| BackgroundApproximately 93 million people in China have serological evidence of present infection with HBV and around 20 million people are chronic hepatitis B (CHB)patients,indicating the prevention and therapy of HBV-related fibrosis and cirrhosis have been being a challenge for our country.The spectrum of the disease and natural history of chronic HBV infection are diverse and variable,ranging from an inactive carrier state to progressive chronic hepatitis B (CHB),which may evolve to cirrhosis and hepatocellular carcinoma (HCC).Longitudinal studies of untreated patients with CHB indicate that,after diagnosis,the 5-year cumulative incidence of developing cirrhosis ranges from 8% to 20%.The 5-year cumulative incidence of hepatic decompensation is approximately 20% for untreated patients with compensated cirrhosis.Untreated patients with decompensated cirrhosis have a poor prognosis with a 14-35% probability of survival at 5 years.Currently available antiviral therapy for chronic HBV includes the interferon and oral nucleos(t)ide analogues (NAs),both of whom have been successfully used to suppress HBV replication and prevent CHB progression.However,as interferon cost more and has more side effects,it is not licensed for HBV-related fibrosis and cirrhosis treatment in most European countries.On the contrary,NAs could successfully suppress HBV replication and therefore recommended for the treatment of HBV-related liver fibrosis and cirrhosis.Nevertheless,it is not enough to merely anti HBV to achieve the goal of reversing the cirrhotic process,as the cascade effect caused by cytokines and hepatic stellate cells(HSC) in the fibrosis progression would not stop even if HBV DNA was suppressed.Besides,it takes at least 5 years to retarddisease progressionand improves disease outcomes in patients with HBV-related fibrosis,making it a great challenge to reverse the cirrhotic process.There have been several clinical trials to verify the efficacy and safety of main compound preparation of traditional Chinese medicine:Anluohuaxian pill,Fufang Biejiaruangan tablet,Fuzheng Huayu capsule are the three main medicines approved for the treatment of HBV-related fibrosis and cirrhosis.Fufang Biejiaruangan table was investigated by the 302 Hospital of Chinese PLA,and was approved by State Food and Drug Administration (SFDA) in 1999.Later then,it was recommended by the guidelines for the diagnosis and treatment of liver fibrosis in integrative medicine in 2006.Fufang Biejiaruangan tablet is established under the theory of TCM differentiation of syndrome,its therapeutic principles of TCM are "softening and resolving hard masses,dissolving blood stasis and detoxieation,and replenishing qi and blood".Animal experiments have confirmed that this tablet could effectively suppress the cirrhotic process,inhibit hepatic stellate cell activation and proliferation,reduce the synthesis of collagen,and reduce excessive deposition of collagen in Diss cavity.Few clinical studies suggest that it could effectively reduce serum HA,LN,PC?,reduce the width of portal vein and spleen thickness,improve the portal vein pressure,and block the occurrence of decompensated cirrhosis.Short-term adefovir dipivoxil (ADV) combine Fufang Biejia Ruangan tablet therapy for CHB results in the suppression of viral replicationand has been associatedwith improvements of liver histology,which was better than the monotherapy group.There have also been few studies suggesting that entecavir combine Fufang Biejiaruangan tablet therapy could also successfully suppress HBV replication and prevent fibrosis progression.However,most of the above studies are retrospectively designed,and the studies conducted have been small sized with short-term follow ups.In addition,improvements in liver functionand fibrosis were evaluated mostly limited to serological indexes,which were much less convincing than liver tissue pathology or other non-invasive diagnostic method.Liver biopsy is considered the gold standard for diagnosing chronic liver disease,grading necroinflammatory activity,and staging liver fibrosis.However,sampling error can lead to underestimation of the degree of liver fibrosis,especially when biopsy specimens are small or fragmented.In addition,interpretation of theresults is subject to significant intra-and inter-observervariability.Moreover,liver biopsy is