Editor’s Note: Improving the prognosis of chronic viral hepatitis is a crucial goal in clinical treatment. Chronic hepatitis B (CHB) has a wide incidence, and its severe harm mainly stems from the progression from liver fibrosis to cirrhosis, leading to decompensated cirrhosis and liver cancer, seriously threatening the patient’s life and health. Therefore, reversing early cirrhosis is of significant importance for reducing the risk of CHB-related liver diseases and death, representing an essential clinical need in CHB treatment. However, antiviral therapy alone has certain limitations, and traditional Chinese medicine (TCM) has enormous potential in combating liver fibrosis. At the recent 10th “Huaxia Shanghai Liver Disease Forum and Progress in Diagnosis and Treatment of Liver Failure and Its Complications,” Dr. Chenghai Liu from the Liver Disease Research Institute of Shanghai Academy of Traditional Chinese Medicine, and the Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine shared the significant clinical benefits that the “dual antagonism” prevention and treatment strategy, combining antiviral therapy with TCM for anti-liver fibrosis, brings to CHB patients. The content has been compiled into an article for readers.
Effectiveness and Limitations of Sole Antiviral Treatment
About 25% to 40% of CHB patients can develop into liver fibrosis, cirrhosis, or even liver cancer, with liver fibrosis being the crucial process in this development. Etiological treatment forms the basis of liver fibrosis treatment. Antiviral treatment for CHB can reverse CHB liver fibrosis and cirrhosis, suppress hepatitis B virus (HBV) to alleviate portal hypertension caused by CHB cirrhosis, and effective antiviral treatment can promote the regression of esophageal varices in CHB cirrhosis. However, in a considerable number of patients, the improvement of liver fibrosis does not parallel virological response. Although effective etiological treatment can delay and improve the status of liver fibrosis for some diseases, the issue of liver fibrosis has not been completely resolved. Taking CHB as an example, the improvement rate of liver fibrosis after one year of nucleoside (acid) treatment is ≤40% [1]. For patients with a baseline Ishak score of ≥F3, one-third of the population still shows no improvement in liver fibrosis after 5-10 years of treatment [2]. Moreover, even with negative HBV DNA, liver fibrosis can still exist and progress, and patients still have the risk of developing liver cancer. Therefore, in clinical practice, it is necessary to adopt a “dual antagonism” strategy, involving both antiviral and anti-liver fibrosis treatments.
The Diagnosis and Treatment Consensus on Liver Fibrosis (2019) [3] states that the treatment of liver fibrosis aims to prevent or reverse fibrosis, improve the patient’s liver function and structure, delay the occurrence of cirrhosis and its decompensation, improve the patient’s quality of life, and prolong their survival. In recent years, with the continuous in-depth research on liver fibrosis, breakthrough progress has been made in the traditional Chinese medicine diagnosis and treatment of chronic hepatitis B-related liver fibrosis. Some Chinese patent medicines with certain anti-liver fibrosis effects are already in clinical use. The widely used ones include Fuzheng Huayu Capsules (tablets), Anluo Huaxian Pills, Compound Biejia Ruangan Tablets (BRC), etc.
Different from the single components of biological and chemical drugs acting through a single target, TCM, especially compound formulations, is mainly characterized by multiple components acting through various pathways. Fuzheng Huayu Pills/Capsules, composed of six medicinal ingredients, currently have a total of 69 detectable components, of which 23 can be absorbed into the blood. At least nine components have been confirmed to exert anti-liver fibrosis effects, including salvianolic acid, rosmarinic acid, caffeic acid, Salvianic acid A sodium, cordycepin, Schisandrin propyl, and some active ingredients in peach kernel. The mechanism of action mainly involves inhibiting the activation of hepatic stellate cells, antioxidation to alleviate hepatocyte damage, regulating hepatic sinusoidal endothelial cells and their extracellular metabolism, and reshaping the liver matrix structure. Fuzheng Huayu Capsules (tablets) can effectively be used in multiple stages of CHB and are recommended by multiple guidelines and consensus (Figure 1).
