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From November 2017 to November 2018, 221 of 250 eligible HBeAg-positive patients with CHB provided signed informed consent to enter the antiviral study. Among them, 116 patients were treated with PEG-IFNα-2a, and 105 patients chose oral NAs. Three patients in the PEG-IFNα-2a group withdrew from the study because of adverse effects of PEG-IFNα-2a, five withdrew because of a fertility plan, and eight patients did not complete the 48-week follow-up. Finally, 100 patients (average age 31, 60 men) treated with PEG-IFNα-2a completed the 48-week follow-up (Figure 1). A total of 55 patients were treated with ETV after 12 weeks of PEG-IFNα-2a, and 10 patients were treated with ETV after 24 weeks of PEG-IFNα-2a. After 48 weeks of treatment, 72 patients achieved virological response, and 64 patients showed ALT normalization; 38 patients achieved serum HBeAg disappearance, and 25 patients achieved HBeAg seroconversion; 37 patients showed an HBsAg decrease ≥ 1 log10 IU/mL, nine patients showed HBsAg disappearance, and eight patients achieved HBsAb positivity.
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There were 38 cases in the HBeAg loss group (26 men) and 62 cases (34 men) in the non-loss group. The age, biochemical indexes [ALT, glutamic oxalacetic transaminase (AST), total bilirubin (TBil), and albumin (ALB)], virological indexes (HBV DNA, HBsAg, and HBeAg), and peripheral blood cytokines between groups are shown in Table 1. Statistically significant differences were observed in the median HBeAg levels between groups at week 12 (HBeAg 13.98 vs. 94.18 S/CO, Z = −3.821, P < 0.001); week 24 (HBeAg 1.29 vs. 22.51 S/CO, Z = −6.908, P < 0.001); week 36 (HBeAg 0.46 vs. 21 S/CO, Z = −7.955, P < 0.001); and week 48 (HBeAg 0.43 vs. 49 S/CO, Z = −8.367, P < 0.001).
Variables Baseline 12 weeks 24 weeks 36 weeks 48 weeks χ2* P# Loss Non-loss Z/ P Loss Non-loss Z/ P Loss Non-loss Z/ P Loss Non-loss Z/ P Loss Non-loss Z/ P ALT (U/L) 228.60
(124.20−355.55)249.80
(129.30−361.30)−0.170/
0.86559.20
(36.70−101.80)69.10
(48.98−83.60)−0.881/
0.37843.15
(27.10−64.55)44.53
(26.90−58.30)−0.181/
0.85633.30
(24.10−40.40)34.90
(29.50−54.60)−1.790/
0.07325.40
(15.58−47.23)33
(16.95−44.40)−0.181/
0.8566.067 0.014 AST (U/L) 131.50
(75.95−201.28)107.70
(60.48−168.90)−0.980/
0.32738.70
(29.70−62.50)45.00
(35.83−55.20)−1.442
−0.14941
(24.40−61.50)36.80
(26.90−50.98)−0.260/
0.79524.90
(23.10−42.45)32.70
(25.30−40.25)−1.904/
0.05722.10
(19.60−34.88)24.85
(17.53−35.60)−0.703/
0.4822.864 0.091 TBil (µmol/L) 13.05
(10.90−16.85)14.30
(11.80−19.13)−0.444
−0.65711.50
(9.50−14.70)11.85
(9.48−13.80)−0.614/
0.5399.90
(8.58−13.10)9.70
(7.85−11.90)−0.995/
0.32010.90
(7.93−12.50)9.80
(7.60−12.30)−1.002/
0.31711.20
(7.70−13.80)10.65
(8.15−12.30)−1.712/
