Efficacy of erzhu jiedu recipe on hepatitis B cirrhosis with hyperalphafetoproteinemia: A randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Hepatitis B cirrhosis with hyperalphafetoproteinemia is the intermediate stage of liver cirrhosis progressing to hepatocellular carcinoma (HCC), there is no effective way to treat precancerous lesions of liver in modern medicine. In recent decades, clinical and experimental evidence shows that Chinese medicine (CM) has a certain beneficial effect on Hepatitis B Cirrhosis. Therefore, this trial aims to evaluate the efficacy and safety of a CM erzhu jiedu recipe (EZJDR) for the treatment of Hepatitis B Cirrhosis with Hyperalphafetoproteinemia. METHODS: We designed a randomized, double blind, placebo-controlled clinical trial. A total of 72 patients of Hepatitis B Cirrhosis with hyperalphafetoproteinemia were randomized in 2 parallel groups. Patients in the control group received placebo granules similar to the EZJDR. In the EZJDR group, patients received EZJDR twice a day, after meals, for 48 weeks. The primary efficacy measures were changes in serum alpha-fetoprotein (AFP) and alpha-fetoprotein alloplasm (AFP-L3); The secondary indicators of efficacy are changes in liver function indicators, HBV-DNA level; Liver stiffness measurement (LSM); Hepatic portal vein diameter; T lymphocyte subgroup indexes during treatment. All data will be recorded in case report forms and analyzed by Statistical Analysis System software. Adverse events will also be evaluated. RESULTS: The results showed that EZJDR can significantly inhibit the levels of AFP and AFP-L3 in patients with hepatitis B cirrhosis and hyperalphafetoproteinemia and have good security. ETHICS AND DISSEMINATION: The study protocol was approved by the Medical Ethics Committee of Shuguang Hospital, affiliated with University of Traditional Chinese Medicine, Shanghai (NO.2018-579-08-01). TRIAL REGISTRATION: This trial was registered on Chinese Clinical Trial Center (NO.ChiCTR1800017165).

Long-Term Traditional Chinese Medicine Combined with NA Antiviral Therapy on Cirrhosis Incidence in Chronic Hepatitis B Patients in the Real-World Setting: A Retrospective Study.

OBJECTIVE: To evaluate the impact of long-term Traditional Chinese Medicine (TCM) syndrome differentiation combined with antiviral therapy with Nucleos (t) ide analogues (NAs) on the incidence of cirrhosis in patients with chronic hepatitis B. METHODS: This retrospective cohort study included 521 patients with chronic hepatitis B who underwent a treatment course of ≥3 years from 1998-2019. Of the 521 patients, 261 were defined as TCM users while 260 were TCM nonusers (control group). All the enrolled subjects were followed up until February 2019 to measure the incidence and hazard ratio (HR) of cirrhosis, and the Cox proportional hazards regression model was used to analyze the independent factors affecting the occurrence of cirrhosis. RESULTS: The cumulative incidence of TCM users and nonusers was 6.9% and 13.5%, respectively (P=0.013). Results of the Kaplan-Meier analysis demonstrated that TCM users had a significantly lower cumulative incidence of cirrhosis than TCM nonusers (P=0.011), and TCM users had a significantly lower liver cirrhosis risk than TCM nonusers (adjusted HR = 0.416, 95% CI, 0.231-0.749). The histological evaluation revealed improved fibrosis in 45.0% of TCM users and 11.1% of TCM nonusers (P=0.033). The analysation of the prescriptions including total 119 single Chinese herbs medicinal demonstrated that "replenish qi and fortify the spleen," "clear heat and dispel dampness," and "soothe the liver and regulate qi" are the main treatment methods of TCM for CHB. CONCLUSIONS: Our study demonstrated that long-term TCM use may attenuate liver cirrhosis risk in patients with chronic hepatitis B (CHB).

Baicalin Is Curative Against Rotavirus Damp Heat Diarrhea by Tuning Colonic Mucosal Barrier and Lung Immune Function.

