Use of plant composition in combination with nas in preparation of drug for treating chronic hepatitis b with low-level viremia

Abstract

Use of a plant composition in combination with NAs in the preparation of a drug for treating chronic hepatitis B with low-level viremia. The plant composition is prepared from the following raw materials in parts by weight: 200-350 parts of Bupleurum chinense, 150-200 parts of Ganoderma lucidum, 300-400 parts of Salvia miltiorrhiza and 300-400 parts of Schisandrae chinensis. By means of using the plant composition in combination with NAs, various biochemical indexes and clinical symptom scores associated with chronic hepatitis B with low-level viremia can be significantly improved, thereby indicating that the plant composition in combination with NAs has significant efficacy in treating chronic hepatitis B with low-level viremia.

Description

Application of a plant composition in combination with NAs in the preparation of a drug for treating hypoviremia in chronic hepatitis B

[0001] Cross-references to related applications

[0002] This application claims priority and benefit to Chinese Patent Application No. 202510005464.X, filed on February 10, 2025, entitled "Application of a Traditional Chinese Medicine Composition Combined with NAs in the Preparation of a Drug for Treating Chronic Hepatitis B Hypoviremia", the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention belongs to the field of human pharmaceutical technology, and particularly relates to the application of a plant composition combined with NAs in the preparation of a drug for treating chronic hepatitis B hypoviremia. Background Technology

[0004] Nucleoside and nucleotide analogues (NAs) are currently key drugs in the treatment of hepatitis B virus (HBV). Among them, the nucleotide analogues tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide fumarate (TAF), and the nucleoside analogue entecavir (ETV), are first-line antiviral drugs recommended by domestic and international guidelines. They can all achieve long-term viral suppression in most patients with chronic hepatitis B (CHB) by directly blocking the antiviral mechanism of HBV reverse transcriptase. Most chronic hepatitis B patients can achieve the therapeutic effects of inhibiting viral replication and delaying disease progression after standardized antiviral therapy with NAs. However, with a deeper understanding of the disease and advancements in detection technology, clinical findings have revealed that some patients, after 48 weeks of standardized NA (non-reactive protein) treatment, have serum HBV DNA levels below 2000 IU / mL, but these levels remain persistently or intermittently above the detection limit, indicating a state of hypoviremia. The mechanism of hypoviremia is currently unclear. Related studies have shown that HBV hypoviremia affects patient clinical prognosis, primarily by promoting the progression of liver inflammation and fibrosis, increasing the risk of decompensated cirrhosis, hepatocellular carcinoma, and drug resistance. Current technology does not offer definitive treatment recommendations for patients with HBV hypoviremia. Summary of the Invention

[0005] The purpose of this invention is to address the problems existing in the prior art by providing an application of a plant composition combined with natural natriuretic peptides (NAs) in the preparation of a drug for treating chronic hepatitis B with low viremia.

[0006] The chronic hepatitis B hypoviremia described in this invention refers to a serum HBV DNA level of 20–2000 IU / mL in patients with chronic hepatitis B who have undergone standard NAs treatment for 48 weeks and have been tested at least twice using a PCR method with a detection limit of 20 IU / mL, with an interval of 3–6 months.

[0007] The objective of this invention is achieved through the following technical solution:

[0008] In a first aspect, the present invention provides the application of a plant composition in combination with NAs in the preparation of a drug for treating low viremia in chronic hepatitis B. The plant composition is prepared by weight of 200-350 parts of Bupleurum chinense, 150-200 parts of Ganoderma lucidum, 300-400 parts of Salvia miltiorrhiza, and 300-400 parts of Schisandra chinensis.

[0009] Preferably, the plant composition is prepared from 340-350 parts by weight of Bupleurum chinense, 170-180 parts by weight of Ganoderma lucidum, 340-350 parts by weight of Salvia miltiorrhiza, and 340-350 parts by weight of Schisandra chinensis.

[0010] Preferably, the plant composition is prepared from 342 parts by weight of Bupleurum chinense, 173 parts by weight of Ganoderma lucidum, 342 parts by weight of Salvia miltiorrhiza, and 342 parts by weight of Schisandra chinensis.

[0011] Preferably, the dosage form of the plant composition is selected from solid dosage forms or liquid dosage forms.

[0012] Preferably, the solid dosage form is selected from capsules, tablets, powders, pills or granules, and the liquid dosage form is selected from syrups, mixtures, oral liquids or decoctions.

[0013] Preferably, the plant composition is Wuling capsules.

[0014] Preferably, the NAs are one or more selected from lamivudine, telbivudine, adefovir dipivoxil, entecavir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, or tenofovir alafenamide.

[0015] Preferably, the specific method of application is as follows: for patients with chronic hepatitis B hypoviremia, the nucleoside analogues (NAs) and the plant composition are administered orally separately, or the plant composition and nucleoside analogues (NAs) are prepared into a compound preparation and then administered orally.

[0016] In a second aspect, the present invention provides a compound medicine for treating chronic hepatitis B hypoviremia, the compound medicine comprising a plant composition and NAs, wherein the plant composition is prepared by weight of 200-350 parts of Bupleurum chinense, 150-200 parts of Ganoderma lucidum, 300-400 parts of Salvia miltiorrhiza, and 300-400 parts of Schisandra chinensis.

[0017] Preferably, the plant composition is prepared from 340-350 parts by weight of Bupleurum chinense, 170-180 parts by weight of Ganoderma lucidum, 340-350 parts by weight of Salvia miltiorrhiza, and 340-350 parts by weight of Schisandra chinensis.

