Hepatitis B virus-specific T cells associate with viral control upon nucleos(t)ide-analogue therapy discontinuation

Laura Rivino, Nina Le Bert, Upkar S Gill, Kamini Kunasegaran, Yang Cheng, Damien Zm Tan, Etienne Becht, Navjyot K Hansi, Graham R Foster, Tung-Hung Su, Tai-Chung Tseng, Seng Gee Lim, Jia-Horng Kao, Evan W Newell, Patrick Tf Kennedy, Antonio Bertoletti

Research output: Contribution to journalArticle (Academic Journal)peer-review

112 Citations (Scopus)


BACKGROUND: The clinical management of chronic hepatitis B virus (HBV) patients is based exclusively on virological parameters that cannot independently determine in which patients nucleos(t)ide-analogue (NUC) therapy can be safely discontinued. NUCs efficiently suppress viral replication, but do not eliminate HBV. Thus, therapy discontinuation can be associated with virological and biochemical relapse and, consequently, therapy in the majority is life-long.

METHODS: Since antiviral immunity is pivotal for HBV control, we investigated potential biomarkers for the safe discontinuation of NUCs within immune profiles of chronic HBV patients by utilizing traditional immunological assays (ELISPOT, flow cytometry) in conjunction with analyses of global non-antigen-specific immune populations (NanoString and CyTOF). Two distinct cohorts of 19 and 27 chronic HBV patients, respectively, were analyzed longitudinally prior to and after discontinuation of 2 different NUC therapy strategies.

RESULTS: Absence of hepatic flares following discontinuation of NUC treatment correlated with the presence, during NUC viral suppression, of HBV core and polymerase-specific T cells that were contained within the ex vivo PD-1+ population.

CONCLUSIONS: This study identifies the presence of functional HBV-specific T cells as a candidate immunological biomarker for safe therapy discontinuation in chronic HBV patients. Furthermore, the persistent and functional antiviral activity of PD-1+ HBV-specific T cells highlights the potential beneficial role of the expression of T cell exhaustion markers during human chronic viral infection.

FUNDING: This work was funded by a Singapore Translational Research Investigator Award (NMRC/STaR/013/2012), the Eradication of HBV TCR Program (NMRC/TCR/014-NUHS/2015), the Singapore Immunology Network, the Wellcome Trust (107389/Z/15/Z), and a Barts and The London Charity (723/1795) grant.

Original languageEnglish
Pages (from-to)668-681
Number of pages14
JournalJournal of Clinical Investigation
Issue number2
Early online date8 Jan 2018
Publication statusPublished - 1 Feb 2018


  • Adult
  • Aged
  • Antiviral Agents/therapeutic use
  • Biomarkers/metabolism
  • CD4-Positive T-Lymphocytes/cytology
  • CD8-Positive T-Lymphocytes/cytology
  • Cell Separation
  • Cohort Studies
  • Female
  • Hepatitis B virus
  • Hepatitis B, Chronic/blood
  • Humans
  • Lamivudine/therapeutic use
  • Leukocytes, Mononuclear/cytology
  • Male
  • Middle Aged
  • T-Lymphocytes/cytology
  • Tenofovir/therapeutic use


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