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Entecavir plus tenofovir combination therapy for chronic hepatitis B in patients with previous nucleos(t)ide treatment failure

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Abstract

Background and aims

In patients with chronic hepatitis B (CHB) who have failed on other nucleos(t)ide analogs (NUCs), the combination of entecavir (ETV) plus tenofovir disoproxil fumarate (TDF), two potent agents with non-overlapping resistance profiles, may provide a single rescue regimen.

Methods

In this single-arm, open-label study, 92 CHB patients with a primary non-response, partial response, or virologic breakthrough on their current NUC were switched to ETV (1 mg) plus TDF (300 mg) and treated for 96 weeks.

Results

At baseline, 62 % of patients were HBeAg(+) and mean HBV DNA was 4.4 log10IU/mL. Patients had received ≥1 line of prior NUC therapy, with the latest regimen consisting of monotherapy with ETV (53 %), lamivudine (LVD 22 %), TDF (12 %), adefovir (ADV 4 %), or telbivudine (2 %), or combinations of these agents (7 %); 58 % had evidence of single- or multidrug resistance mutations (LVD 52 %, ETV 26 %; ADV 7 %). Response rates for HBV DNA <50 IU/mL were 76 % (70/92) at week 48 (primary endpoint), and 85 % (78/92) at week 96, including 80 % (16/20) in prior LVD failures, 100 % (4/4) in ADV failures, 82 % (9/11) in TDF failures, and 88 % (42/48) in ETV failures. No treatment-emergent resistance to ETV or ADV was observed. ETV/TDF was well tolerated, with no significant renal or additive toxicities observed.

Conclusions

In NUC-experienced patients who have failed prior NUC therapy, ETV/TDF was well tolerated and effective, achieving virologic suppression through 96 weeks in the majority (85 %), irrespective of prior NUC exposure, without occurrence of treatment-emergent resistance to either agent.

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Acknowledgements

The authors thank all principal investigators involved in this study: Gioacchino Angarano, Victoria Arama, Christoph Berg, Xavier Causse, Robert De Knegt, Christoph Eisenbach, Robert Galle, Maciej Jabłkowski, Dominique Larrey, Stefan Luth, Hendrik W Reesink, Eckart Schott, Adrian Streinu-Cercel, Andreas Umgelter, Bart Van Hoek, and Stefan Zeuzem, as well as Aleksandra Kedzierska from Bristol-Myers Squibb.

Author information

Authors and Affiliations

  1. Hepatology Department, Hospices Civils de Lyon, INSERM U1052, INSERM, Lyon University, 151 Cours Albert Thomas, 69424, Lyon Cedex 03, France

    Fabien Zoulim

  2. Department of Infectious and Liver Diseases, Medical University of Lodz, Lodz, Poland

    Jolanta Białkowska-Warzecha

  3. Centre of Gastroenterology and Hepatology, Fundeni Clinical Institute, Bucharest, Romania

    Mircea Mihai Diculescu

  4. Clinic of Gastroenterology, University of Medicine, Timisoara, Romania

    Adrian Eugen Goldis

  5. Leberzentrum Checkpoint, Berlin, Germany

    Renate Heyne

  6. Department of Gastroenterology and Hepatology, Jagiellonian University, Krakow, Poland

    Tomasz Mach

  7. Hôpital Beaujon, Assistance Publique–Hôpitaux de Paris, University of Paris 7, Paris, France

    Patrick Marcellin

  8. INSERM Unité 773, Centre de Recherches Claude Bernard sur les Hépatites Virales, Clichy, France

    Patrick Marcellin

  9. IFI Institute for Interdisciplinary Medicine, Asklepios Klinik St Georg, Hamburg, Germany

    Jörg Petersen

  10. Division of Infectious Diseases and Hepatology, Wrocław Medical University, Wrocław, Poland

    Krzysztof Simon

  11. Bristol-Myers Squibb, Braine-I’Alleud, Belgium

    Soumaya Bendahmane

  12. Bristol-Myers Squibb, Paris, France

    Isabelle Klauck

  13. inVentiv Health Clinical Poland, Warsaw, Poland

    Wojciech Wasiak

  14. Department of Gastroenterology and Hepatology, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands

    Harry L. A. Janssen

  15. Liver Clinic, Toronto Western and General Hospital, University Health Network, Toronto, Canada

    Harry L. A. Janssen

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  1. Fabien Zoulim
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  2. Jolanta Białkowska-Warzecha
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Corresponding author

Correspondence to Fabien Zoulim.

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Declaration of funding

The study was sponsored by Bristol-Myers Squibb. The study was designed and conducted by the sponsor in collaboration with the principal investigators. The sponsor collected the data, monitored study conduct, and performed the statistical analyses. All authors had access to the study data, and have reviewed and approved the final manuscript. Editorial assistance was provided by Isabelle Kaufmann of Articulate Science UK, and was supported by a grant from Bristol-Myers Squibb.

Conflict of interest

Fabien Zoulim has received consulting, lecture fees or research grants from Assembly Bioscience, Bristol-Myers Squibb, Gilead Sciences, Janssen, Novira, Roche, and Tekmira. Patrick Marcellin has received grants and research support from Bristol-Myers Squibb, and participated as a speaker and in advisory boards for Bristol-Myers Squibb. Jörg Petersen has received research grants from Bristol-Myers Squibb, Novartis, and Roche, and has received personal fees from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Novartis, and Roche. Krzysztof Simon has received lecturing fees and has participated in advisory boards for AbbVie, Alfa Wassermann, Bristol-Myers Squibb, Gilead, Janssen, MSD, and Roche-Poland. Wojciech Wasiak is an employee of inVentiv Health Clinical. Harry L. A. Janssen has received consulting fees and research grants from Anadys, Bristol-Myers Squibb, Gilead Sciences, Innogenetics, Kirin, Merck, Medtronic, Novartis, Roche, and Santaris. Soumaya Bendahmane and Isabelle Klauck are employees of Bristol-Myers Squibb. Jolanta Białkowska-Warzecha, Mircea Mihai Diculescu, Adrian Eugen Goldis, Renate Heyne, and Tomasz Mach have nothing to declare.

Informed consent

Informed consent was obtained from all patients. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki, as reflected in a priori approval by the institution’s human research committee.

Additional information

Study registration number: NCT01063036.

Electronic supplementary material

Below is the link to the electronic supplementary material.

12072_2016_9737_MOESM1_ESM.pdf

Supplementary Table 1: Baseline HBV variants detected in patients with failure on prior ETV therapy. Supplementary Table 2: Baseline and on-treatment characteristics of the six patients with HBV DNA ≥50 IU/mL at week 96 of ETV/TDF. Supplementary Table 3: Baseline and on-treatment characteristics of the seven patients with primary non-response and/or virologic breakthrough on ETV/TDF (PDF 133 kb)

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Zoulim, F., Białkowska-Warzecha, J., Diculescu, M.M. et al. Entecavir plus tenofovir combination therapy for chronic hepatitis B in patients with previous nucleos(t)ide treatment failure. Hepatol Int 10, 779–788 (2016). https://doi.org/10.1007/s12072-016-9737-2

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  • DOI: https://doi.org/10.1007/s12072-016-9737-2

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