[0018] Preferably, the plant composition is prepared from 342 parts by weight of Bupleurum chinense, 173 parts by weight of Ganoderma lucidum, 342 parts by weight of Salvia miltiorrhiza, and 342 parts by weight of Schisandra chinensis.

[0019] Preferably, the extraction process of the plant composition refers to the extraction steps in the preparation process of Wuling Capsules in the prior art, and will not be repeated here.

[0020] Preferably, the NAs are one or more of lamivudine, telbivudine, adefovir dipivoxil, entecavir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, or tenofovir alafenamide.

[0021] Preferably, the preparation process of the compound drug includes: preparing a plant composition according to the above prescription; after the plant composition is prepared, mixing the plant composition with NAs according to the corresponding dosage, and preparing it into capsules, tablets, powders, pills, granules, syrups, mixtures, oral liquids or decoctions according to conventional processes.

[0022] Preferably, the weight ratio of the plant composition to the NAs is 175:(0.5-3).

[0023] Preferably, the weight ratio of the plant composition to the NAs is 175:1.

[0024] In this application, the plant composition is a traditional Chinese medicine preparation or extract prepared from 200-350 parts of Bupleurum chinense, 150-200 parts of Ganoderma lucidum, 300-400 parts of Salvia miltiorrhiza, and 300-400 parts of Schisandra chinensis.

[0025] Therefore, the present invention also provides an application of a traditional Chinese medicine preparation combined with NAs in the preparation of a drug for treating low viremia in chronic hepatitis B. The traditional Chinese medicine preparation is prepared by weight of 200-350 parts of Bupleurum chinense, 150-200 parts of Ganoderma lucidum, 300-400 parts of Salvia miltiorrhiza, and 300-400 parts of Schisandra chinensis.

[0026] This invention also provides a traditional Chinese medicine preparation for the combined treatment of chronic hepatitis B with NAs and low viremia. The traditional Chinese medicine preparation is prepared by weight of 200-350 parts of Bupleurum chinense, 150-200 parts of Ganoderma lucidum, 300-400 parts of Salvia miltiorrhiza, and 300-400 parts of Schisandra chinensis.

[0027] Preferably, the traditional Chinese medicine preparation is prepared from 340-350 parts of Bupleurum chinense, 170-180 parts of Ganoderma lucidum, 340-350 parts of Salvia miltiorrhiza, and 340-350 parts of Schisandra chinensis, by weight.

[0028] Preferably, the traditional Chinese medicine preparation is prepared from 342 parts by weight of Bupleurum chinense, 173 parts by weight of Ganoderma lucidum, 342 parts by weight of Salvia miltiorrhiza, and 342 parts by weight of Schisandra chinensis.

[0029] Preferably, the dosage form of the traditional Chinese medicine preparation is selected from solid dosage forms or liquid dosage forms.

[0030] Preferably, the solid dosage form is selected from capsules, tablets, powders, pills or granules, and the liquid dosage form is selected from syrups, mixtures, oral liquids or decoctions.

[0031] Preferably, the traditional Chinese medicine preparation is Wuling Capsules.

[0032] Preferably, the NAs are one or more selected from lamivudine, telbivudine, adefovir dipivoxil, entecavir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, or tenofovir alafenamide.

[0033] Preferably, the specific method of application is as follows: for patients with chronic hepatitis B hypoviremia, nucleoside analogs (NAs) and the traditional Chinese medicine preparation are administered orally separately, or the traditional Chinese medicine preparation and nucleoside analogs (NAs) are prepared into a compound preparation and then administered orally. This invention also provides a compound drug for treating chronic hepatitis B hypoviremia, the components of which include traditional Chinese medicine extracts and NAs. According to weight, the traditional Chinese medicine extract is prepared from 200-350 parts of Bupleurum chinense, 150-200 parts of Ganoderma lucidum, 300-400 parts of Salvia miltiorrhiza, and 300-400 parts of Schisandra chinensis.

[0034] Preferably, the herbal extract is prepared from 340-350 parts by weight of Bupleurum chinense, 170-180 parts by weight of Ganoderma lucidum, 340-350 parts by weight of Salvia miltiorrhiza, and 340-350 parts by weight of Schisandra chinensis.

[0035] Preferably, the herbal extract is prepared from 342 parts by weight of Bupleurum chinense, 173 parts by weight of Ganoderma lucidum, 342 parts by weight of Salvia miltiorrhiza, and 342 parts by weight of Schisandra chinensis.

[0036] Preferably, the extraction process of the Chinese herbal extract refers to the steps of the extraction process in the preparation process of Wuling Capsules in the prior art, which will not be repeated here.

[0037] Preferably, the NAs are one or more of lamivudine, telbivudine, adefovir dipivoxil, entecavir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, or tenofovir alafenamide.

[0038] Preferably, the preparation process of the compound drug includes: extracting traditional Chinese medicine extracts according to the above prescription; after the extraction of traditional Chinese medicine extracts is completed, mixing the traditional Chinese medicine extracts with NAs according to the corresponding dosage, and preparing them into capsules, tablets, powders, pills, granules, syrups, mixtures, oral liquids or decoctions according to conventional processes.

[0039] Preferably, the weight ratio of the herbal extract to the natural antiviral agents (NAs) is 175:(0.5-3).

[0040] Preferably, the weight ratio of the herbal extract to the natural antiviral agents (NAs) is 175:1.

[0041] In this specification, the mass parts are used to indicate the relative proportions between the components. Depending on the actual situation, 1 mass part can be any mass number, such as 1g, 10g, 100g, 500g, 1kg, etc.

