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Covalently closed-circular hepatitis B virus DNA reduction with entecavir or lamivudine
Bowden S et al.
cccDNA reduction with entecavir or lamivudine Scott Bowden, Stephen Locarnini, Ting-Tsung Chang, You-Chen Chao, Kwang-Hyub Han, Robert G Gish, Robert A de Man, Miao Yu, Cyril Llamoso, Hong Tang
Scott Bowden, Stephen Locarnini,
Victorian Infectious Diseases Reference Laboratory, Victoria 3000, Australia
Ting-Tsung Chang,
Division of Gastroenterology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan City 704, Taiwan
You-Chen Chao,
Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
Kwang-Hyub Han,
Division of Gastroenterology, Department of Internal Medicine, Severance Hospital of Yonsei University, Seoul 120-752, South Korea
Robert G Gish, Robert G Gish,
Consultants LLC, San Diego, CL 92037, United States
Robert G Gish,
St Joseph’s Hospital and Medical Center, Phoenix, AR 85013, United States
Robert G Gish,
Hepatitis B Foundation, Doylestown, PE 18902, United States
Robert A de Man,
Department of Gastroenterology and Hepatology, Room H375, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands
Miao Yu, Cyril Llamoso, Bristol-Myers Squibb,
Research and Development, 5 Research Pkwy, Wallingford Center, Wallingford, CO 06492, United States
Hong Tang, Bristol-Myers Squibb,
Research and Development, Princeton, Northbrook, IL 60062, United States
Author contributions:
Bowden S, Locarnini S, Gish RG, Llamoso C and Tang H developed the study concept and design; Bowden S, Chang TT, Chao YC, Han KH, Gish RG, de Man RA and Llamoso C carried out data acquisition; Bowden S, Gish RG, Yu M, Llamoso C and Tang H analysed and interpreted the data; statistical interpretation of the data was performed by Gish RG, Yu M, Llamoso C and Tang H. Bowden S, Gish RG, Llamoso C and Tang H provided technical support; The manuscript was drafted by Bowden S, Locarnini S, Gish RG, de Man RA, Llamoso C and Tang H critical revision of the manuscript was performed by all authors; Bowden S, Locarnini S, Chang TT, Chao YC, Han KH, Gish RG and Llamoso C supervised the study.
Supported by
Bristol-Myers Squibb.
Open-Access:
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Scott Bowden, PhD,
Victorian Infectious Diseases Reference Laboratory, 792 Elizabeth Street, Melbourne, Victoria 3000, Australia. [email protected]
Telephone: +61-3-93429615
Fax: +61-3-93429696
Received:
September 8, 2014
Peer-review started:
September 9, 2014
First decision:
October 14, 2014
Revised:
December 22, 2014
Accepted:
January 16, 2015
Article in press: Published online:
Abstract AIM:
To investigate the reduction in hepatitis B virus (HBV) covalently closed-circular DNA (cccDNA) with entecavir (ETV) or lamivudine (LAM).
MATERIALS:
This analysis included patients who had participated in the randomized Phase III study ETV-022 comparing ETV vs LAM in nucleos(t)ide-naive, HBeAg-positive patients. Patients received ETV (0.5 mg daily) or LAM (100 mg daily) for a minimum of 52 weeks. Patients were eligible to participate in this sub-study if they had paired biopsies at baseline and week 48 with evaluable measurements for hepatic HBV cccDNA and total hepatic HBV DNA. The main objective was to compare changes in hepatic HBV cccDNA and total hepatic HBV DNA at week 48 of ETV or LAM treatment, which was a secondary endpoint of study ETV-022. Additional post hoc analyses included linear regression analyses to assess associations of baseline levels and on-treatment changes of cccDNA with other baseline factors [sex, age, serum HBV DNA, alanine aminotransferase (ALT), Knodell necroinflammatory score, Ishak fibrosis score, total hepatic HBV DNA, and HBV genotype], or on-treatment factors (changes from baseline at week 48 in serum HBV DNA, ALT, Knodell necroinflammatory score, Ishak fibrosis score, total hepatic HBV DNA, and HBeAg loss at week 48).
RESULTS:
Overall, 305 patients (ETV: 159; LAM: 146) of ETV-022 had paired baseline and Week 48 liver biopsies with evaluable measurements for hepatic HBV cccDNA and total hepatic HBV DNA, and were included in this analysis. Baseline demographics and disease characteristics were comparable between the two arms. After 48 wk, ETV resulted in significantly greater reductions in hepatic HBV cccDNA (–0.9 log10 copies/human genome equivalent [HGEq] versus –0.7 log
10 copies/HGEq; P = 0.0033) and total hepatic DNA levels (–2.1 log10
copies/HGEq versus –1.6 log 10 copies/HGEq < 0.0001) than LAM. Virologic, biochemical, and histologic response rates at Week 48 were also greater with ETV than with LAM. Baseline HBV cccDNA levels were positively associated with baseline levels of serum HBV DNA and total hepatic HBV DNA, and negatively associated with HBV genotype F. On-treatment changes in HBV cccDNA levels were negatively associated with baseline levels of serum HBV DNA and baseline ALT, and were positively associated with on-treatment changes in the levels of serum HBV DNA, total hepatic HBV DNA levels, and ALT, change in Knodell necroinflammatory score, and HBeAg loss.
CONCLUSION:
Forty-eight weeks of ETV resulted in greater reductions in cccDNA and total hepatic HBV DNA than LAM, but long-term therapy may be needed for cccDNA elimination.
Key words:
Hepatitis B virus; Nucleos(t)ide analog therapy; Intrahepatic HBV DNA; Antiviral suppression; Virologic cure
© The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
Core tip:
In chronic hepatitis B, persistence of hepatitis B virus (HBV) infection is due to an intrahepatic pool of stable, HBV covalently closed-circular DNA (cccDNA), whose elimination is a limiting factor in anti-HBV treatment. This study shows that 48 wk of treatment with entecavir resulted in a greater reduction of
hepatic HBV cccDNA and total hepatic HBV DNA than lamivudine. However, cccDNA was still detectable in most biopsies.
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发表于 2015-2-5 20:01
