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Reply to: “Probability of HBsAg loss after nucleos(t)ide analogue withdrawal depends on HBV genotype and viral antigen levels”

      Linked Article

      To the Editor:
      We would like to thank Sun et al. for their interest in our recent article published in the Journal.
      • Sonneveld M.J.
      • Chiu S.M.
      • Park J.Y.
      • Brakenhoff S.M.
      • Kaewdech A.
      • Seto W.K.
      • et al.
      Probability of HBsAg loss after nucleo(s)tide analogue withdrawal depends on HBV genotype and viral antigen levels.
      ,
      • Deng R.
      • Fan R.
      • Sun J.
      Probability of HBsAg loss after nucleo(s)tide analogue withdrawal depends on HBV genotype and viral antigen levels.
      In our study, we showed that a combination of HBsAg and hepatitis B core-related antigen (HBcrAg) levels can be used to predict the chance of HBsAg loss after cessation of nucleo(s)tide analogue (NUC) therapy. Despite the high rates of HBsAg loss observed among patients with both low HBsAg and low HBcrAg levels, there remains a major unmet need for other biomarkers to further optimize patient selection as only a limited number of patients have sufficiently low HBsAg and HBcrAg to allow for treatment cessation based on these criteria alone. As suggested by Sun et al., serum levels of HBV RNA may be a promising new tool in this regard,
      • Fan R.
      • Peng J.
      • Xie Q.
      • Tan D.
      • Xu M.
      • Niu J.
      • et al.
      Combining Hepatitis B Virus RNA and Hepatitis B Core-Related Antigen: guidance for Safely Stopping Nucleos(t)ide Analogues in Hepatitis B e Antigen-Positive Patients With Chronic Hepatitis B.
      although they are unlikely to be a panacea. In a previous study we have shown that on-treatment kinetics of HBV RNA may differ from those observed for HBsAg and HBcrAg, and that a substantial proportion of patients achieving pronounced HBV RNA declines do not experience a concomitant decrease in viral antigen levels.
      • Brakenhoff S.M.
      • de Man R.A.
      • Boonstra A.
      • van Campenhout M.J.H.
      • de Knegt R.J.
      • van Bommel F.
      • et al.
      Hepatitis B virus RNA decline without concomitant viral antigen decrease is associated with a low probability of sustained response and hepatitis B surface antigen loss.
      Interestingly, patients with HBV RNA responses without concomitant viral antigen declines had low rates of sustained response and HBsAg loss, whereas patients achieving combined HBV RNA and viral antigen declines had high rates of favourable outcomes. We therefore feel that combinations of multiple biomarkers that may include different virological (e.g. HBV RNA, HBsAg and HBcrAg), but also host markers reflecting the activation of the immune system (e.g. anti-HBc and cytokine profiles) will likely be required to identify patients most likely to respond to finite treatment strategies, as highlighted in several recent studies.
      • Fan R.
      • Peng J.
      • Xie Q.
      • Tan D.
      • Xu M.
      • Niu J.
      • et al.
      Combining Hepatitis B Virus RNA and Hepatitis B Core-Related Antigen: guidance for Safely Stopping Nucleos(t)ide Analogues in Hepatitis B e Antigen-Positive Patients With Chronic Hepatitis B.
      ,
      • Brakenhoff S.M.
      • de Knegt R.J.
      • Oliveira J.
      • van der Eijk A.A.
      • van Vuuren A.J.
      • Hansen B.E.
      • et al.
      Anti-HBc levels are associated with liver inflammation and response to peginterferon in chronic hepatitis B patients.
      • Seto W.K.
      • Liu K.S.
      • Mak L.Y.
      • Cloherty G.
      • Wong D.K.
      • Gersch J.
      • et al.
      Role of serum HBV RNA and hepatitis B surface antigen levels in identifying Asian patients with chronic hepatitis B suitable for entecavir cessation.
      • Wubbolding M.
      • Lopez Alfonso J.C.
      • Lin C.Y.
      • Binder S.
      • Falk C.
      • Debarry J.
      • et al.
      Pilot study using machine learning to identify immune profiles for the prediction of early virological relapse after stopping nucleos(t)ide analogues in HBeAg-negative CHB.
      Sun et al. are to be commended for attempting to validate such a strategy in their ongoing prospective study, and the results of such studies are eagerly awaited by the community.
