Advertisement

Antiviral therapy, HBsAg seroclearance and late recurrence of hepatitis B-related hepatocellular carcinoma

  • Si-Yu Liu
    Affiliations
    Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Cancer Center, Affiliated People’s Hospital of Hangzhou Medical College, Zhejiang Provincial People’s Hospital, Zhejiang, China

    The Key Laboratory of Imaging Diagnosis and Minimally Invasive Interventional Research of Zhejiang Province, Zhejiang University Lishui Hospital, Zhejiang, China
    Search for articles by this author
  • Chen Yuan
    Affiliations
    Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Cancer Center, Affiliated People’s Hospital of Hangzhou Medical College, Zhejiang Provincial People’s Hospital, Zhejiang, China
    Search for articles by this author
  • Xiang-Min Tong
    Correspondence
    Corresponding author. Address: Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Cancer Center, Affiliated People’s Hospital of Hangzhou Medical College, Zhejiang Provincial People’s Hospital, Zhejiang, China; or the Key Laboratory of Imaging Diagnosis and Minimally Invasive Interventional Research of Zhejiang Province, Zhejiang University Lishui Hospital, Zhejiang, China.
    Affiliations
    Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Cancer Center, Affiliated People’s Hospital of Hangzhou Medical College, Zhejiang Provincial People’s Hospital, Zhejiang, China

    The Key Laboratory of Imaging Diagnosis and Minimally Invasive Interventional Research of Zhejiang Province, Zhejiang University Lishui Hospital, Zhejiang, China
    Search for articles by this author

      Keywords

      Linked Article

      To the Editor:
      We read with great enthusiasm the recent article in the Journal of Hepatology by Yoo et al.
      • Yoo S.
      • Kim J.Y.
      • Lim Y.S.
      • Han S.
      • Choi J.
      Impact of HBsAg seroclearance on late recurrence of hepatitis B virus-related hepatocellular carcinoma after surgical resection.
      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. Using the time-dependent multivariable Cox model, this study demonstrated that HBsAg seroclearance was independently associated with late recurrence after resection for HBV-related HCC. Although innovative and inspiring, several points warrant further clarification.
      First, it is clear that the decreased risk of late recurrence and HBsAg seroclearance were related to postoperative antiviral therapy. In numerous previous studies on surgery for HBV-related HCC, the presence or absence of antiviral therapy was an important prognostic variable associated with recurrence and survival after liver resection for HBV-related HCC.
      • Yang T.
      • Lu J.H.
      • Zhai J.
      • Lin C.
      • Yang G.S.
      • Zhao R.H.
      • et al.
      High viral load is associated with poor overall and recurrence-free survival of hepatitis B virus-related hepatocellular carcinoma after curative resection: a prospective cohort study.
      • Hu Z.
      • Sun X.
      • Mei J.
      • Hu Z.
      • Yang Z.
      • Hou J.
      • et al.
      Antiviral treatments eliminate the adverse impacts of high baseline HBV loads on the survival of HBV-related HCC patients.
      • Yuan P.
      • Chen P.
      • Qian Y.
      Evaluation of antiviral therapy performed after curative therapy in patients with HBV-related hepatocellular carcinoma: an updated meta-analysis.
      In Yoo et al.’s study, the authors divided all analytic patients into 3 groups: no NUC group, NUC at operation group, and NUC after operation group. However, it is surprising that such an important variable was not included in the univariate and multivariate analysis of late recurrence (Table 3 of Yoo et al.’s study). Did the authors intentionally exclude this variable out of concern for collinearity between antiviral therapy and HBsAg seroclearance? Would the inclusion of “antiviral therapy” cause the loss of independent significance for “HBsAg seroclearance”? We are seriously concerned about this possibility.
      Second, in previous similar studies, other HBV-related variables potentially associated with postoperative recurrence and survival were often included in the prognostic analysis, such as HBV reactivation, viral resistance, irregular use or withdrawal of antiviral therapy, etc.
      • Huang G.
      • Lai E.C.
      • Lau W.Y.
      • Zhou W.P.
      • Shen F.
      • Pan Z.Y.
      • et al.
      Posthepatectomy HBV reactivation in hepatitis B-related hepatocellular carcinoma influences postoperative survival in patients with preoperative low HBV-DNA levels.
      • Huang L.
      • Li J.
      • Lau W.Y.
      • Yan J.
      • Zhou F.
      • Liu C.
      • et al.
      Perioperative reactivation of hepatitis B virus replication in patients undergoing partial hepatectomy for hepatocellular carcinoma.
      • Wu C.Y.
      • Chen Y.J.
      • Ho H.J.
      • Hsu Y.C.
      • Kuo K.N.
      • Wu M.S.
      • et al.
      Association between nucleoside analogues and risk of hepatitis B virus–related hepatocellular carcinoma recurrence following liver resection.
      • Sohn W.
      • Paik Y.H.
      • Kim J.M.
      • Kwon C.H.
      • Joh J.W.
      • Cho J.Y.
      • et al.
      HBV DNA and HBsAg levels as risk predictors of early and late recurrence after curative resection of HBV-related hepatocellular carcinoma.
      Did some patients with HBsAg seroclearance in this cohort return to HBsAg positivity during follow-up? What about the incidence of late recurrence for these cases? It’s a pity that these potentially important variables were missing in Yoo et al.’s study. Fortunately, the information on HBV DNA levels at 2 years after surgery was available in most patients (85.45%, 2,152/2,520) of the analytic cohort. However, why did the authors not include this critical variable of “HBV DNA level at 2 years after surgery” in the univariate and multivariate analysis, given that it is theoretically more significant than “HBV DNA level at surgery” for predicting late recurrence (>2 years after surgery)?
      Third, it should be pointed out that in Table 1 of Yoo et al.’s study, the expression of HBV DNA (log10IU/ml) in terms of mean ± standard deviation did not meet the statistical norm (e.g. 2.0 ± 2.3 for the overall cohort). If the standard deviation is greater than the mean, this variable does not conform to the normal distribution. It should be changed to median with range or interquartile range.
      Fourth, the occurrence of HBsAg seroclearance in Yoo et al.’s cohort was relatively high (6.8%, 172/2,520), which seems better than that reported with NUC monotherapy in the literature. It has been reported that the addition of pegylated alfa-2a interferon to NUCs can increase the occurrence of HBsAg seroclearance.
      • Bourlière M.
      • Rabiega P.
      • Ganne-Carrie N.
      • Serfaty L.
      • Marcellin P.
      • Barthe Y.
      • et al.
      Effect on HBs antigen clearance of addition of pegylated interferon alfa-2a to nucleos(t)ide analogue therapy versus nucleos(t)ide analogue therapy alone in patients with HBe antigen-negative chronic hepatitis B and sustained undetectable plasma hepatitis B virus DNA: a randomised, controlled, open-label trial.
      ,
      • Brouwer W.P.
      • Xie Q.
      • Sonneveld M.J.
      • Zhang N.
      • Zhang Q.
      • Tabak F.
      • et al.
      Adding pegylated interferon to entecavir for hepatitis B e antigen-positive chronic hepatitis B: a multicenter randomized trial (ARES study).
      We wonder if any patients in Yoo et al.’s cohort received pegylated alfa-2a interferon?
      In conclusion, an amendment regarding the aforementioned omissions would immensely solidify this study’s findings.

