Efficacy Evaluation Of Fu Fang Bie Jia Ruan Gan Pian In Treating Liver Fibrosis Based On Meta Analysis And Noninvasive Diagnosis

BackgroundLiver fibrosis is the middle and essential stage of various liver diseases developedinto end stage,if liver fibrosis can be prevented from progress or liver cirrhosis can beregressed in the maximal degree,then the related mortality can be decreased.Traditionalchinese medicine play a unique role in the treatment of liver fibrosis,Fu Fang Bie JiaRuan Gan Pian is one of the effective formulas,which is established under the theory ofTCM differentiation of syndrome,its therapeutic principles of TCM are"softening andresolving hard masses,dissolving blood stasis and detoxication,replenishing qi and blood",anti-fibrosis is the chief efficacy.It has been demonstrated that FFBJRGP has a betterefficacy of anti-fibrosis than the control drug-He Luo Shu Gan Pian through multi-centerclinical control trials before listed,in which HBV-related advanced liver fibrosis and earlycirrhosis are involved,all these participants weren't given anti-virus therapy.Chronic progress of hepatitis B has been delayed remarkably since nucleosideanalogs are used for anti-virus,studies have proved that effective anti-virus therapy canprevent and regress live fibrosis in some degree.In order to save resources and optimizethe integrate therapy of TCM and western medicine,we need to evaluate the efficacy ofFFBJRGP secondly on the basis of anti-virus therapy.Although there have been some reports about the FFBJRGP's clinical efficacy basedon the anti-virus therapy, the following deficiencies still exist:there are less high levelclinical randomized control trials and systematic reviews,indexes of effective evaluationare restricted to "the four serum liver fibrosis marker,liver function,etc",which are morerelated to inflammation than fibrosis.the powerful evidence of liver histology or highercorrelation indexes aren't put into practice,although non-invasive diagnosis such astransient elastography and other predictive models.Considering the drawbacks of liverbiopsy such as invasive operation,high price,and not easily been repeated and so on,non-invasive assessment method for diagnosis and evaluation are urgently needed.Inrecent years,many developments have been accepted in these areas,such as TE and othervarious non-invasive diagnostic models,however,more rigorous evaluations and uses arelacked.Under this condition,our study first make a meta analysis of the literatures accordingwith"randomized control trials about HBV-related liver fibrosis,FFBJRGP is used foranti-fibrosis on the basis of nucleoside analogs used as anti-virus",then some often used non-invasive indexes are assessed with the liver histology,at last we design the clinicalrandomized control study to further evaluate the efficacy.Objective1.Clinical efficacy of FFBJRGP was evaluated through meta analysis on the clinicalrandomized control studies which used nucleoside analogs as anti-virus treatment.2.Correlation and regression analysis between non-invasive diagnostic methods andliver histology was explored,in order to find effective and accurate method to diagnoseand predict the liver fibrosis.3.The clinical efficacy of FFBJRGP are evaluated based on clinical randomizedtrials,the participants included chronic hepatitis B and liver cirrhosis,the control grouponly use entecavir for anti-virus,experimental group add FFBJRGP for anti-fibrosis.thereare two observation time points through the treatment courses.Methods1.Meta analysis was made from the view of evidence-based medicine, literatures areinvolved into if they accord the following conditions:patients of chronic hepatitis B andHBV-related cirrhosis as participants,control group used nucleoside analogs as anti-virusdrug,experimental group added FFBJRGP as anti-fibrosis drug,two groups are randomlydistributed.Software of Revman is used for statistical analysis on the four fibrosisindexes and negative rates of HBVDNA and HBeAg.2.Correlation and multi-linear regression between histological stages andnon-invasive clincal indexes are studied by case analysis,including fibroscan'sresult,APRI predictive model,four fibrosis indexes and other clinical routine tests, theaccuracy between non-invasive diagnostic methods and stages of liver histology isestimated using area under receiver operating characteristics.3.Clinical efficacy of FFBJRGP is evaluated through prospective randomizedcontrol trial which involve patients diagnosed as chronic hepatitis B and livercirrhosis.The control group are treated with Entecavir as anti-virus drug,experimentalgroup are treated with Entecavir and FFBJRGP,the main outcome indexes are FS andAPRI based on Part2's results,liver function and other serum fibrotic markers andHBVDNA and HBeAg negative rates are also compared. There are two observation timepoints which are6and12months after treatments.Two-sample t-test is used to comparecontinuous data between experimental group and control group after treatment,pairedt-test is used to compare the before and after treatment.numeration data use χ2-test. Result1.Meta analysis shows that,after treatment of FFBJRGP,experimental group of CHBand HBV-related liver cirrhosis achieve lower serum fibrotic markers such as HA,LN,PCⅢ, and lower IV.C in LC subgroup;with aspects of HBVDNA and HBeAg negtiverates, FFBJRGP may have synergistic effects with nucleoside analogs.2.(1)Correlation analysis shows indexes of ALB,CHE,LDLC,PLT have negtivecorrelation with stages of liver histology,indexes of AST,DBIL,γ-GT,TBA,PT,FS, APRI,HA,LN,IV.C,PCⅢ have positive correlation with stages of liver histology,among theseall,correlation coefficients between FS and S are maximal(r=0.67).Multi-linearregression analysis shows FS can singly or together with γ-GT enter into the regressionmodel to predict the stages of liver histology.(2)FS can predict and judge the degree ofliver fibrosis,comparing withe APRI, the AUROC are0.866,0.718when predicting S≧2,FS and APRI are6.85,0.456respectively.the AUROC are0.87,0.733when predicting S≧3,FS andAPRI are9.95,0.469respectively.3.(1)FS and APRI are used as the chief outcome to evaluate the efficacy ofFFBJRGP. FS in CHB is significantly lower than control group after6months'treatment,FS and APRI are both significantly lower than control group after6and12months' treatment.(2)The LN and IV.C of the four fibrotic indexes in LC are significantlylower than control group after12months' treatment.(3)AST in CHB is significantlylower than control group after6months' treatment,ALT and AST in CHB are bothsignificantly lower than control group after12months' treatment.AST in LC issignificantly lower than control group,ALB and CHE are higher,after12months'treatment.(4)There is no significant difference in HBVDNA and HBeAg's negative rates.Conclusion1.Meta analysis suggests FFBJRGP is an effective anti-fibrotic traditional chineseformula,it can decrease serum fibrotic markers more significant than control group whichdidn't use FFBJRGP,it can improve the effects of nucleoside analogs in negative rates ofHBVDNA and HBeAg.2.The result of FibroScan called as FS have the highest correlation coefficient withstages of liver histology, which can be used to diagnose and predict liver fibrosissingly,there is high accurate when FS used to diagnose liver fibrosis through calculateAUROC.3.Clinical randomized research shows that FFBJRGP can decrease FS and APRI more significantly compared to control group which used Entecavir only, it can improveliver function in some degree,it didn't have synergistic effects with entecavir on negativerates of HBVDNA and HBeAg through our study.In CHB patients,there is no significantdifference in6or12months treatment, In compensated LC patients,experimental grouphave better results both in6and12months.