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The times they are a-changing – A refined proposal for finite HBV nucleos(t)ide analogue therapy

  • Thomas Berg
    Correspondence
    Corresponding author. Address: Division of Hepatology, Department of Medicine II Leipzig, University Medical Center, Liebigstraße 20, Haus 4, 04103 Leipzig, Germany; Tel.: +49 341 97 12330, fax: +49 341 97 12339.
    Affiliations
    Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
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  • Pietro Lampertico
    Affiliations
    Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, Milan, Italy

    CRC “A. M. and A. Migliavacca” Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
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      Summary

      Although discontinuation of nucleos(t)ide analogue (NA) treatment before HBsAg loss is part of all current HBV treatment guidelines for HBeAg-positive patients who achieve HBeAg seroconversion, a treatment endpoint known to be associated with silencing of HBV transcriptional activity and restoration of HBV-specific immune control, whether it is even appropriate to consider NA discontinuation before HBsAg loss in the HBeAg-negative phase remains highly controversial. Despite the growing evidence that a relevant, albeit small, proportion of patients with HBeAg-negative disease can be cured by stopping NA treatment, the fear of discontinuation-associated relapse and the uncertainty of how to predict off-therapy response and monitor patients after discontinuation have generated scepticism and subsequently led to low implementation of this concept in the clinic. In this article, we propose a concept in which NA discontinuation-associated relapse is an integral part of the stop-to-cure approach and ultimately the trigger for achieving HBsAg loss. However, the relapse in this sense becomes functionally effective only if HBV-specific immune reinvigoration and silencing of HBV transcriptional activity have been achieved during the NA treatment period. The probability of functional cure and the severity of post-discontinuation flares depend on the underlying baseline transcriptional activity of HBV when NA therapy was started, as well as the duration of NA treatment, both factors that should be considered as we move towards individualised approaches to HBV cure.

      Keywords

      Linked Article

      • Disputing issues in the paradigm change to finite antiviral therapy in HBeAg-negative patients
        Journal of HepatologyVol. 75Issue 6
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          The important expert opinion article by Berg and Lampertico1 on the change from indefinite long-term to finite nucleos(t)ide analogue (NA) therapy in HBeAg-negative chronic hepatitis B (CHB) is timely. Together with the claims of a paradigm shift from Asia2 and the US (Terrault N. American Association for the Study of Liver annual conference 2020 HBV SIG), we have finally reached a unanimous global consensus on this matter. The slogan “stop-to-cure” is clearly more straightforward and to the point than the phrase “stop-and-watch” proposed in 2018.
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      • I shall be released (from infinite HBV nucleos(t)ide analog therapy): Japanese experience
        Journal of HepatologyVol. 75Issue 6
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          We read with great interest the article by Berg et al.1 titled “The times they are changing: A refined proposal for finite HBV nucleos(t)ide analog therapy.” The authors proposed that HBV relapse after nucleos(t)ide analog (NA) discontinuation could improve rates of HBsAg seroclearance according to the “stop-to-cure” approach. Therefore, reliable biomarkers to identify patients who could say “I shall be released” (from infinite NA therapy) are indispensable.
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      • Reply to: Correspondence on ‘the times they are a-changing - A refined proposal for finite HBV nucleos(t)ide analogue therapy.’
        Journal of HepatologyVol. 75Issue 6
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          We would like to thank Wen-Juei Jeng and his colleagues for sharing their thoughts on this important topic and also for clarifying again the design of the Taiwanese nucleos(t)ide analogue (NA) discontinuation trials.1 All the issues raised are valid and highlight the need to further evaluate several important aspects of the finite NA strategy, from the duration of consolidation therapy to the predictors of treatment cessation and retreatment strategies.
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      • New concepts regarding finite oral antiviral therapy for HBeAg-negative chronic hepatitis B
        Journal of HepatologyVol. 75Issue 6
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          We read with great interest the recent Expert Opinion by Thomas Berg and Pietro Lampertico on a refined proposal for finite nucleos(t)ide analogue (NA) therapy in HBeAg-negative chronic hepatitis B (CHB).1 This is a timely article by 2 experts in hepatitis B, which proposes a carefully balanced approach for improved implementation of individualized finite NA therapy for HBeAg-negative CHB patients, with the aim of increasing functional cure rates.1–3 In an effort to further clarify a few issues, we would like to share our thoughts based on data from our prospective DARING-B study and our experience from daily clinical practice.
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      Treatment concepts of chronic hepatitis B - times they are a-changing

