| BACKGROUND:Chronic infection with hepatitis B virus(HBV)is a significant health problem wroldwide and a leading cause of cirrhosis and hepatocellular carcinoma(HCC).WHO reports that about two billion people have been infected with HBV and 350 million people are chronic carriers in the whole world.People with HBV are at increased risk of the liver failure,cirrhosis and HCC.The estimated worldwide mortality is one million a year.However,China is a high-endemic arae,the epidemiological investigation on HBV infection in 2006 indicated that hepatitis B surface antigen(HBsAg)carrier rate was 7.18%in less than sixty years old population,below five years old that was 0.96%,and there were more than 2 million patients with chronic hepatitis B,and about 300 thousand patients died of end stage liver disease.Therefore,the treatment of chronic hepatitis B is very improtant.Domestic experts formulated the guideline for prevention and treatment of chronic hepatitis B on the basis of reference to the latest research results,in accordance with the principle of evidence-based medicine,put forward the overall goals for the treatment of CHB clearly:achieve maximum suppression or elimination of HBV,reduce the inflammation of the liver and liver fibrosis,delay and prevent the progression of the disease,to reduce and prevent liver cirrhosis,decompensation,HCC and its complications,so as to improve the life quality of patients,prolong the survival time.The natural history of perinatal HBV infection is divided into four stages:immune tolerant phase,immune clearance phase,inactive disease,and re-activation phase.The characteristics of the immune clearance phase are transaminase level fluctuations,followed by the loss of HBeAg and the development of antibody to hepatitis B e antigen(anti-HBe),thus ahieve HBeAg seroconversion.Some studies report that this phase is the best time of antiviral therapy,can obtain the ideal therapeutic effect.Two strategies are available for treatment of chronic hepatitis B:interferon and nucleos(t)ide analogues in clinic.The drugs have been approved for clinical use by China Food and Drug Administration(CFDA),including conventional ~aIFN and pegylated interferona(PEG-~aIFN),lamivudine(LAM),adefovir dipivoxil(ADV),entecavir(ETV),telbivudine(LDT)and tenofovir disoproxil fumarate(TDF).These medications act primarily through blocking reverse transcription of pregenomic RNA to HBV DNA.However,they are unable to eradicate HBV infection because of the persistence of HBV cccDNA in the infected hepatocytes.Once the therapy is discontinued,virus mutation and/or rebound will occur.So,a long-term antiviral therapy is necessary for sustained suprssion of HBV DNA replication.Interferon can not only directly suppress viral replication,but also controlthe natural killer cells(NK cells)and cytotoxic T lymphocytes(CTL cells)activity,thereby play a role of immune regulation.Interferon have the higher rates of HBeAg seroconversion and HBsAg loss for both sustained suprssion of HBV DNA replication and immune regulation.Antiviral immune deficiency of the patients with chronic hepatitis B may take an important role in the chronicity of hepatitis B.Previous studies have confirmed that HBV specific CTL cells are the main immune components of clearing HBV,however,the persistent replication of HBV is closely related to the damage of virus specific T cells function,directly affect the clear of HBV.Interfron greatly improve the immune function in patients with CHB,achieve better sustained response rate,reduce the incidence of liver cirrhosis and HCC,and increase the survival rate of patients.Thereby,interfron have been recommended for the initial treatment of CHB by guidelines from Asia,Europe,and the United States.In HBeAg positive patients with chronic hepatitis B,the most important relevant factors of beneficial effect to interfron treatment inclued low serum HBV DNA and high levels of ALT before treatment,genotype of HBV,HLAloci,IL-28B of the host,and HBsAg levels or decline in the treatment.Research shows that the rate of HBeAg seroconversion will be less than 20%after 48-week interferon treatment and 24-week follow-up if HBV DNA level would still be more than 105 copies/mL at week 24 for the CHB patients receiving interferon treatment.The specific mechanism is not completely