Editor's note:
is aimed at the progress of liver fibrosis in chronic liver disease. Although preclinical research has been very deep, there is no effective new plan that has been validated by clinical trials and entered clinical treatment. Fufang Biejia Ruangan Tablets (RGP) has been approved in China as an anti-liver fibrosis Chinese medicine for patients with chronic liver disease. It has more than 20 years of clinical experience in my country, benefiting tens of millions of patients with chronic liver disease. The drug has been continuously included in the national “Twelfth Five-Year Plan” and “Thirteenth Five-Year Plan” AIDS and viral hepatitis and other major infectious diseases prevention and control technology major projects. In 2020, the “Twelfth Five-Year Plan” major project has made breakthrough progress. Its effect of blocking and reversing liver fibrosis or cirrhosis has been supported by high-level evidence-based medicine. It has been recognized by international scholars and is a global leader in chronic liver disease patients. There is great hope to help Chinese medicine go to the world.
This article will focus on the clinical efficacy evaluation study of TCM syndrome differentiation and treatment to block and reverse hepatitis B-related liver fibrosis supported by the national "Twelfth Five-Year Plan" AIDS and viral hepatitis and other major infectious diseases prevention and treatment science and technology major projects [1], and Invite to study PI, Professor Yang Yongping, Director of the Department of Liver Disease Medicine of the Chinese People's Liberation Army General Hospital to comment on the research highlights and clinical research significance, Chinese medicine experts, Professor Sun Kewei, director of the Department of Infectious Diseases of the First Affiliated Hospital of Hunan University of Traditional Chinese Medicine to share the mechanism of Chinese medicine against liver fibrosis And thinking about the development of Chinese medicine, as well as Western medicine expert and director of the Beijing Friendship Hospital Liver Disease Research Center of Capital Medical University Professor Jia Jidong commented on the highlights of the research design, the status change of Chinese medicine in chronic liver disease, and the development prospects of integrated Chinese and Western medicine.
published in The Journal of Infectious Diseases (IF 5.022) in 2020:
study introduction
compound Biejia Ruangan tablets combined with entecavir in the treatment of patients with chronic hepatitis B liver fibrosis: a multi-center, randomized, double-blind, placebo-controlled clinical effect Evaluation study
long-term use of nucleoside (acid) analogs (NAs) can reverse liver fibrosis of chronic hepatitis B (CHB), but their effect on reversing liver fibrosis is still limited. Compound Biejia Ruangan Tablets (RGP) has been approved in China as an anti-liver fibrosis Chinese medicine for patients with chronic liver disease.
This multi-center, randomized controlled trial was completed by the National "Twelfth Five-Year" AIDS and viral hepatitis and other major infectious diseases prevention and control science and technology major projects, led by Professor Yang Yongping from the Department of Liver Diseases, General Hospital of the People's Liberation Army, on the treatment of CHB patients with RGP combined with NAs. The reversal effect of liver fibrosis was evaluated and important progress was made, confirming the effectiveness of Compound Biejia Ruangan Tablets in blocking and reversing liver fibrosis and cirrhosis. The results were published in the official journal of the Infectious Diseases Society of America (IDSA) The Journal of Infectious Diseases.
Researchers randomly assigned CHB patients with advanced liver fibrosis or cirrhosis confirmed by histology to receive Entecavir (ETV) (0.5mg, once a day) + RGP (2g, three times a day) or placebo for 72 weeks, two The group of intention-to-treat population was 500. Reversal of liver fibrosis is defined as a reduction of Ishak liver fibrosis stage (IFS) by ≥ 1 point.
Figure 1. RGP blocking and reversing hepatitis B-related liver fibrosis clinical efficacy evaluation research roadmap
In the PP analysis of 705 patients, the reversal rate of liver fibrosis in the RGP+ETV group after 72 weeks of treatment was significantly higher In the control group (59%), in the PP analysis of 388 patients with liver cirrhosis, the reversal rate of liver cirrhosis in the RGP+ETV group was as high as 53.9%
Figure 2. The results of reversal of liver fibrosis in the treatment of chronic hepatitis B with RGP combined with ETV at 72 weeks PP analysis
Therefore, it is concluded that for patients with advanced liver fibrosis or cirrhosis of CHB, adding compound Biejia Ruangan tablets to the existing standard treatment NAs can increase the reversal rate of liver fibrosis/cirrhosis.
