| BackgroundThere are about 20 million CHB patients in China.If these patients are not treated in time,nearly 15%-40%of them will progress to cirrhosis and hepato-cellular carcinoma.Antiviral therapy has been one of the effective measures to improve the prognosis of CHB patients,and the ideal endpoint for CHB treatment is to achieve the HBsAg seroclearance or seroconversion.Studies have showed that the status of HBsAg seroclearance/seroconversion is positively related to the long-term prognosis of CHB patients.Till the end of 2012 in China,kinds of antiviral drugs that had been approved in China were:nucleos(t)ide analogues(including ADV,LAM,ETV and LdT)and interferon(Peg-IFN a and IFN a).Currently,monotherapy has mainly been recommended by the Clinical Guideline.Although many randomized controlled clinical trials were reported on the rate of treatment-induced HBsAg seroclearance,however the effectiveness of antiviral agent were influenced by many factors as:gender,age,economic level,type of health insurance,baseline status,severity of the disease,and tolerance on the drugs etc.of the patients.Based on the real-world population under treatment,it was necessary to explore the HBsAg clearance rate and related predictive factors,so as to improve the value of practical clinical practice.Since the development of quantitative technology on HBsAg detection,number and transcriptional activity of ccc-DNA could better be reflected.The role of index that reacting the status of liver inflammation and stages of development in CHB patients becames more important.According to literatures,HBsAg titer was highly associated with the status of HBsAg seroclearance.In particular,when the CHB patients were cleared of HBeAg,HBsAg titer became the main target in expressing the reaction of HBV replication activity in the hosts.The predictive accuracy and the cut-off value of HBsAg titer reflecting the HBsAg seroclearance at different time-points,were calculated by time-dependent receiver operating characteristic curve that having higher reference values for both clinical diagnosis and treatment.However,published articles on HBsAg titer predictive accuracy were relatively rare.AimsTo evaluate the incidence of HBsAg seroclearance and related predictive factors on HBeAg positive CHB patients treated by nucleos(t)ide analogues/interferon,based on the real-world clinical database.MethodsHBeAg positive CHB patients hospitalized at the Beijing You'an Hospital between February 14,2008 and December 31,2012,were recruited,and the information including demographic characteristics(including ID,birth date,gender,insurance type),antiviral prescrition information(including drug name and prescription date),laboratory records(including HBV DNA,HBsAg,anti-HBs,HBeAg,anti-HBe,ALT)of the CHB patients were collected from the electronic database.A retrospective cohort study was designed and conducted that including the following items:1.HBsAg seroclearance rate and related predictive factors during the treatment process on naive HBeAg positive CHB patients:HBeAg positive CHB patients that receiving the monotherapy during the period of observation were enrolled.Incidence rates of HBsAg seroclearance among patients with different demographic characteristics(including different antiviral agents)were calculated and the predictive factors of HBsAg seroclearance compared.2.Predictive factors related to HBsAg seroclearance after treatment-induced HBeAg seroclearance in CHB patients.A retrospective cohort study was conducted,with status of treatment-induced HBeAg seroclearance of the CHB patients.Evaluated by Time-dependent receiver operating characteristic curve,the predictive accuracy both of HBsAg titer under HBeAg seroclearance and proportion of HBsAg titers reduced after 6 months later.Results1.HBsAg seroclearance rate and related predictive factors during the treatment process on naive HBeAg positive CHB patients:In this study,1767 treatment-naive HBeAg positive CHB patients that under monotherapy,were included.Of them,65.9%were men,with mean age as 36.3±12.4 years.The overall annual rate of HBsAg seroclearance appeared as 0.5%in these 1767 