clear,which may be related to immune escape of HBV in early infection,block the signal pathways induced by interferon.Domestic experts indicated that the change of immune condition induced by interferon may improve the immune response to NAs,but this scheme has not been widely recognized.In order to help more interferon-treated CHB patients with poor virological response obtain ideally virological,serological and biochemical response as far as possible,current study was designed and aimed to assess the long-term sustained curative efficacy of NAs add-on therapy for HBeAg-positive CHB patients who had a poor virological response at week 24 after starting interferon.Previous studies reported that the combination of NAs and interferon could increase the on-treatment virological and/or serological responses as compared to either NAs or interferon monotherapy.In the treatment of patients with CHB,interferon has higher rates of HBeAg seroconversion,and NAs strongly suppress HBV replication.Therefore,whether can add with a NAs(with the exception of telbivudine,because the combination may have the risk of peripheral neuropathy)to improve response rate when HBV DNA levels of HBeAg positive CHB patients treated with interferon decline is not obvious,but the current clinical research reports are rare.At the same time,this study also set up to interferon monotherapy group,change to NAs group and withdrawal group.The comparison of virological,serological and biochemical responses among groups at week 48 and week 72,and evaluate the effect of the combination treatment.To provide a theoretical basis for the optimization of treatment in patients with chronic hepatitis B.Previous studies showed that about a quarter of HBeAg positive patients showed concurrence of HBeAg and anti-HBe during interferon treatment,such patients shown more possibility to get HBeAg seroconversion.Such phenomenon was not uncommon in antiviral treatment-naive patients.However,the clinical characteristics and significance of chronic hepatitis B with the concurrence detection of HBeAg and anti-HBe not been studied in detail to date.AIMS:1.To elucidate the clinical effectiveness of interferon plus nucleos(t)ide analogue(NAs)in suboptimal responders of interferon treatment for HBeAg-positive chronic hepatitis B.2.To elucidate the clinical characteristics of patients with the concurrent detection of HBeAg and anti-HBe in antiviral treatment-naive group.3.To elucidate the clinical significance of chronic hepatitis B with the concurrence detection of HBeAg and anti-HBe during antiviral treatment.METHODS:1.PATIENTS:1.1 To analyze 256 cases of HBeAg positive chronic hepatitis B treated with interferon outpatients and inpatients from September 2010 to December 2014 in the Hepatology Unit,Nanfang Hospital.All patients with HBV DNA≥1.0×10~5 IU/mL and HBV DNA drop≤2log10 IU/mL at week 24 accord to the diagnostic criteria of 2010 Chinese Clinical practice Guidelines.Exclusion criteria were as follows:existence of coinfection with hepatitis A,hepatitis C,hepatitis D,human immunodeficiency virus,Epstein-Barrvirus and cytomegalovirus;existence of combination with cirrhosis,hcpatocellular carcinoma,metabolic disease,autoimmune hepatitis,serious heart,kidney,endocrine,hematopoietic system disease and psychological diseases.This study was approved by nanfang hospital,southern medical university ethics committee.All included patients were devided into interferon plus NAs(group A),interferon alone keeping on(group B),change to NAs(group C),or withdrawal(group D)for 48 weeks according to their own choice.Clinical data were collected at baseline and every 12 weeks to access the efficacy of combanition therapy.1.2 To collect 598 cases with the concurrence of HBeAg and anti-HBe from September 2008 to December 2014 in the Hepatology Unit,Nanfang Hospital.All patients accord to the diagnostic criteria of 2010 Chinese Clinical practice Guidelines,326 cases are antiviral treatment-naive patients(165 patients received different antiviral treatment after HBeAg and anti-HBe double postive)and 272 cases undergoing antiviral therapy.We divided patiens in treatment group into two group:IFN group who received interferon treatment and NAs group who received NAs treatmen.To compare the clinical characteristics between the two groups.2.TEST