Tenofovir discontinuation after long-term viral suppression in HBeAg negative chronic hepatitis B. Can HBsAg levels be useful?

doi:10.1016/j.jcv.2015.05.002

Journal of Clinical Virology

Volume 68, July 2015, Pages 61-68

https://doi.org/10.1016/j.jcv.2015.05.002 Get rights and content

Highlights

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There is scarce data regarding treatment discontinuation in HBeAg-negative patients.
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We stopped TDF in 7 HBeAg negative patients after 7 years of viral suppression.
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62.5% presented sustained response after TDF discontinuation and 12.5% lost HBsAg.
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HBsAg kinetics could be useful to select patients for TDF discontinuation.

Abstract

Background

Recent studies have shown that antiviral treatment discontinuation is safe and associated with virologic remission in HBeAg-negative patients. However, the period of viral suppression and follow-up in these studies was relatively short.

Objectives

To investigate whether continuous viral suppression with tenofovir disoproxil fumarate for more than 7 years is associated with HBsAg loss and sustained response after treatment discontinuation and receiving a full course of hepatitis B vaccination.

Study design

Patients with HBeAg-negative chronic HBV infection and more than 7 years of persistent viral suppression with tenofovir therapy were selected for treatment discontinuation and HBV vaccination. Follow-up with monthly ALT, HBV–DNA, and HBsAg determinations lasted 72 weeks. In patients with viral relapse, the viral quasispecies in the overlapping reverse transcriptase and small surface protein regions was analysed by ultra-deep pyrosequencing.

Results

Eight of 17 HBeAg-negative patients accepted tenofovir discontinuation: 5 patients achieved sustained response (persistent HBV–DNA levels <2000 IU/mL and normal ALT) despite an initial virologic relapse, one lost HBsAg, and two needed re-treatment. All patients with an on-treatment HBsAg level decline >5000 IU/mL achieved sustained response. Patients with HBsAg level <100 IU/mL during an ALT flare after antiviral discontinuation achieved sustained response. Significant changes were seen in the composition of the HBV quasispecies, and half the patients showed changes in HBV genotype.

Conclusions

Even though the majority of patients presented an initial relapse with selection of HBV variants, most achieved sustained response. Changes in HBsAg levels on and off treatment may be useful for predicting the likelihood of virologic remission.

Section snippets

Background

Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus infection (CHB) is the predominant type of CHB in the Mediterranean area and many other regions of the world [1]. In the natural history of CHB, the HBeAg-negative phase represents a later immune-reactive phase and is characterized by periodic reactivation, with a pattern of fluctuating hepatitis B virus (HBV) DNA and alanine aminotransferase (ALT) levels [2]. In HBeAg-negative patients, there is a predominance of HBV virions with

Objectives

The aim of this study was to assess whether prolonged TDF treatment for more than 7 years is associated with a high rate of HBsAg loss and virologic remission after treatment discontinuation in HBeAg-negative patients. Morevoer, at the time of TDF discontinuation, patients received a full course of hepatitis B vaccination. The HBV quasispecies was studied in cases with virologic relapse.

Study design

This was a prospective observational study in HBeAg-negative CHB patients achieving persistent virologic suppression with TDF. The subjects included were recruited from Vall d’Hebron University Hospital and had been previously enrolled in a controlled clinical trial evaluating the efficacy of TDF (GS-Study 102) [14] in 2005. In that trial, participants were randomized to receive TDF or adefovir (ADV) once a day for 48 weeks. After 48 weeks of double-blind comparison of TDF vs ADV, patients

Characteristics of the study patients and outcome

The baseline characteristics of the 8 patients are shown in Table 1. None were coinfected with hepatitis delta virus, hepatitis C virus, or human immunodeficiency virus. All patients had significant liver fibrosis and 1 had liver cirrhosis. Five had been previously exposed to lamivudine (LAM). Three patients were randomized to receive ADV and 5 TDF for 48 weeks. Thereafter, all were treated with TDF for 7 years. During therapy, serum HBV–DNA became undetectable after a median of 18 weeks (IQR

Discussion

In this study, discontinuation of long-term TDF in HBeAg-negative CHB patients after prolonged suppression of viral replication was associated with SR in a considerable number of cases despite an initial virologic relapse. In a study with short-term therapy, treatment discontinuation after 2 years of LAM led to approximately 50% of relapses after 12 months of follow-up [24]. Hadziyannis et al. described a relapse rate of 100% after adefovir discontinuation in HBeAg-negative CHB [7].

Funding

This study was funded in full by Instituto de Salud Carlos III (grants PI11/01973 and PI12/01893), cofinanced by the European Regional Development Fund (ERDF).

Competing interest

Maria Buti and Rafael Esteban have received research grants from Gilead and have served as advisors for Gilead, Bristol–Myers Squibb and Novartis. Mar Riveiro-Barciela has received research grants from Gilead. The other authors have no personal interests to declare.

Ethical approval

All participants provided informed written consent, which included tenofovir discontinuation, acceptance of long-term observation and possible re-treatment.

Acknowledgement

English writing support was provided by Celine Cavallo.

