On-treatment viral factors affect subsequent hepatitis B surface antigen seroclearance in patients treated with nucleos(t)ide analogs for > 10 years

BACKGROUND: Long-term nucleos(t)ide analog (NUC) treatment improves the outcomes of patients with chronic hepatitis B virus (HBV) infection. However, only a limited number of patients treated with NUC can achieve hepatitis B surface antigen (HBsAg) seroclearance, the so-called "functional cure." However, it remains unclear how on-treatment viral factors affect HBsAg seroclearance during long-term NUC treatment. We aimed to investigate whether the baseline and on-treatment HBV markers can predict HBsAg seroclearance and reduction in patients treated with long-term NUC treatment. METHODS: This study included two independent cohorts consisting of 843 patients in the derivation cohort and 1781 patients in the validation cohort. RESULTS: HBsAg seroclearance was infrequent (3.7-6.2%), with annual rates of 4-10/1,000 person-years in the derivation and validation cohorts. In baseline hepatitis B e-antigen (HBeAg)-positive patients, early on-treatment HBeAg loss strongly predicted subsequent HBsAg seroclearance and a reduction of < 10 IU/mL, whereas delayed or absent HBeAg loss rarely followed HBsAg seroclearance. A simple predictive model for HBsAg seroclearance based on earlier HBeAg loss, sex, and age was developed (SLOPES50). In baseline HBeAg-negative patients, low baseline or on-treatment HBsAg levels (< 100 IU/mL) were key predictors of HBsAg seroclearance or a reduction of < 10 IU/mL. Landmark analysis and time-dependent Cox regression analyses confirmed these associations in both cohorts. A substantial number of patients remained HBsAg ≥ 100 even after 15 years of NUC treatment in both cohorts. CONCLUSIONS: Functional cure during prolonged NUC treatment of > 10 years depends on early virological responses in both HBeAg-positive and HBeAg-negative patients.

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Journal
Journal of Gastroenterology
Published
2026-04-21
DOI
https://doi.org/10.1007/s00535-026-02415-3
Primary Topic
Hepatitis B Virus Studies
Type
article
Field-Weighted Citation Impact
0.00

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article

On-treatment viral factors affect subsequent hepatitis B surface antigen seroclearance in patients treated with nucleos(t)ide analogs for > 10 years

Takatoshi Nawa, Kazuki Maesaka, Ryotaro Sakamori, Takeo Usui et al.
Journal of Gastroenterology
Hepatitis B Virus Studies
article

On-treatment viral factors affect subsequent hepatitis B surface antigen seroclearance in patients treated with nucleos(t)ide analogs for > 10 years

Takatoshi Nawa, Kazuki Maesaka, Ryotaro Sakamori, Takeo Usui, Tetsuya Hosaka, Yoshinobu Saito, Takayuki Yakushijin, Tetsuo Takehara, Mitsuru Sakakibara, Kazuhiro Murai, Yuki Tahata, Hiroyuki Ogawa, Yuki Makino, Atsushi Hosui, Yoshinori Doi, Satoshi Egawa, Hayato Hikita, Masanori Miyazaki, Yasutoshi Nozaki, Masanori Nakahara, Kazuho Imanaka, Kumiko Shirai, Kazuyoshi Ohkawa, N Tatsumi, Hisashi Ishida, Takahiro Kodama, Ryoko Yamada, Kengo Matsumoto, Yuichi Yoshida
article en

Abstract

BACKGROUND: Long-term nucleos(t)ide analog (NUC) treatment improves the outcomes of patients with chronic hepatitis B virus (HBV) infection. However, only a limited number of patients treated with NUC can achieve hepatitis B surface antigen (HBsAg) seroclearance, the so-called "functional cure." However, it remains unclear how on-treatment viral factors affect HBsAg seroclearance during long-term NUC treatment. We aimed to investigate whether the baseline and on-treatment HBV markers can predict HBsAg seroclearance and reduction in patients treated with long-term NUC treatment. METHODS: This study included two independent cohorts consisting of 843 patients in the derivation cohort and 1781 patients in the validation cohort. RESULTS: HBsAg seroclearance was infrequent (3.7-6.2%), with annual rates of 4-10/1,000 person-years in the derivation and validation cohorts. In baseline hepatitis B e-antigen (HBeAg)-positive patients, early on-treatment HBeAg loss strongly predicted subsequent HBsAg seroclearance and a reduction of < 10 IU/mL, whereas delayed or absent HBeAg loss rarely followed HBsAg seroclearance. A simple predictive model for HBsAg seroclearance based on earlier HBeAg loss, sex, and age was developed (SLOPES50). In baseline HBeAg-negative patients, low baseline or on-treatment HBsAg levels (< 100 IU/mL) were key predictors of HBsAg seroclearance or a reduction of < 10 IU/mL. Landmark analysis and time-dependent Cox regression analyses confirmed these associations in both cohorts. A substantial number of patients remained HBsAg ≥ 100 even after 15 years of NUC treatment in both cohorts. CONCLUSIONS: Functional cure during prolonged NUC treatment of > 10 years depends on early virological responses in both HBeAg-positive and HBeAg-negative patients.

Journal of Gastroenterology
Osaka Gakuin University (JP), Ashiya University (JP), Osaka Prefectural Medical Center (JP), Toyonaka Municipal Hospital (JP), Osaka National Hospital (JP), Nishinomiya Municipal Central Hospital (JP), Osaka City General Hospital (JP), Ikeda Municipal Hospital (JP), Osaka Rosai Hospital (JP), Kansai Rosai Hospital (JP), Higashi Osaka City General Hospital (JP), Suita Municipal Hospital (JP), Osaka Hospital (JP), Kinki Central Hospital (JP), Itami City Hospital (JP), Japan Community Healthcare Organization (JP), Osaka International Cancer Institute (JP), Otemae Hospital (JP), Minoh City Hospital (JP), Toranomon Hospital (JP), The University of Osaka (JP)
Japan Agency for Medical Research and Development, Ministry of Health, Labour and Welfare
Good health and well-being
Openalex Percentile: Top 16%
Hepatitis B Virus Studies
DOIOpen Access PDFOpenAlex
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