0.0870.502 0.479 ALB (g/L) 45.65
(42.60−47.40)45.20
(42.60−46.95)−0.142
−0.88745.80
(43.60−49.00)46.85
(44.15−48.28)−0.590/
0.55547.20
(43.60−49.10)46.40
(44.58−48.70)−0.253/
0.80047.50
(43.38−50.30)46.20
(43.30−48.90)−1.279/
0.20148.75
(46.53−51)46.90
(45.18−49.70)−2.035/
0.0420.242 0.623 HBsAg (log10 IU/mL) 3.82
(3.47−4.09)3.93
(3.68−4.14)−1.627/
0.1043.18
(2.37−3.89)3.52
(2.96−3.82)−1.657/
0.0982.75
(1.88−3.40)3.30
(2.78−3.74)−2.260/
0.0242.95
(1.48−3.33)3.32
(2.78−3.79)−2.394/
0.0173.12
(1.35−3.41)3.43
(2.85−3.83)−2.484/
0.01311.894 0.001 HBeAg (S/CO) 767.32
(374.40−1166.16)885.98
(547.57−1204.77)−1.115/
0.26513.98
(0.84−122.36)94.18
(25.96−414.47)−3.821/
< 0.0011.29
(0.54−6.06)22.51
(10.17−92.85)−6.908/
< 0.0010.46
(0.36−0.70)21
(7.81−57.04)−7.955/
< 0.0010.43
(0.36−0.56)15.49
(7.01−30.75)−8.367/
< 0.00112.531 < 0.001 HBV DNA (log10 IU/mL) 6.63
(6.23−7.04)6.66
(6.39−7.35)−1.342/
0.1794.18
(3.20−4.65)
(n = 32)4.28
(3.30−5.51)
(n = 48)−0.658/
0.5101.90
(1.78−2.39)
(n = 9)2.28
(1.61−3.37)
(n = 27)−0.494/
0.6221.45
(1.34−1.91)
(n = 13)1.69
(1.51−2.47)
(n = 28)−1.628/
0.1041.64
(1.41−2.08)
(n = 7)1.65
(1.54−2.05)
(n = 21)−0.080/
0.936− − Flt3-L (pg/mL) 29.27
(2.38−86.27)46.37
(1.96−84.13)−0.505/
0.6130.74
(0.06−18.32)2.67
(0.19−36.69)−1.542/
0.1231.17
(0.24−21.64)2.24
(0.20−33.92)−0.724/
0.469− − − − − − 0.102 0.749 IFN-α2 (pg/mL) 32.35
(9.12−59.16)41.60
(12.44−80.08)−1.037/
0.300457.19
(295.80−618.14)442.33
(270.88−722.29)−1.763/
0.078451.19
(200.32−636.95)561.69
(276.18−722.29)−1.563/
0.118− − − − − − 3.266 0.071 IFN-γ (pg/mL) 33.18
(9.17−58.42)17.04
(8.59−120.57)−0.781/
0.43512.59
(9.79−20.77)19.08
(5.95−31.22)−0.931/
0.35214.37
(6.37−26.46)10.01
(4.23−31.55)−0.753/
0.451− − − − − − 0.867 0.352 IL-10 (pg/mL) 7.59
(3.56−19.61)12.57
(4.35−19.57)−0.199/
0.8422.90
(1.23−5.14)2.83
(1.44−4.05)−0.436/
0.6632.61
(1.89−5.94)3.29
(1.30−12.94)−0.213/
0.831− − − − − − 2.450 0.118 IL-17A (pg/mL) 13.30
(4.52−61.16)16.83
(5.64−73.29)−0.270/
0.7874.70
(2.69−6.66)4.70
(1.76−11.56)−0.894/
0.3717.17
(1.83−12.84)4.27
(2.06−8.39)−0.970/
0.332− − − − − − 0.459 0.498 IL-6 (pg/mL) 3.50
(2.39−49.53)7.26
(0.93−18.04)−0.284/
0.7761.76
(1.03−2.62)1.76
(0.74−2.74)−0.590/
0.5551.12
(0.56−2.94)1.37
(0.88−2.42)−0.295/
0.768− − − − − − 0.031 0.860 TNF-α (pg/mL) 15.60
(9.32−43.11)18.61
(16.20−48.14)−1.187/
0.23520.06
(14.05−24.53)17.05
(10.88−18.69)−1.590/
0.12017.69
(12.96−19.36)13.67
(10.63−17.28)−1.544/
0.125− − − − − − 2.364 0.124 TGF-β1 (pg/mL) 4,298
(2,974−8145.5)5,167
(2,911−8291.5)−0.618/
0.5372,501
(1940.50−4791.50)3,039
(1,380−4,895)−0.572/
0.5682,366
(1,121−2639.50)3,461
(1014.45−5,514)−0.625/
0.532− − − − − − 1.802 0.179 TGF-β2 (pg/mL) 416.66
(348.70−623.44)499.84
(361.83−772.51)−0.899/
0.369368.61
(316.29−557.41)471.32
(368.61−608.01)−1.753/
0.080342.62
(271.50−425.81)355.05
(269.68−522.78)−0.662/
