Synergistic Effect of Biejia-Ruangan on Fibrosis Regression in Patients With Chronic Hepatitis B Treated With Entecavir: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

Abstract

Background Long-term nucleos(t)ide analogue (NA) treatment can reverse liver fibrosis in chronic hepatitis B (CHB), but its effect on fibrosis regression remains limited. Biejia-Ruangan (BR) has been approved in China as an antifibrotic traditional Chinese medicine drug in patients with chronic liver diseases. A multicenter randomized controlled trial aims to evaluate the effect of BR on fibrosis regression in CHB patients treated with NAs. Methods CHB patients with histologically confirmed advanced fibrosis or cirrhosis were randomly assigned to receive entecavir (ETV) (0.5 mg per day) plus BR (2 g 3 times a day) or placebo for 72 weeks. Liver fibrosis regression was defined as a reduction of ≥ 1 point by the Ishak fibrosis stage (IFS). Results Overall, 500 patients were enrolled in each group as the intention-to-treat population. The rate of fibrosis regression after 72 weeks of treatment was significantly higher in the ETV + BR group (40% vs 31.8%; P = .0069). Among 388 patients with cirrhosis (ie, IFS ≥ 5) at baseline, the rate of cirrhosis reversal (ie, IFS ≤ 4) was significantly higher in the ETV + BR group (41.5% vs 30.7%; P = .0103). Conclusions Addition of BR to the current standard treatment with NAs in CHB patients with advanced fibrosis or cirrhosis can improve liver fibrosis regression. Clinical Trials Registration NCT01965418.

Comparison on different traditional Chinese medicine therapies for chronic hepatitis B liver fibrosis

“…Following the inclusion and exclusion criteria in search strategies, a total of 5,017 publications were identified using five databases, of which 1,993 records were removed because of duplicates, 928 were excluded by browsing titles and abstracts, and 2,067 were removed by reading full-text articles. Finally, 29 articles were included in this NMA ( Wang et al, 2004 ; Wang, 2005 ; Zhang et al, 2006 ; Wang et al, 2010 ; Zhang et al, 2016 ; Gu, 2018 ; Li, 2018 ; Xiao and Hu, 2018 ; Xu et al, 2018 ; Zhang et al, 2018 ; Zhao, 2018 ; Chen et al, 2019 ; Liang, 2019 ; Shi, 2019 ; Di and Xia, 2020 ; Li et al, 2020 ; Rong et al, 2020 ; Wang, 2020 ; Yin et al, 2020 ; Yu et al, 2020 ; Zhang, 2020 ; Zhang and Li, 2020 ; Du et al, 2021 ; Huang, 2021 ; Li et al, 2021 ; Wang, 2021 ; Zhang, 2021 ; Zhao, 2021 ; Zhu et al, 2021 ). Detailed information of study selection can be found in Figure 1 , and characteristics of the included RCTs are concluded in Table 1 .…”

“…However, the remaining four ( Wang et al, 2004 ; Zhang et al, 2006 ; Liang, 2019 ; Shi, 2019 ) only reported “randomization,” so they were assessed as “unclear risk.” 2) Allocation concealment: only 3 RCTs ( Wang et al, 2010 ; Xu et al, 2018 ; Rong et al, 2020 ) mentioned it while the rest did not. Therefore, the three trials were regarded as “low risk” while the rest as “unclear risk.” 3) Blinding (including participants and personnel, outcome evaluation): only four publications ( Wang et al, 2004 ; Zhang et al, 2006 ; Wang et al, 2010 ; Rong et al, 2020 ) conducted the blinding method, and 25 ( Wang, 2005 ; Zhang et al, 2016 ; Gu, 2018 ; Li, 2018 ; Xiao and Hu, 2018 ; Xu et al, 2018 ; Zhang et al, 2018 ; Zhao, 2018 ; Chen et al, 2019 ; Liang, 2019 ; Shi, 2019 ; Di and Xia, 2020 ; Li et al, 2020 ; Wang, 2020 ; Yin et al, 2020 ; Yu et al, 2020 ; Zhang, 2020 ; Zhang and Li, 2020 ; Du et al, 2021 ; Huang, 2021 ; Li et al, 2021 ; Wang, 2021 ; Zhang, 2021 ; Zhao, 2021 ; Zhu et al, 2021 ) had insufficient information. Therefore, they were successively estimated as “low risk” and “unclear risk.” 4) Incomplete outcome data: only seven trials ( Wang et al, 2004 ; Wang et al, 2010 ; Zhang et al, 2016 ; Liang, 2019 ; Rong et al, 2020 ; Yin et al, 2020 ; Zhang, 2021 ) described the situation of withdrawal or dropout leading to “low risk,” while the rest did not mention it resulting in “unclear risk.” 5) Selective reporting: all of the included studies were regarded as “low risk” due to the acquirement of the complete implementation scheme.…”

“…We evaluated the risk of bias of each included publication’s quality with the aid of the Cochrane risk of bias assessment tool ( Savovic et al, 2014 ). 1) Random sequence generation: 23 articles ( Wang, 2005 ; Wang et al, 2010 ; Zhang et al, 2016 ; Gu, 2018 ; Li, 2018 ; Xiao and Hu, 2018 ; Zhang et al, 2018 ; Zhao, 2018 ; Chen et al, 2019 ; Di and Xia, 2020 ; Li et al, 2020 ; Rong et al, 2020 ; Wang, 2020 ; Yin et al, 2020 ; Yu et al, 2020 ; Zhang, 2020 ; Zhang and Li, 2020 ; Du et al, 2021 ; Huang, 2021 ; Li et al, 2021 ; Zhang, 2021 ; Zhao, 2021 ; Zhu et al, 2021 ) used random number table and two ( Xu et al, 2018 ; Wang, 2021 ) used random envelope, which were viewed as “low risk”. However, the remaining four ( Wang et al, 2004 ; Zhang et al, 2006 ; Liang, 2019 ; Shi, 2019 ) only reported “randomization,” so they were assessed as “unclear risk.” 2) Allocation concealment: only 3 RCTs ( Wang et al, 2010 ; Xu et al, 2018 ; Rong et al, 2020 ) mentioned it while the rest did not.…”

Minimal Hepatic Encephalopathy and Biejia-Ruangan Are Associated with First Hospital Readmission in Nonalcoholic Cirrhosis Patients

“…BR exerts its antifibrotic effect via several mechanisms [ 51 – 53 ]. Recently, a multicenter, randomized, double-blind, placebo-controlled trial showed that addition of BR to nucleoside analog (NAs) in CHB patients with advanced fibrosis or cirrhosis can improve liver fibrosis regression [ 54 ]. Our study found that BR delayed the occurrence of complications of cirrhosis and improved the QOL of nonalcoholic cirrhosis patients without previous OHE or HCC.…”

Unreliable Estimation of Fibrosis Regression During Treatment by Liver Stiffness Measurement in Patients With Chronic Hepatitis B

“…All participants provided written informed consent. Data included in this study were obtained from an ongoing randomized controlled clinical trial (NCT01965418) ( 11 ). Briefly, treatment-naive HBV-infected patients who presented to one of participating centers between October 2013 and October 2014 were recruited and randomly assigned in a 1:1 ratio to the treatment group (ETV 0.5 mg/d plus BJRG 2.0 g/time, 3 times daily) or the control group (ETV plus placebo).…”