patients,with ADV,ETV,LdT and IFN a as 0.5%,0.5%,0.4%and 1.2%,respectively.HBsAg seroclearance was not seen in patients of LAM or of Peg-IFN a group,proobably,due to the short time of observation.The cumulative incidence rates of nucleos(t)ide analogues at different time points were close to each other.The cumulative rates of HBsAg seroclearance were 0.4%,0.9%,0.9%,1.6%and 1.6%,in the ADV group,0.0%,0.3%,1.3%and 1.3%,1.3%in the ETV group,and 0.3%,0.4%,0.9%,0.9%,0.9%in the LDT group,respectively at the 6,12,24,36,42 months of observation.Cumulative seroclearance incidence rates(1.1%,2.3%,2.3%,2.3%,2.3%respectively)in the IFN groups were higher than that of the nucleos(t)ide analogues groups,but the differences were not statistically significant(P=0.3997).Results from the single factor analysis showed that both HBsAg seroclearance and HBsAg titers were associated with age at baseline but not statistically different among parameters as gender,ALT levels or HBV DNA titers.Data from the Cox regression analysis showed that IFN a could significantly induce the HBsAg seroclearance than ETV(Hazard Ratio(HR)=8.3,95%CI:1.2-58.5,P=0.0329)did.However,no differences were observed among patients with different nucleos(t)ide analogues.In patients aged 50 years or older,a higher likelihood of seroclearance(HR=4.9,95%CI:1.4-17.5,P=0.0139)than those under the 50 or younger age groups,was seen.Patients with HBsAg titer<3.0 log10 IU/mL,had a higher probability of developing the HBsAg seroclearance(HR=23.8,95%CI:6.2-91.5,P<0.0001).2.Predictive influencing factors on HBsAg seroclearance after treatment-induced HBeAg seroclearance appeared in CHB patientsAfter finishing a 1,120 person-years follow-up program on 1,072 CHB patients,25 patients developed the status of HBsAg seroclearance.The predictive accuracy and 95%CI of HBsAg titers at HBeAg seroclearance appeared as 89.2%(95%CI:77.4-100.0%),92.5%(95%CI:86.3-98.7%),92.2%(95%CI:87.3-97.2%)and 91.6%(95%CI:86.9-96.4%)respectively at 6,12,18 and 24 months after HBeAg seroclearance,and those of proportion on the reduction of HBsAg titers 6 months after the HBeAg seroclearance,appeared as 89.3%(95%CI:78.4-100.0%),83.2%(95%CI:70.3-96.1%),75.2%(95%CI:62.1-88.2%)and 75.7%(95%CI:63.2-88.2%),respectively,at the above mentioned 4 time points.,Both indexes did not show significant differences at the time points of sixth and twelfth month(P= 0.9999 and 0.3833,respectively),despite that the prediction accuracy of the former appeared higher,both at eighth and twenty-fourth month(P= 0.0292 and 0.0317,respectively).Data from single factor analysis showed that the changes of anti-HBe status were not related to HBsAg seroclearance after HBeAg seroclearamce.And the rate of HBsAg seroclearance among the interferon users was significantly higher than that of the nucleoside(acid)drug users or patients who ceased to receive therapy(P=0.0348).Under the COX regression model,data showed that Compared with the patients with HBsAg titer>2096.00 IU/mL at HBeAg seroclearance,the hazard ratio(HR)of HBsAg clearance for those with HBsAg titer<16.6 IU/mL was 155.2(95%CI:27.6-871.3,P<0.0001),and those with HBsAg level between 16.6 and 2096.00 IU/mL was 14.6(95%CI:4.2-101.2,P=0.0002).Proportion on the reduction of HBsAg titers 6 months after the HBeAg seroclearance>23%had a higher likelihood of HBsAg seroclearance than that<23%(HR=10.9,95%CI:4.4-27.3,P<0.0001).Conclusions1.The annual rate of HBsAg seroclearance was lower among the HBeAg-positive CHB patients who were treated with nucleos(t)ide analogue than that of those treated with interferon.The lower HBsAg titer at baseline was more highly associated with the HBsAg seroclearance.2.The lower the HBsAg titer appeared at the time that HBeAg seroclearance was developed,the higher chance that HBsAg clearance would occur within the 24-month of observation,with the prediction accuracy close to 90%.When larger proportion on the reduction of HBsAg titer appeared six months after HBeAg seroclearance,the occurrence of HBsAg seroclearance became more possible in 12 months,the prediction accuracy could reach above 80%. |
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