0.508− − − − − − 4.520 0.033 TGF-β3 (pg/mL) 182.71
(131.84−220.14)145.19
(131.69−188.53)−1.543/
0.123121.91
(112.08−156.35)130.03
(115.35−141.84)−0.062/
0.951143.18
(115.57−173.92)138.80
(110.33−156.35)−0.746/
0.456− − − − − − 0.672 0.412 Note. *The statistics of repeated measurement indexes relating to the biochemistry, virus, and immunity of the two groups was analyzed with generalized estimation equations. #The P values of repeated measurement indexes relating to the biochemistry, virus, and immunity of the two groups were statistically analyzed with generalized estimation equations. ALT, glutamic-pyruvic transaminase. AST, glutamic oxalacetic transaminase. TBil, total bilirubin. ALB, albumin. Table 1. Comparison of clinical indicators between the HBeAg loss group (n = 38) and non-loss group (n = 62) at baseline, and weeks 12, 24, 36, and 48 during IFN therapy
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The patients were divided into a response group (n = 37) and non-response group (n = 63) according to their decrease in HBsAg (≥ 1 log10 IU/mL) at week 48. Table 2 shows the dynamic changes in clinical indexes between groups, and Figure 2 shows cytokines at baseline, and weeks 12 and 24 during IFN therapy.
Variables Baseline 12 weeks 24 weeks 36 weeks 48 weeks χ2* P# Good response Poor response Z/ P Good response Poor response Z/ P Good response Poor response Z/ P Good response Poor response Z/P Good response Poor response Z/ P ALT (U/L) 252.70
(130.10−377.40)252.90
(129.30−336.80)−0.346/
0.72969.20
(50.20−119.30)60.60
(38.60−79.60)−1.410/
0.15960.80
(44.60−69.10)40.30
(24.60−51.70)−3.240/
0.00137.80
(28.20−56)32.55
(27.10−46.80)−1.679/
0.09333
(18.8−47.9)29.20
(45.10)−0.473/
0.636155.899 < 0.001 AST (U/L) 136.10
(61.50−203.50)121.50
(61.50−171.30)−0.810/
0.41846.50
(31.60−66.60)38.70
(29.70−53.90)−1.386/
0.16643.10
(34.60−63.70)34.20
(24.40−46.75)−2.939/
0.00333.90
(27.80−50.90)28.60
(23.10−36.80)−2.625/
0.00931.50
(20.60−45.50)23.20
(17.70−30.30)−1.918/
0.05595.627 < 0.001 TBil (µmol/L ) 14.60
(12.50−20.40)12.90
(11.40−17.50)−1.176/
0.23912.50
(10.30−17.60)11.50
(9.50−13.40)−1.488/
0.1379.60
(7.70−12.60)9.80
(8.18−11.60)−0.287/
0.77411.20
(7.50−12.30)10.05
(7.83−12.80)−0.649/
0.51611.50
(6.50−12.30)10.80
(8.70−12.80)−0.737/
0.461100.942 < 0.001 ALB (g/L) 44.50
(43−47.70)45.50
(42−47.10)−0.161/
0.87245.50
(42.90−48.60)46.20
(44.20−47.90)−0.434/
0.66446.30
(43.40−49.10)46.30
(44.58−49.10)−0.366/
0.71447.10
(42.10−50.30)46.75
(44.85−49.00)−0.210/
0.83446.80
(43−50.30)47.10
(45.70−50.40)−0.952/
0.34146.323 < 0.001 HBsAg (log10 IU/mL ) 3.87
(3.56−4.09)3.88
(3.67−4.09)−0.717/
0.4732.95
(2.61−3.42)3.68
(3.18−3.92)−3.548/
< 0.0012.55
(1.61−2.75)3.55
(3.14−3.92)−5.556/
< 0.0012.28
(1.27−2.51)3.53
(3.05−3.85)−6.065/
< 0.0011.92
(1.27−2.56)3.56
(3.11−3.92)−6.232/