[0042] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0043] The present invention uses the plant composition in combination with NAs to improve HBV DNA levels and increase viral response rate, with significantly better results than NAs alone.

[0044] The present invention uses the plant composition in combination with NAs to improve serum HBsAg, HBeAg, and HBsAb levels, with significantly better results than NAs alone;

[0045] The present invention uses the plant composition in combination with NAs, which improves liver enzyme levels better than NAs alone;

[0046] The present invention uses the plant composition in combination with NAs, and the liver enzyme normalization rate is significantly better than that of NAs alone;

[0047] The present invention uses the plant composition in combination with NAs, which reduces liver stiffness value and is superior to NAs alone;

[0048] The present invention uses the plant composition in combination with NAs to improve clinical symptom scores, which is significantly better than NAs alone. Detailed Implementation

[0049] The present invention is further described below through specific embodiments, but the present invention is not limited to the following embodiments. Modifications, combinations, or substitutions made to the present invention within the scope of the present invention or without departing from the content, spirit, and scope of the present invention will be obvious to those skilled in the art and are included within the scope of the present invention.

[0050] Example 1: A plant composition

[0051] The plant composition described in this embodiment is a traditional Chinese medicine preparation selected from granules, tablets, powders, capsules, pills, syrups, mixtures, oral liquids, or decoctions, prepared from 342 parts by weight of Bupleurum chinense, 173 parts by weight of Ganoderma lucidum, 342 parts by weight of Salvia miltiorrhiza, and 342 parts by weight of Schisandra chinensis.

[0052] Example 2

[0053] This embodiment provides the application of a plant composition combined with NAs in the preparation of a drug for treating chronic hepatitis B with low viremia. The plant composition in this embodiment is prepared by weight parts of Bupleurum chinense 342 parts, Ganoderma lucidum 173 parts, Salvia miltiorrhiza 342 parts, and Schisandra chinensis 342 parts. The plant composition in this embodiment is a capsule prepared by conventional process.

[0054] Example 3: A Five-Spirits Capsule

[0055] A type of Wuling capsule is prepared from Bupleurum, Ganoderma lucidum, Salvia miltiorrhiza, and Schisandra chinensis. Specifically, the prescription for preparing 1000 Wuling capsules is: Bupleurum 342g, Ganoderma lucidum 173g, Salvia miltiorrhiza 342g, and Schisandra chinensis 342g; it is prepared by the following method: weigh the above four medicinal materials according to the prescription, crush Bupleurum chinense, sieve it, and take 171g of fine powder for later use; extract the coarse powder of Bupleurum chinense and Ganoderma lucidum twice with 75% (v / v) ethanol under reflux, 1 hour each time, filter, combine the filtrates, recover the ethanol and concentrate under reduced pressure to a thick paste I with a relative density of 1.36-1.38 (60-70℃). Extract Schisandra chinensis and Salvia miltiorrhiza three times with ethanol under reflux, 1 hour each time, filter, combine the filtrates, recover the ethanol and concentrate under reduced pressure to a thick paste II with a relative density of 1.36-1.38 (60-70℃). Thick paste I and thick paste II are combined, mixed with fine powder of Bupleurum chinense, dried, pulverized, and filled into capsules, each containing 0.35g, to make 1000 capsules.

[0056] Example 4

[0057] This embodiment provides an application of a traditional Chinese medicine preparation combined with NAs in the preparation of a drug for treating low viremia in chronic hepatitis B. The traditional Chinese medicine preparation in this embodiment is prepared by weight parts of Bupleurum chinense 342 parts, Ganoderma lucidum 173 parts, Salvia miltiorrhiza 342 parts, and Schisandra chinensis 342 parts. The traditional Chinese medicine preparation in this embodiment is a capsule prepared by conventional process.

[0058] Example 5

[0059] This embodiment provides a compound drug for treating low viremia in chronic hepatitis B. The compound drug comprises a plant composition and NAs. By weight, the plant composition is prepared from 342 parts of Bupleurum chinense, 173 parts of Ganoderma lucidum, 342 parts of Salvia miltiorrhiza, and 342 parts of Schisandra chinensis. The NAs are selected from one or more of lamivudine, telbivudine, adefovir dipivoxil, entecavir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, or tenofovir alafenamide. The compound drug is prepared into granules, tablets, powders, capsules, pills, syrups, mixtures, oral liquids, or decoctions after mixing the NAs and the plant composition. In this embodiment, the weight ratio of the plant composition to the NAs is 175:1.

[0060] Example 6

[0061] This embodiment provides a compound drug for treating low viremia in chronic hepatitis B. The compound drug comprises a traditional Chinese medicine extract and natural antiviral agents (NAs). By weight, the traditional Chinese medicine extract is prepared from 342 parts of Bupleurum chinense, 173 parts of Ganoderma lucidum, 342 parts of Salvia miltiorrhiza, and 342 parts of Schisandra chinensis. The NAs are selected from one or more of lamivudine, telbivudine, adefovir dipivoxil, entecavir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, or tenofovir alafenamide. The compound drug is prepared into granules, tablets, powders, capsules, pills, syrups, mixtures, oral liquids, or decoctions by mixing the NAs and the traditional Chinese medicine extract. In this embodiment, the weight ratio of the traditional Chinese medicine extract to the NAs is 175:1.

[0062] Example 7

[0063] This embodiment provides a compound drug for treating low viremia in chronic hepatitis B. The compound drug comprises a plant composition and adefovir dipivoxil. By weight, the plant composition is prepared from 342 parts of Bupleurum chinense, 173 parts of Ganoderma lucidum, 342 parts of Salvia miltiorrhiza, and 342 parts of Schisandra chinensis. The compound drug is prepared into granules, tablets, powders, capsules, pills, syrups, mixtures, oral liquids, or decoctions by mixing adefovir dipivoxil and the plant composition. In this embodiment, the weight ratio of the plant composition to adefovir dipivoxil is 175:1.