      Inducing long-term immune control of chronic hepatitis B by a finite treatment approach has been the cornerstone of treatment strategies for decades and was driven by the specific mode of action of interferons which were the only licensed drugs available at that time. At the beginning of the nucleos(t)ide analogue (NA) era, studies also aimed to achieve long-term off-treatment responses through a time-limited administration of these direct antiviral drugs. However, randomised studies proved that NAs were inferior to pegylated-interferon alpha in terms of inducing long-term remission, HBeAg seroconversion as well as HBsAg loss.
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      It was also shown that virologic relapses, although seen in both interferon- and NA-treated patients, may confer differing risks of relapse-associated disease decompensation in patients with advanced fibrosis or cirrhosis, with decompensation mainly seen in the NA-treated cohort when HBV replication reached high levels shortly after treatment cessation.
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      Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B.
      The high efficacy and safety of second-generation NAs – together with data showing, for the first time, that the level of HBV replication is the main determinant of disease progression – has led to sustained viral load suppression becoming an increasingly desirable endpoint of therapy.
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      • Papatheodoridis G.
      • et al.
      EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection.
      The prospective tenofovir studies designed to treat patients for 8 years irrespective of features of on-treatment serologic response (i.e. HBeAg or HBsAg loss) together with the results of longitudinal real-world studies with entecavir and tenofovir have been an important step towards promoting long-term suppression of HBV replication as the main goal of treatment. They have shown that it cannot only halt disease progression but also lead to regression of fibrosis and even cirrhosis in the majority of treated patients.
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      Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B.
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      • Jacobson I.M.
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      Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study.
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      • Chi H.
      • van Boemmel F.
      • et al.
      The risk of hepatocellular carcinoma decreases after the first 5 years of entecavir or tenofovir in Caucasians with chronic hepatitis B.
      • Papatheodoridis G.V.
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      • Sypsa V.
      • Van Boemmel F.
      • Buti M.
      • et al.
      Similar risk of hepatocellular carcinoma during long-term entecavir or tenofovir therapy in Caucasian patients with chronic hepatitis B.
      Nevertheless, discontinuation of NAs is still part of all current treatment guidelines and is recommended when certain features of response to treatment known to be associated with silencing HBV transcriptional activity and restoration of HBV-specific immune control can be induced.
      • Lampertico P.
      • Agarwal K.
      • Berg T.
      • Buti M.
      • Janssen H.L.A.
      • Papatheodoridis G.
      • et al.
      EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection.
      ,
      • Terrault N.A.
      • Lok A.S.F.
      • McMahon B.J.
      • Chang K.-M.
      • Hwang J.P.
      • Jonas M.M.
      • et al.
      Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.
      ,
      • Sarin S.K.
      • Kumar M.
      • Lau G.K.
      • Abbas Z.
      • Chan H.L.Y.
      • Chen C.J.
      • et al.
      Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update.
      The on-treatment induction of HBeAg loss or seroconversion, a serologic hallmark of silenced disease activity in the natural course of the infection, represents such a feature. The main controversy as to when and if NAs can be discontinued at all exists in patients who start antiviral treatment in the HBeAg-negative chronic hepatitis phase, as no serologic markers have yet been established that herald silencing of viral activity on-treatment (Table 1). However, recent long-term follow-up studies after cessation of NA treatment in HBeAg-negative patients, after prolonged on-treatment suppression of HBV replication, showed a relatively high proportion of patients remaining in treatment-free remission or even achieving functional cure, i.e. loss of HBsAg, a finding which has challenged the dogma of lifelong treatment necessity in these circumstances.
      • Hadziyannis S.J.
      • Sevastianos V.
      • Rapti I.
      • Vassilopoulos D.
      • Hadziyannis E.
      Sustained responses and loss of HBsAg in HBeAg-negative patients with chronic hepatitis B who stop long-term treatment with adefovir.
      • Berg T.
      • Simon K.G.
      • Mauss S.
      • Schott E.
      • Heyne R.
      • Klass D.M.
      • et al.
      Long-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients - FINITE study.
      • van Bömmel F.
      • Berg T.
      Stopping long-term treatment with nucleos(t)ide analogues is a favourable option for selected patients with HBeAg-negative chronic hepatitis B.
      • van Bömmel F.
      • Stein K.
      • Heyne R.
      • Möller H.
      • Petersen J.
      • Buggisch P.
      • et al.
      Response to discontinuation of long-term nucleos(t)ide analogue treatment in HBeAg negative patients: results of the Stop-NUC trial.
      • Papatheodoridis G.V.
      • Rigopoulou E.I.
      • Papatheodoridi M.
      • Zachou K.
      • Xourafas V.
      • Gatselis N.
      • et al.
      DARING-B: discontinuation of effective entecavir or tenofovir disoproxil fumarate long-term therapy before HBsAg loss in non-cirrhotic HBeAg-negative chronic hepatitis B.
      Treatment discontinuation-associated relapses in HBV replication are now being discussed as a possible important trigger for the induction of immune-mediated long-term control and functional cure.
      • Lampertico P.
      • Berg T.
      Less can be more: a finite treatment approach for HBeAg-negative chronic hepatitis B.
      The emergence of new direct antiviral and immune-mediated treatment strategies that also aim to induce a functional cure of HBV infection through a finite duration of treatment have prompted widespread discussion on flare management on the one hand, but also on how to distinguish potential flare-associated HBV responses from the specific modes of action of the studied antiviral regimens. Therefore, there is a heated debate about the extent to which discontinuation of NAs and the associated flare should be part of a new approach aimed at increasing functional cure rates in patients with HBeAg-negative disease.
      Table 1Current recommendations from international guidelines on early discontinuation of NA before HBsAg loss in patients with HBeAg-negative hepatitis B.
      APASL 2016EASL 2017AASLD 2018
      In patients without cirrhosis, the treatment can be withdrawn after treatment for at least 2 years with undetectable HBV DNA documented on 3 separate occasions,