Research PI Comments
Professor Yang Yongping
Director of the Department of Hepatology, Chinese People's Liberation Army General Hospital
Why do we need to conduct large-scale research again?
Traditional Chinese medicine in my country is a medical system that can rival modern medicine among many medical systems in the world. Why do large-scale scientific researches be carried out again on the traditional Chinese medicine compound Biejia Ruangan Tablets that has been on the market for many years? Mainly out of two considerations.
First, I hope to solve the problem that hinders the development of Chinese medicine.
Chinese medicine is a treasure of the country. After long-term efforts, the international community has a high understanding of it. However, there are still some problems that seriously hinder Chinese medicine from going abroad, such as At present, there is little clinical evidence that has gained international recognition. Especially in the most important clinical efficacy and safety, there have always been international doubts, and the answer to "why is effective" in traditional Chinese medicine is not enough. Fufang Biejia Ruangan Tablet is the first anti-liver fibrosis traditional Chinese medicine approved by the country. It has benefited millions of patients in its clinical application for more than 20 years. However, due to the limitations of clinical verification at the time and the incomplete recognition of liver fibrosis, its international recognition needs to be improved.
Second, I hope to solve the clinical dilemma of Western medicine with the help of Chinese medicine
Over time, the treatment of chronic hepatitis B has undergone tremendous changes. How to maximize the benefits of patients is a major scientific proposition. NAs antiviral therapy has become the first choice for chronic hepatitis B, which can inhibit the virus for a long time, but its effect in reversing liver fibrosis or cirrhosis is limited. Whether the overall advantage of traditional Chinese medicine in blocking and reversing liver fibrosis can play a role in it. attention.
Therefore, with the national special support, in accordance with the internationally recognized clinical trial standards for blocking and reversing liver fibrosis, the highest-level double-blind randomized multi-center controlled clinical study was adopted to conduct scientific evaluation again. From the "Twelfth Five-Year Plan" to the "Thirteenth Five-Year Plan", it fully embodies the advantages of the national system of concentrating efforts on major events, and using the powerful weapons of modern medicine to confidently evaluate the effectiveness and safety of traditional Chinese medicine in blocking and reversing liver fibrosis. Compared with previous domestic researches of the same type, what are the highlights of
?
highlight 1, the research design adopts the internationally recognized test standard for blocking and reversing liver fibrosis, that is, a single cause must cover different stages of liver fibrosis, including significant liver fibrosis, advanced liver fibrosis and cirrhosis, with special emphasis on patients with liver cirrhosis Not less than 30%, and the proportion of cirrhosis in this study reached 52.6%.
highlights 2, and the evaluation is more scientific. The internationally recognized "gold standard" was used to evaluate the degree of liver fibrosis, and two liver biopsies were performed before and after. 1000 patients enrolled in the group had liver biopsy results, and 705 patients received a second liver biopsy after 72 weeks of double-blind treatment to evaluate the efficacy. In addition, the introduction of new international concepts, in addition to evaluating the reversal of liver fibrosis, also evaluates the proportion of reversal of liver cirrhosis. The reversal rate of liver cirrhosis in this study reached 54%, which was significantly higher than the ETV monotherapy group. The highlight of
, 3, is a classic case study of the combination of evidence-based medicine and Chinese medicine. Combining evidence-based medicine with the characteristics of traditional Chinese medicine, put it into clinical practice, and produce the highest level of evidence-based evidence to prove the clinical efficacy of Chinese medicine compound Biejia Ruangan Pian in blocking and reversing liver fibrosis, and its results are more likely to be recognized internationally. Recognize and accept.
highlight 4, which is the first clinical study on reversing liver fibrosis with traditional Chinese medicine published in mainstream international professional journals with the highest evidence-based medical evidence. This is a major breakthrough. The detailed description of the place of origin, production method, heavy metal and organic pesticide residues of each Chinese medicine provided great help for the research to be accepted and published in international journals. What are the important findings of the
study?
