Application Of Serum HBV RNA To Predict The Antiviral Response Of Nucleos(t)ide Analogues

BackgroundNucleos(t)ide analogues(NAs)have been widely used to treat chronic hepatitis B(CHB)patients.Some patients may achieve serological response including hepatitis B e antigen(HBeAg)loss or seroconversion,hepatitis B surface antigen(HBsAg)loss or seroconversion during antiviral treatment and have the chance to stop treatment conditionally,but there is still risk of replase after cessation.A lot of biomarkers to predict antiviral response has been reported in previous studies.However,their predictive performance are unsatifactory.Therefore,it is still clinically useful to explore new biomarkers to predict the antiviral response.Objective1.To evaluate the role of serum HBV RNA in predicting HBeAg loss during entercavir(ETV)treatment.2.To evaluate the role of serum HBV RNA in predicting the relapse after NAs cessation.3.To evaluate whether serum HBV RNA combined with hepatitis B core-related antigen(HBcrAg)can improve the performance to predict the relapse after NAs cessation.Method1.Study population(1)Seventy-eight treatment naive HBeAg-positive CHB patients treated with ETV and followed up for 2 years are enrolled in treatment cohort.(2)The single-center,real-world prospective discontinuation study enrolled 135 patients who stopped NAs treatment and were followed up for 6 years.(3)The evaluation cohort is a multi-center,prospective discontinuation study consisting of 127 patients,who were mainly treated by telbivudine before discontinuation and meet the NAs-discontinuation criteria of APASL.The validation cohort is a part of the above single-center,real-world prospective discontinuation cohort consisting of 59 patients treated only by ETV or tenofovir disoproxil fumarate before discontinuation.All patients in the two cohorts are followed up for 4 years.2.Definitions(1)NAs-discontinuation criteria of 2012 APASL guideline:1)For HBeAg positive CHB patients,therapy can be stopped when HBeAg seroconversion with undetectable HBV DNA has been maintained for at least 1 year;2)For HBeAg positive CHB patients,the therapy can be stopped if patients have been treated for at least 2 years with undetectable HBV DNA documented on three separate occasions 6 months apart.(2)The disappearance of HBeAg from serum is defined as HBeAg loss.HBeAg disappearance accompanied by the detection of hepatitis B e antibody is defined as HBeAg seroconversion.(3)Clinical relapse is defined as HBV DNA>2,000 IU/ml and alanine aminotransferase>2 × upper limit of normal.Results1.The levels of HBV DNA or HBV RNA on month 6 of ETV treatment can predict 2-year HBeAg loss.The area under the receiver operating characteristic curves of HBV DNA,DT-RNA and S-RNA are 0.721,0.84 and 0.838.2.The 6-year cumulative incidence of clinical relapse after NAs cessation in the real-world single-center prospective discontinuation study is 48.3%.End of treatment(EOT)HBV RNA is an independent risk factor of clinical relapse after cessation(hazard ratio 1.34;p<0.001).If grouped by EOT HBV RNA levels,the 6-year cumulative incidence of clinical relapse in the group of EOT HBV RNA levels<1,000 copies/mL is lower(24%)and the 6-year cumulative incidence of HBsAg loss is higher(30.9%),when compared with other groups.3.The evaluation cohort and validation cohort have proved that both EOT HBV RNA and HBcrAg were the independent predictors of clinical relapse,with predictive efficacy improved if these two biomarkers were combined.When grouped by EOT HBV RNA and HBcrAg,the 4-year cumulative incidences of clinical relapse in the group of HBV RNA negative and HBcrAg<4 log10 U/mL were lower(0%)in both cohorts,while the corresponding incidences in the group of HBV RNA positive and HBcrAg>4 log10 U/mL were higher in the two cohorts(46.8%and 69.4%).When the two cohorts were combined for the analysis of HBsAg loss,we found that the 4-year cumulative incidence of HBsAg loss in the group of HBV RNA negative and HBcrAg<4 log10 U/mL was as high as 16.1%.Conclusion1.Serum HBV RNA can be used as a predictor of HBeAg loss during ETV treatment.2.HBV RNA can predict clinical relapse after NAs discontinuation,with the predictive efficacy can be improved when combined with HBcrAg,which may be helpful to reduce the incidence of replase.