      6 months apart.
      Discontinuation of NAs in selected non-cirrhotic HBeAg-negative patients who have achieved long-term (≥3 years) virological suppression under NAs may be considered if close post-NA monitoring can be guaranteed.The AASLD suggests indefinite antiviral therapy for adults with HBeAg-negative, immune-active CHB unless there is a compelling rationale for treatment discontinuation.
      According to references
      • Lampertico P.
      • Agarwal K.
      • Berg T.
      • Buti M.
      • Janssen H.L.A.
      • Papatheodoridis G.
      • et al.
      EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection.
      ,
      • Terrault N.A.
      • Lok A.S.F.
      • McMahon B.J.
      • Chang K.-M.
      • Hwang J.P.
      • Jonas M.M.
      • et al.
      Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.
      and
      • Sarin S.K.
      • Kumar M.
      • Lau G.K.
      • Abbas Z.
      • Chan H.L.Y.
      • Chen C.J.
      • et al.
      Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update.
      ; NAs, nucleos(t)ide analogues; CHB, chronic hepatitis B.

      NA discontinuation in HBeAg-negative chronic hepatitis B - where do we stand?

      Despite the 2017 EASL guideline recommendation to consider discontinuation of NA therapy prior to HBsAg loss in selected patients with HBeAg-negative chronic hepatitis B
      • Lampertico P.
      • Agarwal K.
      • Berg T.
      • Buti M.
      • Janssen H.L.A.
      • Papatheodoridis G.
      • et al.
      EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection.
      (Table 1), the overall use of this strategy in clinical practice is limited. In our personal experience, less than 10% of physicians currently caring for these patients would use this strategy today. There are several possible explanations for this attitude (Table 2). Over the past 20 years, guidelines, reviews, original publications, and, not least, presentations at national and international congresses have highlighted the importance of virologic response. The relevance of undetectable HBV DNA as a surrogate biomarker for a clinically robust endpoint such as hepatocellular carcinoma (HCC) prevention has been confirmed by the last 10 years of experience with potent NAs, which showed a significant reduction in HCC incidence rates in patients under long-term virologic suppression.
      • Lampertico P.
      • Agarwal K.
      • Berg T.
      • Buti M.
      • Janssen H.L.A.
      • Papatheodoridis G.
      • et al.
      EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection.
      ,
      • Papatheodoridis G.V.
      • Idilman R.
      • Dalekos G.N.
      • Buti M.
      • Chi H.
      • van Boemmel F.
      • et al.
      The risk of hepatocellular carcinoma decreases after the first 5 years of entecavir or tenofovir in Caucasians with chronic hepatitis B.
      ,
      • Terrault N.A.
      • Lok A.S.F.
      • McMahon B.J.
      • Chang K.-M.
      • Hwang J.P.
      • Jonas M.M.
      • et al.
      Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.
      ,
      • Sarin S.K.
      • Kumar M.
      • Lau G.K.
      • Abbas Z.
      • Chan H.L.Y.
      • Chen C.J.
      • et al.
      Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update.
      This is one of the strongest arguments for physicians, as well as patients, not to discontinue NAs before HBsAg loss. Indeed, a rebound of HBV replication with detectable HBV DNA levels after NA discontinuation is almost universal.
      • Hadziyannis S.J.
      • Sevastianos V.
      • Rapti I.
      • Vassilopoulos D.
      • Hadziyannis E.
      Sustained responses and loss of HBsAg in HBeAg-negative patients with chronic hepatitis B who stop long-term treatment with adefovir.
      • Berg T.
      • Simon K.G.
      • Mauss S.
      • Schott E.
      • Heyne R.
      • Klass D.M.
      • et al.
      Long-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients - FINITE study.
      • van Bömmel F.
      • Berg T.
      Stopping long-term treatment with nucleos(t)ide analogues is a favourable option for selected patients with HBeAg-negative chronic hepatitis B.
      • van Bömmel F.
      • Stein K.
      • Heyne R.
      • Möller H.
      • Petersen J.
      • Buggisch P.
      • et al.
      Response to discontinuation of long-term nucleos(t)ide analogue treatment in HBeAg negative patients: results of the Stop-NUC trial.
      • Papatheodoridis G.V.
      • Rigopoulou E.I.
      • Papatheodoridi M.
      • Zachou K.
      • Xourafas V.
      • Gatselis N.
      • et al.
      DARING-B: discontinuation of effective entecavir or tenofovir disoproxil fumarate long-term therapy before HBsAg loss in non-cirrhotic HBeAg-negative chronic hepatitis B.
      Whether this rebound is associated with an increased risk of HCC development in the long-term is still unknown. Prevention of progression to cirrhosis is also closely linked to virologic response but does not require complete suppression of HBV replication with undetectable HBV DNA levels, but rather the reduction of HBV DNA to <2,000 IU/ml with normalisation of alanine aminotransferase (ALT), which has been demonstrated to be a valuable endpoint in numerous trials using interferon.