BACKGROUND: Previous studies have indicated that rotavirus (RV) is a causative factor for diarrhea and gastroenteritis in pediatric and neonatal settings. Baicalin has many functions, including antibacterial, antiinflammatory, and antihypertensive activities. However, the immunological mechanism of RV-induced diarrhea with heat-dampness syndrome (RV-DH) remains unclear. AIMS: The aim of this study is to explore the role of baicalin in RV-DH diarrhea and its underlying mechanism. METHODS: A mouse model of pediatric RV-DH diarrhea was established and treated with baicalin. The concentrations of cytokines were detected by enzyme-linked immunosorbent assay. Messenger RNA (mRNA) expression levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR), while protein expression levels were determined by Western blotting and immunohistochemistry. Flow cytometry was used to detect the frequency of lymphocytes. RESULTS: The concentrations of interleukin-1ß (IL-1ß), IL-2, IL-6, IL-8, RVvb, and secretory immunoglobulin A (SIgA) in bronchoalveolar lavage fluid (BALF) and colonic mucosa were significantly increased in the RV-DH group. Decreased expression of occludin, claudin-1, and zonula occludens-1 (ZO-1) indicated loss of tight junction function and disturbances in intestinal mucosal permeability in the RV-DH group. Flow cytometry analysis showed a high rate of CD8+ lymphocytes and low amount of CD4+ lymphocytes in the RV-DH group. Treatment of RV-DH mice with baicalin significantly reduced the duration of diarrhea and ameliorated the symptoms and pathological and immunological changes. Furthermore, baicalin inhibited STAT1 and activated STAT3 signaling pathways. CONCLUSIONS: These findings indicate the curative and immunoregulatory properties of baicalin and have direct practical and clinical relevance for the treatment of RV-DH enteritis in humans.

Effect of Shuanghu Qinggan Granule () and Yigan Yiqi Jieyu Granule () plus lamivudine on chronic hepatitis B patients: A randomized double-blind placebo-controlled trial.

OBJECTIVE: To observe the clinical efficacy and safety of Shuanghu Qinggan Granule ( , SQG) plus Yigan Yiqi Jieyu Granule (, YYJG) combined with lamivudine (LAM) on chronic hepatitis B (CHB) patients. METHODS: The study was a multicenter, randomized, double-blinded and parallel controlled trial. A total of 320 patients were randomly allocated into 2 groups equally: 160 patients (treatment group) were given SQG and YYJG combined with LAM; and 160 patients (control group) were given LAM plus Chinese herb placebo, respectively. Liver functions, hepatitis B envelop antigen (HBeAg) titer levels, and hepatitis B virus DNA (HBV-DNA) load were monitored. RESULTS: (1) In the 48th week, the treatment group showed superior HBeAg seroconversion rate than that in the control group (38.0% vs. 24.0%, P<0.05). (2) In the 48th week, the treatment group demonstrated lower HBeAg titer than that in the control group (P<0.05). (3) In the 12th, 24th, 48th week, there was no statistical significance in HBV-DNA response rate between the two groups. (4) In the 12th week, the level of glutamyl transpeptidase (GGT) was significantly decreased in the treatment group compared with the control group (P<0.05); in the 36th week, the levels of alanine aminotransferase and aspartate transaminase were significantly lower in the treatment group than those in the control group (P<0.05). CONCLUSION: The protocol of SQG and YYJG combined with LAM to treat CHB showed superior efficacy than LAM monotherapy.

Antiviral activities of atractylon from Atractylodis Rhizoma.

Atractylodis Rhizoma is a traditional medicinal herb, which has antibacterial, antiviral, anti­inflammatory and anti­allergic, anticancer, gastroprotective and neuroprotective activities. It is widely used for treating fever, cold, phlegm, edema and arthralgia syndrome in South­East Asian nations. In this study, 6 chemical compositions of Atractylodis Rhizoma were characterized by spectral analysis and their antiviral activities were evaluated in vitro and in vivo. Among them, atractylon showed most significant antiviral activities. Atractylon treatment at doses of 10­40 mg/kg for 5 days attenuated influenza A virus (IAV)­induced pulmonary injury and decreased the serum levels of interleukin (IL)­6, tumor necrosis factor­α and IL­1ß, but increased interferon­ß (IFN­ß) levels. Atractylon treatment upregulated the expression of Τoll­like receptor 7 (TLR7), MyD88, tumor necrosis factor receptor­associated factor 6 and IFN­ß mRNA but downregulated nuclear factor­κB p65 protein expression in the lung tissues of IAV­infected mice. These results demonstrated that atractylon significantly alleviated IAV­induced lung injury via regulating the TLR7 signaling pathway, and may warrant further evaluation as a possible agent for IAV treatment.

