Clinical Trials Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 14, 2017; 23(2): 306-317
Published online Jan 14, 2017. doi: 10.3748/wjg.v23.i2.306
Phase IIb trial of in vivo electroporation mediated dual-plasmid hepatitis B virus DNA vaccine in chronic hepatitis B patients under lamivudine therapy
Fu-Qiang Yang, Gui-Rong Rao, Gui-Qiang Wang, Yue-Qi Li, Yao Xie, Zhan-Qing Zhang, Cun-Liang Deng, Qing Mao, Jun Li, Wei Zhao, Mao-Rong Wang, Tao Han, Shi-Jun Chen, Chen Pan, De-Ming Tan, Jia Shang, Ming-Xiang Zhang, Yue-Xin Zhang, Ji-Ming Yang, Guang-Ming Chen
Fu-Qiang Yang, Gui-Rong Rao, Guang-Ming Chen, Liver Disease Research Center, 458th Hospital of PLA, Guangzhou 510062, Guangdong Province, China
Gui-Qiang Wang, Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China
Yue-Qi Li, Beijing 302 Hospital, Beijing 100039, China
Yao Xie, Ninth Clinical Department, Beijing Ditan Hospital, Beijing 100011, China
Zhan-Qing Zhang, Department of Liver Diseases, Public Health Center, Fudan University, Shanghai 201508, China
Cun-Liang Deng, Department of Infectious Diseases, Affiliated Hospital of Luzhou Medical College, Luzhou 646000, Sichuan Province, China
Qing Mao, PLA Institute of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing 400038, Sichuan Province, China
Jun Li, Jiangsu Province People’s Hospital, Nanjing 210029, Jiangsu Province, China
Wei Zhao, Nanjing 2nd Hospital, Nanjing 210003, Jiangsu Province, China
Mao-Rong Wang, Nanjing PLA 81 Hospital, Nanjing 210002, Jiangsu Province, China
Tao Han, Tianjin 3rd Center Hospital, Tianjin 300170, China
Shi-Jun Chen, Jinan Infectious Disease Hospital, Jinan 250000, Shandong Province, China
Chen Pan, Fuzhou Infectious Disease Hospital, Fuzhou 350025, Fujian Province, China
De-Ming Tan, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
Jia Shang, Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
Ming-Xiang Zhang, The Sixth People’s Hospital of Shenyang, Shenyang 110006, Liaoning Province, China
Yue-Xin Zhang, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, Xinjiang Uygur Autonomous Region, China
Ji-Ming Yang, Infectious Disease Hospital of Tianjin, Tianjin 300101, China
Author contributions: Yang FQ, Rao GR, Wang GQ and Chen GM contributed to the study conception and design; Wang GQ is the leader of multiple centers and PI of the clinical research; Yang FQ, Rao GR, Wang GQ, Li YQ, Xie Y, Zhang ZQ, Deng CL, Mao Q, Li J, Zhao W, Wang MR, Han T, Chen SJ, Pan C, Tan DM, Shang J, Zhang MX, Zhang YX, Yang JM and Chen GM contributed to data acquisition, analysis or interpretation; Yang FQ, Rao GR, Wang GQ, Li YQ, Xie Y, Zhang ZQ, Deng CL, Mao Q, Li J, Zhao W, Wang MR, Han T, Chen SJ, Pan C, Tan DM, Shang J, Zhang MX, Zhang YX, Yang JM and Chen GM have been involved in drafting the manuscript or revising it critically for important intellectual content; all authors have given final approval of the version to be published.
Supported by Yigan Biological Products Co., Ltd. of Guangzhou Pharmaceutical Holdings Ltd. (GPC, Guangzhou, China); Guangdong Provincial Sci. & Tech. Project, No. 2012A080204009; Guangdong Provincial Natural Science Fund, No. 2014A030313770; Guangdong Provincial Public Benefit Foundation, No. 2015A010107011; and National Key Program for Management of AIDS and Viral Hepatitis during the China “ 11th 5-Year Plan” Period, No. 2008ZX10002-003.
Institutional review board statement: The study was reviewed and approved by the ethics committee of the Peking University First Hospital, as well as by the committee of each of the participating centers.
Clinical trial registration statement: This trial has been registered in ClinicalTrials.org (NCT01487876).
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: Not declared.
Data sharing statement: No additional data are available.
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: Guang-Ming Chen, MD, Liver Disease Research Center, 458th Hospital of PLA, No. 801 Dongfeng E. Road, Guangzhou 510062, Guangdong Province, China. chgm0616@sina.com
Telephone: +86-20-87376240 Fax: +86-20-87376240
Received: July 22, 2016
Peer-review started: July 22, 2016
First decision: September 20, 2016
Revised: September 30, 2016
Accepted: October 27, 2016
Article in press: October 27, 2016
Published online: January 14, 2017
Processing time: 174 Days and 20.9 Hours
Abstract
AIM

To assess the efficacy and safety of in vivo electroporation (EP)-mediated dual-plasmid hepatitis B virus (HBV) DNA vaccine vs placebo for sequential combination therapy with lamivudine (LAM) in patients with chronic hepatitis B.

METHODS

Two hundred and twenty-five patients were randomized to receive either LAM + vaccine (vaccine group, n = 109) or LAM + placebo (control group, n = 116). LAM treatment lasted 72 wk. Patients received the DNA vaccine or placebo by intramuscular injection mediated by EP at weeks 12 (start of treatment with vaccine or placebo, SOT), 16, 24, and 36 (end of treatment with vaccine or placebo, EOT).

RESULTS

In the modified intent-to-treat population, more patients had a decrease in HBV DNA > 2 log10 IU/mL in the vaccine group at week 12 after EOT compared with the control group. A trend toward a difference in the number of patients with undetectable HBV DNA at week 28 after EOT was obtained. Adverse events were similar. In the dynamic per-protocol set, which excluded adefovir (ADV) add-on cases at each time point instantly after ADV administration due to LAM antiviral failure, more patients had a decrease in HBV DNA > 2 log10 IU/mL in the vaccine group at week 12 and 28 after EOT compared with the control group. More patients with undetectable HBV DNA at week 28 after EOT in the vaccine group were also observed. Among patients with a viral load < 1000 copies/mL at week 12, more patients achieved HBeAg seroconversion in the vaccine group than among controls at week 36 after EOT, as well as less virological breakthrough and YMDD mutations.

CONCLUSION

The primary endpoint was not achieved using the HBV DNA vaccine. The HBV DNA vaccine could only be beneficial in subjects that have achieved initial virological response under LAM chemotherapy.

Keywords: Chronic hepatitis B; DNA vaccine; In vivo electroporation; Lamivudine-resistant mutants; Randomized placebo-controlled trial

Core tip: The study aimed to assess the efficacy and safety of in vivo electroporation-mediated dual-plasmid hepatitis B virus (HBV) DNA vaccine vs placebo for sequential combination therapy with lamivudine (LAM) in patients with chronic hepatitis B. The results indicated that the primary endpoint was not achieved using the HBV DNA vaccine. The HBV DNA vaccine might only be beneficial in subjects that have achieved initial virological response under LAM chemotherapy.