      • Lampertico P.
      • Agarwal K.
      • Berg T.
      • Buti M.
      • Janssen H.L.A.
      • Papatheodoridis G.
      • et al.
      EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection.
      Table 2Pros and Cons of NA discontinuation before HBsAg loss in patients with HBeAg-negative chronic hepatitis B.
      ProsCons
      Higher HBsAg loss rates
      Approximately 5-10% at year 1, higher in selected patients and higher over time.
      Universal HBV DNA rebound
      Inactive carrier state in approx. 20-30%Abnormal ALT levels in many patients
      Long-term off therapy in approx. 50% of the patients
      Estimated at year 1-2.
      ALT flares in some patients
      More intensive monitoring
      At least for the first year off therapy because of the intense virological and clinical monitoring.
      Retreatment with NA in 50% of the patients
      For retreatment rules, see article.
      Excellent patients’ adherence required
      Compliance to extensive monitoring at least for the first year.
      Careful patients’ selection
      Patients with any evidence of current or previous cirrhosis must continue NAs.
      Assessment of predictors
      EOT HBsAg levels may help selecting patients with higher likelihood of HBsAg loss off therapy.
      Unpredictability of virological and clinical outcomes
      The virological and clinical outcomes cannot be easily predicted.
      ALT, alanine aminotransferase; EOT, end-of-treatment; NAs, nucleos(t)ide analogues.
      a Approximately 5-10% at year 1, higher in selected patients and higher over time.
      b Estimated at year 1-2.
      c At least for the first year off therapy because of the intense virological and clinical monitoring.
      d For retreatment rules, see article.
      e Compliance to extensive monitoring at least for the first year.
      f Patients with any evidence of current or previous cirrhosis must continue NAs.
      g EOT HBsAg levels may help selecting patients with higher likelihood of HBsAg loss off therapy.
      h The virological and clinical outcomes cannot be easily predicted.
      Another argument often made against stopping NA therapy before HBsAg loss in the HBeAg-negative disease is the risk of significant disease relapse and even liver failure, with close follow-up and high patient adherence required to avoid these adverse consequences. For both patients and physicians, the monitoring associated with the finite treatment approach makes discontinuation of NA therapy more challenging than simply continuing treatment.
      However, there is a contradiction between the clear general recommendation to discontinue NA therapy after HBeAg seroconversion and the strong caveat to discontinuation of treatment in HBeAg-negative hepatitis B.
      • Lampertico P.
      • Agarwal K.
      • Berg T.
      • Buti M.
      • Janssen H.L.A.
      • Papatheodoridis G.
      • et al.
      EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection.
      ,
      • Terrault N.A.
      • Lok A.S.F.
      • McMahon B.J.
      • Chang K.-M.
      • Hwang J.P.
      • Jonas M.M.
      • et al.
      Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.
      First, the fact that HBeAg seroconversion cannot be used as a serologic marker associated with silencing of covalently closed circular DNA (cccDNA) in HBeAg-negative hepatitis does not mean that a similar silencing of HBV transcriptional activity cannot be achieved with antiviral treatment in a proportion of HBeAg-negative patients. Second, if not only HBsAg loss but also silencing of the transcriptional activity of HBV and the induction of a true “inactive carrier state” remains an appropriate endpoint in HBeAg-positive hepatitis B, why should this not also be the case for HBeAg-negative disease. Third, concerns about virologic relapses as the driving argument for the general recommendations not to stop therapy in HBeAg-negative patients are conflicting, because discontinuation of NAs is still recommended in HBeAg-positive patients with treatment-induced HBeAg seroconversion, although the risk of relapse in this group does not seem to differ from that in those who started NA treatment in the HBeAg-negative hepatitis phase.
      • Papatheodoridis G.
      • Vlachogiannakos I.
      • Cholongitas E.
      • Wursthorn K.
      • Thomadakis C.
      • Touloumi G.
      • et al.
      Discontinuation of oral antivirals in chronic hepatitis B: a systematic review.
      The opposite is probably true, as recently demonstrated in a prospective study in which pre-treatment HBeAg-positive patients were 3x more likely than HBeAg-negative patients to require retreatment for a clinically relevant relapse after stopping NAs.
      • Liem K.S.
      • Fung S.
      • Wong D.K.
      • Yim C.
      • Noureldin S.
      • Chen J.
      • et al.
      Limited sustained response after stopping nucleos(t)ide analogues in patients with chronic hepatitis B: results from a randomised controlled trial (Toronto STOP study).

