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Impact of early viral kinetics on T-cell reactivity during antiviral therapy in chronic hepatitis B.

AbstractBACKGROUND:
The patterns of hepatitis B viral dynamics during different antiviral therapies and the associated changes in HBV-specific T-cell reactivity are not well defined.
METHODS:
We investigated the impact of early viral load decline on virus-specific T-cell reactivity in 30 hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B randomized to monotherapy with adefovir dipivoxil (ADV) or in combination with emtricitabine (ADV/FTC). Viral kinetics were analysed by mathematical modelling. T-cell reactivity to HBV core and/or surface antigens and natural killer T cell frequency were tested longitudinally, baseline to week 48, using EliSPOT assays and/or flow cytometry.
RESULTS:
Mathematical modelling of early HBV kinetics identified two subsets of patients: 11 fast responders (undetectable viraemia by week 12; eight on ADV/FTC three on ADV) and 19 slow responders who remained viremic (six on ADV/FTC 13 on ADV). The rate of infected hepatocyte loss was higher in fast than in slow responders (P = 0.0007), and correlated inversely with pre-treatment levels of intrahepatic covalently closed circular HBV DNA. The frequency of HBV core-specific CD4+ T-cells increased significantly only in fast responders, peaking between week 16 and 24, while the HBV surface-specific CD4+ T-cells increased in both subsets. These changes in CD4+ T-cell reactivity were transient however, and no increase in HBV-specific CD8+ T-cells was observed. By week 48, HBeAg seroconversion occurred only in 3/30 (10%) patients.
CONCLUSIONS:
Early viraemia clearance facilitates recovery of virus-specific CD4+ T-cell reactivity, but appears insufficient to establish clinically relevant antiviral immunity.
AuthorsGeorge K K Lau, Helen Cooksley, Ruy M Ribeiro, Kimberly A Powers, Emi Shudo, Scott Bowden, Chee-Kin Hui, Jane Anderson, Jeff Sorbel, Elsa Mondou, Franck Rousseau, Sharon Lewin, Alan S Perelson, Stephen Locornini, Nikolai V Naoumov
JournalAntiviral therapy (Antivir Ther) Vol. 12 Issue 5 Pg. 705-18 ( 2007) ISSN: 1359-6535 [Print] England
PMID17713154 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Antiviral Agents
  • DNA, Viral
  • Hepatitis B Antibodies
  • Hepatitis B Antigens
  • Organophosphonates
  • Deoxycytidine
  • Emtricitabine
  • Adenine
  • adefovir dipivoxil
Topics
  • Adenine (analogs & derivatives, pharmacology, therapeutic use)
  • Adult
  • Antiviral Agents (pharmacology, therapeutic use)
  • DNA, Viral (biosynthesis, drug effects)
  • Deoxycytidine (analogs & derivatives, pharmacology, therapeutic use)
  • Double-Blind Method
  • Drug Therapy, Combination
  • Emtricitabine
  • Female
  • Hepatitis B Antibodies (blood)
  • Hepatitis B Antigens (immunology)
  • Hepatitis B virus (drug effects, genetics, growth & development, immunology)
  • Hepatitis B, Chronic (drug therapy, genetics, immunology)
  • Hepatocytes (drug effects, virology)
  • Humans
  • Immunity, Cellular
  • Kinetics
  • Male
  • Middle Aged
  • Models, Immunological
  • Organophosphonates (pharmacology, therapeutic use)
  • T-Lymphocytes (drug effects, virology)
  • Treatment Outcome
  • Viral Load
  • Viremia (drug therapy, genetics, immunology, virology)
  • Virus Replication (drug effects)

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