Letter: Suggestions for Improving Study Design and Incorporating Virological Markers in HBV Functional Cure Research

With great interest, we read the seminal work by Zhou et al (1), titled “Quantitative Change of Hepatitis B Surface Antigen Leading to Final Hepatitis B Surface Antigen Loss in Patients With Chronic Hepatitis B Receiving Nucleos(t)ide Analogs in China.” This study explored the correlation between baseline serum HBsAg levels and their decline within 12 months with HBsAg loss in patients with chronic hepatitis B (CHB) using the Cox proportional hazards regression method. CHB remains a significant public health concern, and since 2022, relevant guidelines have recommended that some patients with CHB, including children, who meet certain criteria should pursue functional cure (2). HBsAg loss is key to achieving functional cure of CHB. The study indicated that a low baseline level of HBsAg was an independent predictor of HBsAg loss. Moreover, longitudinal dynamic changes in HBsAg could accurately predict the outcome of HBV functional cure (3). Although we fully recognize and agree with the statistical conclusions of the article, we still have questions about the data and the study.

First, although the study meticulously described HBV DNA quantification methodologies (Applied Biosystems 7500 Fast Real-Time Polymerase Chain Reaction System; Roche COmputer-BAsed System Hepatitis B Virus Amplification Preparation Monitor ), it did not sufficiently characterize baseline virological profiles across cohorts. In addition, although qHBsAg and its changes are important for functional cure, the titer of HBV DNA can further reflect the patient's virological replication capacity. Apart from qHBsAg levels, a low titer of HBV DNA can facilitate the serological conversion of HBsAg, and undetectable HBV DNA levels are associated with the serological clearance of HBsAg in patients with CHB on long-term nucleos(t)ide analog therapy (4). Furthermore, a recent study by Wang et al (5) indicated that treatment-naive HBeAg-negative patients with low serum HBsAg levels and undetectable HBV DNA had a higher rate of HBsAg clearance. Therefore, the study still needs to elaborate on the virological levels of HBV in treatment-naive and previously treated patients with CHB. The absence of this information limits the comprehensive understanding of the patients' conditions.

Finally, we suggest further stratified research. In patients with high viral loads (HBV DNA >200,000 IU/mL), immune modulatory therapy can induce the recovery of T-cell function and re-establish HBV-specific T-cell antiviral responses. The sustained high level may affect the rate of decline and eventual loss of HBsAg, while patients with low viral loads (HBV DNA <2,000 IU/mL) may experience more pronounced HBsAg loss. Moreover, in patients with CHB who have achieved virological suppression with long-term antiviral therapy, how qHBsAg affects HBsAg loss and the related mechanisms need to be explored.

In summary, I suggest incorporating novel virological markers, such as serum HBV RNA, HBcrAg, and antibodies, in addition to serum HBsAg and HBV DNA, for more comprehensive monitoring in future studies to better assess HBV functional cure. This will provide a more solid scientific basis for optimizing personalized treatment.

CONFLICTS OF INTEREST

Guarantor of the article: Jinsong Huang.

Specific author contributions: C.Y.: conceptualization. C.Y.: investigation. J.H.: supervision. H.S., C.Y., J.H.: writing—original draft. H.S., C.Y., J.H.: writing—review and editing.

Financial support: None to report.

Potential competing interests: None to report.