      Outcome studies – geographical differences matter

      Most of our knowledge on NA discontinuation comes from Asian studies that retrospectively evaluated the outcome of their discontinuation regimens in terms of virologic and biochemical relapse rates in HBeAg-negative patients. It is important to emphasise that this discontinuation approach was mostly driven by local reimbursement policies and not by an attempt to induce a post-discontinuation flare-associated long-term remission. In contrast to prospective European studies that showed that virologic relapses after discontinuation of NAs prior to HBsAg loss are almost universal in HBeAg-negative patients, these retrospective studies showed a rather heterogeneous picture with highly variable biochemical and virologic relapse patterns depending on the relapse definitions, duration of the preceding NA treatment period, as well as specific disease characteristics.
      • Liu Y.
      • Jia M.
      • Wu S.
      • Jiang W.
      • Feng Y.
      Predictors of relapse after cessation of nucleos(t)ide analog treatment in HBeAg-negative chronic hepatitis B patients: a meta-analysis.
      • Chang M.L.
      • Liaw Y.F.
      • Hadziyannis S.J.
      Systematic review: cessation of long-term nucleos(t)ide analogue therapy in patients with hepatitis B e antigen-negative chronic hepatitis B.
      • Papatheodoridis G.V.
      • Manolakopoulos S.
      • Su T.H.
      • Siakavellas S.
      • Liu C.J.
      • Kourikou A.
      • et al.
      Significance of definitions of relapse after discontinuation of oral antivirals in HBeAg-negative chronic hepatitis B.
      • Jeng W.J.
      • Chen Y.C.
      • Chien R.N.
      • Sheen I.S.
      • Liaw Y.F.
      Incidence and predictors of hepatitis B surface antigen seroclearance after cessation of nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B.
      However, prospective Asian studies confirmed virologic relapse rates of over 90% after NA discontinuation, implying that transient mild virologic relapses may have been overlooked in the aforementioned Asian studies due to their retrospective nature.
      • Seto W.K.
      • Hui A.J.
      • Wong V.W.
      • Wong G.L.
      • Liu K.S.
      • Lai C.L.
      • et al.
      Treatment cessation of entecavir in Asian patients with hepatitis B e antigen negative chronic hepatitis B: a multicentre prospective study.
      In some of these Asian studies, up to 40% of the patients in whom treatment was stopped had cirrhosis at baseline, which was a contraindication to stopping NAs in all Western studies.
      • Jeng W.J.
      • Chen Y.C.
      • Chien R.N.
      • Sheen I.S.
      • Liaw Y.F.
      Incidence and predictors of hepatitis B surface antigen seroclearance after cessation of nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B.
      And indeed, to date, liver decompensation and death associated with post-treatment flares have only been observed in patients with cirrhosis.
      • Chang M.L.
      • Liaw Y.F.
      • Hadziyannis S.J.
      Systematic review: cessation of long-term nucleos(t)ide analogue therapy in patients with hepatitis B e antigen-negative chronic hepatitis B.
      ,
      • Jeng W.J.
      • Chen Y.C.
      • Chien R.N.
      • Sheen I.S.
      • Liaw Y.F.
      Incidence and predictors of hepatitis B surface antigen seroclearance after cessation of nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B.
      The fact that most Asian studies did not apply predefined rules for the timing of treatment resumption further complicates comparisons between studies because the timing of retreatment has been shown to have important implications for whether complete post-treatment remission and HBsAg loss can be achieved. Early initiation of NA retreatment could potentially jeopardise the beneficial effect of flare-associated immune activation, as previously demonstrated.
      • Jeng W.J.
      • Chen Y.C.
      • Chien R.N.
      • Sheen I.S.
      • Liaw Y.F.
      Incidence and predictors of hepatitis B surface antigen seroclearance after cessation of nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B.
      ,
      • Liaw Y.F.
      • Jeng W.J.
      • Chang M.L.
      HBsAg kinetics in retreatment decision for off-therapy hepatitis B flare in HBeAg-negative patients.
      Stephanos Hadziyannis’ study was the first to open the window to a new finite treatment approach in HBeAg-negative disease that went beyond counting the number of virologic and biochemical flares. After a follow-up period of 6 years following discontinuation of NAs that were administered for 4–5 years, 39% of patients lost HBsAg without any treatment.
      • Hadziyannis S.J.
      • Sevastianos V.
      • Rapti I.
      • Vassilopoulos D.
      • Hadziyannis E.
      Sustained responses and loss of HBsAg in HBeAg-negative patients with chronic hepatitis B who stop long-term treatment with adefovir.
      He hypothesised that part of this success was related to post-treatment flares, which, however, remained untreated and thus may have helped to stimulate immune-mediated mechanisms, leading to long-lasting immune control, much like flares that occur in the natural course of the HBV infection and are known to be followed by long-term remissions and seroconversions.
      Fascinated by this concept, authors of prospective studies have since aimed to induce a functional cure using a stop-to-relapse approach with predefined retreatment rules wherein biochemical flares are tolerated if they are not indicative of an incipient impairment in liver function. These studies provided strong evidence that discontinuation of NA, compared to continued NA therapy, is generally safe and associated with a more pronounced decline in HBsAg levels and a significantly higher rate of HBsAg loss, which can reach 10–20% during a relatively short follow-up period of 2–3 years.
      • Berg T.
      • Simon K.G.
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      • Schott E.
      • Heyne R.
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      ,
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      Stopping long-term treatment with nucleos(t)ide analogues is a favourable option for selected patients with HBeAg-negative chronic hepatitis B.
      In addition, up to 40% enter a true off-treatment carrier stage with suppressed viral activity.
      • Hadziyannis S.J.
      • Sevastianos V.
      • Rapti I.
      • Vassilopoulos D.
      • Hadziyannis E.
      Sustained responses and loss of HBsAg in HBeAg-negative patients with chronic hepatitis B who stop long-term treatment with adefovir.
      • Berg T.
      • Simon K.G.
      • Mauss S.
      • Schott E.
      • Heyne R.
      • Klass D.M.
      • et al.
      Long-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients - FINITE study.
      • van Bömmel F.
      • Berg T.
      Stopping long-term treatment with nucleos(t)ide analogues is a favourable option for selected patients with HBeAg-negative chronic hepatitis B.
      • van Bömmel F.
      • Stein K.
      • Heyne R.
      • Möller H.
      • Petersen J.
      • Buggisch P.
      • et al.
      Response to discontinuation of long-term nucleos(t)ide analogue treatment in HBeAg negative patients: results of the Stop-NUC trial.
      • Papatheodoridis G.V.
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      • et al.
      DARING-B: discontinuation of effective entecavir or tenofovir disoproxil fumarate long-term therapy before HBsAg loss in non-cirrhotic HBeAg-negative chronic hepatitis B.
      From these studies, it also became evident that HBV infection goes through different phases after discontinuation of NA treatment, the lag phase, the reactivation phase, and the consolidation phase.
      • Lampertico P.
      • Berg T.
      Less can be more: a finite treatment approach for HBeAg-negative chronic hepatitis B.
      The HBV DNA and ALT flares observed during the reactivation phase are often transient and their further fate can only be assessed during the consolidation phase. Whether there are favourable and unfavourable flares in terms of the induction of long-term remission and HBsAg response and how to distinguish between them is controversial, as is the question of why only a minority of patients achieve a functional cure.