      The association between Caucasian ethnicity and favourable outcomes after therapy withdrawal is very interesting, and has now been consistently reported in multiple international studies.
      • Sonneveld M.J.
      • Park J.Y.
      • Kaewdech A.
      • Seto W.K.
      • Tanaka Y.
      • Carey I.
      • et al.
      Prediction of sustained response after nucleo(s)tide analogue cessation using HBsAg and HBcrAg levels: a multicenter study (CREATE).
      ,
      • Hirode G.
      • Choi H.S.J.
      • Chen C.H.
      • Su T.H.
      • Seto W.K.
      • Van Hees S.
      • et al.
      Off-therapy response after nucleos(t)ide analogue withdrawal in patients with chronic hepatitis B: an international, multicenter, multiethnic cohort (RETRACT-B study).
      In our report, HBV genotypes A and D, which predominate in Caucasian patients, were associated with higher rates of HBsAg clearance.
      • Sonneveld M.J.
      • Chiu S.M.
      • Park J.Y.
      • Brakenhoff S.M.
      • Kaewdech A.
      • Seto W.K.
      • et al.
      Probability of HBsAg loss after nucleo(s)tide analogue withdrawal depends on HBV genotype and viral antigen levels.
      Unfortunately, the number of Asian patients with genotypes A/D (and non-Asians with B/C) was too limited to further explore whether the association between ethnicity and outcomes can be fully accounted for by HBV genotype distribution alone.
      Sun et al., also highlight the discordant results reported by previous studies regarding the association between pretreatment HBeAg status and outcomes after therapy cessation. The Toronto-STOP study identified pretreatment HBeAg positivity as an important risk factor for retreatment after therapy cessation,
      • Liem K.S.
      • van Campenhout M.J.H.
      • Xie Q.
      • Brouwer W.P.
      • Chi H.
      • Qi X.
      • et al.
      Low hepatitis B surface antigen and HBV DNA levels predict response to the addition of pegylated interferon to entecavir in hepatitis B e antigen positive chronic hepatitis B.
      whereas no association between pretreatment HBeAg status and HBsAg loss was observed in our cohort. In this context, it is important to note that pretreatment HBeAg-positive patients are often younger, and are more likely to have high HBsAg and high HBcrAg at the time of treatment cessation. As such, careful multivariable analysis taking into consideration all of these factors is required to fully understand whether HBeAg status is truly an independent predictor of outcomes after treatment withdrawal, and these factors should be considered when comparing differences in associations reported across cohorts.
      In conclusion, our data indicate that quantification of HBsAg and HBcrAg may facilitate personalised decision-making regarding the possibility of finite NUC therapy in patients with chronic hepatitis B. Other biomarkers, including HBV RNA and anti-HBc, could be useful to further optimize patient selection, particularly among the subset of patients with high HBsAg and/or HBcrAg levels.

      Financial support

      The CREATE study was supported by Fujirebio. Materials for HBcrAg testing were provided free of charge to several participating centers.

      Authors’ contributions

      Study design, collection of data, data analysis, writing of the manuscript and approval of final version: MJS, SMC, CHC, BM.

      Role of the funding source

      Fujirebio had no influence on CREATE study design, data collection, data analysis, writing of the current manuscript nor the decision to submit for publication.

      Conflicts of interest

      MJS has received speaker’s fees and research support from Roche, Gilead, BMS, Fujirebio. SMC: Nothing to disclose. CHC: Nothing to disclose. BM: received speaker and/or consulting fees from Abbott Molecular, Astellas, Intercept, Falk, AbbVie, Norgine, Bristol Myers Squibb, Fujirebio, Janssen-Cilag, Merck (MSD), and Roche. He also received research support from Abbott Molecular, Altona Diagnostics, Fujirebio and Roche.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Acknowledgements

      The authors would like to thank Laura Vernoux (Fujirebio) for supporting the CREATE project.

      Supplementary data

      The following are the supplementary data to this article:

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