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Background <p>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.</p> Methods <p>This study included two independent cohorts consisting of 843 patients in the derivation cohort and 1781 patients in the validation cohort.</p> Results <p>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 &lt; 10&#xa0;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 (&lt; 100&#xa0;IU/mL) were key predictors of HBsAg seroclearance or a reduction of &lt; 10&#xa0;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&#xa0;years of NUC treatment in both cohorts.</p> Conclusions <p>Functional cure during prolonged NUC treatment of &gt; 10&#xa0;years depends on early virological responses in both HBeAg-positive and HBeAg-negative patients.</p>

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

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  • 发表日期：

    2026年4月21日

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

摘要

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.