[0064] Example 8

[0065] This embodiment provides a compound drug for treating low viremia in chronic hepatitis B. The compound drug comprises a traditional Chinese medicine extract and adefovir dipivoxil. By weight, the traditional Chinese medicine extract is prepared from 342 parts of Bupleurum chinense, 173 parts of Ganoderma lucidum, 342 parts of Salvia miltiorrhiza, and 342 parts of Schisandra chinensis. The compound drug is prepared into granules, tablets, powders, capsules, pills, syrups, mixtures, oral liquids, or decoctions by mixing adefovir dipivoxil and the traditional Chinese medicine extract. In this embodiment, the weight ratio of the traditional Chinese medicine extract to adefovir dipivoxil is 175:1.

[0066] Example 9

[0067] This embodiment provides a compound drug for treating low viremia in chronic hepatitis B. The compound drug comprises a plant composition and tenofovir disoproxil fumarate. By weight, the plant composition is prepared from 342 parts of Bupleurum chinense, 173 parts of Ganoderma lucidum, 342 parts of Salvia miltiorrhiza, and 342 parts of Schisandra chinensis. The compound drug is prepared into granules, tablets, powders, capsules, pills, syrups, mixtures, oral liquids, or decoctions by mixing tenofovir disoproxil fumarate and the plant composition. In this embodiment, the weight ratio of the plant composition to tenofovir disoproxil fumarate is 175:3.

[0068] Example 10

[0069] This embodiment provides a compound drug for treating low viremia in chronic hepatitis B. The compound drug comprises a traditional Chinese medicine extract and tenofovir disoproxil fumarate. By weight, the traditional Chinese medicine extract is prepared from 342 parts of Bupleurum chinense, 173 parts of Ganoderma lucidum, 342 parts of Salvia miltiorrhiza, and 342 parts of Schisandra chinensis. The compound drug is prepared into granules, tablets, powders, capsules, pills, syrups, mixtures, oral liquids, or decoctions by mixing tenofovir disoproxil fumarate and the traditional Chinese medicine extract. In this embodiment, the weight ratio of the traditional Chinese medicine extract to tenofovir disoproxil fumarate is 175:3.

[0070] Example 11

[0071] This embodiment provides a compound drug for treating low viremia in chronic hepatitis B. The compound drug comprises a plant composition and entecavir. By weight, the plant composition is prepared from 342 parts of Bupleurum chinense, 173 parts of Ganoderma lucidum, 342 parts of Salvia miltiorrhiza, and 342 parts of Schisandra chinensis. The compound drug is prepared into granules, tablets, powders, capsules, pills, syrups, mixtures, oral liquids, or decoctions by mixing entecavir and the plant composition. In this embodiment, the weight ratio of the plant composition to entecavir is 175:0.5.

[0072] Example 12

[0073] This embodiment provides a compound drug for treating low viremia in chronic hepatitis B. The compound drug comprises a traditional Chinese medicine extract and entecavir. By weight, the traditional Chinese medicine extract is prepared from 342 parts of Bupleurum chinense, 173 parts of Ganoderma lucidum, 342 parts of Salvia miltiorrhiza, and 342 parts of Schisandra chinensis. The compound drug is prepared into granules, tablets, powders, capsules, pills, syrups, mixtures, oral liquids, or decoctions by mixing entecavir and the traditional Chinese medicine extract. In this embodiment, the weight ratio of the traditional Chinese medicine extract to entecavir is 175:0.5.

[0074] Example 13

[0075] This embodiment provides a compound drug for chronic hepatitis B with low viral load. The compound drug comprises a plant composition and tenofovir alafenamide fumarate. By weight, the plant composition is prepared from 342 parts of Bupleurum chinense, 173 parts of Ganoderma lucidum, 342 parts of Salvia miltiorrhiza, and 342 parts of Schisandra chinensis. The compound drug is prepared into granules, tablets, powders, capsules, pills, syrups, mixtures, oral liquids, or decoctions by mixing tenofovir alafenamide fumarate and the plant composition. In this embodiment, the weight ratio of the plant composition to tenofovir alafenamide fumarate is 175:2.

[0076] Example 14

[0077] This embodiment provides a compound drug for treating chronic hepatitis B low viral load. The compound drug comprises a traditional Chinese medicine extract and tenofovir alafenamide fumarate. By weight, the traditional Chinese medicine extract is prepared from 342 parts of Bupleurum chinense, 173 parts of Ganoderma lucidum, 342 parts of Salvia miltiorrhiza, and 342 parts of Schisandra chinensis. The compound drug is prepared into granules, tablets, powders, capsules, pills, syrups, mixtures, oral liquids, or decoctions by mixing tenofovir alafenamide fumarate and the traditional Chinese medicine extract. In this embodiment, the weight ratio of the traditional Chinese medicine extract to tenofovir alafenamide fumarate is 175:2.

[0078] Clinical research example

[0079] The purpose of this study is to further evaluate the efficacy and safety of Wuling capsules combined with NAs in the treatment of chronic hepatitis B with low viremia.

