Research ArticleLong-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients – FINITE study☆
Graphical abstract
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.
References (23)
- et al.
Long-term follow-up of patients with anti-HBe/HBV DNA-positive chronic hepatitis B treated for 12 months with lamivudine
J Hepatol
(2000) - et al.
Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5- year open-label follow-up study
Lancet
(2013) - et al.
The role of hepatitis B surface antigen quantification in predicting HBsAg loss and HBV relapse after discontinuation of lamivudine treatment
J Hepatol
(2014) - et al.
Hepatitis B flares in chronic hepatitis B: pathogenesis, natural course, and management
J Hepatol
(2014) - et al.
Effect on HBs antigen clearance of addition of pegylated interferon alfa-2a to nucleos(t)ide analogue therapy vs. nucleos(t)ide analogue therapy alone in patients with HBe antigen-negative chronic hepatitis B and sustained undetectable plasma hepatitis B virus DNA: a randomised, controlled, open-label trial
Lancet Gastroenterol Hepatol
(2017) - et al.
Switching from entecavir to PegIFN alfa-2a in patients with HBeAg-positive chronic hepatitis B: A randomised open-label trial (OSST trial)
J Hepatol
(2014) EASL Clinical Practice Guidelines: management of hepatitis B virus infection
J Hepatol
(2017)- et al.
Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012 update
Hepatol Int
(2012) - et al.
Chronic hepatitis B
Hepatology
(2007) - et al.
Chronic hepatitis B: update 2009
Hepatology
(2009)
Safety of long-term nucleos(t)ide treatment in chronic hepatitis B
Expert Opin Drug Saf
Cited by (224)
Sustained response and HBsAg loss after nucleo(s)tide analogue discontinuation in chronic hepatitis B patients: the prospective SNAP study
2024, Clinics and Research in Hepatology and GastroenterologyStopping nucleos(t)ide analogues treatment in non-cirrhotic HBeAg-negative patients: Yes, we can!
2023, Digestive and Liver Disease
- ☆
Guest Editor: Didier Samuel.