| BackgroundHepatitis B virus(HBV)infection is one of the most important public health problems in the world.Before nucleot(s)ide analogues were invented,the natural history of chronic hepatitis B(CHB)is generally evolved along with the trilogy-"chronic hepatitis-cirrhosis-hepatocellular carcinoma(HCC)"[1].In CHB patients,the cumulative incidence of decompensated cirrhosis for 5 years is 15-20%,and the annual incidence of HCC is 3-6%.Besides,the 5-year survival rate of patients with compensated or decompensated cirrhosis is 80-85%and 30-50%,respectively[2].Therefore,effectively preventing the progression of liver fibrosis or maximally reversing early stage cirrhosis will largely reduce the occurrence of end-stage liver disease(such as decompensated cirrhosis,HCC).Since the use of nucleot(s)ide analogues(NAs)for antiviral treatment of hepatitis B,it has fundamentally reversed the natural progression of CHB and greatly reduced the mortality of CHB associated end stage of liver disease[3].Tenofovir disoproxil fumarate(TDF)and entecavir(ETV)are the first-line antiviral drugs with potent antiviral ef’fects.Adefovir dipivoxil(ADV)is not susceptible to drug resistance and has been applied in clinical treatment for a long time with a relatively low expense[4].However,although NAs can rapidly and effectively inhibit HBV DNA replication,once liver fibrosis is initiated,it will continue and there is no specific western medicine for fibrosis treatment[5].Therefore,it is urgent to explore effective anti-fibrosis Chinese medicine combined with anti-viral treatment to block the progression of liver fibrosis,thereby reducing the incidence of hepatitis B-related cirrhosis and HCC.Traditional Chinese medicine has the unique advantages in the treatment of liver fibrosis.The good effect on anti-liver fibrosis of Fufang Biejia Ruangan Pill(FFBJ)has been confirmed by a large number of clinical studies.It is an herbal medicant consisted by 11 herbal medicines.It is the first anti-fibrosis drug approved by the China State Food and Drug Administration,which has been demonstrated to have a certain anti-liver fibrosis efficacy for its TCM effects,which including inhibiting collagen deposition,as well as alleviating hepatic injury.Recent studies have shown that CHB patients with fibrosis or even cirrhosis may benefit from the combination of NAs with anti-fibrotic drugs.But in the long run,there are no long-term follow-up results to evaluate whether they can reduce the development of HCC.Besides,these studies usually have some common deficiencies,such as small sample size and lack of clinical randomized controlled trial design.Therefore,a prospective,well controlled study cohort with larger samples is needed for further demonstration of above efficacy.ObjectiveThe aim of our study was to evaluate the efficacy,safety and development of HCC of-different antiviral agents(ETV/TDF/ADV)combined with FFBJ for CHB patients with hepatic fibrosis,including ETV cohort(divided into ETV monotherapy group and ETV+FFBJ combination therapy group),TDF cohort(divided into TDF monotherapy group and TDF+FFBJ combination therapy group)and ADV cohort(divided into ADV monotherapy group and ADV+FFBJ combination therapy group)three prospective study cohorts.MethodsCHB patients with fibrosis were recruited and divided into ETV monotherapy group and ETV+FFBJ combination therapy group(ETV cohort)according to gender,age(defference≤5 years),HBeAg status,and liver stiffness measurement(LSM).The same method was followed by pairing 1:1 into the TDF monotherapy group and TDF+FFBJ combination therapy group(TDF cohort),as well as ADV monotherapy group and ADV+FFBJ combination therapy group(ADV cohort).HBV DNA cumulative negative rate,ALT cumulative normal rate,LSM,HBsAg levels,HBeAg conversion rate and rates of virologic breakthrough,drug resistance,disease progression(including the reversal of liver fibrosis and the incidence rate of HCC)and adverse events of special cases are recorded and analyzed.ResultsAfter 144 weeks of follow-up,a total of 749 CHB patients with fibrosis were eligible and recruited into analysis.Among them,185 patients in ETV group and 180 in ETV+FFBJ group;131 in TDF group and 135 in TDF+FFBJ group;58 in ADV group and 60 in ADV+FFBJ group,respectively.There were no significant differences in age,gender ratio,HBsAg level,HBeAg positive rate,HBV DNA quantification,ALT,AFP and LSM levels between the six groups(P>0.05).With the prolongation of treatment,the cumulative negative rate of HBV DNA was gradually increased at each follow-up time in all the groups(p<0.001).Both ETV and TDF had a potent antiviral effect.At 48 weeks of treatment,the cumulative negative rate of HBV DNA in the two cohorts was 85.5%(312/365)and 89.5%(238/266),respectively.At 144 weeks,the cumulative negative rate of HBV DNA was 94.0%(343/365)and 96.6%(257/266),respectively,and the difference has no statistical significance(X48 week2=2.194,P=0.139;X144 week2=2.302,P=0.129).However,the efficacy of ADV was not as powerful as ETV or TDF.The cumulative negative conversion rates of HBV DNA at 48 weeks,96 weeks,and 144 weeks were 43.2%(51/118),69.5%(82/118),and 80.5%(95/118),respectively.The median time of HBV DNA normalization in the six groups were 24.,12,12,12,72 and 72 weeks,respectively,and the difference was statistically significant(X2=32.820,P<0.001).The abnormal rate of ALT in each group also decreased with the prolongation of treatment(P<0.001),which confirmed that all the six treatment regimens can effectively inhibit the liver inflammation.The median time of ALT normalization in six groups was 24,12,12,12,36,and 24 weeks,respectively.The difference between the groups has statistical significance(x2 =9.568,P=0.002).At 48,96 and 144 weeks of treatment,liver fibrosis was reversal in all six groups(P<0.001).The degree of liver fibrosis reversal in the combination therapy group was significantly better than that in the monotherapy group(x2 ETV队列 2=11.345,X TDF 队列2=10.160,XADV 队列 2=6.358,each P<0.05),suggesting that the combination of FFBJ and NAs has a good antiviral and anti-fibrosis effect,while the three nucleoside drugs have no significant difference in anti-fibrosis.In addition,no patients were found to have HCC in the TDF cohort during follow-up to 144 weeks,but the incidence of HCC in ETV group,ETV+FFBJ group,ADV group,and ADV+FFBJ group was 2.2%,1.7%,1.7%and 3.3%,respectively.The incidence density was 7.2/1000 person-years,5.5/1000 person-years,5.7/1000 person-years,and 11.1/1000 person-years.There was no significant difference in the incidence of HCC between the groups(x=6.813,P=0.138).Compared with CHB patients without antiviral therapy(cumulative incidence of HCC in three years was 7.2%),the incidence of HCC in CHB patients included in this study was significantly lower than that in patients without antiviral therapy.Conclusion1.The combined therapy of NAs with FFBJ has potent antiviral and anti-fibrosis effects,and the degree of liver fibrosis reversal in the combination therapy group is significantly better than that in the mono-therapy group.2.The antiviral effect of TDF and ETV is significantly better than ADV,but there is no statistical difference between TDF and ETV.The addition of FFBJ do not influence the antiviral effects of these three NAs.3.Long-term antiviral and anti-fibrosis treatment can significantly reduce the development of HCC compared with CHB patients who do not receive antiviral therapy.4.All six treatment regimens are well tolerant and no serious adverse events are observed during the follow-up. |
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