Clinical Trials Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Cases. Oct 6, 2022; 10(28): 10085-10096
Published online Oct 6, 2022. doi: 10.12998/wjcc.v10.i28.10085
One hundred and ninety-two weeks treatment of entecavir maleate for Chinese chronic hepatitis B predominantly genotyped B or C
Jing-Hang Xu, Sa Wang, Da-Zhi Zhang, Yan-Yan Yu, Chong-Wen Si, Zheng Zeng, Zhong-Nan Xu, Jun Li, Qing Mao, Hong Tang, Ji-Fang Sheng, Xin-Yue Chen, Qin Ning, Guang-Feng Shi, Qing Xie, Xi-Quan Zhang, Jun Dai
Jing-Hang Xu, Yan-Yan Yu, Chong-Wen Si, Zheng Zeng, Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Beijing 100094, China
Sa Wang, Clinical and Research Center of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
Da-Zhi Zhang, Department of Infectious Diseases, The Second Affiliated Hospital with Chongqing Medical University, Chongqing 400010, China
Zhong-Nan Xu, Xi-Quan Zhang, Jun Dai, Jiangsu Chia-tai Tianqing Pharmaceutical Co., Ltd, Nanjing 222006, Jiangsu Province, China
Jun Li, Department of Infectious Diseases, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
Qing Mao, Department of Infectious Diseases, Southwest China Hospital, Chongqing 400038, China
Hong Tang, Department of Infectious Diseases, West China Hospital, Chengdu 610041, Sichuan Province, China
Ji-Fang Sheng, Department of Infectious Diseases, The First Affiliated Hospital of Zhejiang University, Hangzhou 310010, Zhejiang Province, China
Xin-Yue Chen, Department of International Medicine, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
Qin Ning, Department and Institute of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
Guang-Feng Shi, Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China
Qing Xie, Department of Infectious Diseases, Ruijin Hospital, Jiaotong University School of Medicine, Shanghai 200025, China
Author contributions: Yu YY, Si CW, Dai J, Zhang XQ, and Xu ZN designed the study; Xu JH, Wang S, Zeng Z, Li J, Mao Q, Zhang DZ, Tang H, Sheng JF, Chen XY, Ning Q, Shi GF, and Xie Q collected data; Xu JH, Wang S, and Zhang DZ analyzed and interpreted the data and wrote the manuscript; Yu YY approved the final manuscript; Si CW supervised the study; all authors had full access to the final version of the report and agreed to the submission.
Institutional review board statement: The study was reviewed and approved by the Ethics Committee of Peking University First Hospital (Approval No. 2008-clinical trial-56).
Clinical trial registration statement: This study is registered at https://clinicaltrials.gov/ct2/show/NCT01926288. The registration identification number is NCT01926288.
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: Qing Xie has acted as a consultant for Novar’s, Bristol-Myers Squibb and Roche; Guang-Feng Shi has been a member of advisory committees or review panels, received consulting fees from Novar’s, GlaxoSmithKline and Bristol-Myers Squibb; Guang-Feng Shi has acted as a consultant for Novar’s, Bristol-Myers Squibb, GlaxoSmithKline and Roche; other authors have nothing to declare.
Data sharing statement: No additional data are available.
CONSORT 2010 statement: The authors have read the CONSORT 2010 statement, and the manuscript was prepared and revised according to the CONSORT 2010 statement.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (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: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Yan-Yan Yu, Doctor, MD, PhD, Doctor, Professor, Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100094, China. yyy@bjmu.edu.cn
Received: April 13, 2022
Peer-review started: April 13, 2022
First decision: May 30, 2022
Revised: June 12, 2022
Accepted: August 24, 2022
Article in press: August 24, 2022
Published online: October 6, 2022
Processing time: 166 Days and 23.8 Hours
Abstract
BACKGROUND

Entecavir (ETV) is a potent and selective nucleotide analog with significant activity against hepatitis B virus (HBV). ETV maleate is a derivative compound of ETV and was reported to have an efficacy and safety profile that is comparable to ETV (Baraclude) when used in Chinese patients with chronic hepatitis B (CHB) in phase III clinical trials (Clinical Trials.gov number, NCT01926288) at weeks 48, 96, and 144.

AIM

To investigate the antiviral potency and safety of ETV maleate at week 192 in Chinese CHB patients predominantly genotyped B or C.

METHODS

In this double-blind study, we randomly assigned patients to receive 0.5 mg/d ETV (Group A) or ETV maleate (Group B) (ratio, 1:1), each with a placebo tablet for 48 wk. Then, all patients received open-label treatment with 0.5 mg/d ETV maleate starting at week 49. The primary efficacy endpoint was the reduction in HBV DNA levels from baseline. Secondary endpoints included the proportion of patients with undetectable HBV DNA (< 20 IU/mL), serologic response, serum alanine aminotransferase (ALT) normalization and development of resistance mutations.

RESULTS

Two hundred eighteen patients who were hepatitis B e antigen (HBeAg) positive and 57 who were HBeAg negative were analyzed and predominantly presented with genotype B (49.82%) or C (48.73%). For the HBeAg-positive CHB patients, the mean HBV DNA level decrease (6.61 Log10 IU/mL vs 6.69 Log10 IU/mL, P > 0.05), viral suppression with HBV DNA < 20 IU/mL (83.33% vs 79.17%, P > 0.05) and HBeAg seroconversion (28.77% vs 20.00%, P > 0.05) occurred similarly between Groups A and B at week 192. However, there was a significant difference in the proportion of patients with normal ALT levels (91.14% vs 78.38%, P < 0.05). For the HBeAg-negative CHB patients, no significant difference was found between Groups A and B at week 192 in terms of reductions in HBV DNA levels from baseline (6.05 Log10 IU/mL vs 6.03 Log10 IU/mL, P > 0.05), percentages of patients who achieved undetectable HBV DNA (100% vs 100%, P > 0.05) and rates of ALT normalization (95.65% vs 100.00%, P > 0.05). Safety and adverse event profiles were similar between Groups A and B. Two HBeAg-positive patients in Group A and 5 in Group B developed genotypic resistance to ETV.

CONCLUSION

Long-term ETV maleate treatment for up to 192 wk is effective and safe in Chinese CHB patients predominantly genotyped as B or C.

Keywords: Chronic hepatitis B; Entecavir maleate; Randomized controlled trial; Treatment outcome; Mutation; Genotype

Core Tip: This randomized, double-blind, double-dummy, controlled, multicenter trial showed that long-term treatment with entecavir (ETV) maleate provides safe, potent and reliable suppression of hepatitis B virus replication for 192 wk in Chinese chronic hepatitis B patients predominantly genotyped as B or C with little chance of developing ETV-resistant mutations.