Noninvasive Diagnosis Of Liver Fibrosis And Early Prediction Of Response To Antiviral Therapy In Chronic Hepatitis B

Background and aims:Patients with chronic hepatitis B(CHB)usually present with liver fibrosis,and may develop into decompensated cirrhosis,hepatocellular carcinoma(HCC)and other serious complications if they do not receive timely and appropriate treatment.Effective antiviral therapy can relieve and even reverse cirrhosis.Diagnosing the stage of liver fibrosis and predicting efficacy of antiviral therapy are the focuses of research on chronic hepatitis B.The aim of this study is to evaluate the diagnostic value of GPR and RPR in the assessment of hepatic fibrosis in treatment-na?ve chronically HBV infected patients in China,and to establish a new diagnostic algorithm in combination with other indices to improve the accuracy.We want to analyze the utility of a novel fibrosis glycobiomarker Wisteria floribunda agglutinin-positive Mac-2 binding protein(WFA~+-M2BP)for evaluating liver fibrosis in patients with chronic HBV infection and in the follow-ups of patients treated with nucleos(t)ide analogues(NAs).The other aim of our study is to investigate the predictive efficacy of WFA~+-M2BP in patients with HBeAg-positive chronic hepatitis B during the treatment of Peg-IFNα.Patients and methods:Part one:A total of 775 treatment-na?ve chronically HBV-infected patients who underwent liver biopsy were retrospectively enrolled from two clinical centers.Receiver operating characteristic(ROC)curves were used to analyze the performance of GPR,RPR,FIB-4,APRI and HBV DNA level against liver histology measured by Metavir scoring system in the diagnosis of significant fibrosis(≥F2)and a novel algorithm,RPR-HBV DNA,was developed using the recursive partitioning and regression tree(RPART)method.Part two:774 patients with chronic HBV infection were enrolled.Among them,89patients with continuous serum samples during NAs therapy were collected.Serum WFA~+-M2BP values were measured and compared with FIB-4,APRI,and AAR using ROC analysis.The correlation between WFA~+-M2BP and FibroScan was investigated by using Spearman’s analysis and the value of WFA~+-M2BP in the follow-ups of patients treated with NAs was evaluated.Part three:A total of 104 HBeAg-positive treatment-na?ve patients who were treated with Peg-IFNαfor at least 48 weeks were collected.Quantification of serum WFA~+-M2BP,ALT,HBsAg,HBeAg and HBV DNA levels were measured at baseline and during antiviral treatment(week 4,12,and 24).Virologic response(VR)was defined as an undetectable HBV DNA level(<500 IU/ml)after 48 weeks of treatment.HBeAg seroconversion at week 48 of treatment was defined as a serological response(SR).Results:Part one:Fibrosis stage was positively correlated with GPR,RPR,FIB-4 and APRI but was inversely correlated with HBV DNA.In the training cohort,the AUC of FIB-4 was0.712(95%CI=0.665-0.755)and was significantly higher than that of APRI and comparable to those of HBV DNA,GPR,and RPR.In the validation cohort,the diagnostic efficacy of GPR and RPR was not significantly higher than that of APRI and FIB-4.Using the RPART method,we established a novel assessment algorithm,RPR-HBV DNA,which was found to have the optimal diagnostic value for significant fibrosis in chronically HBV-infected patients.Part two:Area under the ROC curve(AUC(95%):0.753(0.687-0.812))of WFA~+-M2BP for diagnosing significant fibrosis was higher than that of FIB-4,APRI,and AAR.And the optimal cutoff value was 1.06,and the corresponding sensitivity,specificity,PPV and NPV were 60.5%,79.8%,68.1%and 74.0%respectively.Spearman correlation analysis showed that the serum WFA~+-M2BP level was significantly correlated with the detection of FibroScan.In the validation group,we applied a published FibroScan cut-off value of7.3kPa and the corresponding sensitivity and specificity were 64.9%and 76.9%.When FibroScan and WFA~+-M2BP were combined,utility of the two indexes together improved sensitivity 68.0%and specificity 89.7%for the detection of significant fibrosis.The mean levels of serum WFA~+-M2BP were gradually decreased in 89 consecutive patients during follow-up.The change in WFA~+-M2BP showed a similar tendency to that of FibroScan(P=0.023).Part three:67 patients(64.4%)developed VR and 35(33.7%)patients developed SR.Univariate analysis found that HBeAg levels(baseline,week 12,week 24),HBV DNA levels(week 12,week 24)and HBV DNA declines(from week 24 to baseline)can predict VR and SR.HBsAg levels at week 24,and WFA~+-M2BP declines(from week 24to baseline)can predict VR;baseline WFA~+-M2BP levels,HBeAg levels(week 12 and week 24),HBV DNA declines(from week 24 to baseline)can predict SR.Multivariate analysis found that WFA~+-M2BP at baseline,HBeAg at week 12,HBeAg at week 24 and HBV DNA declines(from week 24 to baseline)were independent risk factors for predicting SR.The AUC(95%CI)of WFA~+-M2BP at baseline for predicting SR was0.676(0.561-0.778),with the optimal cutoff value of 1.88,and the corresponding sensitivity,specificity,PPV and NPV were 36.7%,89.6%,68.7%and 69.4%,respectively.Conclusion:The GPR represents good performance in patients with chronic HBV infection in West Africa,but the performance is not superior to that of APRI and FIB-4 in China.The established RPR-HBV DNA algorithm might improve the diagnostic accuracy of liver fibrosis in treatment-na?ve patients with chronic HBV infection.Serum WFA~+-M2BP level provides a simple,reliable and non-invasive method for assessing early stages of fibrosis in patients with chronic HBV infection in China.Our study also revealed that WFA~+-M2BP may not only serve as a non-invasive indicator for monitoring regression of fibrosis during NAs therapy in CHB patients.but also serve as an independent predictor of response to Peg-IFNαin HBeAg-positive chronic hepatitis B patients.