[Distribution of Syndrome Types of Chinese Medicine in Acute Infectious Diarrhea].

OBJECTIVE: To observe syndrome types of Chinese medicine (CM) and distribution features of acute infectious diarrhea patients. METHODS: A retrospective study was performed in 465 acute infectious diarrhea patients. The distribution of CM syndrome and syndrome types in different seasons and genders were analyzed. RESULTS: Lack of appetite [381 (81.94%)], fatigue [350 (75.27%)], abdominal pain [338 (72.69%)], tenesmus [325 (69.89%)], anal scorching hot [276 (59.35%)], nausea [25 (55.48%)], diarrhea [249 (53.55%)], short yellow-urine [240 (51.61%)], thirsty [210 (45.16%)], and abdominal distention [206 (44.30%)] were most often seen. The syndrome distribution were sequenced as intestinal damp heat syndrome [268 (57.63%)], dyspeptic retention in intestine and stomach syndrome [106 (22.80%)], cold-damp invading exterior syndrome [47 (10.11%)], Pi-Wei qi deficiency syndrome [23 (4.95%)], cold-damp disturbing Pi syndrome [21 (4.52%)]. The incidence ratio of intestinal damp heat syndrome was the highest in autumn (P < 0.01), while that of cold-damp invading exterior syndrome was the highest in winter (P < 0.01). Cold-damp disturbing Pi syndrome was more often seen in females than in males (P < 0.01), and its incidence ratio was the highest in autumn (P < 0.05). The incidence ratio of dyspeptic retention in intestine and stomach syndrome was the highest in winter (P < 0.01). CONCLUSIONS: Intestinal damp heat syndrome was the most often seen in acute infectious diarrhea. Incidence ratios of in- testinal damp heat syndrome and cold-damp disturbing Pi syndrome were higher in autumn, while those of cold-damp invading exterior syndrome and dyspeptic retention in intestine and stomach syndrome were higher in winter. Cold-damp disturbing Pi syndrome was more often seen in females.

[Effects of nano-selenium on antioxidant capacity and histopathology of Cyprinus carpio liver under fluoride stress].

To evaluate the protection effect of nano-selenium (NSe) on the antioxidant capacity and histopathology of Cyprinus carpio liver under fluoride stress, a total of 750 C. carpio individuals were randomly divided into five groups, i. e., no fluoride stress and NSe addition (CK), fluoride (100 mg F- x L(-1))-stressed (FS), and fluoride-stressed plus NSe added with a dosage of 0.1 mg Se x L(-1) (NSe L), 0.5 mg Se x L(-1) (NSe M), and 1.0 mg Se x kg(-1)(NSe H). The NSe was mixed with fish foods, and the fishes of FS and NSe groups were exposed to the fluoride stress for 30 days. As compared with CK, fluoride stress decreased the SOD, CAT, and GSH-Px activities and increased the MDA content of C. carpio liver, and induced a definite damage on the histopathology of the liver. Compared with FS, NSe increased the liver SOD, CAT, and GSH-Px activities, decreased the liver MDA content, and mitigated the damage of fluoride stress on the histopathology of the liver. The results demonstrated that in some extent, the addition of NSe into fish foods could alleviate the decline of the antioxidant capacity of C. carpio liver and the damage on the liver histopathology caused by fluoride stress.

[Syndrome distribution among patients with chronic hepatitis C and interventions of integrated traditional Chinese and Western medicine: study protocol].