not suitable for repeated evaluations,because it is invasive and cancause major complications.There is growing interest in the use of non-invasive methods,including serum markers and transient elastography,to assess hepatic fibrosis to complement or avoid a liver biopsy.Transient elastography (TE) recently emerged as anovel,rapid,non-invasive and reproducible tool forassessing the degree of liver fibrosis by measuring liver stiffness (LS).In a large-scale meta-analysis of50 studies,the mean areas under the receiver operatingcharacteristic curves (AUROCs) for the diagnosis of significantfibrosis and cirrhosis were 0.84 and 0.94,respectively.ObjectiveTo establish ETV+FFBJ,ADV,ADV+FFBJ,ETV prospective study cohort,compare the efficacy and safety data of different regimens for treatment of chronic hepatitis B (chronic,hepatitis B CHB) CHB liver fibrosisMethods1.Expected to recruit 280 patients of chronic hepatitis B (CHB) liver fibrosis,every two patients matched for demographic and baseline data,according to gender,age (?5 years old),HBeAg status,liver stiffness values (liver stiffness values,LSM) basic matched 1:1 respectively into the ETV cohort study included ETV+FFBJ group,single ETV group;by pairing the same way according to 1:1,respectively,into the adv cohort study included ADV+FFBJ group,single ADV group2.ETV+FFBJ group was treated with ETV (Sino American Shanghai Squibb Pharmaceuticals Co., Ltd., the same below),once a day,0.5mg every time and take FFBJ (Inner Mongolia Ferrer in Mongolian Medicine Technology Co., Ltd.,the same below),3 times a day,4 tablets each time;single with ETV,1 times a day,each time 0.5 mg;adv (Tianjin Pharmaceutical Research Institute of pharmaceutical limited liability company),1 times a day,every 10 mg;FFBJ (Inner Mongolia Ferrer in Mongolian medicine science and Technology Co., Ltd.),3 times a day,4 tablets each time.3.Blood routine test,liver function,renal function,serum HBsAg,HBeAg,HBeAb in serum,serum HBV DNA quantitative,LSM,abdominal ultrasound (monitoring for HCC occurrence) every three months before 48weeks,after 48 weeks to do the test every six months,if the ALT or HBV DNA below the detection limit,to check the liver function and HBV DNA every three months.4.4 groups of patients at each follow-up time point of HBV DNA comparison cumulative negative rate,ALT cumulative abnormal rate,at each follow-up time point of LSM,APRI and FIB-4 and HBsAg median levels,HBeAg conversion rate,records of virologic breakthrough,resistance,chemical breakthrough,disease progression(including the incidence of liver cirrhosis rate,acute on chronic liver failure incidence,the incidence rate of HCC) and adverse reactions of special cases.5 Application of SPSS20 software to process data.For the measurement data of normal distribution,and between the four groups compared with completely random data variance analysis;Non normal distribution between the 4 groups were compared using multiple independent samples rank sum test,the same group of different follow-up time points compared with the use of multiple groups of related sample rank sum test method(Kruskal-Wallis H test/Wilcoxon test/Friedman test),rate compared with contingency table analysis method.p<0.05 difference was statistically significant.Result1.Eventually there were 98 cases,99 cases,35 cases,36 cases of patients into group ETV+FFVJ,ETV group,ADV+FFBJ,ADV group and follow-up to 96weeks,with the prolongation of treatment time,the group at each follow-up time point of HBV DNA cumulative negative rate increased gradually (?2=303.176,322.898,314.223,298.435,P<0.001).The median duration of four groups of HBV DNA negative respectively for 12 weeks,12 weeks,48weeks,48 weeks,significant difference (?2=29.540,p<0.001).The results suggest that ETV and ADV have potent antiviral effects,and ETV is stronger,and the combination of FFBJ did not affect the antiviral effects of these two drugs.2 In the follow-up time point of 96 weeks abnormal rate of ALT ETV cohort abnormal rate of ETV+FFBJ was 2.04%,abnormal rate of ETV group was 2.02%,ADV cohort abnormal rate of ADV+FFBJ was 14.29%,abnormal rate of ADV group was 19.44%(?2=21.401,p<0.001),confirmed that the four kinds of treatment can effectively inhibit the inflammatory response in the liver tissue,provide the basis for the reversal of liver fibrosis.ETV+FFBJ,ETV,ADV+FFBJ,single