, the first , confirmed the effectiveness and safety of Chinese medicine compound Biejia Ruangan Pian in blocking and reversing liver fibrosis, and this safety is accepted, based on the current standard antiviral treatment recommended by major international guidelines The addition of Compound Biejia Ruangan Tablets did not increase the incidence of adverse events (AE), and there were no new AEs.
and the second , confirmed the synergistic reversal of liver fibrosis of traditional Chinese medicine relapse Biejia Ruangan tablets. When antiviral drugs are available, more patients will benefit from the overall advantages of blocking and reversing liver fibrosis and the advantages of synergistic reversing liver fibrosis with Chinese medicine.
, the third , embodies the concept of "treating the same disease with the same disease and treating the same disease with different diseases" in traditional Chinese medicine. What is the significance of
for clinical and scientific research?
From the perspective of clinical practice, this research has given an important enlightenment, that is, as NAs treatment has reached the ceiling today, clinical promotion and widespread benefitThe use of traditional Chinese medicines that are proven to be effective through scientific and evidence-based medical research can break through the dilemma of Western medicine clinical treatment. The enlightenment of
to scientific research needs to answer why Chinese medicine is effective, so that Chinese patent medicines can become more vigorous and accepted by the world. This classic "Twelfth Five-Year" case can be used as a reference for future research institutes. We should continue to summarize and avoid the phenomenon of high investment, low publication, and unacceptable international acceptance.
In addition, good top-level design is very important for scientific research. It is very important to proceed with a wide field of vision and a high format on the standards recognized by the world. Strictly record what we do every day, conduct scientific and fine analysis, and then let the data form a pattern, change our clinical practice, and improve the effectiveness of clinical treatment.
In the past, we did not have scientific research funds, but now we have scientific research funds. How to make good use of scientific research funds and how to do clinical scientific research is what we must answer and do well at this stage. Traditional Chinese medicine is not without science, but we need to use modern medical methods to discover, recognize and understand. Only in this way can we know the greatness of Chinese medicine.
entered the "13th Five-Year Plan" open clinical observation after completing 72 weeks of double-blind treatment from the "Twelfth Five-Year Plan". The "Thirteenth Five-Year Plan" focuses on whether compound Biejia Ruangan Tablets combined with ETV can reduce HBV-related liver cancer and whether it can reduce the incidence of decompensated liver cirrhosis. In the post- era of nucleosides, blocking and reversing liver fibrosis, reducing liver cirrhosis, and reducing HBV-related liver cancer will be the future way for compound Chinese medicine combined with antiviral drugs. In the current new strategy of advocating combined and comprehensive treatment of chronic hepatitis B, my country's proven effective Chinese medicine can play an indispensable role.
Chinese medicine experts comment
Professor Sun Kewei
Director of the Department of Infectious Diseases of the First Affiliated Hospital of Hunan University of Traditional Chinese Medicine
What is the treatment principle and mechanism of Chinese medicine in the treatment of liver fibrosis?
At present, everyone's ideas are gradually converging. For chronic hepatitis B, especially in the case of complicated liver fibrosis, it is indeed necessary to treat liver fibrosis. Traditional Chinese medicine has a history of nearly 40 years of anti-liver fibrosis. It originated in the 1980s when Chinese liver disease experts discovered that a batch of Chinese herbal compound prescriptions can reverse liver fibrosis. This pioneering concept overturned the view that liver cirrhosis cannot be reversed. Research on traditional Chinese medicine including compound Biejia Ruangan tablets has gradually increased and made great progress.
The treatment principle of anti-liver fibrosis with traditional Chinese medicine is based on compound prescriptions, targeting 4 to 5 syndrome types. Since the main pathogenesis of liver fibrosis in traditional Chinese medicine is blood stasis to block the collaterals, the existing Chinese patent medicines are all based on promoting blood circulation and removing blood stasis as the basic treatment, throughout the entire anti-liver fibrosis treatment process. The mechanism of TCM treatment is different from that of Western medicine. According to individual differences, treatment based on syndrome differentiation, such as soothing the liver, strengthening the spleen, and invigorating the kidney, is a multi-step, multi-level and multi-target comprehensive treatment.