BACKGROUND: Chronic hepatitis C is one of the major causes of end-stage liver disease with a high incidence rate, amounting to a grave and serious problem of public health. Currently, interferon-based (with or without ribavirin) antiviral therapy has limited use due to its stringent indications, possible contraindications and side effects. Traditional Chinese medicine (TCM) may have advantages in the prevention and treatment of chronic hepatitis C and it is of significant value to discover the advantages. Through this research, a safe and effective treatment protocol of TCM or integrated TCM and Western medicine for chronic hepatitis C can be formed. To this end, during China's Eleventh Five-Year Plan, special research projects on acquired immune deficiency syndrome (AIDS), viral hepatitis and the other major infectious diseases were established. Our studies on chronic hepatitis C constitute one of the major special research topics. METHODS AND DESIGN: Clinical information of patients with chronic hepatitis C will be first collected in a large, multicenter epidemiological survey. Positive symptoms will be analyzed by rapid cluster analysis, principal constituent analysis and factor analysis, and syndrome types will be diagnosed based on expert advice. Concurrently, a large, multicenter, randomized, parallel-group prospective study will be launched based on evidence-based medical principles to evaluate the effects and safety of the treatment protocol for chronic hepatitis C. The evaluated indexes will include the normalization rate of liver function, virological improvement and quality of life improvement for the short-term efficacy and the incidence of liver cirrhosis and (or) primary liver cancer and mortality for the long-term efficacy. DISCUSSION: This study will investigate the TCM syndrome differentiation norms and the syndrome distribution rules of chronic hepatitis C and evaluate the efficacy and safety of a treatment protocol for chronic hepatitis C based on TCM theory or combined treatment of TCM and Western medicine. The study results will be helpful to developing a TCM treatment program for chronic hepatitis C. TRIAL REGISTRATION: The research program was registered in the Chinese Clinical Trial Registry in English and Chinese in January 2010. REGISTRATION NUMBER: ChiCTR-TRC-10000770.

Clinical observation on treatment of 32 patients with measles by qingzhen decoction.

OBJECTIVE: To observe the clinical effect of Qingzhen Decoction (QZD) on measles. METHODS: Adopting the randomizing digital table, 62 patients with measles were assigned to two groups, 32 in the treated group and 30 in the control group. All patients were treated with routine therapy, but QZD was given to the treated group additionally for 5 days. Changes of clinical symptoms, blood routine and liver function before and after treatment were observed, and the medical cost was calculated. RESULTS: After the 5-day treatment, the normalization rate of irritative cough in the treated and the control group was 88.9% (24/27) and 56.0% (14/25) respectively, that of conjunctival congestion was 90.0% (27/30) and 65.5% (19/29) respectively, showing significant differences between groups (P<0.05). The liver function normalization rate in the two groups was 28.6% (2/7) and 25.0% (2/8), and the average medical cost yen 740.7 and yen 749.3, respectively. The total effective rate in the two groups was 96.9% and 93.3% respectively, showing insignificant difference between groups (P>0.05). CONCLUSION: QZD could actively improve the respiratory symptoms like irritative cough and the inflammatory symptoms of eye like conjunctival congestion in patients with measles.

Effectiveness of Danning Tablet in patients with non-alcoholic fatty liver of damp-heat syndrome type: a multicenter randomized controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of Danning Tablet (DNT) in patients with non-alcoholic fatty liver disease (NAFLD) of damp-heat syndrome type. METHODS: A multicenter, randomized, double-blinded and positive drug parallel controlled trial was performed. One hundred and thirty-five patients were enrolled into the study and divided into two groups: DNT-treated group (n=102) and ursodeoxycholic acid (UDCA)-treated group (n=33). Body mass index (BMI), principal symptoms, liver function, blood lipids, iconographic, and compositional parameters were measured before and after treatment, respectively. RESULTS: In the two groups, BMI, distress in hepatic region, fatigue, anorexia, liver function, blood lipids and iconographic parameters were significantly improved, and the improvements of BMI, distress in hepatic region were better in DNT-treated group than in UDCA-treated group. The histological study also showed that DNT had positive effect in treatment of NAFLD. CONCLUSION: DNT is an effective drug to treat patients with NAFLD of damp-heat syndrome type and is more effective than UDCA.

[Clinical study on effect of bushen granule combined with marine injection in treating chronic hepatitis B of Gan-shen deficiency with damp-heat syndrome type].