[0080] 1. Materials and Methods:

[0081] 1.1 General Information

[0082] From December 2021 to March 2024, a randomized, controlled, multicenter clinical study was conducted simultaneously in four hospitals: the Third Hospital of Hebei Medical University, Guangdong Provincial Hospital of Traditional Chinese Medicine, Xi'an Eighth Hospital, and the First Affiliated Hospital of Henan University of Traditional Chinese Medicine. A total of 100 patients were enrolled and randomly divided into an experimental group (Wuling Capsules combined with NAs, n=50) and a control group (NAs, n=50) according to the treatment method. Informed consent was obtained from each participant.

[0083] 2. Diagnostic criteria

[0084] 2.1 Western Medicine Diagnostic Criteria

[0085] According to the 2018 American Association for the Study of Liver Diseases (AASLD) guidelines, the "Guidelines for the Prevention and Treatment of Chronic Hepatitis B" (2019) formulated by the Chinese Society of Hepatology, and the "Research Status of Hypoviralemia in Patients with Chronic Hepatitis B Treated with Nucleoside (Acid) Analogs" (Lu Fengmin, et al. Research Status of Hypoviralemia in Patients with Chronic Hepatitis B Treated with Nucleoside (Acid) Analogs [J]. Journal of Clinical Hepatology, 2021, 37(6):1268-1274), the diagnostic criteria for hypoviralemia in chronic hepatitis B are as follows:

[0086] Patients who have received antiviral drug treatment for more than 48 weeks should still be able to detect serum HBV DNA by at least two tests using a high-sensitivity PCR method (with a detection limit of 20 IU / ml) at intervals of 3 to 6 months, and both tests should be <2000 IU / ml.

[0087] 2.2 Traditional Chinese Medicine Diagnostic Criteria

[0088] The TCM diagnosis for chronic hepatitis B with low viral load is: Liver Qi stagnation and Spleen deficiency with blood stasis. This is determined based on the patient's clinical presentation.

[0089] Main symptoms: ① Distending pain in the hypochondrium; ② Abdominal distension and loose stools.

[0090] Secondary symptoms: ① poor appetite and reduced food intake; ② fatigue and weakness; ③ pale tongue with teeth marks.

[0091] (1) Those who have all the main symptoms; (2) Those who have the main symptom ① and two of the secondary symptoms ② and ③; (3) Those who have the main symptom ② and any two of the three secondary symptoms; are judged to belong to the syndrome of liver stagnation and spleen deficiency with blood stasis.

[0092] 3. Inclusion and exclusion criteria:

[0093] 3.1 Inclusion criteria

[0094] (1) Age 18-65 years; (2) Patients with chronic hepatitis B and compensated chronic hepatitis B cirrhosis; (3) Patients diagnosed with chronic hepatitis B low viral load (HBV DNA 20-2000 IU / mL) based on past medical history; (4) Patients diagnosed with liver stagnation and spleen deficiency with blood stasis according to traditional Chinese medicine; (5) Patients with positive serum HBsAg, negative or positive HBeAg; (6) Patients who have not used anti-hepatic fibrosis drugs (such as Fuzheng Huayu Capsules, Compound Turtle Shell Softening Liver Tablets, Heluo Shugan Tablets, Anluo Huaxian Pills) within 6 months; (7) Patients who voluntarily sign informed consent forms.

[0095] 3.2 Exclusion Criteria

[0096] (1) Patients with hepatitis and other viral infections (HAV, HCV, HDV, HEV, CMV, EBV, HIV) combined with other hepatotropic virus infections; (2) Patients with drug-induced liver disease, alcoholic liver disease or non-alcoholic fatty liver disease and related severe hepatitis, liver cancer and patients; (3) Patients with serious primary diseases of the heart, kidneys, lungs, endocrine, blood, metabolism and gastrointestinal tract; or patients with mental illness; (4) Patients during pregnancy or lactation; (5) Patients with allergic constitution or allergy to Wuling Capsules and its ingredients; (6) Patients with poor adherence to antiviral treatment; (7) Patients who have participated in other clinical trials or other drug clinical trials and whose participation ended within 1 month.

[0097] 3.3 Exclusion Criteria

[0098] (1) Those who do not meet the diagnostic and inclusion criteria; (2) Those who naturally drop out during the observation period and have no usable data; (3) Those who drop out after baseline due to failure to adhere to treatment for any reason; (4) Those whose liver fibrosis is caused by other reasons, rather than chronic hepatitis B.

[0099] 3.4 Shedding Criteria

[0100] (1) Researcher's decision to withdraw

[0101] If a participant who has already been enrolled develops any of the following conditions during the trial that make it unsuitable for them to continue, the researchers will decide to withdraw that participant from the trial:

[0102] (a) The subject experienced a worsening of his condition, or a comorbidity, comorbidity (such as a tendency to develop chronic severe hepatitis) or special physiological change (such as pregnancy) that contradicted the treatment drugs used in this study but required active treatment.

[0103] (b) Poor subject compliance affects the determination of efficacy and safety;

[0104] (c) An adverse event or a serious adverse event occurs.

[0105] (2) Subjects voluntarily withdrew from the trial.

[0106] 3.5 Criteria for Terminating the Test

[0107] (1) The patient fails to take the medication for more than one week according to the prescribed dosage, frequency, and course of treatment; or the patient has poor compliance, with a medication rate (actual amount of medication taken / number of medications to be taken) <80% or >120%; or other diseases occur during the medication process that affect the observation of drug efficacy; (2) Serious adverse events or unintended pregnancy; (3) The study subject requests to withdraw; (4) The researcher believes that it is necessary for the study subject to terminate this study.