METHOD:Serum ALT was detected by Olympus AU5421 full-automatic biochemical detector,HBeAg/anti-HBe and HBsAg contents were detected by Architech i2000,and the serum HBV DNA load was determined by Roche lightcycler480 fluorescence quantitative PCR method kit(lower detection limit 100 IU/mL,Daan Company,Guangzhou city,China)according to production instruction.The tested specimens are fasting venous blood serum.3.DEFINITION:3.1 Virological response was defined as a undetectable HBV DNA,that is HBV DNA negative.3.2 Serological response was defined as either confirmed loss of HBsAg or as confirmed seroconversion of HBeAg.3.3 Serum biochemical response was defined as a persistent normalization of ALT.4.SAFETY ASSESSMENT:To observe and record the adverse events in patients undergoing treatment,and drug resistance to nucleos(t)ide analogues.5.STATISTICAL METHOD:The SPSS 13.0 was used for statistical analysis.Quantitative variables were expressed as mean and median,comparisons among groups of normal distribution datas were performed using t-test or One-Way ANOVA,and skewed distribution datas were performed using Wilcoxon rank sum test.Categorical variables were presented as percentages,were performed using chi-square test.P<0.05 was considered statistically significant.RESULTS:1.A total of 256 interferon-treated CHB patients with poor virological response were included and analyzed in the study,which comprised of 99 patients in group A,52 patients in group B,70 patients in group C and 35 patients in group D.The age(P=0.278),sex(P=0.091),HBV DNA load(P=0.379),serum HBsAg titers(P=0.890),HBeAg titers(P=0.262),ALT levels(P=0.963)at baseline and HBV DNA load(P=0.065),serum HBsAg titers(P=0.650),HBeAg titers(P=0.692),ALT levels(P=0.557)at week 24 were well matched among groups.In D group,HBV DNA loads,HBeAg levels and ALT levels are maintained at a higher level,and have been upward trend at week 24 and 48 after therapy discontinued.The virological serological and biochemical responses were evaluated at 48 and 72 during the antiviral therapy among other three groups.The percentage of patients with HBV DNA levels below 100 IU/ml(virological response)was significantly higher in group A and in group C than in group B at week 48 and week 72(48W:P<0.001;X~2=22.657,P<0.001&72W:)X~2=24.545,P<0.001;X~2=16.854,P<0.001).Among the patients in group A,39.4%(39/99)achieved HBeAg seroconversion,significaIltly higher of the patients in group B and C at week 72(X~2=5.121,P=0.024;X~2=8.346,P=0.004).The percentage of patients with normal ALT levels was significantly higher in group A and in group C than in group B at week 48 and week 72(48W:x2=6.782,P=0.009;X~2=7.800,P=0.005&72W:X~2＝13.186,P<0.001;X~2=7.062,P=0.008).The ETV combination therapy subgroup had a significantly higher virological response rates than the ADV combination therapy subgroup at week 48 and week 72(48W:X~2=6.904,P=0.009&72W:X~2=11.990,P=0.001).Among the patients in ETV combination therapy subgroup,10.1%achieved HBsAg loss at week 72,however,none achieved HBsAg loss in other groups.2.598 chronic hepatitis B patients with concurrent detection of HBeAg and anti-HBe were included and analyzed in the study,326 cases are antiviral treatment-naive patients(spontaneous group)and 272 cases undergoing antiviral therapy(treatment group).The median age of patiengs in spontaneous group older than treatment group(34 years and 29.5 years;Z=-4.415,P<0.001).When patients in the spontaneous group were detected concurrence of HBeAg and anti-HBe,57(17.5%)achieved HBV DNA loss,and 159(58.5%)achieved HBV DNA loss,the difference was significant between the two groups(x2=107.877,P<0.001).HBeAg titers and ALT levels of patients in the spontaneous group were significant higher than in treatment group(t=-2,774,P=0.006;t=-4.929,P<0.001).The sex,serum HBsAg levels,HBeAb levels were well matched between the two groups(P=0.188,P=0.367,P=0.288).3.165 patients who underwent antiviral treatment in spontaneous group were divided into two groups:aIFN group who accepted interferon treatment(n=42)and aNAs group who accepted nucleos(t)ide analogues treatment(n=123).The sex,cases of HBV DNA negative,serum HBsAg levels,HBeAg levels,HBeAb levels and ALT levels were well matched between the two groups,unless age.Among the patients in aIFN group,27(64.3%)achieved HBeAg