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Impact of HBsAg seroclearance on late recurrence of hepatitis B virus-related hepatocellular carcinoma after surgical resection

  • Author Footnotes
    † S Yoo and JY Kim contributed equally to this work and deserve co-first authorship.
    Sun Yoo
    Footnotes
    † S Yoo and JY Kim contributed equally to this work and deserve co-first authorship.
    Affiliations
    Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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  • Author Footnotes
    † S Yoo and JY Kim contributed equally to this work and deserve co-first authorship.
    Ji Yoon Kim
    Footnotes
    † S Yoo and JY Kim contributed equally to this work and deserve co-first authorship.
    Affiliations
    Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
    Search for articles by this author
  • Young-Suk Lim
    Affiliations
    Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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  • Seungbong Han
    Affiliations
    Department of Biostatistics, Korea University College of Medicine, Seoul, Republic of Korea
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  • Jonggi Choi
    Correspondence
    Corresponding author. Address: Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea; Tel.: +82-2-3010-1328.
    Affiliations
    Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
    Search for articles by this author
  • Author Footnotes
    † S Yoo and JY Kim contributed equally to this work and deserve co-first authorship.

      Highlights

      • Whether HBsAg seroclearance affects the risk of late (≥2 years) HCC recurrence after liver resection remains unanswered.
      • 2,520 consecutive Korean patients who underwent curative-intent liver resection for HBV-related HCC of BCLC 0 or A were analyzed.
      • HBsAg seroclearance after liver resection was independently associated with a reduced risk of late (≥2 years) HCC recurrence.

      Background & Aims

      It is unknown whether HBsAg seroclearance affects the risk of hepatocellular carcinoma (HCC) recurrence after liver resection. We aimed to investigate the impact of HBsAg seroclearance on the recurrence of HCC after curative liver resection, with a focus on late recurrence.

      Methods

      This study comprised 2,520 consecutive patients who received curative liver resection for HBV-related HCC of Barcelona Clinic Liver Cancer stage 0 or A in Korea between 2000 and 2017. To focus on late recurrence, patients with recurrence or a follow-up duration less than 2 years were excluded. The impact of HBsAg seroclearance on HCC recurrence was assessed by landmark analysis (2-, 5-and 8-year after liver resection), time-dependent Cox and multistate modeling.

      Results

      The mean patient age was 54.4 years and 75.7% were men. A total of 891 (35.4%) patients developed HCC recurrence at rates of 11.2%, 25.5%, and 46.8% at 3, 5, and 10 years after resection. HBsAg seroclearance was achieved in 172 (6.8%) patients during a median follow-up duration of 6.9 years after resection. HBsAg seroclearance, compared with persistent HBsAg positivity, was associated with a lower risk of late HCC recurrence in the 2-, 5-, and 8-year landmark analysis (p = 0.04, p = 0.02 and p = 0.03, respectively) and on time-dependent multivariable Cox modeling (adjusted hazard ratio 0.62; p = 0.005). Based on a 3-state unidirectional illness–death model, patients without HBsAg seroclearance transitioned to HCC recurrence more rapidly than patients who experienced HBsAg seroclearance.

      Conclusions

      HBsAg seroclearance is associated with a lower risk of late recurrence of HBV-related HCC among Korean patients who undergo curative liver resection.

      Lay summary

      Hepatitis B virus (HBV) infection is a leading cause of chronic liver disease and hepatocellular carcinoma (HCC). Suppression of HBV replication is known to lower the risk of HCC recurrence after liver resection (a procedure used to treat and in some cases cure HCC). However, whether the loss of a specific HBV protein (hepatitis B surface antigen or HBsAg) has an impact on recurrence after liver resection remains unknown. Herein, we show that loss of HBsAg is associated with a reduce risk of late recurrence of HCC after liver resection in patients with HBV-related HCC.

      Graphical abstract

      Keywords

      Linked Article

      • HBsAg seroclearance and reduction in late recurrence of HBV-related HCC: Causality or co-existence?
        Journal of HepatologyVol. 77Issue 5
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          We read with great interest the recent article in Journal of Hepatology by Yoo et al.1 Among 2,520 patients who were alive and recurrence free 2 years after curative resection for HBV-related early-stage (BCLC stage 0/A) hepatocellular carcinoma (HCC), 891 (35.4%) patients developed late recurrence (>2 years after surgery) while 172 (6.8%) achieved HBsAg seroclearance during a median follow-up duration of 6.9 years after resection. Using univariate and multivariate analysis, the authors demonstrated that HBsAg seroclearance was independently associated with a significantly lower risk of late recurrence of HBV-related HCC.
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      • HBsAg seroclearance reduces the risk of late recurrence in HBV-related HCC
        Journal of HepatologyVol. 77Issue 5
        • Preview
          We read with great interest the article published in the Journal of Hepatology by Yoo et al. and colleagues.1 This study found that HBsAg loss was associated with a 38% lower risk of late recurrence of hepatocellular carcinoma (HCC) after curative liver resection compared with persistent HBsAg positivity. We appreciate their efforts to provide new insights into the postoperative recurrence of HBV-related HCC. However, we believe that there are some issues that merit further discussion to ensure that the results of this study are more convincing.
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      • Antiviral therapy, HBsAg seroclearance and late recurrence of hepatitis B-related hepatocellular carcinoma
        Journal of HepatologyVol. 77Issue 5
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          We read with great enthusiasm the recent article in the Journal of Hepatology by Yoo et al.1 To investigate the association between HBsAg seroclearance and late recurrence (2 years) after curative-intention liver resection for patients with HBV-related hepatocellular carcinoma (HCC), a total of 2,520 patients were enrolled into this retrospective cohort study. Among them, 172 (6.8%) patients achieved HBsAg seroclearance on nucleos(t)ide analogues (NUCs) during the follow-up after surgery. Compared with persistent HBsAg positivity, patients with HBsAg seroclearance had a lower risk of HCC recurrence in the 2-, 5-, and 8-year landmark analyses.
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      • Reply to: Correspondence on “Impact of HBsAg seroclearance on late recurrence of hepatitis B virus-related hepatocellular carcinoma after surgical resection”
        Journal of HepatologyVol. 77Issue 5
        • Preview
          In reply to the concern from Diao et al.,1 regardless of HBsAg seroclearance, all patients in our study were followed until HCC recurrence, transplantation, death from any cause, or last follow-up date.2 A patient was censored at the time of HCC recurrence whether or not HBsAg seroclearance occurred subsequently. No patient with HBsAg seroclearance following HCC recurrence was included in the HBsAg seroclearance group in our analysis. Diao et al. demonstrated that both HBsAg seroclearance and the risk reduction in late recurrence of HCC were the consequences of antiviral therapy, and these coexisted in patients with antiviral therapy during follow-up.
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