[0108] 4. Treatment methods and course of treatment

[0109] The control group continued taking NAs, while the experimental group received the original treatment plus Wuling Capsules (Approval Number: National Drug Approval Number Z20090068, 60 capsules / bottle. Wuling Capsules are provided by Tsinghua Deren Xi'an Xingfu Pharmaceutical Co., Ltd.). Dosage and administration: Wuling Capsules 5 capsules / time, 3 times / day, taken half an hour after meals; NAs, taken according to the instructions. Treatment duration: 180 days. During the trial, no drugs with anti-hepatitis B virus, anti-liver fibrosis, or liver-protective and enzyme-lowering effects other than those specified in the protocol should be used. If other underlying diseases (such as hypertension) require continued use of other drugs and treatments, records must be kept for analysis and reporting during the summary.

[0110] 5. Observation Indicators

[0111] 5.1 Therapeutic Indicators

[0112] (1) Serum HBV DNA load: Tested once each on day 0, day 90 and day 180.

[0113] (2) Quantitative analysis of five hepatitis B markers: Hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B e antigen (HBeAg), hepatitis B e antibody (HBeAb), and hepatitis B core antibody (HBcAb): tested once each on day 0 and day 180.

[0114] (3) Liver function (ALT, AST, GGT, ALP, TBIL, DBIL): Tested once each on day 0, day 90 and day 180.

[0115] (4) VAS scale score: Tested once each on day 0, day 90 and day 180.

[0116] (5) Clinical symptom score: Tested once each on day 0, day 90 and day 180.

[0117] (6) Liver stiffness value: Tested once each on day 0, day 90 and day 180.

[0118] (7) Abdominal ultrasound (to observe changes in liver imaging and spleen size): once each on day 0, day 90, and day 180.

[0119] 5.2 Safety Observation Indicators

[0120] (1) Complete blood count: Tested once on day 0 and once on day 180;

[0121] (2) Kidney function: Tested once on day 0 and once on day 180;

[0122] (3) Alpha-fetoprotein: Tested once each on day 0, day 90 and day 180;

[0123] (4) Adverse events, serious adverse events;

[0124] (5) Women of childbearing age need to undergo a urine pregnancy test to rule out pregnancy.

[0125] Except for alpha-fetoprotein and urine pregnancy test, the above items should be tested once before and after treatment; adverse events and serious adverse events should be observed, examined and recorded immediately if they occur.

[0126] 6. Efficacy evaluation criteria

[0127] (1) Compare the serum HBV DNA seroconversion rate (detected by high-sensitivity PCR method (lowest detection limit is 20 IU / ml) and the degree of decrease in viral load between the two groups of patients after treatment;

[0128] (2) Compare the changes in the five quantitative indicators of hepatitis B, VAS score (Table 1), clinical symptom score (Table 2), liver stiffness value, and upper abdominal ultrasound before and after treatment in the two groups of patients.

[0129] (3) Compare the liver function levels and recovery rate of the two groups of patients after treatment.

[0130] Table 1 VAS Scale

[0131] Scoring rules:

[0132] 1) 0cm: 0 points, painless, no pain sensation;

[0133] 2) 1-3cm: 1-3 points, mild pain, does not affect work or daily life;

[0134] 3) 4-6cm: 4-6 points, moderate pain, affecting work but not daily life;

[0135] 4) 7-10cm: 7-10 points, severe pain, intense pain, affecting work and life.

[0136] Table 2 Clinical Symptom Scoring Table

[0137] 7. Data Statistical Analysis Methods

[0138] SPSS 20.0 software was used for statistical analysis. Categorical variables were described using the number of cases, while continuous variables were described using the number of cases and mean ± standard deviation. Independent samples t-tests or Wilcoxon rank-sum tests were used for comparisons between groups of continuous variables, while chi-square tests or Wilcoxon rank-sum tests were used for categorical variables. P < 0.05 was considered statistically significant. The negative conversion rate and normalization rate after treatment were compared using chi-square tests.

[0139] The safety dataset (SS) refers to actual data from patients who received at least one treatment and for whom safety indicators were recorded. The incidence of adverse reactions is calculated using the number of cases in the safety dataset as the denominator.

[0140] The full analysis set (FAS) is a set of subjects that is as close as possible to the intention-to-analyze principle. This dataset is derived by minimizing and reasonably eliminating all randomized subjects.

[0141] The protocol set (PPS) refers to a collection of cases that meet the inclusion criteria, do not meet the exclusion criteria, and have completed the treatment protocol. PPS is mainly used for the analysis of primary efficacy endpoints.

[0142] 8. Specific statistical results

[0143] 8.1 Enrollment Information and Dataset

[0144] All 100 participants (50 in the experimental group and 50 in the control group) were included in the safe dataset (SS). 96 participants (47 in the experimental group and 49 in the control group) were included in the full analysis set (FAS), representing 96% of the cases. 91 participants (46 in the experimental group and 45 in the control group) were included in the protocol-compliant set (PPS), representing 91% of the cases.

[0145] 8.2 Detachment Status

[0146] In this clinical trial, a total of 3 cases dropped out, with an overall dropout rate of 3.13%. Among them, there was 1 case in the experimental group with a dropout rate of 2.13%, and 2 cases in the control group with a dropout rate of 4.08%. There was no statistically significant difference in dropout rates between the two groups.

[0147] 8.3 Baseline Analysis

[0148] There were no statistically significant differences between the two groups in general characteristics (age, gender) and baseline efficacy indicators (serum HBV DNA load, quantitative hepatitis B five markers, liver function, VAS score, clinical symptom score, alpha-fetoprotein, and liver stiffness value) (P > 0.05), making them comparable. See Table 3 for details.

[0149] Table 3 Comparison of general information of patients in the experimental group and the control group.

