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Negligible HCC risk during stringently defined untreated immune-tolerant phase of chronic hepatitis B

  • Author Footnotes
    1 Equally contributed to this work as co-first authors.
    Hye Won Lee
    Footnotes
    1 Equally contributed to this work as co-first authors.
    Affiliations
    Department of Internal medicine, Yonsei University College of medicine, Seoul, Republic of Korea

    Institute of Gastroenterology, Yonsei University College of medicine, Seoul, Republic of Korea

    Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
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  • Author Footnotes
    1 Equally contributed to this work as co-first authors.
    Young Eun Chon
    Footnotes
    1 Equally contributed to this work as co-first authors.
    Affiliations
    Department of Internal Medicine, Cha Bundang Medical Center, Cha University, Seongnam, Republic of Korea
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  • Author Footnotes
    1 Equally contributed to this work as co-first authors.
    Beom Kyung Kim
    Footnotes
    1 Equally contributed to this work as co-first authors.
    Affiliations
    Department of Internal medicine, Yonsei University College of medicine, Seoul, Republic of Korea

    Institute of Gastroenterology, Yonsei University College of medicine, Seoul, Republic of Korea

    Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
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  • Terry Cheuk-Fung Yip
    Affiliations
    Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China

    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China

    State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong; Hong Kong SAR, China
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  • Yee-Kit Tse
    Affiliations
    Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China

    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China

    State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong; Hong Kong SAR, China
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  • Grace Lai-Hung Wong
    Affiliations
    Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China

    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China

    State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong; Hong Kong SAR, China
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  • Vincent Wai-Sun Wong
    Affiliations
    Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China

    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China

    State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong; Hong Kong SAR, China
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  • Henry Lik-Yuen Chan
    Correspondence
    Corresponding author at: Department of Medicine and Therapeutics, 9/F Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, Hong Kong.
    Affiliations
    Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China

    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China

    State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong; Hong Kong SAR, China
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  • Sang Hoon Ahn
    Correspondence
    Corresponding author at: Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun–gu, Seoul 03722, Republic of Korea.
    Affiliations
    Department of Internal medicine, Yonsei University College of medicine, Seoul, Republic of Korea

    Institute of Gastroenterology, Yonsei University College of medicine, Seoul, Republic of Korea

    Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
    Search for articles by this author
  • Author Footnotes
    1 Equally contributed to this work as co-first authors.
Published:December 04, 2020DOI:https://doi.org/10.1016/j.ejim.2020.10.022

      Highlights

      • The definition of immune-tolerant phase of chronic hepatitis B and their prognosis is controversial.
      • Some studies suggest that early antiviral treatment are required for patients with immune-tolerant phase, but not others.
      • In this multi-center study from the East Asia, we used stringent criteria to define the genuine immune-tolerant phase with both age < 40 years and HBV DNA > 6 log10 IU/mL.
      • The risk of hepatocellular carcinoma development during the untreated immune-tolerant phase is negligible.

      Abstract

      Background & aims: Whether chronic hepatitis B (CHB) patients during immune-tolerant (IT) phase are at low risk of hepatocellular carcinoma (HCC) is still controversial. We performed a multicenter study to determine their long-term prognosis.
      Methods: Untreated IT group included patients < 40 years of age, with persistently hepatitis B e antigen [HBeAg] positivity, serum HBV-DNA>6 log10IU/mL, and ALT level < 40 U/L, using age and HBV-DNA criteria by the American Association for the Study of Liver Diseases (AASLD) guideline. Cumulative HCC risk of untreated IT group (n=194) was compared to HBeAg-positive patients undergoing antiviral therapy according to the practice and reimbursement guidelines (treated HBeAg[+] group, n=454). Patients with history of cirrhosis or HCC at baseline were excluded.
      Results: During follow-up (median 62.1 months), HCC did not develop in any patient among untreated IT group, whereas the cumulative probability of HCC at 3, 5, and 9 years in the treated HBeAg(+) group was 0.5%, 0.7%, and 1.3%, respectively (p=0.203). Ninety-seven patients among untreated IT group entered immune-active phase, of whom 86 (88.7%) started antiviral treatment. A high normal ALT level (20–39 U/L) was associated with an increased risk of a phase change, compared to ALT < 20 U/L. After censoring at the time of phase change, the cumulative HCC risk was also not significantly different between two groups (p=0.258).
      Conclusions: No actual HCC risk during untreated IT phase defined by age and HBV-DNA criteria of the AASLD guideline exists, supporting their diagnostic validity from the perspective of long-term prognosis. Further validation studies are required.

      Keywords

      Abbreviations:

      CHB (chronic hepatitis B), HBV (hepatitis B virus), NUCs (nucleos(t)ide analogues), IT phase (immune-tolerant phase), EASL (European Association for the Study of Liver Diseases), ALT (alanine aminotransferase), AVT (antiviral therapy), HBeAg (hepatitis B e antigen), HCC (hepatocellular carcinoma), PT INR (prothrombin time international normalized ratio), CDARS (Clinical Data Analysis and Reporting System), ULN (upper limit of normal), HBsAg (hepatitis B surface antigen), HRs (hazard ratios), 95% CIs (95% confidence intervals), AASLD (American Association for the Study of Liver Diseases)
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