Kinetics of hepatitis B surface antigen loss in patients with HBeAg-positive chronic hepatitis B treated with tenofovir disoproxil fumarate

Abstract

Background & aims: In a study of 266 chronic hepatitis B e antigen (HBeAg)-positive patients, 23 experienced hepatitis B surface antigen (HBsAg) loss with up to 5 years of tenofovir disoproxil fumarate (TDF) treatment. HBsAg kinetics in patients with and without HBsAg loss and predictors of HBsAg loss were evaluated.

Methods: HBsAg levels were quantified every 12 weeks. A multivariable regression analysis, involving prespecified baseline characteristics and on-treatment response parameters, was performed; a stepwise procedure identified independent predictors of HBsAg loss.

Results: Among patients with HBsAg loss, 14 (61%), 1 (4%), 0 and 7 (30%) were genotypes A through D, respectively; 1 (4%) was genotype F. HBsAg loss was preceded by viral suppression (HBV DNA <29 IU/ml; n=23) and HBeAg loss (n=19). Among treated patients the strongest independent predictors of HBsAg loss were Caucasian race with genotype A/D and ⩽4 years of infection (HR=14.3, 95% confidence interval [CI] 4.7-43.4; p<0.0001) and an HBsAg decline of ⩾1 log10 IU/ml at week 24 (HR=13.7, 95% CI 5.6-33.7; p<0.0001). Among TDF-treated patients, a reduction in HBsAg level of ⩾1-log10 by week 12 or 24 had a positive predictive value of 35%-45%, respectively, and a negative predictive value of 94%-97%, respectively.

Conclusions: HBsAg loss in HBeAg-positive patients receiving TDF involves a chronology of virologic and serologic responses; patients with HBV genotypes A or D and a rapid early decline in HBsAg are more likely to lose HBsAg.

Keywords: Chronic hepatitis B; Hepatitis B surface antigen; Tenofovir disoproxil fumarate.

Conflict of interest statement

Conflict of interest

Patrick Marcellin has received research grants from Hoffman-La Roche, Gilead Sciences, Inc., Bristol-Myers Squibb, Vertex Pharmaceuticals, Novartis Pharmaceuticals, Janssen/Tibotec, Merck, Boehringer Ingelheim, Abbott Laboratories, and Pfizer and has received financial compensation for consultancy and/or lecture activities from Hoffman-La Roche, Gilead Sciences, Inc., Bristol- Myers Squibb, Novartis Pharmaceuticals, Janssen/Tibotec, and Merck. Maria Buti has received research grants from Gilead Sciences, Inc. and served on advisory boards for Gilead Sciences, Inc. and Bristol-Myers Squibb. Zahari Krastev has received research grants from Gilead Sciences, Inc. Robert A. de Man has received research grants from Gilead Sciences, Inc. Stefan Zeuzem has received financial compensation for consultancy and/or lecture activities from Abbott Laboratories, Achillion, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead Sciences, Inc., Idenix, Janssen-Cilag, Merck, Novartis Pharmaceuticals, Presidio, Roche, Santaris, and Vertex Pharmaceuticals. Robert Flisiak has received financial compensation for consultancy and/or lecture activities from Gilead Sciences, Inc. Selim Gurel serves on the advisory board for Bristol-Myers Squibb, Merck, and Roche. Geoffrey M. Dusheiko has received research grants and financial compensation for consultancy activities from Bristol-Myers Squibb and Gilead Sciences, Inc. E. Jenny Heathcote has no commercial relationships to disclose. Anuj Gaggar, John F. Flaherty, Jr., Lillian Lou, Benedetta Massetto, Lanjia Lin, Phillip Dinh, G. Mani Subramanian, and John G. McHutchison are employees and stockholders of Gilead Sciences, Inc.

Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1. Time to loss of HBsAg (Kaplan-Meier estimate) and corresponding chronology of virologic and serologic responses in 23 HBeAg-positive patients who achieved HBsAg loss

(A) Time to loss of HBsAg by initial blinded treatment assignment. TDF-TDF and ADV-TDF correspond to subjects randomized to receive TDF or ADV, respectively, for the first 48 weeks of double-blind treatment, followed by open-label TDF through week 240. (B) Time to first confirmed virologic (HBV DNA

Fig. 2. Dynamics of change in plasma HBV DNA concentrations (log10 copies/ml), serum ALT levels (U/L), and serum HBsAg levels (log10 IU/ml) over 240 weeks

(A) Changes in HBV DNA (triangles), ALT (diamonds), and HBsAg (circles) levels in the 16 HBeAg-positive patients initially randomized to TDF (TDF-TDF). (B) Changes in the 7 HBeAg-positive patients initially randomized to ADV (ADV-TDF) who achieved HBsAg loss. (This figure appears in colour on the web.)

Fig. 2. Dynamics of change in plasma HBV DNA concentrations (log10 copies/ml), serum ALT levels (U/L), and serum HBsAg levels (log10 IU/ml) over 240 weeks

(A) Changes in HBV DNA (triangles), ALT (diamonds), and HBsAg (circles) levels in the 16 HBeAg-positive patients initially randomized to TDF (TDF-TDF). (B) Changes in the 7 HBeAg-positive patients initially randomized to ADV (ADV-TDF) who achieved HBsAg loss. (This figure appears in colour on the web.)

Fig. 3. Kinetics of HBsAg decline in relation to viral genotype

Included are results for 22 HBeAg-positive patients (genotype A [n = 14], B [n = 1], and D [n = 7] – closed circles) who achieved HBsAg loss and 224 HBeAg-positive patients (genotype A [n = 45], B [n = 34], C [n = 68], and D [n = 77] – open circles) who did not achieve loss of HBsAg over 240 weeks.