      Inducing functional cure – the stop-to-relapse hypothesis

      There is no longer any doubt that the recurrence of HBV replication after NA discontinuation represents an important trigger leading to altered HBsAg dynamics and HBsAg loss. But why does this desired HBsAg response occur in only a minority of patients, even though HBV replication rebound happens universally? Does the outcome depend primarily on the course of the post-treatment discontinuation phase and the flare pattern, or is the fate of what happens after discontinuation already determined during the treatment phase?
      From what we know so far, it is not the severe flares with pronounced HBV replication and high ALT levels that are associated with a favourable HBsAg response. Mild HBV DNA rebounds often without marked ALT elevations, along with low HBsAg levels, are the typical features seen in patients who have lost HBsAg.
      • Berg T.
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      • Schott E.
      • Heyne R.
      • Klass D.M.
      • et al.
      Long-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients - FINITE study.
      ,
      • van Bömmel F.
      • Berg T.
      Stopping long-term treatment with nucleos(t)ide analogues is a favourable option for selected patients with HBeAg-negative chronic hepatitis B.
      ,
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      • et al.
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      In our opinion what matters most is what happened during the NA treatment phase: Stopping NA prematurely before HBsAg loss can only be successful in terms of inducing a functional cure if the transcriptional activity of cccDNA has been silenced to some degree during treatment. The probability with which this goal can be achieved depends on the underlying baseline transcriptional activity of HBV when NAs were initiated, as well as the duration of NA treatment, i.e. the higher the viral activity in the beginning, the longer the treatment phase must be. However, other characteristics, such as the overall duration of the infection, history of vertical transmission, patients’ ethnicity, age, HBV genotypes and perhaps also the NA class may also play a role.
      Sulsov and colleagues
      • Suslov A.
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      Transition to HBeAg-negative chronic hepatitis B virus infection is associated with reduced cccDNA transcriptional activity.
      recently described different patterns of viral control in the HBeAg-negative hepatitis phase. Viral replication appeared to be mostly controlled by a combination of cytolytic and non-cytolytic antiviral mechanisms, the latter leading to more efficient viral control in a subset of HBeAg-negative patients characterised by reduced replication efficiency downstream of pregenomic RNA. It is tempting to speculate that this subset of patients with low-replicative HBeAg-negative hepatitis may respond differently to NAs and may not only be less likely to suffer from a severe flare after treatment cessation than their high-replicative HBeAg-negative counterparts but may also have a higher chance of losing HBsAg.
      The reinvigoration of a previously dysfunctional innate and adaptive immune response under NA treatment, as evidenced by an increased HBV-specific T cell response, decreased natural killer cell killing of HBV-specific T cells, and an increase in serum cytokine and chemokine levels could be the sine qua non for safe and effective NA discontinuation.
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      Perspectives on stopping nucleos(t)ide analogues therapy in patients with chronic hepatitis B.
      • Ghany M.G.
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      • et al.
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      • García-López M.
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      • et al.
      Viral and immune factors associated with successful treatment withdrawal in HBeAg-negative chronic hepatitis B patients.
      Under the condition of both silenced HBV transcriptional activity and reinvigoration of innate and adaptive immune responses, innate immune cells in the liver might be activated after NA treatment cessation by a threshold exposure to HBV, leading them to express various inflammatory cytokines and chemokines which in turn may lead to long-term immune control of the infection and eventually HBsAg loss (as summarised in 29 and 30) (Fig. 1).
      Figure thumbnail gr1
      Fig. 1Chances of functional cure and severity of discontinuation-related flares depend on the silencing of HBV transcriptional activity and restoration of the exhausted HBV-specific immune response.
      The chances of functional cure after premature NA discontinuation before HBsAg loss in patients with HBeAg-negative hepatitis B, but also the severity of post-discontinuation flares, depend on whether silencing of HBV transcriptional activity as well as reinvigoration of the exhausted HBV-specific immune response can be achieved during the NA treatment period. If baseline HBV transcriptional activity is already low, further silencing of its activity by NA-induced viral suppression together with a reinvigoration of HBV-specific immune functions can be achieved after only a limited treatment period. In contrast, a more pronounced baseline HBV transcriptional activity may require longer treatment periods to allow some restoration of exhausted immune functions. It is tempting to speculate that individual factors related to HBV infection and the host immune system may mean that there is a group in whom it will never be possible to reach a stage where safe and effective discontinuation of NAs is possible. Under the condition of silenced HBV transcriptional activity and reinvigoration of innate and adaptive immune responses, rebound of HBV replication after discontinuation of NA treatment is typically mild and represents the trigger required for long-term immune control of the infection and ultimately HBsAg loss. Severe flares after discontinuation of NAs are probably a reflection of high HBV cccDNA transcriptional activity still persisting under NA treatment, indicated by high HBsAg, HBcrAg and HBV RNA levels despite undetectable HBV DNA, and are typically associated with a high probability of needing retreatment and low rates of HBsAg loss. cccDNA, covalently closed circular DNA; HBcrAg, HBV core-related antigen; NAs, nucleos(t)ide analogues.