[0150] 8.4 Evaluation of therapeutic effect

[0151] 8.4.1 Serum HBV DNA load level / seroconversion rate

[0152] FAS results showed that HBV DNA load decreased in both groups after 90 and 180 days of treatment compared to before treatment, with no statistically significant difference between the two groups (P > 0.05). See Table 4 for details.

[0153] Table 4 Comparison of serum HBV DNA load levels between the experimental group and the control group (FAS)

[0154] The efficacy of PPS is similar to that of FAS.

[0155] 8.4.2 Serum HBV DNA seroconversion rate

[0156] FAS results showed that after 90 and 180 days of treatment, the serum HBV DNA seroconversion rate in the experimental group was higher than that in the control group, and the difference between the two groups at 180 days was statistically significant (P<0.05).

[0157] After 90 days of treatment, the serum HBV DNA seroconversion rate in the experimental group was 59.09%, which was better than that in the control group (47.62%). There was no statistically significant difference between the two groups (P = 0.286).

[0158] After 180 days of treatment, the serum HBV DNA seroconversion rate in the experimental group was 67.39%, which was better than that in the control group (48.98%). The difference between the two groups was statistically significant (P = 0.01).

[0159] The efficacy of PPS is similar to that of FAS.

[0160] 8.4.3 Quantitative analysis of the five hepatitis B markers

[0161] FAS results showed that after 180 days of treatment, the levels of HBsAg, HBeAg, and HBcAb in the experimental group were lower than those in the control group, and the differences between the two groups were statistically significant (P < 0.05). Compared with before treatment, the change in HBsAb was higher in the experimental group than in the control group, and the difference was statistically significant (P < 0.05). See Table 5 for details.

[0162] Table 5. Quantitative comparison of hepatitis B five markers (FAS) between the experimental group and the control group.

[0163] The efficacy of PPS was similar to that of FAS, and the decrease in HBcAb in the experimental group compared with that in the control group was statistically significant (P = 0.040), as detailed in Table 6.

[0164] Table 6. Quantitative comparison of hepatitis B five markers (PPS) between the experimental group and the control group.

[0165] 8.4.4 Liver function level / normalization rate

[0166] 8.4.4.1 Liver function (ALT, AST, ALP, GGT, TBIL, DBIL)

[0167] FAS results showed that after 90 days of treatment, there was no statistically significant difference in liver function levels between the two groups; after 180 days of treatment, the experimental group had lower levels of ALT, AST, and TBIL than the control group, and the differences were statistically significant (P < 0.05), as detailed in Table 7.

[0168] Table 7 Comparison of liver function levels (FAS) between the experimental group and the control group after 90 and 180 days of treatment.

[0169] The efficacy of PPS is similar to that of FAS.

[0170] 8.4.4.2 Liver function (ALT, AST, ALP, GGT, TBIL, DBIL) normalization rate

[0171] FAS results showed that after 90 days of treatment, the normalization rates of ALT, AST, and GGT in the experimental group were better than those in the control group (P < 0.05); after 180 days of treatment, the normalization rates of AST and GGT in the experimental group were significantly higher than those in the control group, and the differences were statistically significant (P < 0.05). See Table 8 for details.

[0172] Table 8 Comparison of liver function normalization rates between the experimental group and the control group (FAS)

[0173] The efficacy of PPS is similar to that of FAS.

[0174] 8.4.5 VAS score

[0175] FAS results showed that the reduction scores in the experimental group were higher than those in the control group at 90 and 180 days of treatment, and the differences were statistically significant (P < 0.05). See Table 9 for details.

[0176] Table 9. Comparison of VAS scores (FAS) between the experimental group and the control group after 90 days and 1800 days of treatment.

[0177] The efficacy of PPS is similar to that of FAS.

[0178] 8.4.6 Clinical Symptom Scoring

[0179] FAS results showed that the reduction scores in the experimental group were higher than those in the control group at 90 and 180 days of treatment. Furthermore, after 180 days of treatment, the symptom scores and reduction scores in the experimental group were significantly different from those in the control group (P < 0.05). See Table 10 for details.

[0180] Table 10 Comparison of clinical symptom scores (FAS) between the experimental group and the control group after 90 and 180 days of treatment.

[0181] The efficacy of PPS is similar to that of FAS.

[0182] 8.4.7 Clinical Single Symptom Scoring

[0183] FAS results showed that the scores of individual symptoms in the experimental group were lower than those in the control group at both 90 and 180 days of treatment. In particular, after 180 days of treatment, the scores and reduction values ​​of hypochondriac pain, belching, and loss of appetite were significantly different from those in the control group (P < 0.05). See Table 11 for details.

[0184] Table 11 Comparison of individual clinical symptom scores (FAS) between the experimental group and the control group after 90 and 180 days of treatment.

[0185] The efficacy of PPS is similar to that of FAS.

[0186] 8.4.8 Liver stiffness value

[0187] FAS results showed that after 90 days of treatment, there was no statistically significant difference in liver stiffness between the experimental group and the control group (P>0.05). After 180 days of treatment, there was also no statistically significant difference in liver stiffness between the experimental group and the control group (P>0.05). See Table 12 for details.

[0188] Table 12 Comparison of liver stiffness values ​​(FAS) between the two groups of patients after treatment

[0189] The efficacy of PPS is similar to that of FAS.

[0190] 8.4.9 Abdominal ultrasound

[0191] FAS results showed that after 90 and 180 days of treatment, there were no significant changes in the upper abdominal ultrasound images compared with before treatment in either group, and there was no difference between the two groups. See Table 13 for details.

[0192] Table 13 Comparison of upper abdominal ultrasound imaging results between the two groups (FAS)

[0193] The efficacy of PPS is similar to that of FAS.

