| Objective: To investigate the predictors of HBs Ag clearance in HBe Ag negative chronic hepatitis B patients who received combination therapy.Methods: 1. Enrolled population:The diagnosis of HBe Ag negative CHB patients conform to The guideline of prevention and treatment for chronic hepatitis B(2010 version), 18-65 years old, any sex, naive patients or patients who use NAs before without drug resistance. 2. Therapy: Peg-IFN-α-2a+NAs, 48 to 96 weeks’ treatment. NAs dose: entecavir 0.5mg/d used in the patients with HBV DNA>2× 105IU/m L. Adefovir 10mg/d used in the patients with HBV DNA ≤ 2× 105IU/m L. Peg IFN-α-2a dose: 180ug/w used in the patients with weight≥75kg. 135ug/w used in the patients with weight<75kg. 3. Evaluation Index: The main index is the clearance of HBs Ag. Secondary index include HBs Ag levels, HBV DNA and ALT levels. 4. Efficacy and group: The patients who obtain the clearance of HBs Ag during treatment were classified HBs Ag clearance group(clear group), otherwise HBs Ag uncleared group(unclear group). 5. Discontinued endpoint: The actual withdrawal end of clear group is consolidated another 24 weeks after HBs Ag cleared, otherwise we will stop IFNand continue NAs treatment.Results: 1. General conditions and treatment efficacy 108 patients were enrolled, 78 males and 30 females, mean age were 38.98 ± 10.37 years old. 25 patients used peg-IFN-α-2a 135ug+ETV. 4 patients used peg-IFN-α-2a 180ug+ETV. 72 patients used peg-IFN-α-2a 135ug+ADV. 7 patients used peg-IFN-α-2a 180ug+ADV. 3 patients lost after 12 weeks treatment(2 males and 1 female). 1 patient(female) stopped IFN in 24 weeks treatment for SAE(hyperthyroidism). Therefore, 104 patients were followed up as a target. At the treatment of 48 weeks, 17.3%(18/104) of patients obtained the clearance of HBs Ag. At the treatment of 96 weeks, 34.6%(36/104) of patients obtained the clearance of HBs Ag. These 36 patients were departed into clear group, others were unclear group. 2. The clinic factors of the clearance of HBs Ag. 2.1 Univariate analysis To investigate the clinic factors of the clearance of HBs Ag, gender, age, ALT, HBV DNA, HBs Ag were analyzed. The results shows that the gender composition in clear group and unclear group has no significant difference(26/10 vs. 50/18, p=0.886). The average age of two group has no significant difference(36.69 ± 10.23 vs. 40.76 ± 10.33, p=0.058). The average baseline ALT in clear group is higher than unclear group, but the difference has not statistically significant(70.61±55.60U/L vs. 51.52±44.11U/L, p=0.074); but during the treatment ALT increased again in two groups has statistically difference(10/36 vs. 6/68, p=0.011)The baseline HBV DNA in clear group is lower than unclear group, the difference is statistically significant(3.78±0.78 lg IU/m L vs. 4.45±1.79 lg IU/m L, p=0.009). The baseline HBs Ag in clear group is lower than unclear group, the difference is statistically significant(2.60±0.39 lg IU/m L vs. 2.97±0.66 lg IU/m L, p=0.003). The decline of HBs Ag in the treatment of 24 th week in clear group is bigger than the other(1.75±1.52 lg IU/m L vs. 0.36±0.50 lg IU/m L, p<0.001). The decline of HBs Ag in the treatment of 48 th week in clear group is also bigger than the other(2.83±1.18 lg IU/m L vs. 0.50±0.60 lg IU/m L, p<0.001). 