      Definitions of the patient populations benefiting from the finite approach – the role of HBV biomarkers

      Inducing a functional cure is, in our opinion, the main justification for treatment discontinuation in HBeAg-negative disease. Since the overall HBsAg loss rates are however limited, reliable predictors and better definitions of the patient populations that will benefit from this finite treatment approach are needed. This is even more true when the alternative strategy, continuous NA administration, is associated with excellent efficacy and ease of use. Several studies have investigated whether new biomarkers, such as HBV RNA, HBV core-related antigen (HBcrAg), and anti-HBc antibody levels, can be used to stratify patients who are more likely to respond after stopping NA or, conversely, those who are more likely to require retreatment.
      • Fan R.
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      • Tan D.
      • Niu J.
      • Wang H.
      • et al.
      Chronic Hepatitis B Study Consortium. Association between negative results from tests for HBV DNA and RNA and durability of response after discontinuation of nucleos(t)ide analogue therapy.
      • Seto W.K.
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      • 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.
      • Carey I.
      • Gersch J.
      • Wang B.
      • Moigboi C.
      • Kuhns M.
      • Cloherty G.
      • et al.
      Pregenomic HBV RNA and hepatitis B core-related antigen predict outcomes in hepatitis B e antigen-negative chronic hepatitis B patients suppressed on nucleos(t)ide analogue therapy.
      • 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).
      • Brakenhoff S.M.
      • de Man R.A.
      • Boonstra A.
      • van Campenhout M.J.H.
      • de Knegt R.J.
      • van Bömmel 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.
      • Hsu Y.C.
      • Nguyen M.H.
      • Mo L.R.
      • Wu M.S.
      • Yang T.H.
      • Chen C.C.
      • et al.
      Combining hepatitis B core-related and surface antigens at end of nucleos(t)ide analogue treatment to predict off-therapy relapse risk.
      Although both serum HBV RNA and HBcrAg levels reflect intrahepatic HBV transcriptional activity to some extent and thus could be valuable tools for predicting outcomes after NA discontinuation, they are not yet ready for "prime time".
      • Charre C.
      • Levrero M.
      • Zoulim F.
      • Scholtès C.
      Non-invasive biomarkers for chronic hepatitis B virus infection management.
      • Buti M.
      • Riveiro-Barciela M.
      • Rodríguez-Frías F.
      • Tabernero D.
      • Esteban R.
      Role of biomarkers in guiding cure of viral hepatitis B.
      • Papatheodoridi M.
      • Papatheodoridis G.
      Emerging diagnostic tools to decide when to discontinue nucleos(t)ide analogues in chronic hepatitis B.
      While detectable levels of HBV RNA and HBcrAg at the end-of-treatment clearly predict an unfavourable outcome, the opposite – non-detectability of these markers – is not highly predictive of HBsAg loss.
      • Fan R.
      • Zhou B.
      • Xu M.
      • Tan D.
      • Niu J.
      • Wang H.
      • et al.
      Chronic Hepatitis B Study Consortium. Association between negative results from tests for HBV DNA and RNA and durability of response after discontinuation of nucleos(t)ide analogue therapy.
      ,
      • 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.
      ,
      • 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).
      • Brakenhoff S.M.
      • de Man R.A.
      • Boonstra A.
      • van Campenhout M.J.H.
      • de Knegt R.J.
      • van Bömmel 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.
      • Hsu Y.C.
      • Nguyen M.H.
      • Mo L.R.
      • Wu M.S.
      • Yang T.H.
      • Chen C.C.
      • et al.
      Combining hepatitis B core-related and surface antigens at end of nucleos(t)ide analogue treatment to predict off-therapy relapse risk.
      Almost all of these biomarker studies were retrospective post hoc observations which is another limitation, as well as the fact that the endpoints for which these markers were assessed differed from study to study. In addition, HBV RNA is not commercially available, and HBcrAg still suffers from limited sensitivity and lack of reimbursement. Currently, quantitative HBsAg levels are the most reliable predictive marker, and a HBsAg decline during treatment and low HBsAg levels at the end-of-treatment correlate highly with the likelihood of achieving HBsAg loss after discontinuation of NAs.
      • Chen C.-H.
      • Lu S.-N.
      • Hung C.-H.
      • Wang J.-H.
      • Hui T.-H.
      • Chngchien C.-S.
      • et al.
      The role of hepatitis B surface antigen quantification in predicting HBsAg loss and HBV relapse after discontinuation of lamivudine treatment.
      ,
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      The HBsAg cut-off at the end-of-treatment that best predicts functional cure is still under debate and appears to differ between Caucasian and Asian patient populations. However, it has now been convincingly demonstrated that HBsAg levels of <1,000 IU/ml in the Caucasian population and <100 IU/ml in the Asian population are associated with HBsAg loss rates of more than 20%–30%.
      • van Bömmel F.
      • Stein K.
      • Heyne R.
      • Möller H.
      • Petersen J.
      • Buggisch P.
      • et al.
      Response to discontinuation of long-term nucleos(t)ide analogue treatment in HBeAg negative patients: results of the Stop-NUC trial.
      ,
      • Jeng W.J.
      • Chen Y.C.
      • Chien R.N.
      • Sheen I.S.
      • Liaw Y.F.
      Incidence and predictors of hepatitis B surface antigen seroclearance after cessation of nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B.
      ,
      • Tout I.
      • Lampertico P.
      • Berg T.
      • Asselah T.
      Perspectives on stopping nucleos(t)ide analogues therapy in patients with chronic hepatitis B.
      ,
      • García-López M.
      • Lens S.
      • Pallett L.J.
      • Testoni B.
      • Rodríguez-Tajes S.
      • Mariño Z.
      • et al.
      Viral and immune factors associated with successful treatment withdrawal in HBeAg-negative chronic hepatitis B patients.
      ,
      • Liu J.
      • Li T.
      • Zhang L.
      • Xu A.
      The role of hepatitis B surface antigen in nucleos(t)ide analogues cessation among Asian patients with chronic hepatitis B: a systematic review.
      These functional cure rates appear to justify efforts related to discontinuing NAs, and they are in the efficacy range being targeted by studies investigating novel antiviral and immunomodulatory agents for HBV cure.
      • Cornberg M.
      • Lok A.S.-F.
      • Terrault N.A.
      Zoulim F, and the 2019 EASL-AASLD HBV Treatment Endpoints Conference Faculty. Guidance for design and endpoints of clinical trials in chronic hepatitis B - Report from the 2019 EASL-AASLD HBV treatment endpoints conference.

