Dynamic Profiles And Clinical Application Of Serum HBcrAg And PgRNA In HBV Infected Pregnant Women

PART 1.DYNAMIC PROFILES OF SERUM HBCRAG AND PGRNA IN HBV INFECTED PREGNANT WOMENObjective: We aimed to describe dynamic profiles of HBcr Ag and pg RNA in different phases of pregnant CHB patients and evaluate the associations of these biomarkers with conventional HBV biomarkers,providing theoretical basis for follow-up monitoring and treatment effect of HBV infected pregnant women.Methods: A total of 121 HBV infected pregnant women were included.According to the status of HBe Ag,HBV DNA and ALT levels,participants were categorized into HBe Ag+ immune tolerant(IT),HBe Ag+indeterminant(IND),HBe Ag-immune active(IA)and HBe Ag-inactive carriers(IC)phase.Serum samples were collected at 24-28 weeks of gestation,32-36 weeks of gestation and 4-8 weeks postpartum to measure HBcr Ag,pg RNA and traditional virological markers.Parametric or non-parametric statistical methods were performed to analyze the dynamic kinetic of each group;Spearman’s correlation test and principal component analysis was used to evaluate the correlation between viral markers and explore key HBV markers between four groups respectively.Results: Among 121 HBV infected pregnant women,HBe Ag+ andpatients accounted for 82.6%(100/121)and 17.4%(21/121)respectively.Serum HBcr Ag and pg RNA in HBe Ag+ patients were moderately correlated with HBV DNA(r = 0.36,P < 0.001;r = 0.48,P < 0.001)and HBs Ag(r = 0.59,P < 0.001;r = 0.64,P = 0.03),which was stable during pregnancy and postpartum.Serum HBcr Ag and pg RNA in HBe Agpatients were significantly correlated with HBV DNA(r = 0.42,P < 0.001;r = 0.47,P < 0.001),but not with HBs Ag(r = 0.25,P > 0.05;r = 0.12,P >0.05).According to HBV DNA and ALT levels,patients were further categorized into IT group(n=96),IND group(n=4),IA group(n=15)and IC group(n=6).The median levels of HBV markers of HBe Ag-patients were lower than those of HBe Ag+ patients,and the age,ALT and APRI of IA patients were higher than those of IT patients.When exploring the key viral markers of the four groups,we found that the contribution values of serum HBcr Ag,pg RNA and HBs Ag to the principal components were higher than those of HBV DNA and HBe Ag,which could better differentiate different phases of CHB with pregnancy.Conclusion: Serum HBcr Ag and pg RNA levels correlate significantly with HBV DNA irrespective of HBe Ag status while correlate significantly with HBs Ag only among HBe Ag positive patients.Compared with HBV DNA and HBe Ag levels,serum HBcr Ag,pg RNA and HBs Ag have better value in classifying different phases of CHB with pregnancy.PART 2.PREDICTORS OF NON-REBOUND AFTER POSTPARTUM TREATMENT CESSATION IN HBV-INFECTED PREGNANT WOMEN WITH MOTHER-TO-CHILD TRANSMISSION PREVENTIONObjective: Virological rebound often occurs following postpartum treatment cessation in HBV-infected women with mother-to-child transmission(MTCT)prevention,while a few of patients do not experience virological rebound.We aimed to analyze the difference between the two groups,and develop a prediction model for predicting non-rebound in this cohort.Methods: We included 92 pregnant women with MTCT prevention and postpartum treatment cessation,with an average follow-up of 48 weeks(range: 32-92 weeks).Serum HBcr Ag and pg RNA were collected at 24-28 weeks of gestation(baseline),32-36 weeks of gestation(before delivery)and 4-8 weeks postpartum(the end of treatment(EOT)).Nomogram was constructed based on predictive factors selected by the logistic regression model.Calibration curve and decision curve were performed to estimate the clinical application of this model.Results: Of 92 included patients,16 and 76 experienced non-rebound and virologic rebound within 48 weeks of postpartum NAs cessation,respectively.There existed significant differences between non-rebound and virologic rebound groups in clinical characteristics and laboratory results at baseline,near delivery and at the end of treatment.Three variables including PLR near delivery(PLR34),HBs Ag reduction from baseline to near delivery(Δlog10HBs Ag34),and HBV DNA reduction from baseline to EOT(Δ HBV DNAEOT),were determined as independent predictors for non-rebound.We further constructed a nomogram by combining these three prognostic factors.Its C-index was0.91(95% CI,0.82–0.99)and reached as high as 0.88 after internal validation.The calibration curve and decision curve showed that this model had good predictive application.The decision tree suggested that the probability of non-rebound after treatment cessation could be as high as57% when the patient’s PLR near delivery< 124 and the Δ HBV DNAEOT < 3.5log10 IU/ml.Conclusion: Based on the cohort of HBV infected pregnant women with MTCT prevention,we developed a nomogram for predicting non-rebound following postpartum treatment cessation.PLR near delivery,ΔHBs Ag near delivery and ΔHBV DNA at the end of treatment were independent predictors,which were negatively correlated with non-rebound outcome.PART 3.THE ROLE OF SERUM HBCRAG AND PGRNA IN PREDICTING HBEAG SEROCONVERSION AND HBSAG REDUCTION AMONG PREGNANT CHB CARRIERSObjective: The research on HBV infected pregnant women mainly focused on the kinetic of established HBV markers and the outcome of mother-to-child transmission.We aimed to explore the role of HBcr Ag and pg RNA in predicting HBe Ag seroconversion and HBs Ag decline.Methods: Seventy-six pregnant chronic HBV carriers were included.Serum pg RNA and HBcr Ag levels were measured at baseline,at 32-36 weeks of gestation,and treatment withdrawal postpartum.The patients were followed until 96 weeks postpartum after treatment cessation.Logistic regression was used to analyze the role of HBcr Ag,pg RNA and other markers in predicting HBe Ag seroconversion and HBs Ag reduction >0.3 log10IU/m L.Results: Of 76 included CHB patients,HBe Ag seroconversion and HBs Ag reduction >0.3 log10IU/m L at 96 weeks postpartum were observed in 8(10.5%)and 13(17.1%)patients,respectively.Multivariable logistic regression model revealed that baseline HBs Ag and pg RNA decline from baseline to postpartum as independent factors of HBs Ag reduction.The area under curve of logistics regression model was 0.82 and reached as high as 0.79 through bootstrapping validation.The calibration plot showed that the nomogram had similar performance to the ideal model.The decision tree showed that when Δpg RNA >0.45 log10 copies/m L plus baseline HBs Ag > 4.1log10IU/m L,the possibility of HBs Ag reduction >0.3log10IU/m L could be as high as 40%.In addition,baseline ALT and HBcr Ag reduction could be the independent factors of HBe Ag seroconversion after postpartum withdrawal,while the calibration performance of the combined index prediction model was poor.Conclusion: Pg RNA decline postpartum together with baseline HBs Ag may identify patients with a higher probability of HBs Ag reduction after drug discontinuation postpartum,providing theoretical basis for better management of HBV-infected pregnant women receiving NAs therapy.