Entecavir plus Biejia-Ruangan compound reduces the risk of hepatocellular carcinoma in Chinese patients with chronic hepatitis B
Dong Ji 1 , Yan Chen 1 , Jingfeng Bi 2 , Qinghua Shang 3 , Huabao Liu 4 , Jia-Bo Wang 5 , Lin Tan 6 , Jing Wang 7 , Yongping Chen 8 , Qin Li 9 , Qinghua Long 10 , Laicheng Song 11 , Li Jiang 12 , Guangming Xiao 13 , Zujiang Yu 14 , Liang Chen 15 , Xiaodong Wang 8 , Da Chen 9 , Zhiqin Li 14 , Zheng Dong 1 , Yongping Yang 16
1
Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.
2
Senior Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.
3
Diagnosis and Treatment Center for Liver Diseases, The 960th Hospital of Chinese PLA Joint Logistics Support Force, Tai'an, Shandong, China.
4
Traditional Chinese Medicine Hospital of Chongqing, Chongqing, China.
5
Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China; School of Traditional Chinese Medicine, Capital Medical University, Beijing, China.
6
Liver Disease Department, The Second People's Hospital of Fuyang City, Fuyang, Anhui, China.
7
Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, China.
8
Department of Infectious and Liver Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
9
Fuzhou Infectious Diseases Hospital, Fuzhou, Fujian, China.
10
Department of Infection and Liver Disease, Yichun People's Hospital, Yichun, Jiangxi, China.
11
Traditional Chinese Medicine Hospital of Taihe, Taihe, Anhui, China.
12
Department of Infectious Diseases, The First Affiliated Hospital (the Southwest Hospital) of the Third Military Medical University, Chongqing, China.
13
Guangzhou 8th People's Hospital, Guangzhou, Guangdong, China.
14
Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
15
Department of Hepatic Diseases, Shanghai Public Health Clinical Center, Shanghai, China.
16
Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China. Electronic address: [email protected].
PMID: 35985545 DOI: 10.1016/j.jhep.2022.07.018
Abstract
Background & aims: Chronic hepatitis B (CHB) and liver fibrosis are high-risk factors for hepatocellular carcinoma (HCC). We assessed whether ETV plus Biejia-Ruangan compound (BRC), an anti-fibrotic traditional Chinese medicine, can further reduce the risk of HCC in treatment-naïve Chinese CHB patients with Ishak fibrosis score of ≥3 points derived from our parent double-blind randomized placebo-controlled trial.
Methods: After a 72-week comparison between ETV+BRC and ETV+placebo treatment, participants were eligible to enter an open-label treatment phase and were followed up every 6 months. The primary [secondary] endpoints were the incidence of HCC [liver-related deaths, non-HCC events, and non-liver-related deaths]. Modified intention-to-treat (mITT), intention-to-treat (ITT), and per-protocol (PP) populations were defined for the time-to-event analysis.
Results: A total of 1000 patients were recruited, the median age was 42.0 years, 69.9% were male, 58.3% had positive HBeAg. In the mITT population, the 7-year cumulative incidence of HCC [liver-related deaths] was 4.7% [0.2%] for ETV+BRC, which was significantly lower than 9.3% [2.2%] for ETV (p =0.008 [p =0.030]). Notably, ETV+BRC treatment yielded a lower incidence of HCC in those who did not achieve regression of fibrosis at week 72 than did ETV treatment (p =0.018). There were no differences in the other two secondary endpoints or safety profiles between the groups. Multivariable Cox proportional regression analysis including the treatment allocation as a parameter also demonstrated that ETV+BRC treatment was a protective factor for the incidence of HCC. The ITT and PP analyses showed consistent results.
Conclusions: ETV plus BRC combination treatment could further reduce the risk of HCC and liver-related deaths in CHB patients with advanced fibrosis or cirrhosis, which may have important clinical implications for HCC prevention. Lay summary ●It is clinically important to determine how to further reduce the risk of hepatocellular carcinoma (HCC) when it is not possible to eliminate hepatitis B virus with entecavir (ETV) treatment. ●We performed a long-term extension of our 72-week parent prospective randomized placebo-controlled trial, which revealed that the Biejia-Ruangan compound (BRC), an anti-fibrotic traditional Chinese medicine (TCM), could further reduce the incidence of HCC by 51.1% and liver-related deaths by 89.9% in Chinese CHB patients receiving ETV treatment.●Given the poor prognosis of HCC, the findings may have important clinical implications and serve as a basis for further mechanism studies of TCM to explore a more effective strategy to reduce the risk of HCC.
Keywords: Hepatitis B virus; Liver biopsy; Liver stiffness measurement; Long-term outcomes; Nucleot(s)ide analogs; Traditional Chinese medicine.
