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Original article
High risk of hepatocellular carcinoma and death in patients with immune-tolerant-phase chronic hepatitis B
  1. Gi-Ae Kim1,
  2. Young-Suk Lim2,
  3. Seungbong Han3,
  4. Jonggi Choi2,
  5. Ju Hyun Shim2,
  6. Kang Mo Kim2,
  7. Han Chu Lee2,
  8. Yung Sang Lee2
  1. 1 Health Screening and Promotion Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
  2. 2 Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
  3. 3 Department of Applied Statistics, Gachon University, Seongnam-si, Gyeonggi-do, Republic of Korea
  1. Correspondence to Professor Young-Suk Lim, Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Songpa-gu, Seoul 138-736, Korea; limys{at}


Objective High serum HBV DNA levels are associated with high risks of hepatocellular carcinoma (HCC) and cirrhosis in patients with chronic hepatitis B (CHB). Although the immune-tolerant (IT) phase is characterised by high circulating HBV DNA levels, it remains unknown whether antiviral treatment reduces risks of HCC and mortality.

Design This historical cohort study included HBeAg-positive patients with CHB with high HBV DNA levels (≥20 000 IU/mL) and no evidence of cirrhosis at a tertiary referral hospital in Korea from 2000 to 2013. The clinical outcomes of 413 untreated IT-phase patients with normal alanine aminotransferase (ALT) levels (females, <19 IU/mL; males, <30 IU/mL) were compared with those of 1497 immune-active (IA)-phase patients (ALT ≥80 IU/mL) treated with nucleos(t)ide analogues.

Results The IT group was significantly younger than the IA group (mean age, 38 vs 40 years at baseline, p=0.04). The 10-year estimated cumulative incidences of HCC (12.7% vs 6.1%; p=0.001) and death/transplantation (9.7% vs 3.4%; p<0.001) were significantly higher in the IT group than the IA group. In multivariable analyses, the IT group showed a significantly higher risk of HCC (HR 2.54; 95% CI 1.54 to 4.18) and death/transplantation (HR 3.38; 95% CI 1.85 to 6.16) than the IA group, which was consistently identified through inverse probability treatment weighting, propensity score-matched and competing risks analyses.

Conclusions Untreated IT-phase patients with CHB had higher risks of HCC and death/transplantation than treated IA-phase patients. Unnecessary deaths could be prevented through earlier antiviral intervention in select IT-phase patients.

  • antiviral therapy
  • chronic viral hepatitis
  • hepatitis B
  • hepatocellular carcinoma
  • liver transplantation

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  • Contributors G-AK and Y-SL were responsible for the concept and design of the study, the acquisition, analysis and interpretation of the data, and the drafting of the manuscript. SH performed the statistical analyses. JC, JHS, KMK, HCL and YuSL helped with the acquisition of the data and critically revised the manuscript for important intellectual content.

  • Funding This study was supported by grants from the Korean National Health Clinical Research Project, Ministry of Health & Welfare, Republic of Korea (HC15C3380); the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI14C1061 and HI17C1862); the Proteogenomic Research Program through the National Research Foundation of Korea funded by the Korean government (MSIP); and Korean Gastroenterology Fund for Future Development.

  • Disclaimer The interpretation and reporting of the data were the sole responsibility of the authors.

  • Competing interests Y-SL is an advisory board member of Bayer Healthcare, Gilead Sciences and Roche and receives research funding from Bayer Healthcare and Gilead Sciences. The remaining authors have nothing to disclose relevant to this manuscript.

  • Ethics approval Asan Medical Center.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Correction notice This article has been corrected since it published Online First. Figure 3 has been updated.

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