Figure 1. Effects of Fuzheng Huayu in Multiple Stages of CHB (Adapted from Presenter’s Slides)
“Dual Antagonism” Treatment Promotes Histological Reversal of CHB
In terms of anti-liver fibrosis, the “dual antagonism” treatment of Fuzheng Huayu + Entecavir (ETV) shows an increased improvement rate compared to single anti-liver fibrosis treatment. In a randomized, double-blind, double-center, controlled study conducted by the academic team of Dr. Qing Xie and Dr. Lieming Xu, 46 patients with Ishak scores of ≥F3 were enrolled in the “dual antagonism” (Fuzheng Huayu + ETV) treatment group. The efficacy was verified through two liver biopsies, and the results showed that the improvement rate of liver fibrosis in CHB patients reached 81.8% under the “dual antagonism” therapy, an increase of 27.6% compared to the single anti-liver fibrosis treatment (Figure 2) [4]. This indicates that the combination of “dual antagonism” can better reverse liver fibrosis in CHB.
Figure 2. Improved Rate of Liver Fibrosis with “Dual Antagonism” Treatment of Fuzheng Huayu + ETV compared to Single Antagonism (Adapted from Presenter’s Slides)
For CHB patients with initial treatment of liver cirrhosis, the combination of dual antagonism increases the rate of cirrhosis reversal by 14.6%. In the national “Twelfth Five-Year Plan” major research project [5], 648 patients in the compensated stage of CHB liver cirrhosis with Ishak scores ≥F5 were enrolled in 20 centers. The single-antagonism group received ETV antiviral treatment, while the “dual antagonism” group received a combination of Fuzheng Huayu and ETV for 48 weeks. A follow-up observation was conducted for 12 weeks, and liver biopsies were performed before and after treatment. The results revealed that the improvement rate of liver cirrhosis in the “dual antagonism” group reached 64.6%, compared to 50% in the ETV-only group. The dual antagonism combination showed a significant increase of 14.6% over ETV alone (Figure 3). This indicates that Fuzheng Huayu can enhance the rate of liver fibrosis reversal in patients with CHB liver cirrhosis. For CHB patients with treated liver cirrhosis, the addition of Fuzheng Huayu still resulted in improvement in fibrosis for 56% of patients (Figure 4).
Figure 3. National “Twelfth Five-Year Plan” Major Research Project(Adapted from Presenter’s Slides)
Figure 4. Improvement in Fibrosis in Liver Cirrhotic Patients with the Addition of Compound Fuzheng Jiedu(Adapted from Presenter’s Slides)
Zhao et al.’s study results[6] revealed that the combination of Compound Fuzheng Huayu and entecavir treatment for 48 weeks resulted in a fibrosis reversal in 56.06% (74/132) of compensated cirrhotic patients, a 15% higher rate compared to entecavir monotherapy.
Dual Anti-treatment Alleviates Portal Hypertension in CHB Cirrhosis
Portal hypertension (HVPG≥10 mmHg) is an independent risk factor for the decompensation of compensated cirrhosis. As portal venous pressure increases, cirrhotic patients may develop complications such as ascites, splenomegaly, variceal bleeding, hepatic encephalopathy, hepatorenal syndrome, and spontaneous bacterial peritonitis, posing a serious threat to patients’ life and health. Therefore, actively preventing and treating portal hypertension is of great significance for the treatment of cirrhosis. Various methods, including surgery, endoscopic intervention, transjugular intrahepatic portosystemic shunt (TIPS), and drug therapy, are available for the treatment of portal hypertension. Drug treatment can reduce portal venous pressure, stop bleeding, and improve kidney function, playing a crucial role in the treatment of complications such as upper gastrointestinal bleeding and refractory ascites. The pathological mechanism of portal hypertension in cirrhotic patients determines the treatment measures. The main cause of increased portal blood flow is the high dynamic circulation outside the liver, which is an important factor in maintaining and aggravating portal hypertension. Increased cardiac output, vasodilation of visceral vessels, and decreased blood pressure and systemic vascular resistance are the reasons for high dynamic circulation. Therefore, reducing cardiac output and contracting visceral blood vessels can reduce portal blood flow and lower portal hypertension in cirrhosis[7].
Compound Fuzheng Huayu preparations and Biejia Ruangan tablets, anti-fibrotic Chinese medicine products, have been proven to have a certain effect on lowering portal venous pressure. In a multicenter randomized double-blind study[8] conducted by Dinghong Xiao et al., 181 cirrhotic patients were divided into groups with mild/moderate/severe esophageal varices and a rebleeding prevention group (basic treatment + Compound Fuzheng Huayu capsules). Each group had a control group (propranolol or placebo, etc., as basic treatment). The main endpoint was esophageal variceal bleeding, and secondary endpoints included death, primary liver cancer, and liver transplantation for any reason. After a 2-year observation period, it was found that Compound Fuzheng Huayu capsules could reduce the cumulative incidence of bleeding in patients with different degrees of esophageal varices due to cirrhosis (Figure 5).