[0194] 8.4.10 Security Analysis

[0195] In the 100 cases included in this study, no adverse events occurred, and the alpha-fetoprotein levels did not increase compared with pre-treatment levels.

[0196] 8.4.10.1 Alpha-fetoprotein

[0197] FAS results showed that after 90 and 180 days of treatment, the alpha-fetoprotein (AFP) levels were (3.23±1.74) ng / ml in the experimental group and (3.47±1.98) ng / ml in the control group, with no statistically significant difference between the two groups (P>0.05). See Table 14 for details.

[0198] Table 14 Comparison of alpha-fetoprotein (FAS) levels after treatment in different patient groups

[0199] The efficacy of PPS is similar to that of FAS.

[0200] 8.4.10.2 Drug Dependence

[0201] Except for those lost to follow-up, the other subjects had good compliance, and there was no statistically significant difference between the two groups.

[0202] 8.4.10.3 Laboratory test indicators

[0203] Table 15 shows the changes in laboratory indicators of all cases in the Safety Analysis Set (SS) before and after the trial.

[0204] Table 15 Laboratory Test Safety Analysis (SS)

[0205] 9. Conclusion

[0206] This study, through a randomized, controlled, multicenter trial conforming to international standards, yielded the following clinical evidence:

[0207] After treatment, the serum HBV DNA seroconversion rate in the experimental group was higher than that in the control group (P < 0.05); the levels of HBsAg, HBeAg, and HBcAb were lower in the experimental group than in the control group, with statistically significant differences (P < 0.05). Compared with before treatment, the change in HBsAb was significantly different in the experimental group than in the control group (P < 0.05); the levels of ALT, AST, and TBIL were better in the experimental group than in the control group, with statistically significant differences (P < 0.05); the normalization rate of ALT, AST, and GGT was higher in the experimental group than in the control group, with statistically significant differences (P < 0.01, P < 0.05); the VAS score and clinical symptom score were better in the experimental group than in the control group, with statistically significant differences between the two groups (P < 0.05, P < 0.01); and the improvement in symptoms such as hypochondriac pain, belching, and loss of appetite was better in the experimental group than in the control group, with statistically significant differences (P < 0.05).

[0208] This clinical study showed that Wuling Capsules combined with NAs were significantly effective in treating chronic hepatitis B with low viral load. They significantly improved the serum HBV DNA seroconversion rate, the quantitative results of the five hepatitis B markers, liver function levels, and clinical symptoms. Furthermore, no adverse events or reactions related to Wuling Capsules occurred during the treatment, indicating good safety.

[0209] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. The application of a plant composition in combination with natural natriuretic peptides (NAs) in the preparation of a drug for treating low viremia in chronic hepatitis B, characterized in that, The plant composition is prepared by weight of 200-350 parts Bupleurum chinense, 150-200 parts Ganoderma lucidum, 300-400 parts Salvia miltiorrhiza, and 300-400 parts Schisandra chinensis.

2. The application according to claim 1, characterized in that, The dosage form of the plant composition is selected from solid dosage forms or liquid dosage forms.

3. The application according to claim 2, characterized in that, The solid dosage form is selected from capsules, tablets, powders, pills or granules, and the liquid dosage form is selected from syrups, mixtures, oral liquids or decoctions.

4. The application according to claim 3, characterized in that, The plant composition is Wuling Capsules.

5. The application according to claim 4, characterized in that, The NAs are one or more of lamivudine, telbivudine, adefovir dipivoxil, entecavir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, or tenofovir alafenamide.

6. The application according to claim 5, characterized in that, The specific method of application is as follows: for patients with chronic hepatitis B and low viremia, NAs and the plant composition are administered orally separately, or the plant composition and NAs are prepared into a compound preparation and then administered orally.

7. A compound drug for treating low viremia in chronic hepatitis B, characterized in that, The compound drug comprises a plant composition and NAs. The plant composition is prepared by weight of 200-350 parts Bupleurum chinense, 150-200 parts Ganoderma lucidum, 300-400 parts Salvia miltiorrhiza, and 300-400 parts Schisandra chinensis.

8. The compound drug according to claim 7, characterized in that, The NAs are one or more of lamivudine, telbivudine, adefovir dipivoxil, entecavir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, or tenofovir alafenamide.

9. The compound drug according to claim 7, characterized in that, The weight ratio of the plant composition to the NAs is 175:(0.5-3).

10. The compound drug according to claim 9, characterized in that, The weight ratio of the plant composition to the NAs is 175:

1.

11. The application according to claim 1, characterized in that, The plant composition, by weight, is prepared from 340-350 parts of Bupleurum chinense, 170-180 parts of Ganoderma lucidum, 340-350 parts of Salvia miltiorrhiza, and 340-350 parts of Schisandra chinensis.

12. The application according to claim 11, characterized in that, The plant composition, by weight, is prepared from 342 parts of Bupleurum chinense, 173 parts of Ganoderma lucidum, 342 parts of Salvia miltiorrhiza, and 342 parts of Schisandra chinensis.

13. The compound drug according to claim 7, characterized in that, The plant composition, by weight, is prepared from 340-350 parts of Bupleurum chinense, 170-180 parts of Ganoderma lucidum, 340-350 parts of Salvia miltiorrhiza, and 340-350 parts of Schisandra chinensis.

14. The compound drug according to claim 13, characterized in that, The plant composition, by weight, is prepared from 342 parts of Bupleurum chinense, 173 parts of Ganoderma lucidum, 342 parts of Salvia miltiorrhiza, and 342 parts of Schisandra chinensis.

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