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This process occurs more frequently in patients with low HBsAg levels (<100 IU/ml) at the time of stopping treatment. Still, it should be emphasized that relapse rates are substantial, and even patients without cirrhosis can experience ALT flares.57,61 Therefore, patients who stop therapy should be monitored for HBV DNA and ALT levels.
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HBV relapse is particularly common when administration of nucleoside analogues is interrupted. A recent report showed significant variations in the mutant spectrum of the HBV reverse transcriptase between baseline and treatment discontinuance, despite more than seven years of viral suppression (Buti et al., 2015a). Remarkably, half of the patients exhibited changes in the HBV genotype.
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However, stopping NA might be more complex than anticipated. Some studies suggest that HBV DNA rebounds shortly after NA cessation in most cases [93,95]. This may induce ALT flares [93,95] indicating immune responses, which may be the key for subsequent immune control and HBsAg loss [96].
In the past 10 years, there has been a lot of enthusiasm surrounding the use of serum hepatitis B surface antigen (HBsAg) quantification to predict disease activity and monitor treatment response in chronic hepatitis B. The measurement of HBsAg levels have been standardized in IU/ml, and nowadays it is almost a mandatory measurement due to the development of new antiviral treatments aiming at HBsAg seroclearance, i.e., functional cure of hepatitis B. Recently, there has been an improved understanding of the molecular virology of HBsAg, and particularly the relative roles of covalently closed circular DNA and integrated hepatitis B virus (HBV) DNA. This has shed new light on the interpretation of HBsAg levels in different phases of chronic hepatitis B. HBsAg level can assist the differentiation of immune tolerance and immune clearance in hepatitis B e antigen (HBeAg)-positive patients, and it can predict inactive disease and spontaneous HBsAg seroclearance in HBeAg-negative patients. The determination of HBsAg level is pivotal to individualize pegylated interferon (PegIFN) treatment; it is the key investigation to decide early termination of PegIFN among non-responders. Among patients treated by nucleos(t)ide analogues, responders tend to have dramatic reduction of HBsAg to low levels, which may be followed by HBsAg seroclearance. With newer data on combination treatment of PegIFN and nucleos(t)ide analogues as well as emerging new antiviral agents, HBsAg quantification is expected to become increasingly important to monitor and guide antiviral therapy for chronic hepatitis B.
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The Hong Kong ETV study also showed late relapse (71.8% at 24 weeks).10 Early relapse (within 3 months) also was observed in 6 of 8 HBeAg-negative patients treated with TDF for more than 7 years,14 and in 19 (90%) of the 21 patients who stopped TDF in an ongoing randomized controlled trial.15 The timing of relapse after cessation of the 2 other nucleoside analogues (LAM and LdT) was similar to that of the 2 nucleotide analogues ADV and TDF.7–9
Of the hepatitis B e antigen–negative chronic hepatitis B patients with more than 1 year of sustained hepatitis B virus (HBV) suppression during therapy, the 1-year clinical relapse rate after cessation of entecavir therapy was 45%, of which 25.6% occurred within 6 months. The events after cessation of another preferred drug tenofovir were investigated.
A retrospective-prospective study was conducted in 85 hepatitis B e antigen–negative chronic hepatitis B patients with sustained HBV suppression who had stopped tenofovir therapy and were monitored every 1 to 3 months for a median duration of 39 weeks (range, 4–133 wk).
Clinical relapse occurred in 38 patients, 57.9% and 86.8% within 3 and 6 months, respectively, with an estimated 1-year cumulative incidence of 52%. The optimal duration of therapy and consolidation therapy were calculated to be 3 and 2 years, respectively. Of the relapsers, 81.6% and 57.9% showed an alanine aminotransferase level greater than 5 and 10 times the upper limit of normal, respectively, 23.7% showed a bilirubin level of 2 mg/dL or greater, and 2 developed hepatic decompensation. Relapsers had significantly higher pretherapy baseline hepatitis B surface antigen level, more prior anti-HBV therapy experience, later alanine aminotransferase level normalization, and a shorter duration of treatment and consolidation therapy. Cox regression analyses showed that treatment for more than 3 years combined with consolidation therapy for more than 2 years was an independent significant manageable factor of clinical relapse (adjusted hazard ratio, 0.387; P = .008). With this combination, the clinical relapse rate was reduced to 30%.
Clinical relapses occurred mostly within 6 months, with high alanine aminotransferase and serum bilirubin levels. Closer monitoring, monthly in the first 3 to 6 months, with timely re-treatment is mandatory for a safe cessation of tenofovir therapy.
A switch from tenofovir to entecavir prior to hepatitis B treatment cessation is associated with a reduced risk of off-therapy relapse: An observational study
2022, Journal of Gastroenterology and Hepatology (Australia)
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View full text

Tenofovir discontinuation after long-term viral suppression in HBeAg negative chronic hepatitis B. Can HBsAg levels be useful?

Highlights

Abstract

Background

Objectives

Study design

Results

Conclusions

Section snippets

Background

Objectives

Study design

Characteristics of the study patients and outcome

Discussion

Funding

Competing interest

Ethical approval

Acknowledgement

J. Hepatol.

J. Hepatol.

J. Hepatol.

Gastroenterology

Gastroenterology

Antivir. Res.

J. Hepatol.

Gastroenterology

J. Hepatol.

J. Clin. Virol.

J. Hepatol.

The natural history of chronic HBV infection and geographical differences

Antivir. Ther.

Hepatitis B. e antigen-negative chronic hepatitis B: natural history and treatment

Semin. Liver Dis.

EASL clinical practice guidelines: Management of chronic hepatitis B virus infection

J Hepatol.

Chronic hepatitis B: update 2009

Hepatology

Renal tubular dysfunction during long-term adefovir or tenofovir therapy in chronic hepatitis B

Aliment Pharmacol. Ther.

Asian Pacific association for the study of the liver consensus recommendations on hepatocellular carcinoma

Hepatol. Int.