OBJECTIVE: To evaluate the antiviral efficacy of Bushen Granule (BSG) combined with Marine Injection (MI) in treating patients with chronic hepatitis B of Gan-shen deficiency with Damp-Heat (GSD) syndrome type. METHODS: A total of 90 patients, who were HBV DNA, HBsAg, and HBeAg positive and of GS-DD type, were enrolled, and they were randomly assigned into 2 groups. The 49 patients in the treated group were treated with the combined therapy of BSG and MI and the 41 were administered with lamivudine, the therapeutic course for both groups was 1 year. The negative conversion rate of HBeAg and HBV DNA and the changes in HBV DNA titre, liver function, symptoms and physical signs were observed in the two groups before and after treatment. RESULTS: In the treated group, the negative conversion rate of HBV DNA was 42.6% (20/ 47), insignificantly different to that in the control group (61.0%, 25/41, P > 0.05); the negative conversion rate of HBeAg and HBeAg/anti-HBe sero-conversion rate was 42.6% and 36.2%, respectively, significantly higher than those in the control group (22.0% and 17.0%, P < 0.05); the ALT normalizing rate was 74.4%, higher than that in the control group (51.4%, P < 0.05); the improvement of liver function (ALB and GLB) and clinical symptoms, especially the dizziness, soreness of waist, hypochondrial distending pain, and yellowish urine, were significantly superior to those in the control group(P < 0.01 or P < 0.05); and the partial response rate was 29.8%, insignificant different to that in the control group (14.6%, P > 0.05). CONCLUSIONS: Combined treatment of BSG and MI has an ideal short-term effect in treating patients with chronic hepatitis B of Gan-shen deficiency with Damp-Heat syndrome type, it can inhibit HBV replication and improve patients' liver function and physical signs.

[Relationship between basal core promoter combined point mutation of hepatitis B virus and TCM syndrome type].

OBJECTIVE: To investigate the relationship between basal core promoter (BCP) combined point mutation of hepatitis B virus (HBV) and TCM syndrome type. METHODS: One hundred and two patients with chronic hepatitis with positive HBV DNA and hadn't ever been treated by Lamivudine and interferon were differentiated according TCM syndrome differentiation into 5 types, two excess types (damp-heat blocking zhong-jiao type and blood stasis blocking collaterals type) and three deficiency types, gan-stagnation with pi-dificiency type, gan-shen yin-deficiency type and pi-shen yang-deficiency type. The serum HBV DNA, hepatic biochemical indexes, and the mutation of BCPnt 1762A-T and nt1764G-A combined point were determined, respectively. RESULTS: The variant strain positive rate detected in the excess type was significantly higher than that in the deficiency type, the highest rate appeared in patients of damp-heat blocking zhong-jiao type. CONCLUSION: BCP combined point mutation may be liable to happen in patients of TCM excess type, especially in patients of damp-heat blocking zhong-jiao type.

[Clinical study on treatment of non-alcoholic fatty liver of damp-heat syndrome type by danning tablet].

OBJECTIVE: To evaluate the therapeutic effect of Danning Tablet (DNT) on patients with non-alcoholic fatty liver (NAFL) of damp-heat Syndrome type. METHODS: Multi-center randomized double-blinded positive medicine parallel controlled method was adopted. One hundred and two patients were treated with DNT and 33 patients treated with Ursodeoxycholic acid (UDCA) as control. Indexes including body mass index (MBI), principal symptom, liver function, blood lipids, iconographic parameters and comprehensive efficacy were measured before and after treatment in the two groups respectively. RESULTS: DNT and UDCA had the effect in improving BMI, distress in hepatic region, fatigue, anorexia, liver function, blood lipids and iconographic parameters, etc. DNT showed effects in improving BMI and distress in hepatic region better than those of UDCA. Histological examination also showed that DNT had good therapeutic effect. CONCLUSION: DNT is an effective medicine for NAFL patients of damp-heat Syndrome type, and its efficacy is better than that of UDCA.

[Portal hemodynamics in patients with different syndromes of cirrhosis].