< 0.001165.279 < 0.001 HBeAg (S/CO) 658.44
(179.39−1022.28)878.35
(607.46−1194.74)−1.342/
0.18098.59
(9.60−430.59)56.01
(13.98−382.71)−0.102/
0.9186.20
(1.29−32.36)19.18
(5.57−74.53)−2.043/
0.0410.62
(0.50−13.74)17.22
(4.10−49.03)−2.718/
0.0070.56
(0.49−10.46)8.36
(0.97−26.76)−2.464/
0.014325.758 < 0.001 HBV DNA (log10 IU/mL) 6.66
(6.29−7.34)6.64
(6.25−7.30)−0.232/0.816 4.18
(3.26−5.16)
(n = 29)4.23
(3.35−5.25)
(n = 51)−0.350/
0.7261.82
(1.44−2.35)
(n = 10)2.28
(1.78−3.67)
(n = 26)−2.103/0.035
(n = 12)1.52
(1.43−1.73)
(n = 29)1.86
(1.43−2.43)−1.708/
0.0881.55
(1.44−1.95)
(n = 8)1.67
(1.63−2.22)
(n = 20)−1.530/
0.126− − Note. *The statistics of repeated measurement indexes relating to the biochemistry and virus in the two groups was analyzed with generalized estimation equations. #The P values of repeated measurement indexes relating to the biochemistry and virus in the two groups were statistically analyzed with generalized estimation equations. ALT, glutamic-pyruvic transaminase. AST, glutamic oxalacetic transaminase. TBil, total bilirubin. ALB, albumin. Table 2. Comparison of clinical indicators between the HBsAg response group (n = 37) and non-response group (n = 63) at baseline, and weeks 12, 24, 36, and 48 after IFN therapy
Figure 2. Comparison of cytokines between the HBsAg response group (R: n = 37) and non-response group (NR: n = 63) at baseline, and weeks 12 and 24 of IFN therapy. P < 0.013 is considered statistically significant.
A statistically significant difference was observed in median HBsAg levels between groups at week 24 (HBsAg 2.95 log10 vs. 3.68 log10 IU/mL, Z = −3.548, P < 0.001), week 24 (HBsAg 2.55 vs. 55 log10 IU/mL, Z = −5.556, P < 0.001), week 36 (2.28 log10 vs. 3.53 log10 IU/mL, Z = −6.065, P < 0.001), and week 48 (HBsAg 1.92 log10 vs. 3.56 log10 IU/mL, Z = −6.232, P < 0.001).
A statistically significant difference was observed in the median TGF-β2 level (368.61 vs.499.84 pg/mL, Z = −2.999, P = 0.003) and TNF-α level at week 12, and the ALT and AST levels (ALT 60.80 vs. 40.30 U/L, Z = −3.240, P = 0.001; AST 43.10 vs. 34.20 U/L, Z = −2.939, P = 0.003) at week 24. A statistically significant difference was found in the median HBeAg levels between groups at week 36 (0.62 vs. 17.22 S/CO, Z = −2.718, P = 0.007), and the median AST level significantly differed between groups (33.90 vs. 28.60 U/L, Z = −2.625, P = 0.009).
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Table 3 shows an analysis of the predictors of HBeAg loss after 48 weeks of IFN treatment. Multivariate analysis indicated that HBeAg at week 12 was independently associated with 48-week HBeAg serological disappearance (OR = 1.003, 95% CI: 1.000–1.005, P = 0.039), with a cut-off value of 22.95 S/CO. The sensitivity was 63.20%, the specificity was 77.40%, and the AUC was 0.728 (95% CI: 0.622–0.835).