      Financial support

      The authors received no financial support to produce this manuscript.

      Authors’ contributions

      Conception: Xiang-Min Tong; Manuscript preparation: Si-Yu Liu, Chen Yuan; Critical revision: Xiang-Min Tong. Si-Yu Liu and Chen Yuan contribute equally to this work. All authors reviewed the paper and approved the final version.

      Conflict of interest

      All authors declared no conflict of interest.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the supplementary data to this article:

      References

        • Yoo S.
        • Kim J.Y.
        • Lim Y.S.
        • Han S.
        • Choi J.
        Impact of HBsAg seroclearance on late recurrence of hepatitis B virus-related hepatocellular carcinoma after surgical resection.
        J Hepatol. 2022; 77: 939-946
        • Yang T.
        • Lu J.H.
        • Zhai J.
        • Lin C.
        • Yang G.S.
        • Zhao R.H.
        • et al.
        High viral load is associated with poor overall and recurrence-free survival of hepatitis B virus-related hepatocellular carcinoma after curative resection: a prospective cohort study.
        Eur J Surg Oncol. 2012; 38: 683-691
        • Hu Z.
        • Sun X.
        • Mei J.
        • Hu Z.
        • Yang Z.
        • Hou J.
        • et al.
        Antiviral treatments eliminate the adverse impacts of high baseline HBV loads on the survival of HBV-related HCC patients.
        J Hepatocell Carcinoma. 2022; 9: 315-325
        • Yuan P.
        • Chen P.
        • Qian Y.
        Evaluation of antiviral therapy performed after curative therapy in patients with HBV-related hepatocellular carcinoma: an updated meta-analysis.
        Can J Gastroenterol Hepatol. 2016; 20165234969
        • Huang G.
        • Lai E.C.
        • Lau W.Y.
        • Zhou W.P.
        • Shen F.
        • Pan Z.Y.
        • et al.
        Posthepatectomy HBV reactivation in hepatitis B-related hepatocellular carcinoma influences postoperative survival in patients with preoperative low HBV-DNA levels.
        Ann Surg. 2013; 257: 490-505
        • Huang L.
        • Li J.
        • Lau W.Y.
        • Yan J.
        • Zhou F.
        • Liu C.
        • et al.
        Perioperative reactivation of hepatitis B virus replication in patients undergoing partial hepatectomy for hepatocellular carcinoma.
        J Gastroenterol Hepatol. 2012; 27: 158-164
        • Wu C.Y.
        • Chen Y.J.
        • Ho H.J.
        • Hsu Y.C.
        • Kuo K.N.
        • Wu M.S.
        • et al.
        Association between nucleoside analogues and risk of hepatitis B virus–related hepatocellular carcinoma recurrence following liver resection.
        JAMA. 2012; 308: 1906-1914
        • Sohn W.
        • Paik Y.H.
        • Kim J.M.
        • Kwon C.H.
        • Joh J.W.
        • Cho J.Y.
        • et al.
        HBV DNA and HBsAg levels as risk predictors of early and late recurrence after curative resection of HBV-related hepatocellular carcinoma.
        Ann Surg Oncol. 2014; 21: 2429-2435
        • Bourlière M.
        • Rabiega P.
        • Ganne-Carrie N.
        • Serfaty L.
        • Marcellin P.
        • Barthe Y.
        • et al.
        Effect on HBs antigen clearance of addition of pegylated interferon alfa-2a to nucleos(t)ide analogue therapy versus nucleos(t)ide analogue therapy alone in patients with HBe antigen-negative chronic hepatitis B and sustained undetectable plasma hepatitis B virus DNA: a randomised, controlled, open-label trial.
        Lancet Gastroenterol Hepatol. 2017; 2: 177-188
        • Brouwer W.P.
        • Xie Q.
        • Sonneveld M.J.
        • Zhang N.
        • Zhang Q.
        • Tabak F.
        • et al.
        Adding pegylated interferon to entecavir for hepatitis B e antigen-positive chronic hepatitis B: a multicenter randomized trial (ARES study).
        Hepatology. 2015; 61: 1512-1522