OBJECTIVE: To explore the relationship between the portal hemodynamics or the indices of liver fibrosis and the liver function score in patients with different traditional Chinese medical syndromes of liver cirrhosis. METHODS: One hundred and forty-seven cases of liver cirrhosis with different syndromes were included in the study. Diameters and blood flow velocities of the portal vein and splenic vein were tested by color Doppler sonarography. The indices of liver function (TBIL, ALT, AST, Alb, Glb, PTA) and the indices of hepatic fibrosis (HA, PC-III, LN, VI-C) were tested. RESULTS: The diameters of portal vein in liver cirrhosis patients with different syndromes (internal accumulation of of damp-heat, stagnation of liver-qi, superabundance of dampness due to spleen-asthenia, asthenia of liver and kidney yin, asthenia of spleen and kidney yang, blood stasis) were not significantly different. The blood flow velocities and flow volumes of portal vein in patients with the blood stasis syndrome and the internal accumulation of damp-heat syndrome were significantly different (P < 0.05). The diameter of splenic vein in patients with the internal accumulation of damp-heat syndrome was significantly different to that of the asthenia of liver and kidney yin syndrome, or the blood stasis syndrome, or the asthenia of spleen and kidney yang syndrome, respectively (P < 0.05 or P < 0.01). The blood flow velocity of splenic vein in patients with the blood stasis syndrome or the asthenia of spleen and kidney yang syndrome was significantly different to that of the internal accumulation of damp-heat syndrome, or the stagnation of liver-qi syndrome, or the asthenia of liver and kidney yin syndrome, respectively (P < 0.01). The blood flow volume of splenic vein in patients with the internal accumulation of damp-heat syndrome was significantly different to that of the asthenia of liver and kidney yin syndrome, or the asthenia of spleen and kidney yang syndrome, or the blood stasis syndrome, respectively (P < 0.01). The liver cirrhosis indices HA and PC-III in patients with the asthenia of liver and kidney yin syndrome were significantly different to those of the internal accumulation of damp-heat syndrome (P < 0.05). In Child-Pugh classification, the incidence of Child-Pugh C was the highest in the asthenia of spleen and kidney yang syndrome, while the incidence of Child-Pugh A was the highest in the stagnation of liver qi syndrome. CONCLUSION: The changes of portal vein dynamics in liver cirrhosis patients with the asthenia of liver and kidney yin syndrome, or the asthenia of spleen and kidney yang syndrome, or the blood stasis syndrome are significantly different to those of the internal accumulation of damp-heat syndrome and the stagnation of liver-qi syndrome.

[Effect of anti-fibrosis compound contained serum on procollagen Type I and IV, matrix metalloproteinase and its tissue inhibitor-1 gene expression in HSC-LI90 cell line].

OBJECTIVE: To study the effects of Anti-fibrosis Compound contained serum (AFCS) on procollagen type I and IV (ProC-I and ProC-IV), matrix metalloproteinase (MMP) and its tissue inhibitor (TIMP-1) gene expression in hepatic stellate cell line LI90 (HSC-LI90). METHODS: AFCS was prepared by gastric infusing different dosage (0.5 g/kg, 2.0 g/kg and 4.0 g/kg) of Anti-fibrosis Compound Recipe to rats. After HSC-LI90 cells were exposed to AFCS for 48 hrs, levels of ProC-I, ProC-IV, gene expression of MMP-2, MMP membrane type 1 (MT1-MMP) and TIMP-1 in the cells were detected by Northern blot, and gelatinase activity of MMP-2 was measured by zymography. RESULTS: AFCS of different concentrations could inhibit ProC-I and ProC-IV and TIMP-1 gene expression (P < 0.05 or P < 0.01), increase MT1-MMP gene expression (P < 0.01), but it showed no effect on gene expression and activity of MMP-2 (P > 0.05). CONCLUSION: Anti-fibrosis Compound Recipe has anti-liver fibrosis action, its effects in inhibiting TIMP-1 gene expression of HSC-LI90 cells and promoting degradation of collagen might be one of the mechanisms of the action.

[Therapeutic efficacy of combined application of lamivudine and bushen recipe in treating chronic hepatitis B and its influence on YMDD motif].

OBJECTIVE: To observe the effect of combined application of Lamivudine and Bushen recipe (BSR) in treating patients with chronic hepatitis B (CHB) and its influence on tyrosine-methionine-aspartate-aspartate (YMDD) motif. METHODS: Eighty-eight patients of CHB with positive HBV-DNA were divided into 3 groups, Group A treated with Lamivudine, Group B treated with Lamivudine plus BSR1 and Group C treated with Lamivudine plus BSR2, the serum HBV-DNA, hepatic biological parameters and YMDD motif mutation were observed. RESULTS: The positive rate of HBV-DNA (6.45%) and YMDD motif mutation (3.23%) in Group C were lower than those in Group A respectively, after 52 weeks treatment. CONCLUSION: Combined application of Lamivudine and BSR could enhance the therapeutic effect in treating CHB to certain extent, and could reduce the mutation of YMDD motif.