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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”

  • 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.: +82-02-3010-1328, fax: +82-02-485-5782.
    Affiliations
    Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Republic of Korea
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Published:August 17, 2022DOI:https://doi.org/10.1016/j.jhep.2022.07.032

      Linked Article

      • HBsAg seroclearance reduces the risk of late recurrence in HBV-related HCC
        Journal of HepatologyVol. 77Issue 5
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          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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      • 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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      • Impact of HBsAg seroclearance on late recurrence of hepatitis B virus-related hepatocellular carcinoma after surgical resection
        Journal of HepatologyVol. 77Issue 4
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          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.
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      To the Editor:
      In reply to the concern from Diao et al.,
      • Diao Y.K.
      • Kong Q.Y.
      • Yang T.
      HBsAg seroclearance and reduction in late recurrence of HBV-related HCC: causality or co-existence?.
      regardless of HBsAg seroclearance, all patients in our study were followed until HCC recurrence, transplantation, death from any cause, or last follow-up date.
      • 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.
      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. We partly agree with their viewpoint. However, 467 (18.5%) patients in the present study did not receive antiviral therapy and these patients were devoid of any potential antiviral therapy-related effects. Antiviral therapy is reported to reduce the incidence of HCC recurrence. Longer use of antiviral therapy was associated with a reduction of HCC recurrence but was not independently associated with HBsAg seroclearance as indicated in the Discussion (Table S7). This may be due to the fact that HBsAg seroclearance is very uncommon with current antiviral therapy.
      Jin et al. addressed significant baseline differences between the HBsAg seroclearance and HBsAg-persistent-positive groups.
      • Jin B.
      • Du S.
      • Yang H.
      HBsAg seroclearance reduces the risk of late recurrence in HBV-related HCC.
      Despite our efforts in adjusting possible confounders, we concur with their assessment that potential bias and residual confounders cannot be completely eliminated from the observational study. However, differences in baseline characteristics between the 2 groups were already incorporated into our time-dependent Cox model, as shown in Table 3. We also agree that preoperative AFP level is highly associated with HCC recurrence. The preoperative median AFP level did not significantly differ between the 2 groups (19.6 and 14.8 in the HBsAg-positive and HBsAg seroclearance groups, respectively; p = 0.308). In addition, previous studies reported that tumor-related factors tended to be more strongly associated with early recurrence, whereas characteristics of the underlying liver diseases tended to be more significantly associated with later recurrence.
      • Imamura H.
      • Matsuyama Y.
      • Tanaka E.
      • Ohkubo T.
      • Hasegawa K.
      • Miyagawa S.
      • et al.
      Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy.
      ,
      • Poon R.T.
      • Fan S.T.
      • Ng I.O.
      • Lo C.M.
      • Liu C.L.
      • Wong J.
      Different risk factors and prognosis for early and late intrahepatic recurrence after resection of hepatocellular carcinoma.
      The role of transarterial chemoembolization as an adjuvant therapy after curative liver resection remains debatable and is not routinely recommended by the international guidelines for HCC.
      European Association for the Study of the Liver
      EASL Clinical Practice Guidelines: management of hepatocellular carcinoma.
      • Heimbach J.K.
      • Kulik L.M.
      • Finn R.S.
      • Sirlin C.B.
      • Abecassis M.M.
      • Roberts L.R.
      • et al.
      AASLD guidelines for the treatment of hepatocellular carcinoma.
      • Omata M.
      • Cheng A.L.
      • Kokudo N.
      • Kudo M.
      • Lee J.M.
      • Jia J.
      • et al.
      Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update.
      Regarding the lengthy period investigated in our study, HBsAg seroclearance occurs naturally or as a result of therapy relatively infrequently. Moreover, only 172 (6.8%) of 2,520 patients in our study achieved HBsAg seroclearance during the nearly 7 years of follow-up after liver resection. To achieve sufficient statistical power by analyzing the impact of HBsAg seroclearance on the HCC outcomes following surgery, many patients should be enrolled with extended follow-up. Finally, more patients have been included in recent years based on the timing of liver resection. Indeed, undergoing liver resection in 2009–2012 and 2013–2017, relative to 2000–2004, was associated with a reduced risk of HCC recurrence based on our data, possibly owing to advances in surgical technique. However, even after including this variable in multivariable analysis, HBsAg seroclearance remained independently associated with a reduced risk of late HCC recurrence (adjusted hazard ratio: 0.67; p = 0.01).