2.2 Logistic regression and ROC curve analysis The Factors Logistic regression analysis of aboved factors with statistics differences showed that only the difference of HBs Ag level and trend between two groups is statistically significant. Lower baseline HBs Ag level, the significantly decline during the treatment of 24 th weeks and 48 th weeks are conducive to HBs Ag cleared(p=0.015, 0.049, <0.001). ROC curve analysis shows that baseline HBs Ag level predict the clearance of HBs Ag. Its AUC is 0.683(95%CI: 0.585-0.781), cutoff value is 3.0lg IU/m L(correspond to 1008 IU / m L in this study), PPV is 47.62 %, NPV is 85.37%. The decline of HBs Ag at 24 th week predicts the clearance of HBs Ag. Its AUC is 0.777(95%CI: 0.670-0.885), cutoff value is 1.1lg IU/m L, PPV increased to 84.62%, NPV is 82.05%. The decline of HBs Ag at of 48 th week predicts the clearance of HBs Ag. Its AUC was 0.940(95%CI: 0.881-1.000), cutoff value is 1.8lg IU/m L, PPV is up to 90.91%, NPV is 92.55%.3. Correlation analysis of host genetic susceptibility and HBs Ag clearance For the further investigating the correlation of host genetic susceptibility and HBs Ag clearance, we added 14 HBe Ag negative patients who used same treatment and enrolled our standard into clear group. We only investigated IL-28 B rs12979860, rs12980275, rs8099917 and PD-1 rs10204525 locus. Conventional Taq Man probe was used to detect genotypes. The results of two group were tested by hardy-weinberg equilibrium, p>0.05. It is in line with the laws of inheritance and have group representation. 3.1 IL-28 B In rs12979860, clear group consist of 43 CC type and 7 non-CC type(6 CT and 1 TT). Unclear group consist of 59 CC type and 9 non-CC type(9 CT and 0 TT). There is no significant difference between two group(p=0.965). The allele frequency of C and T also has no significant difference(p=0.853). In rs12980275, clear group consist of 43 AA type and 7 non-AA type(6 AG and 1 GG). Unclear group consist of 59 AA type and 9 non-AA type(9 AG and 0 GG). There is no significant difference between two group(p=0.965). The allele frequency of A and G also has no significant difference(p=0.853). In rs8099917, clear group consist of 44 TT type and 6 non-TT type(5 TG and 1 GG). Unclear group consist of 58 TT type and 10 non-TT type(10 TG and 0 GG). There is no significant difference between two group(p=0.671). The allele frequency of C and T also has no significant difference(p=0.756). 3.2 PD-1 In rs10204525, clear group consist of 25 AA type and 25 non-AA type(19 AG and 6 GG). Unclear group consist of 30 AA type and 38 non-AA type(33 AG and5 GG). There is no significant difference between two group(p=0.527). The allele frequency of C and T also has no significant difference(p=0.920).Conclusion: 1. In our study, using combination therapy of peg-IFN-α+NAs and prolonging treatment strategy in HBe Ag negative CHB patients inprove HBs Ag clear rate to 34.2%. It is higher than the previous monotherapy or fixed course(0%-8%). 2. Univariate analysis showed that age, gender,baseline ALT level have no significantly impact on the clearance of HBs Ag. ALT increased again during the treatment, low baseline HBV DNA load, low baseline HBs Ag level,and significantly decline during treatment are favorable factors in HBs Ag clearance. Logistic regression analysis shows that HBs Ag level is a good predictor in HBs Ag clearance, including low baseline level(AUC is 0.683, cutoff value is 3.0lg IU/m L, PPV is 47.62%, NPV is 85.37%) and significantly decline during treatment, in which the most valurable predict is declineing at 48 th week(AUC is 0.940, cutoff value is 1.8lg IU/m L, PPV is 90.91%). All of these shows that low baseline HBs Ag level and significantly decline during treatment is important screening index to choose “advantage people”. It also means the patients have a better answer for IFN treatment. They are worthy to prolong course to pursuit the clearance of HBs Ag and achieve clinical cure. 3. rs12979860, rs12980275, rs8099917 and rs10204525 sites neucleotide polymorphism have no significant correlation with the clearance of HBs Ag. |
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