Elsevier

Journal of Hepatology

Volume 67, Issue 5, November 2017, Pages 918-924
Journal of Hepatology

Research Article
Long-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients – FINITE study

https://doi.org/10.1016/j.jhep.2017.07.012Get rights and content

Highlights

  • The potential to discontinue tenofovir disoproxil fumarate (TDF) therapy in HBeAg-negative patients was investigated.

  • Of the patients who stopped TDF therapy, 62% remained off-therapy to Week 144.

  • Four patients (19%) achieved HBsAg loss and three of them achieved HBsAg seroconversion.

  • Discontinuing TDF therapy was well-tolerated.

  • There is potential for HBsAg loss and/or sustained virological response in non-cirrhotic HBeAg-negative patients stopping long-term TDF therapy.

Background & Aims

There is currently no virological cure for chronic hepatitis B but successful nucleos(t)ide analogue (NA) therapy can suppress hepatitis B virus (HBV) DNA replication and, in some cases, result in HBsAg loss. Stopping NA therapy often leads to viral relapse and therefore life-long therapy is usually required. This study investigated the potential to discontinue tenofovir disoproxil fumarate (TDF) therapy in HBeAg-negative patients.

Methods

Non-cirrhotic HBeAg-negative patients who had received TDF for ≥4 years, with suppressed HBV DNA for ≥3.5 years, were randomly assigned to either stop (n = 21) or continue (n = 21) TDF monotherapy. Standard laboratory tests including HBV DNA viral load, HBsAg and alanine aminotransferase (ALT) measurements, and adverse event reporting were carried out during treatment and post-treatment follow-up for 144 weeks.

Results

Of the patients who stopped TDF therapy, 62% (n = 13) remained off-therapy to Week 144. Median HBsAg change in this group was −0.59 log10 IU/ml (range −4.49 to 0.02 log10 IU/ml) vs. 0.21 log10 IU/ml in patients who continued TDF therapy. Four patients (19%) achieved HBsAg loss. Patients stopping therapy had initial fluctuations in viral load and ALT; however, at Week 144, 43% (n = 9) had either achieved HBsAg loss or had HBV DNA <2,000 IU/ml. There were no unexpected safety issues identified with stopping TDF therapy.

Conclusions

This controlled study demonstrated the potential for HBsAg loss and/or sustained virological response in non-cirrhotic HBeAg-negative patients stopping long-term TDF therapy.

Lay summary: Nucleos(t)ide analogue (NA) is usually a life-long therapy for HBV patients. This randomised controlled study investigated the discontinuation of tenofovir disoproxil fumarate (TDF) therapy in HBeAg-negative patients. Of the patients who stopped TDF therapy, 62% remained off-therapy to Week 144, of which 43% of patients had achieved either HBsAg loss or HBV DNA <2,000 IU/ml. This offers a potential for long-term HBV-suppressed patients without cirrhosis to stop NA therapy under strict surveillance.

Clinical trial number: NCT01320943.

Introduction

Although there is currently no cure for chronic hepatitis B virus (HBV) infection, the virus can be effectively controlled with current antiviral treatment strategies using either interferon (IFN) or nucleos(t)ide analogues (NA). Treatment for chronic HBV therefore aims to provide sustained suppression of viral replication, thus lessening the risk of fibrosis progression and decreasing the risk of hepatocellular carcinoma (HCC).1 The ideal endpoint of treatment for hepatitis B ‘e’ antigen (HBeAg)-positive patients is HBeAg seroconversion; this is sometimes followed by hepatitis B surface antigen (HBsAg) loss, which is considered to be the closest to clinical cure of chronic HBV infection. In contrast, the only endpoint defined for HBeAg-negative patients is HBsAg loss. As this is rarely achieved with the currently available agents, life-long therapy is usually required in HBeAg-negative patients.[1], [2], [3], [4]

The concept of perpetual therapy is not an ideal option for many patients when considering life-long pill burden and safety concerns for women of childbearing age.5 Therefore, studies are now striving for cure of chronic HBV infection, and to define a finite treatment strategy with a focus on increased rates of HBsAg loss. The most promising data published to date are from Hadziyannis et al. who showed that, in HBeAg-negative patients, adefovir dipivoxil (ADV) could be discontinued 4–5 years after initiating therapy in patients who had sustained viral suppression.6 In this study, 55% of patients had a sustained response (HBV DNA <2,000 IU/L and normal alanine aminotransferase [ALT] levels) and 39% experienced HBsAg loss during the 5.5-year follow-up after stopping treatment. However, other studies have shown that the response is not durable following treatment discontinuation.[7], [8], [9] This is the first randomised study to investigate the potential to discontinue tenofovir disoproxil fumarate (TDF) therapy in non-cirrhotic HBeAg-negative patients who had been virally suppressed for at least 3.5 years and had been receiving TDF for at least 4 years.

Section snippets

Study design

In this randomised, open-label, multicentre, controlled study (NCT01320943), patients were randomly assigned 1:1 to either stop (arm A) or continue (arm B) TDF monotherapy. All patients were followed up to Week 144. For patients in arm A, clinical visits occurred every 2 weeks in the first 3 months, every 4 weeks until Week 48 and every 12 weeks thereafter until Week 144. Patients in arm B had clinical visits at Weeks 4 and 12, and every 12 weeks thereafter until Week 144.

Patients in arm A, with at

Results

Of the 44 patients included in the study, two withdrew consent before randomisation, 21 were randomised to arm A (stop-TDF therapy) and 21 patients randomised to arm B (continue TDF therapy) (Fig. 1).

The demographic and baseline clinical characteristics were generally balanced between the two treatment groups (Table 1). The majority of the patients enrolled were male (78.6%), white (88.1%) and with a mean age of 44.7 years. HBV genotyping was possible in 17 patients (15 in arm A and two in arm

Discussion

In this first controlled study of stopping TDF therapy in HBeAg-negative patients without advanced liver disease, rates of HBsAg loss were significantly higher in patients who discontinued TDF therapy for 144 weeks than in those who continued TDF therapy. Four patients who discontinued TDF therapy achieved HBsAg loss and three of them achieved HBsAg seroconversion compared with none of the patients that continued TDF therapy. Although there were clear fluctuations in HBV DNA levels and ALT

Financial support

This study was funded by Gilead Sciences, Inc who also supported the collection and analysis of data.

Conflict of interest

Thomas Berg: Grants and personal fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Bayer, Vertex, Tibotec, Intercept, Merck Sharp & Dohme, and Roche.

Karl-Georg Simon: Consultant for AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharp & Dohme and Roche. Lecturer for AbbVie, Gilead Sciences, Janssen, Falk Foundation, Merz, Norgine and Merck Sharp & Dohme.

Stefan Mauss: Grant and research support from AbbVie. Honoraria or consultation fees from AbbVie, Bristol-Myers

Authors’ contributions

The study was designed and conducted according to the protocol by the sponsor (Gilead Sciences) in collaboration with the principal investigators. The sponsor collected the data, monitored the study conduct and performed the statistical analyses. All authors were involved in data acquisition and analysis, interpretation of the data, and contributed to drafting the manuscript and critical revision of the manuscript with regards to important intellectual content. All authors approved the final

Acknowledgements

Medical writing support was provided by Claire Demenis, Ph.D. (Elements Communications Ltd, Westerham, UK), funded by Gilead Sciences, Inc.

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