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. 2025 Sep;55(9):1228-1238.
doi: 10.1111/hepr.14225. Epub 2025 Jun 16.

The Risk of Developing Hepatocellular Carcinoma Persists in Chronic Hepatitis B Patients Even After the Long-Term Administration of Nucleos(t)ide Analogs

Kazuhiro Murai  1 , Hayato Hikita  1 , Ryoko Yamada  1 , Yuki Nishimura  2 , Masanori Miyazaki  3 , Hisashi Ishida  4 , Atsushi Hosui  5 , Ryotaro Sakamori  6 , Nobuyuki Tatsumi  7 , Kazuyoshi Ohkawa  8 , Yoshinori Doi  9 , Takatoshi Nawa  10 , Satoshi Egawa  11 , Yuichi Yoshida  12 , Yasutoshi Nozaki  13 , Kazuho Imanaka  14 , Masanori Nakahara  15 , Mitsuru Sakakibara  16 , Takayuki Yakushijin  17 , Hiroyuki Ogawa  18 , Takeo Usui  19 , Kengo Matsumoto  20 , Tsugiko Oze  21 , Shinji Kuriki  1 , Emi Sometani  1 , Jihyun Sung  1 , Akiyoshi Shimoda  1 , Satoshi Shigeno  1 , Kazuki Maesaka  1 , Kumiko Shirai  1 , Akira Doi  1 , Yuki Tahata  1 , Yoshinobu Saito  1 , Takahiro Kodama  1 , Tomohide Tatsumi  1 , Tomomi Yamada  2 , Tetsuo Takehara  1
Affiliations

The Risk of Developing Hepatocellular Carcinoma Persists in Chronic Hepatitis B Patients Even After the Long-Term Administration of Nucleos(t)ide Analogs

Kazuhiro Murai et al. Hepatol Res. 2025 Sep.

Abstract

Background and aim: Nucleos(t)ide analogs (NUCs) are used in the treatment of chronic hepatitis B (CHB). It is still uncertain whether the risk of incident hepatocellular carcinoma (HCC) continues beyond 5 or 10 years after the initiation of NUC treatment. We aimed to elucidate this in CHB patients receiving long-term NUC treatment.

Methods: This was a multicenter, observational study that included patients who began NUC treatment between July 2000 and March 2019; patients were retrospectively enrolled up to March 2019 and followed up until August 2024.

Results: Among 737 CHB patients (156 with cirrhosis) who started NUC treatment, 147 developed HCC during a median follow-up period of 144.2 months. The 5-, 10-, and 15-year cumulative HCC rates were 11.2%, 18.4%, and 23.1%, respectively. Independent risk factors for subsequent HCC occurrence included older age, male sex, cirrhosis, low platelet count, low ALT levels, and high γ-GTP levels at NUC initiation. After 5 years, the risk factors were cirrhosis, high γ-GTP levels, and high AFP levels, whereas after 10 years, they were cirrhosis and diabetes. Landmark analysis revealed that the 5-year cumulative HCC incidence was 8.1% at 5 years and 5.8% at 10 years after NUC initiation. In noncirrhotic patients, cumulative HCC incidence at 5 years was 5.8%, whereas 5-year cumulative incidences starting at 5 and 10 years were 4.1% and 4.8%, respectively, remaining stable over time.

Conclusion: The risk of HCC persists long after NUC initiation. In noncirrhotic patients, the risk remains stable more than 10 years after NUC treatment initiation.

Keywords: CHB; HBV; HCC; NUC; cirrhosis.

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