      Summary and conclusions

      The answer to the question of whether we can go beyond the guidelines in terms of discontinuing NA in HBeAg-negative patients is that it is not a matter of going beyond, but rather of becoming more specific in our recommendations. In early 2017, when the EASL guidelines were written, we underestimated the importance of NA treatment duration in the context of baseline viral activity and overestimated the role of discontinuation-associated relapse as the essential trigger in eliciting the functional cure. Although NA discontinuation-associated relapse is an integral part of the stop-to-cure approach and ultimately the trigger for achieving HBsAg loss, the relapse becomes functional in this sense only if HBV-specific immune reinvigoration and silencing of HBV transcriptional activity have previously been achieved during the NA treatment period. The chances of the immune system being awakened from its slumber depend critically on the baseline transcriptional activity of HBV infection at the start of NA treatment and on the duration for which HBV replication has been completely suppressed by NA treatment. Therefore, as mentioned in the guidelines, we are opposed to using specific treatment duration cut-offs to decide on treatment discontinuation, as it may take either more or less time to achieve the desired therapeutic effects, depending on the baseline transcriptional activity of HBV and the individual constitution of the host immune system. Wider use of biomarkers that reflect the transcriptional activity of cccDNA in the HBV DNA-suppressed settings, such as HBV RNA and HBcrAg, but also the ability to monitor innate and adaptive HBV immune responses, will be important to refine the finite approach. Among the routinely available biomarkers, baseline HBV DNA and the dynamics of quantitative HBsAg under treatment help to guide the finite treatment strategy. In the subset of patients who achieve on-treatment HBsAg levels <1,000 IU/ml (in Caucasians) and <100 IU/ml (in Asians), treatment discontinuation may result in high functional cure rates of more than 20%–30%, and importantly, the risk of developing severe flares is low. These cure rates, together with the fact that treatment initiation thresholds related to ALT and HBV DNA levels have become more liberal over time, allowing us to start treatment earlier, are in our opinion a strong argument for recommending a finite NA approach as the therapeutic goal right from the start, based on meeting the aforementioned conditions. Early prediction of the long-term outcome of finite treatment approaches not only by end-of-treatment markers but also by early relapse kinetics may further facilitate acceptance of the finite approach. Conversely, novel antiviral and immunomodulatory agents that can help to accelerate the time to achieve silencing of HBV transcriptional activity are particularly important for patients in whom both baseline and on-treatment characteristics make achievement of a functional cure through a finite NA approach unlikely.

      Abbreviations

      ALT, alanine aminotransferase; cccDNA, covalently closed circular DNA; HBcrAg, HBV core-related antigen; HCC, hepatocellular carcinoma; NAs, nucleos(t)ide analogues.

      Financial support

      The authors received no financial support to produce this manuscript.

      Authors’ contributions

      TB and PL both drafted the concept of this expert opinion article and wrote the manuscript.

      Conflict of interest

      TB – Receip of grants/research supports: Abbvie, BMS, Gilead Sciences, MSD/Merck, Humedics, Intercept, Merz, Sequana Medical. Receipt of honoraria or consultation fees or participation in a company sponsored speaker’s bureau: Abbvie, Alexion, Bayer, Gilead Sciences, GSK, Eisai, Intercept, Ipsen, Janssen, MSD/Merck, Novartis, and Spring Bank, Sequana Medica. PL: Advisory Board/Speaker Bureau for: - BMS, Roche, Gilead Sciences, GSK, Abbvie, MSD, Arrowhead, Alnylam, Janssen, Spring Bank, MYR, Eiger.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Acknowledgement

      We would like to thank Dr. Toni Herta for his help in designing the figure and Dr. Florian van Bömmel for carefully reading the manuscript and his helpful comments.

      Supplementary data

      The following is the supplementary data to this article:

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