      In response to Liu et al.’s letter,
      • Liu S.Y.
      • Yuan C.
      • Tong X.M.
      Antiviral therapy, HBsAg seroclearance and late recurrence of hepatitis B-related hepatocellular carcinoma.
      examining the influence of 2 time-dependent factors (HBsAg seroclearance and antiviral therapy in our study) on outcomes is relatively challenging in an observational study. Given that not all patients began antiviral treatment simultaneously, the timing of HBsAg seroclearance varied for each patient. Consequently, further sophisticated statistical adjustment may be necessary. As we share the concerns expressed by Liu et al. regarding this issue, time-dependent sequential matching propensity score (PS) analysis was first used to exactly match the use and duration of antiviral therapy. Despite this adjustment, our PS analysis revealed that HBsAg seroclearance was associated with decreased risk of HCC recurrence (hazard ratio [HR] 0.65; 95% CI 0.43–0.98; p = 0.04). Furthermore, when antiviral treatment was included as a variable in our multivariable model, the adjusted HR of HBsAg seroclearance on the risk of HCC recurrence was statistically significant (adjusted HR 0.57; 95% CI 0.40–0.81; p = 0.002). Nonetheless, we engaged in extensive discussion with the reviewers and statisticians throughout the review process. Estimating the causal effect of factors (antiviral therapy in our study) other than the intervention (HBsAg seroclearance) using causal inference methods (PS, in particular) and more particularly in a time-dependent setting, remains controversial. Statistically, applying time-dependent sequential PS matching analysis and simultaneous inclusion of 2 time-dependent variables in a multivariable model may be premature in our study.
      • Rubin D.B.
      Comment: which ifs have causal answers.
      As a result, we excluded these analyses in the revised manuscript, although our results might be somewhat weakened from a causality aspect. However, to assess the late recurrence of HCC based on HBsAg seroclearance (Fig. 3), we used a multistate model using 3 potential transitions and then estimated cumulative HRs using Nelson–Aalen estimates.
      In our study, almost all patients (97.2%) had undetectable HBV DNA. No statistical difference was observed in this rate between the 2 groups, and undetectable HBV DNA was not statistically significant even in univariate analysis. Once HBsAg seroclearance is achieved, its recurrence is known to be very rare and experienced only temporarily.
      • Yip T.C.
      • Wong G.L.
      • Wong V.W.
      • Tse Y.K.
      • Lui G.C.
      • Lam K.L.
      • et al.
      Durability of hepatitis B surface antigen seroclearance in untreated and nucleos(t)ide analogue-treated patients.
      ,
      • Choi J.
      • Yoo S.
      • Lim Y.S.
      Comparison of long-term clinical outcomes between spontaneous and therapy-induced HBsAg seroclearance.
      Based on previous studies, HBV reactivation, viral resistance, and adherence to antiviral therapy may also influence the likelihood of HCC recurrence. However, most of these characteristics are not easily quantifiable and they are extremely hard to combine with potential factors into a multivariable model in an observational study, making this a limitation that should be considered. Nonetheless, we assume that 2,174 (86.3%) of the included patients underwent liver resection after 2007 when entecavir became available. Therefore, antiviral resistance and inadequate viral suppression may not significantly affect the long-term outcomes of our study’s population. In contrast to Liu et al.’s assertion, the incidence of HBsAg seroclearance in our study is not relatively high, considering the study period (median 7 years). A recent meta-analysis demonstrated that the pooled annual HBsAg seroclearance rate was 1.02% and that cumulative incidence rates were 4.03% and 8.16% at 5 and 10 years, respectively.
      • Yeo Y.H.
      • Ho H.J.
      • Yang H.I.
      • Tseng T.C.
      • Hosaka T.
      • Trinh H.N.
      • et al.
      Factors associated with rates of HBsAg seroclearance in adults with chronic HBV infection: a systematic review and meta-analysis.
      Lastly, in our database, only 13 (0.5%) patients (11 and 2 from the HBsAg positive and HBsAg seroclearance groups, respectively) received interferon treatment after liver resection, which would likely have had a negligible impact on our main finding.
      In conclusion, our study showed that HBsAg seroclearance was independently associated with a reduced risk of HCC recurrence after curative liver resection. This observational study may not provide sufficient evidence of a causal relationship between the 2 outcomes because of its inherent limitations. Further study is required to corroborate these findings.

      Financial support

      This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (Ministry of Science and ICT) (No. 2021R1G1A1009506).

      Authors’ contributions

      J. Choi had full access to all data used in the study, takes responsibility for the integrity of the data and the accuracy of the data analysis. J. Choi approved the final version of this letter.

      Conflict of interest

      No industry funded or supported this study.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the supplementary data to this article:

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