| Objective: It is important to identify the key factors affecting the clearance of Hepatitis B surface antigen(HBs Ag)in order to identify the groups that would benefit from a "functional cure" of hepatitis B and to further optimise the strategies for achieving HBs Ag loss.In addition,follow-up and monitoring after HBs Ag loss is still necessary,but the strategies and procedures for monitoring after HBs Ag loss are not yet clear.The impact of hepatitis B core antibody(HBs Ab or anti-HBs)on long-term outcomes after HBs Ag loss is one of the major controversies.Based on the above situation,this study analyses the factors influencing the achievement of HBs Ag loss and the adverse outcomes after HBs Ag loss.Methods: In Study 1,patients with chronic HBV infection who received Pegylated interferon alpha(peg-IFN-α)treatment for more than 24 weeks were included.The subjects were categorized based on their treatment response(HBs Ag loss or not)and univariate and multivariate binary Logistic regression were used to analyze the predictors of patients’ response.The Receiver operating characteristic(ROC)curve was plotted to evaluate the predictive value of the related indicators affecting Peg-IFN-α response.In Study 2,195 patients who achieved HBs Ag loss in Study 1 and underwent further clinical follow-up after HBs Ag loss were included.Additionally,37 patients were included who continued clinical follow-up after spontaneous or Nucleoside/Nucleotide analogue(NAs)therapy induced HBs Ag loss in our center.The cumulative probability of HBs Ag serological reversal was estimated using Kaplan-Meier analysis,and the Log-rank test was used for between-group comparisons.The risk factors of serological reversal of HBs Ag after HBs Ag loss were analyzed by constructing the cumulative risk function and the COX regression risk model of multiple and single factors.Study 3 used data from the National Health and Nutrition Examination Survey(NHANES)from 2001 to 2018 to analyze the prevalence and risk factors of cirrhosis/advanced fibrosis in patients with resolved hepatitis B using proxy indicators of cirrhosis/advanced fibrosis.Study 4 used NHANES data from 1999 to 2018 to investigate the possible influencing factors of increased mortality risk after HBs Ag loss in3455 patients with resolved hepatitis B,with an average follow-up duration of 10.3 years.Subjects were grouped according to HBs Ab status and propensity score matching was used to balance and correct for potential confounders between groups.Kaplan-Meier analysis and log-rank tests were used to estimate differences in the risk of death between groups.COX regression was used to calculate relative hazards and confidence intervals between each characteristic and risk of death.Results: Of the 378 subjects in Study 1 who were treated with interferon for 24 weeks,The combination of HBs Ag levels at baseline and 12-week HBs Ag reductions were better predictors of treatment response over the short course of treatment.265 subjects were included in the predictive analysis of response to the standard course of treatment,The combination of HBs Ag levels at baseline and the reduction in HBs Ag at 12 or 24 weeks of treatment predicted treatment response at 48 weeks of treatment.During follow-up after HBs Ag loss in Study 2,serological reversal of HBs Ag occurred in 2(2/37)of 37 patients in the spontaneous/NAs treatment group.In contrast,of the 195 patients in the peg-IFN-α-mediated HBs Ag loss,57(57/195)subjects showed serological reversal of HBs Ag.The results of the multifactorial COX analysis indicated that anti-HBc levels at baseline and HBs Ab levels at cessation of peg-IFN-α treatment were significant influences on serological reversal after HBs Ag loss.Restricted cubic spline curves suggested a significant linear quantitative association between HBs Ab levels and risk of serological reversal.In Study 3,3115 adults with resolved hepatitis B were enrolled based on NHANES 2001-2018 data.Using FIB-4,3.76% of patients with resolved hepatitis B had cirrhosis.Multivariate regression analysis identified gender,age,race,education,alcohol consumption,income,diabetes,liver status,HBs Ab status,and presence of chronic diseases as significant factors for cirrhosis in adults with resolved hepatitis B.In Study 4,3455 patients with resolved hepatitis B were enrolled based on NHANES data from 1999 to 2018.During a mean follow-up of 10.3 years,741 patients died.The risk of all-cause mortality(HR:1.23,95% CI:1.02-1.46)and cancer-related mortality(HR:1.44,95% CI:1.01-2.05)was significantly increased in HBs Ab negative patients compared to HBs Ab positive patients.Conclusions: 1.Baseline HBs Ag and the magnitude of HBs Ag decline early in treatment were key factors in response to peg-IFN-α treatment,in addition to higher anti-HBc levels at baseline and a small increase in HBs Ab early in treatment were also associated with a good treatment response.2.The differences in the persistence of HBs Ag loss induced by NAs and peg-IFN-α suggest that monitoring and follow-up after functional cure may still be required after HBs Ag loss.Further analysis of the predictors of persistence after pegIFN-α treatment-induced HBs Ag loss confirmed that HBs Ab level was an important predictor of serological reversal after HBs Ag loss.3.NHANES data showed that 3.76% of resolved hepatitis B patients had cirrhosis/advanced fibrosis,with a higher prevalence in adults than in the general population.The difference in the prevalence of cirrhosis between HBs Ab-negative and HBs Ab-positive populations suggests that more rigorous clinical surveillance may be necessary for the former.4.HBs Ab-negative patients are at a higher risk of all-cause and cancer-related death,emphasizing the importance of HBs Ab in these patients.On the public health level,more rigorous surveillance was needed for populations of individuals who were isolated anti-HBc positive. |
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