seroconversion and 6(14.3%)achieved HBsAg loss,were significantly higher than aNAs group(X~2=7.532,P=0.006;X~2=6.695,P=0.010).Patients in aNAs group had a significantly higher virological response rates than aIFN group(77.2%and 85.7%;)X~2=6.287,P=0.012).4.The treatment group have 272 patients.The patients were treated with PEG-~aIFN or ~aIFN in the bIFN group,ETV or LDT in the ~bNAs group.The sex,HBV DNA load,serum HBsAg levels,HBeAg levels,HBeAb levels and ALT levels were well matched between the two groups,unless age,and all serum indexs were no significant difference in group respectively.5.When patients in the bIFN group were detected concurrence of HBeAg and anti-HBe for the first time,HBsAg titers,ALT levels and cases of HBV DNA negative have significant difference than ~bNAs group.HBeAg titers,HBeAb titers,HBsAg titers,ALT levels and cases of HBV DNA negative in PEG-~aIFN group and ~aIFN group,the differences were no significant between the two groups.The same results also occur in ETV group and LDT group.6.Patients in bIFN group needed a shroter median time[25.86(4.71-216.57)W]to achieved concurrence of HBeAg and anti-HBe for the first time as compared to patients in ~bNAs group[42.86(6.29-235.43)W],and the difference between two groups was significant(Z=-4.473,P<0.001).The median time to achieved HBeAg seroconversion was 55.14(9.00-284.14)W in bIFN group as compared to 113.43(40.86-215.57)W of that in ~bNAs group,and the difference between two groups was significant(Z=-5.794,P<0.001).Patients in PEG-~aIFN group needed same median time[24.43(4.71-84.71)W]to achieved concurrence of HBeAg and anti-HBe for the first time as compared to patients in ~aIFN group[29.57(3.71-216.57)W](Z=-1.099,P=0.272).The median time to achieved HBeAg seroconversion was 65.14(9.00-100.57)W in PEG-~aIFN group as compared to 81.00(11.00-284.14)W of that in ~aIFN group,and the difference between two groups was statistically significant(Z=-3.888,P<0.001).However,the median time to achieved concurrence of HBeAg and anti-HBe for the first time and HBeAg seroconversion was not significant difference between ETV group and LDT group(Z=-0.937,P=0.349;Z=-0.122,P=0.903).7.As of December 2014,among the patients in bIFN,49.7%(79/159)achieved HBeAg seroconversion,8.8%(14/159)achieved HBsAg loss,were significantly higher than ~bNAs group(27.4%and 0%)(X~2=13.579,P<0.001;X~2=10.490,P=0.001).However,the rates of HBV DNA negative in bIFN group were significantly lower than ~bNAs group(59.7%and 83.2%;X~2=17.113,P<0.001).The rate of HBeAg seroconversion in PEG-~aIFN group was higher than ~aIFN(61.3%and 39.0%;X~2=8.614,P=0.003),however,22(27.2%)achieve HBeAg seroconversion in ETV group,compared to LDT group,the difference was no significant(X~2=0.011,P=0.918).To analyze 14 patients with HBsAg loss,9 cases of male patients,age from 18 to 31 years old,average treatment time was(59.74±19.93)weeks,average loss of HBV DNA time was(21.21±6.18)weeks.Among the patients in PEG-IFNα group,10(12.5%)achieved HBsAg loss,4(5.1%)achieved HBsAg loss in IFNα group,and the difference between two groups was not significant(X~2=2.738,P=0.098).8.A total of 854 patients were included in the safety analysis.No serious adverse event happens.CONCLUSIONS:1.It is not a good clinical choice to choose drug withdrawl or keep interferon monotherapy in suboptimal responders to 24-week interferon monotherapy.particularly those with drug withdrawl,HBV DNA loads,HBsAg levels,HBeAg levels and ALT levels were maintained at a higher level,and showed worsened trends at week 24 and 48 after IFN therapy discontinued,could accelerate the progress of the liver disease.2.Therapy of add-on NAs or change to NAs could effectively inhibit HBV DNA replication,improve liver function.3.Therapy of add-on NAs could achieve higher HBeAg seroconversion rate at week 72,the ETV add-on therapy subgroup showed a significantly higher HBsAg loss rate than that in other subgroup.4.CHB patients with concurrent positive for HBeAg and anti-HBe treated with interferon could acheive higher HBsAg loss rate and HBeAg seroconversion rate than with NAs both in spontaneous group and treatment group.5.Early virological and concurrent positive for HBeAg and anti-HBe may be a combination predictive factor of HBsAg loss. |
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