方法：共有 640 名患者以 1:1 的比例随机分配到治疗组（接受 BSJPF 联合 ETV 96 周）或对照组（接受安慰剂联合 ETV 96 周）。主要终点是乙型肝炎表面抗原（HBsAg）的丢失率。次要结果包括 HBsAg 浓度降至 ≥1 lg·IU/mL 的速率、HBV DNA 抑制、肝脏中共价闭合环状 DNA (cccDNA) 水平的下降、组织学改善以及ALT正常化。
结果：治疗组HBsAg消失率明显高于对照组（5.5% vs 1.8%，P=0.031）。治疗组有11.1%的患者HBsAg下降≥1 lg·IU/mL，优于对照组的5.9%（P=0.043）。两组HBV DNA清除率、肝内cccDNA减少率、ALT正常化率差异无统计学意义（P>0.05）。治疗组肝纤维化改善率优于对照组（35.5% vs 11.8%，P=0.031），但坏死性炎症改善率差异无统计学意义（P>0.05）。除肾功能异常外，两组的不良事件（AEs）相似，对照组为2.2%，治疗组为0.0%（P=0.028）。
结论：BSJPF联合ETV可提高慢性乙型肝炎患者HBsAg消失率和组织学纤维化改善率，且无严重不良事件。 试用注册。 本试验于2016年11月16日在ChiCTR-IOR-16009880注册-回顾性注册，http://www.chictr.org.cn/showproj.aspx?proj=16836。
Bushen Jianpi Formula Combined with Entecavir for the Treatment of HBeAg-Negative Chronic Hepatitis B: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial
Jing-Hao Zhang 1 , Xin Zhang 2 , Zhen-Hua Zhou 2 , Xiao-Jun Zhu 1 , Chao Zheng 1 , Man Li 2 , Shu-Gen Jin 2 , De-Wen Mao 3 , Jing-Dong Xue 4 , Wei-Bing Shi 5 , Xiao-Ling Chi 6 , Xian-Bo Wang 7 , Xiao-Dong Li 8 , Yong Li 9 , Hui Wang 10 , Qin Li 11 , Da-Qiao Zhou 12 , Cheng-Bao Wang 13 , Chang-He Shi 14 , Cheng-Zhong Li 15 , Jian-Hua Wu 16 , Xiao-Ni Kong 17 , Xue-Hua Sun 1 , Yue-Qiu Gao 1 2
Affiliations
Affiliations
1
Department of Hepatopathy, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
2
Laboratory of Cellular Immunity, Shanghai Key Laboratory of Traditional Chinese Medicine, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
3
Department of Hepatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, China.
4
Department of Hepatology, Shaanxi Hospital of Traditional Chinese Medicine, Xi'an 710003, China.
5
Department of Infectious Diseases, First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei 230031, China.
6
Department of Hepatology, Guangdong Hospital of Traditional Chinese Medicine, Guangzhou 510006, China.
7
Department of Integrated TCM and Western Medicine, Ditan Hospital Affiliated of Capital Medical University, Beijing 100015, China.
8
Department of Hepatology, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan 430061, China.
9
Department of Hepatology, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250011, China.
10
Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
11
Department of Hepatology, Department of Infectious Disease, Fuzhou Infectious Diseases Hospital, Fuzhou 350000, China.
12
Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, China.
13
Department of Infectious Diseases, Linyi People's Hospital, Linyi 276003, China.
14
Qingdao Liver Diseases Institute, Qingdao Hospital of Infectious Diseases, Qingdao 266033, China.
15
Department of Infectious Diseases, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China.
16
Department of Hepatopathy, Xiamen Hospital of Traditional Chinese Medicine, Xiamen 361001, China.
17
Central Laboratory, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Background: Bushen Jianpi formula (BSJPF, also known as Lingmao formula) is a traditional Chinese medicine for chronic hepatitis B (CHB). The previous study has suggested that the treatment combination of BSJPF and entecavir (ETV) can achieve a significant loss of hepatitis B e antigen (HBeAg) and a significant decrease in serum level of hepatitis B virus (HBV) DNA in HBeAg-positive CHB patients with mildly elevated alanine aminotransferase.
Objective: This study aimed to evaluate the efficacy and safety of BSJPF combined with ETV for treating HBeAg-negative CHB patients.
Methods: A total of 640 patients were assigned randomly to the treatment group (receiving BSJPF combined with ETV for 96 weeks) or the control group (receiving a placebo combined with ETV for 96 weeks) in a 1 : 1 ratio. The primary endpoints are the rate of loss of hepatitis B surface antigen (HBsAg). The secondary outcomes included the rate of decrease in the HBsAg concentration to ≥1 lg·IU/mL, the HBV DNA suppression, the decline of the level of covalently closed circular DNA (cccDNA) in the liver, histological improvements, and the rate of ALT normalization.
Results: The rate of HBsAg loss in the treatment group was significantly higher than that of the control group (5.5% versus 1.8%, P=0.031). There were 11.1% of patients in the treatment group who recorded a reduction in HBsAg ≥1 lg·IU/mL, which is better than 5.9% of patients in the control group (P=0.043). There was no significant difference between the two groups with regard to the rate of HBV DNA clearance, the reduction in intrahepatic cccDNA, and the rate of ALT normalization (P > 0.05). The rate of liver fibrosis improvement in the treatment group was better than that of the control group (35.5% versus 11.8%, P=0.031), but there was no difference in necroinflammatory improvement (P > 0.05). The adverse events (AEs) were similar between the two groups, except for the abnormal kidney function, with 2.2% in the control group and 0.0% in the treatment group (P=0.028).
Conclusion: The combination of BSJPF and ETV can increase the rate of HBsAg loss and the rate of histological fibrosis improvement without serious adverse events in CHB patients. Trial Registration. This trial is registered with ChiCTR-IOR-16009880 on November 16, 2016-retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=16836.