, respectively, in our study), indicating the multifactorial nature of liver damage in patients with CHB. We concur with their insights that prescribing NUC therapy does not guarantee improved outcomes for all patients living with HBV. Although our study was not specifically designed to investigate the causes of untoward clinical outcomes in CHB patients on antiviral therapy, the post-hoc analyses suggested that factors like hepatic steatosis and incomplete virological suppression may contribute to suboptimal outcomes. In line with their comment, we believe that addressing modifiable risk factors, such as metabolic conditions and lifestyle habits, should be a fundamental component of comprehensive CHB management.

Drs. Wang and Yu further caution that expanding treatment eligibility must consider potential impacts on healthcare systems, especially in resource-limited settings where the existing inequalities in HBV care may worsen [11]. We concur that strategies such as access to generic drugs, decentralized care, and sustainable funding will be critical for an equitable implementation of treatment expansion.

Dr. Huang and colleagues commend our study for providing evidence in support of antiviral therapy in patients with mild ALT elevation but note the absence of a comparative group with ALT >2 times upper limit of normal (ULN) [12]. Their multi-center cohort study adds valuable context by demonstrating similar virological and biochemical responses between the two groups, with lower hepatitis B e antigen (HBeAg) clearance rates in patients with ALT between 1 to 2 times ULN. We acknowledge that our study did not include patients with higher ALT for direct comparison and agree that Dr. Huang and colleagues’ findings complement ours in building the bulk of empirical data that is essential to inform clinical practice.

Pretreatment ALT levels have been shown to correlate with HBeAg seroconversion rates in HBeAg-positive patients [13], as also demonstrated by Huang et al. Moreover, higher pretreatment ALT levels are associated with increased probability of HBsAg loss during NUC therapy [14]. These relationships suggest that serum ALT levels may help predict the likelihood of serological conversion after initiating antiviral therapy.

Therefore, it is important to clarify that the rationale for expanding treatment eligibility to patients without substantial ALT elevation is not based on their chance of clearing HBeAg or HBsAg. Rather, we demonstrated that patients with minimally raised serum ALT can benefit from currently available treatment in terms of histological outcomes, along with virological and biochemical endpoints as shown in Huang et al.’s study. The serological outcomes in our current study showed that NUC therapy was limited by its inefficacy for seroclearance of HBeAg or HBsAg. This limitation suggests that the treatment duration with NUC therapy is likely to be indefinite to avoid hepatitis flares from treatment withdrwal [15], particularly for individuals with low probability of HBsAg seroclearance. This information must be carefully discussed when considering the initiation of NUC therapy in patients with ALT <2×ULN.

In conclusion, the perspectives offered by Dr. Wong, Dr. Yu, and Dr. Huang and their colleagues reinforce the urgent need to revisit current CHB treatment guidelines and confront the multifaceted challenges of HBV management. Our study adds to the growing body of evidence that patients with mildly elevated ALT can benefit from antiviral therapy, even without the promise of imminent serological clearance. However, these benefits must be considered alongside persistent therapy-related limitations, the importance of addressing modifiable comorbidities, and the inequities in global access to treatment. We believe that ongoing dialogue, further research into innovative combination therapies and immunomodulatory approaches, and greater attention to public health policy and resource allocation will collectively guide more inclusive, effective, and sustainable strategies to curb the global burden of CHB.