Figure 5. Compound Fuzheng Huayu Reduces the Incidence of Esophageal Variceal Bleeding/Rebleeding in Cirrhotic Patients(Adapted from Presenter’s Slides)
A randomized, controlled, non-blind, multicenter clinical trial was conducted in eight centers in China to study the impact of Compound Fuzheng Huayu tablets on portal hypertension in CHB cirrhosis [9]. The trial enrolled patients from May 2018 to March 2021 and conducted a 2-year treatment follow-up. The results showed that Compound Fuzheng Huayu tablets significantly reduced the occurrence of clinical events in patients with cirrhotic portal hypertension. In the trial group, a total of 9 patients experienced clinical events, accounting for 8.2%, while in the control group, 21 patients experienced clinical events, accounting for 19.4%, with a statistically significant difference. Notably, the incidence of ascites in the trial group was significantly lower than in the control group. Additionally, the analysis of endoscopic variceal changes before and after treatment in both groups showed a significant improvement in variceal degree in the trial group compared to the control group. Simultaneously, the analysis of the risk of clinically significant portal hypertension (CSPH) in both groups before and after treatment revealed a significant reduction in CSPH risk in the trial group after treatment, significantly better than the control group. These results indicate that Compound Fuzheng Huayu tablets have a positive therapeutic effect on portal hypertension in CHB cirrhosis.
Dual Anti-treatment Reduces the Occurrence of HCC in CHB Cirrhosis
Cirrhosis is a key risk factor for liver cancer. Several studies have confirmed that dual anti-treatment can reduce the incidence of liver cancer. For instance, a study demonstrated that combination therapy with entecavir (ETV) and BRC further reduces the risk of HCC and liver-related death in CHB patients with advanced fibrosis or cirrhosis [10].
For compensated and decompensated CHB cirrhosis populations, Compound Fuzheng Huayu can lower the risk of developing liver cancer. A retrospective cohort study conducted by Dr. Xianbo Wang and his team at Beijing Ditan Hospital, Capital Medical University [11], found that, compared to the control group, Compound Fuzheng Huayu capsules combined with antiviral therapy significantly reduced the risk of liver cancer occurrence within 5 years in patients with CHB cirrhosis. The study included 842 CHB cirrhosis patients undergoing entecavir or tenofovir treatment, with 270 patients having taken Compound Fuzheng Jiedu capsules for over 6 months. Using a 1:1 propensity score matching analysis, the patients were divided into the Compound Fuzheng Huayu group (n=259) and the control group (n=259). After matching, there were no significant baseline differences between the two groups, and Compound Fuzheng Huayu combined with antiviral therapy significantly reduced the 5-year incidence of liver cancer in patients with CHB cirrhosis by 13.2%, reducing the risk of liver cancer by 56.9% (Figure 6).
Figure 6. Compound Fuzheng Huayu Reduces the Risk of Hepatocellular Carcinoma (HCC) in Compensated and Decompensated CHB Cirrhosis Population (Adapted from Presenter’s Slides
Conclusion
In summary, traditional Chinese medicine (TCM) has demonstrated significant potential in the field of anti-liver fibrosis. Compound Fuzheng Huayu is effective in various stages of CHB and has been recommended by multiple guidelines and consensus in China. With the accumulation of evidence-based data, Compound Fuzheng Huayu has covered the entire course of chronic liver disease. Multiple research results indicate that dual anti-treatment not only effectively alleviates hepatocellular inflammation and fibrous tissue proliferation but also delays and reduces the occurrence of decompensated cirrhosis, hepatocellular carcinoma, and other complications, prolonging the survival time of CHB patients. This approach assists patients with chronic liver disease in achieving better disease management and improving their quality of life.
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- Chinese Society of Hepatology, Chinese Society of Gastroenterology, Chinese Society of Infectious Diseases. Consensus on Diagnosis and Treatment of Liver Fibrosis in China (2019). Chin J Hepatol. 2019;27(9):657-667.
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- Dong Ji, Yan Chen, Jingfeng Bi, et al. Entecavir plus Biejia-Ruangan compound reduces the risk of hepatocellular carcinoma in Chinese patients with chronic hepatitis B. Journal of Hepatology 2022;77:1515–1524.
- Shi K, et al. Adjuvant Fuzheng Huayu capsule reduces the incidence of hepatocellular carcinoma in patients with hepatitis B-caused cirrhosis. Evid Based Complement Alternat Med. 2020:8826091.
TAG: Insight; Chronic Liver Disease