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Antimicrobial Agents and Chemotherapy, January 2008, p. 312-320, Vol. 52, No. 1
0066-4804/08/$08.00+0     doi:10.1128/AAC.00467-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Hepatitis B Virus e Antigen Loss during Adefovir Dipivoxil Therapy Is Associated with Enhanced Virus-Specific CD4⁺ T-Cell Reactivity

Helen Cooksley,^1, Shilpa Chokshi,^1, Yafit Maayan,² Heiner Wedemeyer,³ Pietro Andreone,⁴ Richard Gilson,⁵ Thomas Warnes,⁶ Simona Paganin,⁷ Fabien Zoulim,⁸ David Frederick,⁹ Avidan U. Neumann,² Carol L. Brosgart,⁹ and Nikolai V. Naoumov^1*

Institute of Hepatology, University College London, London WC1E 6HX, England,¹ Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel,² Department of Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany,³ Department of Medicine, University of Bologna, Bologna, Italy,⁴ Department of Sexually Transmitted Diseases, University College London, London, England,⁵ Manchester Royal Infirmary, Manchester, England,⁶ Department of Medicine, University of Turin, Turin, Italy,⁷ INSERM U871, Universite Lyon 1, IFR62 Laennec, Hospices Civils de Lyon, Lyon, France,⁸ Gilead Sciences, Inc., Foster City, California⁹

Received 4 April 2007/ Returned for modification 10 July 2007/ Accepted 25 October 2007

Weak T-cell reactivity to hepatitis B virus (HBV) is thought to be the dominant cause for chronic HBV infection. Treatment with adefovir dipivoxil (ADV) increases the rate of HBV e antigen (HBeAg) loss; however, the immune mechanisms associated with this treatment response are not understood. Serial analysis of HBV-specific CD4⁺ T-cell reactivity was performed during 48 weeks of therapy with ADV and correlated with treatment outcome for 19 HBeAg-positive patients receiving ADV (n = 13) or the placebo (n = 6). We tested T-cell reactivity to HBV at seven protocol time points by proliferation, cytokine production, and enzyme-linked immunospot assays. A panel of serum cytokines was quantitated by cytokine bead array. ADV-treated patients showed increased CD4⁺ T-cell responses to HBV and lower serum levels of cytokines compared to those of placebo-treated patients. Enhanced CD4⁺ T-cell reactivity to HBV, which peaked at treatment week 16, was confined to a subgroup of ADV-treated patients who achieved greater viral suppression (5.3 ± 0.3 log₁₀ copies/ml [mean ± standard error of the mean {SEM}] serum HBV DNA reduction from baseline) and HBeAg loss, but not to ADV-treated patients with moderate (3.4 ± 0.2 log₁₀ copies/ml [mean ± SEM]) viremia reduction who remained HBeAg positive or to patients receiving the placebo. In conclusion, T-cell reactivity to HBV increases in a proportion of ADV-treated patients and is associated with greater suppression of HBV replication and HBeAg loss.

Published ahead of print on 5 November 2007.

These authors contributed equally to this work.