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

Impact of HBsAg seroclearance on late recurrence of hepatitis B virus-related hepatocellular carcinoma after surgical resectionJournal of HepatologyVol. 77Issue 4PreviewIt 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. Full-Text PDF 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 5PreviewIn 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. Full-Text PDF We read with great enthusiasm the recent article in the Journal of Hepatology by Yoo et al.[1]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: 939-946Abstract Full Text Full Text PDF Scopus (13) Google Scholar 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.2Yang 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: 683-691Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 3Hu 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: 315-325Crossref PubMed Google Scholar, 4Yuan 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; 20165234969Google Scholar 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.5Huang 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: 490-505Crossref PubMed Scopus (107) Google Scholar, 6Huang 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: 158-164Crossref PubMed Scopus (42) Google Scholar, 7Wu 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: 1906-1914Crossref PubMed Scopus (713) Google Scholar, 8Sohn 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: 2429-2435Crossref PubMed Scopus (82) Google Scholar 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.[9]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: 177-188Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar,[10]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: 1512-1522Crossref PubMed Scopus (146) Google Scholar 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. The authors received no financial support to produce this manuscript. 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. All authors declared no conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details. The following are the supplementary data to this article: Download .pdf (.22 MB) Help with pdf files Multimedia component 1