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Severity of Hepatitis B Relapse After Cessation of Nucleos(t)ide Analog: Need a Closer Look!

Published:September 08, 2021DOI:https://doi.org/10.1016/j.cgh.2021.09.004
      Dear Editor:
      We read with interest the research article by Hsu et al
      • Hsu Y.C.
      • et al.
      regarding the severe acute exacerbation (SAE) after cessation of nucleos(t)ide analog (NA) for hepatitis B e antigen–negative chronic hepatitis B. Many important issues need further consideration.
      First, stopping NA in patients with cirrhosis is never recommended in any practice guidelines because they are at high risk of hepatic decompensation and acute-on-chronic liver failure after NA withdrawal.
      • Sarin S.K.
      • et al.
      ,
      • Terrault N.A.
      • et al.
      It is hard to justify why NA was stopped in so many patients with cirrhosis (12%) in this study.
      Second, the chances of functional cure and severity of discontinuation-related flares depend on the silencing of hepatitis B virus transcriptional activity and restoration of the exhausted hepatitis B specific immune response.
      • Berg T.
      • et al.
      For this, we need to know the hepatitis B surface antigen (HBsAg) levels at baseline and at the time of NA discontinuation.
      • Berg T.
      • et al.
      Moreover, pronounced baseline hepatitis B virus transcriptional activity may require longer treatment periods to allow some restoration of exhausted immune functions. The dynamics of HBsAg decline after stopping NA is also important. Data from multiple small prospective studies support use of hepatitis B core-related antigen and/or HBsAg and tenofovir disoproxil discontinuation to predict risk of relapse.
      • Hsu Y.C.
      • et al.
      ,
      • Papatheodoridi M.
      • et al.
      Third, the mean duration of SAE after NA cessation was 16.3 months. Such delayed flares are uncommon because almost all relapse in the studies involving White patients occur within 3–6 months after stopping NA and up to 90% at 1 year even in the Asian studies.
      • Berg T.
      • et al.
      ,
      • Seto W.K.
      • et al.
      The study should have evaluated the relationship of SAE with the severity of alanine aminotransferase flare and peak hepatitis B DNA. Moreover, we need to evaluate closely the dynamic variability of HBsAg and alanine aminotransferase to detect viral associated flares (bad flares) because this allows for retreatment early preventing SAE and acute-on-chronic liver failure.
      Finally, the role of hepatitis B genotype in predicting the relapse and SAE need evaluation.

      References

        • Hsu Y.C.
        • et al.
        Clin Gastroenterol Hepatol. 2021;
        • Sarin S.K.
        • et al.
        Hepatol Int. 2016; 10: 1-98
        • Terrault N.A.
        • et al.
        Hepatology. 2016; 63: 261-283
        • Berg T.
        • et al.
        J Hepatol. 2021; 75: 474-480
        • Hsu Y.C.
        • et al.
        Aliment Pharmacol Ther. 2019; 49: 107-115
        • Papatheodoridi M.
        • et al.
        Cells. 2020; 9: 493
        • Berg T.
        • et al.
        J Hepatol. 2017; 67: 918-924
        • Seto W.K.
        • et al.
        Gut. 2015; 64: 667-672

      Linked Article

      • Severe Acute Exacerbation After Cessation of Nucleos(t)ide Analog for Chronic Hepatitis B: A Real-World Study of Routine Practice
        Clinical Gastroenterology and Hepatology
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          There is an ongoing debate as to whether patients with chronic hepatitis B (CHB) may discontinue nucleos(t)ide analogue (NA) therapy before seroclearance of hepatitis B surface antigen (HBsAg).1 Whereas treatment discontinuation may facilitate HBsAg seroclearance and avoid indefinite drug exposure,2 reactivation of viral replication almost always follows treatment cessation and frequently leads to clinical flares.3 In patients who encounter withdrawal flares, severe acute exacerbation (SAE) could occur with fatal consequences.4 Quantitative knowledge about the risk of SAE is imperative to inform the debate and also the practice.
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        Clinical Gastroenterology and Hepatology
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          We thank Dr Jindal for his interests in and comments on our study, which we address herein. First, not all chronic hepatitis B (CHB) patients with cirrhosis were indefinitely reimbursed for antiviral therapy by the national health insurance in Taiwan. For patients whose viremia did not exceed 2000 IU/mL or those without overt features of portal hypertension, the reimbursement was finite (up to 3 years in general) despite a clinical diagnosis of cirrhosis throughout the study period. Because our analysis was deliberately based on real-world data from consecutive patients who discontinued treatment as a routine practice, we did not select patients according to a particular stopping rule endorsed by any guidelines.
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