with ALT of ADV group complex often position respectively for 12weeks,24weeks,48weeks,48 weeks were compared with significant difference (?2=15.141,p <0.05)3.Compared APRI value between ETV+FFBJ and ETVgroup in the 24w 0.81 (0.54,1.15),0.98 (0.78,1.55),P=0.006;48wAPRI value was 0.46 (0.38,0.62),0.66 (0.56,0.87),p <0.001,there are significant differences;96wAPRI value of 0.43 (0.35,0.53),0.44 (0.27,0.52),p=0.338,no statistical difference.Combined with group and single group of ADV cohort in 24w the APRI value were 0.70 (0.47,0.93),0.86 (0.53,1.26),p=0.301;48W were 0.50 (0.40,0.72) and 0.62 (0.52,1.13),p=0.016 have significant difference;96w were 0.43 (0.38,0.59),0.51 (0.38,0.79),p=0.160 no statistical difference.The statistical difference may be related to the change of AST.In the decline of APRI,the combination of the group and the use of a single group with a statistically significant difference may be associated with the decline in the group AST.4.Compared FIB-4 value between ETV+FFBJ and ETVgroup in the 24w were 2.26(1.68,342).2.88 (2.31,4.24),p=0.017;48w FIB-4 value for 1.68 (1.20,2.07) and 2.37(1.71,3.43),p <0.001,the differences were statistically;96w FIB-4 value were 1.36(1.03,2.14),1.79 (1.20,2.26) ,p=0.277, no statistical difference.Statistical differences between the two groups of FIB-4 in the ETV cohort may be related to changes in the AST/ALT ratio.Compared FIB-4 value between ADV+FFBJ and ADV group in 24wAPRI value 2.20 (1.44,2.81) and 1.94 (1.50,3.33),p=0.746;48W respectively for 1.85 (1.19,2.45)and 1.98 (1.27,2.81),p=0.509;when the laptop was 1.65 (1.15,2.13),156 (1.09,2.36),p=0.962,between the groups had no statistically significant sample size might be too small.5.Compared LSM between ETV+FFBJ and ETV group in the 24w,the LSM were14.20 (8.30,16.50),13.40 (10.30,20.50),p=0.249;48w LSM value for 10.50 (7.10,12.70),12.30 (9.10,16.70),p=0.004;96w LSM value is 8.00 (6.70,10.20),10.30(9.30,13.10),p <0.001,statistical difference.Compared LSM between ETV+FFBJ and ETV group in 24w LSM value for were 14.40 (8.89,16.70),12.40 (9.00,20.30),p=0.962;in 48W were10.45 (8.50,12.70),10.60 (8.70,19.40),p=0.262;96w were 8.50(7.80,9.68),10.30 (8.00,17.90),p=0.005,to 96w ETV cohort,ADV cohort,the comparison groups combined with FFBJ between single group showed significant difference,and clinical significance,combined with compound Biejiaruangan tablets can significantly reduce the LSM.6 Breakthrough and variation of the virusIn the course of treatment,group ETV+FFBJ and single with ETV group without resistance.ADV+FFBJ and adv monotherapy group 1and 2 cases of patients with drug-resistant mutation and resistance loci respectively for rtA181V and rtA181V and rtn236t and converted to ETV+FFBJ,ETV,single with ETV treatment and achieved virological response.7 HCC incidenceETV+FFBJ group,single use ETV group no HCC occurred,ADV+FFBJ group of 2 cases (all patients received surgical treatment,follow-up so far),single use ADV group of 1 cases (for giant block type hepatocellular carcinoma,portal vein wide cancer bolt,death)8 Incidence of adverse reactionsETV+FFBJ group,ADV+FFBJ group,respectively,5,5 cases of patients with gastrointestinal discomfort after taking FFBJ,changed to eat after the disappearance of symptoms.No adverse reactions were observed in patients with elevated serum creatinine and serum phosphorus.Conclusion1.The combination group showed the exact antiviral efficacy.In cohort,the comparison of HBV DNA cumulative negative rate,median duration of negative between group was no statistical difference,the combined use of compound Biejiaruangan tablets did not affect the antiviral efficacy of entecavir or adefovir.The comparison between cohort shows that entecavir antiviral effects of entecavir is superior to adefovir group group2.The comparison of two group in the same cohort shows that FFBJ still has a certain effection of protecting liver,reducing enzyme activity (P<0.05)3.The anti-virus and anti liver fibrosis combination therapy showed better anti liver fibrosis effect at 48 and 96 weeks,The comparison between the two group in the same cohort showed that LSM value decreased significantly in combined treatment group (P <0.05),suggesting that the combination therapy has synergistic anti liver fibrosis effect.4.4 therapy showed good safety... |
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