We sincerely appreciate Yang et al for their comments on our study, which demonstrated that a significant and rapid decline in quantitative change of hepatitis B surface antigen (qHBsAg) in 12-month nucleos(t)ide analogs (NAs) treatment was statistically associated with eventual loss of HBsAg in Chinese patients with chronic hepatitis B (CHB) (1,2). We would like to address the insightful observations concerning virological markers with the following clarifications.
Regarding the completeness of virological characteristics, we did not include them for the following reasons:
In the treatment-naive cohort, there was a significantly higher viral load (median: 5 × 105 IU/mL), whereas most patients in the treatment-experienced cohort were hepatitis B virus (HBV) DNA-negative. Among the few HBV DNA-positive cases (due to NAs resistance, low-level viremia, inconsistent NAs administration, etc), almost none achieved HBsAg loss in this study nor did they exhibit a significant and rapid decline in qHBsAg. Furthermore, the latest research by Wang et al has confirmed that untreated HBeAg-negative patients with both low HBsAg levels (<100 IU/mL) and undetectable HBV DNA have a 3–5 times higher HBsAg clearance rate (3). According to clinical guidelines (4–6), such patients were typically not indicated for antiviral therapy and were therefore excluded from this study.
As suggested, for treatment-naïve patients, we performed a stratified analysis based on viral load: high viral load (HBV DNA >2 × 105 IU/mL) vs. low viral load (HBV DNA <2 × 103 IU/mL). HBsAg loss occurred in 8/ of 639 (high-load) and 3 of 238 (low-load) cases. When further stratified into < 2 × 103, 2 × 103–2 × 105, and >2 × 105 IU/mL, neither univariate nor multivariate Cox regression showed significance for HBsAg loss, and qHBsAg reduction remained unchanged. In addition, patients receiving immunomodulatory therapy (e.g., interferon) were also excluded from this study.
Furthermore, the suggestion to investigate novel virological markers, including serum HBV RNA, HBcrAg, and specific antibodies, represent a particularly valuable direction for future research. These emerging biomarkers show significant potential to provide deeper insights into the virological dynamics of CHB, potentially offering improved predictive capacity for monitoring disease progression and HBsAg seroclearance. We fully acknowledge the importance of these markers and plan to incorporate them in subsequent studies to enhance our methodological approach and facilitate the development of more precise, individualized treatment regimens for patients with CHB.
We are profoundly grateful for these constructive critiques, which have both strengthened our current findings and illuminated valuable paths for future research. We warmly welcome potential collaborations to advance CHB clinical science and patient care.
CONFLICTS OF INTEREST
Guarantor of the article: Wei Cai, MD, PhD.
Specific author contributions: T.Z., M.S., Y.D.: formal analysis, manuscript writing. W.C.: conceptualization, supervision, manuscript writing.
Financial support: None to report.
Potential competing interests: None to report.
Contributor Information
Tianhui Zhou, Email: 453276017@qq.com.
Meng Shu, Email: mshu3@ITS.JNJ.com.
Yanan Du, Email: xiaodunn@126.com.
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