From the current point of view, anti-liver fibrosis treatment with traditional Chinese medicine can target the entire process of liver fibrosis. On the one hand, it is mainly aimed at the production and degradation of liver fiber; on the other hand, it promotes the improvement of liver fibrosis by other means, such as regulating intestinal microecology, anti-inflammatory and inhibiting hepatic stellate cells. These methods involve various treatments. In the link, the research of traditional Chinese medicine for this type of treatment is consistent with the research of new drugs for anti-liver fibrosis in western medicine. What are the guiding significance of
research results for clinical treatment? Which TCM patients have more advantages?
This research is a model of traditional Chinese medicine research in recent decades and is of great significance. It is of great significance for improving the clinical research level of Chinese medicine. It will not only increase the international influence of Chinese medicine, but also promote the development of Chinese medicine in China.
The results are gratifying. The compound Biejia Ruangan Tablet plus ETV has a significantly higher reversal effect of liver fibrosis than the antiviral effect of ETV alone. The reversal rate can be increased by at least 10%, and it can reduce liver cirrhosis or liver fibrosis. The end event occurred.
The biggest reminder from this study is that for chronic liver diseases, especially hepatitis B-related liver fibrosis and cirrhosis, in order to improve the curative effect, the compound Biejia Ruangan tablet can be added to the treatment while antiviral. This study provides relatively high evidence-based medical evidence for the clinical application of Compound Biejia Ruangan Tablets, which also enables everyone to have a better understanding of the drug.
According to the formula of the compound Biejia Ruangan tablets, the medicines that mainly promote blood circulation and remove blood stasis, such as Biejia and Zedoary, are more suitable for patients with congestion and spleen deficiency. Based on Chinese MedicineTheoretically, for patients with spleen deficiency and blood stasis or liver stagnation and blood stasis, the clinical manifestations may include poor appetite, bloated stomach, loose stools, tongue examination found obvious tortuous sublingual veins, and symptomatic treatment is needed. What enlightenment does
bring to the clinical research of Chinese medicine?
I have been doing research on Chinese medicine, and there was a lot of confusion in the process. This study is a multi-center RCT study with a large sample. The design is relatively rigorous. The evaluation standard is liver biopsy. 70.5% of patients have completed two liver biopsies. This data is a relatively large cohort at home and abroad. At the same time, pathological diagnosis uses a central laboratory, and multiple experts blindly read the film, which reduces systematic errors and conforms to the general principles of international new drug research. The results obtained in this way are scientific and reliable.
Therefore, I think our subsequent research on Chinese medicine should be conducted with reference to this model. In addition, the remarkable curative effect of the compound Biejia Ruangan Tablet has increased our confidence in the curative effect of Chinese medicine. The results of Professor Yang's study are very encouraging. At the same time, it has also verified that Chinese medicine is a great treasure house and should be explored and improved. Artemisinin and arsenic trioxide also come from the excavation of Chinese medicine, which increases our expectations for the efficacy of Chinese medicine.
Thinking on the future development of Chinese medicine
The first point , Chinese medicine should take this as an opportunity to carry out systematic research. Unlike Western medicine which has a set of relatively mature scientific norms, high-level evidence research on Chinese medicine has just started, and a systematic study needs to be established. Unlike western medicine, which has fixed proportions of chemical components, the efficacy of traditional Chinese medicine preparations is affected by many factors such as the quality of the original medicinal materials and the extraction method of the effective ingredients. Many Chinese medicinal materials have good effects in clinical research, but after they are marketed, poor control of the quality of medicinal materials and preparation technology affects the efficacy. This is a key issue. In the clinical application of
, we have already experienced the efficacy of Compound Biejia Ruangan Tablets (not only in research), but also very stable (for more than 20 years). Taking Compound Biejia Ruangan Tablets as an example, can we strengthen the preclinical For example, extracting the effective ingredients of each medicine in Compound Biejia Ruangan Tablets, and then combining the different effective ingredients to conduct research and development of this component of Chinese medicine, which may significantly improve the preclinical research level of Chinese medicine preparations .
The second point is , our Chinese medicine practitioners must strengthen the awareness and ability of clinical research. We must have the quality of scientific research, treat every patient in the clinic as the object of observation, and use new research methods, such as real-world research, so that we can have a better understanding of the curative effects of Chinese medicine, including Chinese patent medicines. It may bring even greater gains.
This also suggests that our Chinese doctors do not have many clinical cases, but that their clinical research capabilities are relatively insufficient. Therefore, Professor Yang's research (about Fufang Biejia Ruangan Tablets) is beneficial for us to strengthen our clinical research awareness, improve clinical research capabilities, and strengthen data mining capabilities, and even the development of Chinese medicine. This is also a question I often emphasize and think about.
Western medicine experts comment
Professor Jia Jidong
Director of the Liver Research Center of Beijing Friendship Hospital, Capital Medical University
How to see the role of traditional Chinese medicine in the treatment of chronic liver disease against liver fibrosis?
Liver fibrosis is the only way for various chronic liver diseases to lead to cirrhosis, so removing the underlying cause is the most important and effective treatment. Many studies have confirmed that elimination of HCV or effective suppression of HBV, abstinence from alcohol, weight loss, immunosuppressive therapy, etc., can effectively reverse liver fiber caused by chronic hepatitis C or chronic hepatitis B, alcoholic, metabolic-related fatty liver disease, and autoimmune hepatitis And even early liver cirrhosis. However, in a small number of patients, despite effective etiological treatment, such as chronic hepatitis B patients with long-term potent and low drug-resistant nucleoside (acid) analogs, liver fibrosis may continue to progress. The reasons are more complicated, and may be related to the fact that the cause is not really removed or effectively controlled (such as HBV hypoviremia), or it may be related to patient factors (such as drinking, obesity or diabetes).
At present, there is no drug that has been officially approved by the drug regulatory authority after strict clinical trial verification in the world. The older generation of scholars of integrated Chinese and Western medicine in my country have a relatively deep research foundation in the treatment of liver fibrosis. Scholars in Shanxi, Beijing, Shanghai and other places have found through a large number of animal experiments that some Chinese medicine prescriptions, effective parts of medicines and even chemical monomers have anti-liver fibrosisIt also preliminarily clarified its multi-target and multi-link mode of action at the cellular and molecular level; clinical studies also initially showed the clinical efficacy of these anti-liver fibrosis Chinese medicines. However, due to the complexity of clinical research on the efficacy of liver fibrosis and the standardization of clinical research at that time, the clinical efficacy studies of anti-fibrotic Chinese medicines are rarely published in international mainstream professional journals.
In recent years, the treatment of the cause of chronic hepatitis B has been continuously improved, and the view that liver fibrosis and early cirrhosis may be reversed has been accepted and recognized by more and more scholars. In order to improve the reversal rate of liver fibrosis, Chinese scholars actively try to adopt standardized clinical research methods to explore the efficacy of antiviral drugs combined with anti-fibrotic traditional Chinese medicines. The results are increasingly accepted and published by international mainstream professional journals. How does
see the clinical significance of this study?
The treatment goal of chronic hepatitis B is to maximize long-term inhibition of HBV replication, reduce hepatocyte inflammation and necrosis and liver fibrous tissue hyperplasia, delay and reduce the occurrence of liver failure, cirrhosis decompensation, HCC and other complications, and improve patient life Quality and prolong its survival time.
Existing antiviral drugs can effectively inhibit HBV replication, thereby reducing severe necrosis and liver fibrosis. However, in some patients, liver fibrosis and cirrhosis cannot be completely prevented. The research results of Chinese scholars show that the combination of anti-liver fibrosis Chinese medicine compound can effectively inhibit the virus and obtain a better anti-liver fibrosis effect. It is worthwhile for liver disease doctors to apply rationally according to relevant guidelines and the specific conditions of patients in clinical practice.
References:
[1] Rong G, Chen Y, Yu Z, et al. Synergistic Effect of Biejia-Ruangan on Fibrosis Regression in Patients with Chronic Hepatitis B Treated with Entecavir: A Multicenter, Randomized, Double-Blinded, Placebo- Controlled Trial. J Infect Dis. 2020 May 21;jiaa266.