Univariate analysis OR 95% CI P value HBsAg (log10 IU/mL) 1.770 0.853−3.671 0.125 HBV DNA (log10 IU/mL) 0.739 0.457−1.196 0.218 HBeAg (S/CO) 1.000 1.000−1.001 0.282 ALT (U/L) 1.000 0.998−1.001 0.761 AST (U/L) 0.999 0.997−1.001 0.382 TBil (µmol/L) 1.009 0.949−1.074 0.767 ALB (g/L) 1.033 0.939−1.137 0.499 Flt3-L (pg/mL) 1.000 0.998−1.002 0.761 IFN-α2 (pg/mL) 1.000 0.999−1.001 0.782 IFN-γ (pg/mL) 1.000 0.997−1.002 0.811 IL-10 (pg/mL) 0.999 0.989−1.008 0.766 IL-17A (pg/mL) 0.999 0.995−1.003 0.736 IL-6 (pg/mL) 0.998 0.992−1.003 0.392 TNF-α (pg/mL) 1.017 0.974−1.063 0.437 TGF-β1 (pg/mL) 1.000 1.000−1.000 0.184 TGF-β2 (pg/mL) 1.001 1.000−1.002 0.226 TGF-β3 (pg/mL) 0.992 0.982−1.002 0.113 HBsAg decreased in
12 weeks (log10 IU/mL)0.815 0.525−1.266 0.362 HBeAg decreased in
12 weeks (S/CO)1.000 0.999−1.001 0.818 HBsAg decreased in
24 weeks (log10 IU/mL)0.776 0.524−1.149 0.205 HBeAg decreased in
24 weeks (S/CO)1.000 0.999−1.001 0.918 Multivariate analysis
(3 months)HBV DNA (log10 IU/mL) 0.537 0.275−1.048 0.068 HBsAg (log10 IU/mL) 2.776 0.920−8.370 0.070 HBeAg (S/CO) 1.003 1.000−1.005 0.039 Multivariate analysis
(6 months)HBeAg (S/CO) 1.050 1.014−1.087 0.006 HBeAg decreased in
24 weeks (S/CO)0.953 0.921−0.987 0.007 Note. ALT, glutamic-pyruvic transaminase. AST, glutamic oxalacetic transaminase. TBil, total bilirubin. ALB, albumin. Table 3. Logistic regression analysis of predictors of HBeAg loss at week 48 of IFN treatment
Both the HBeAg level (OR = 1.050, 95% CI: 1.014–1.087, P = 0.006) and the HBeAg decline (OR = 0.953, 95% CI: 0.921–0.987, P = 0.007) at week 24 were independently associated with the serological disappearance of HBeAg at week 48. The cut-off value of HBeAg at week 24 for predicting the HBeAg disappearance at week 48 was 3.69 S/CO, the sensitivity was 75.70%, the specificity was 96.80%, and the AUC was 0.916 (95% CI: 0.855–0.977). The cut-off value of the HBeAg decline level at week 24 for predicting the HBeAg disappearance at week 48 was 733.61 S/CO, the sensitivity was 54.10%, the specificity was 64.50%, and the AUC was 0.557 (95% CI: 0.436–0.677).
There was no statistically significant difference in cytokines between patients with or without HBeAg disappearance during treatment (P > 0.013).
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Table 4 shows an analysis of the predictors of HBsAg decline ≥ 1 log10 IU/mL at week 48 after IFN treatment. The cut-off value of HBsAg levels at week 12 for predicting the HBsAg response (HBsAg decline ≥ 1 log10 IU/mL from baseline) at week 48 was 3.375 log10 IU/mL, the sensitivity was 89.20%, the specificity was 71.40%, and the AUC was 0.829 (95% CI: 0.740–0.918). The cut-off value of the HBsAg decline level at week 12 for predicting the HBsAg response at week 48 was 0.530 log10 IU/mL, the sensitivity was 86.50%, the specificity was 81.00%, and the AUC was 0.858 (95% CI: 0.778–0.938). The cut-off value of the HBeAg level at week 12 for predicting the HBsAg response at week 48 was 13.915 S/CO, the sensitivity was 40.50%, the specificity was 76.20%, and the AUC was 0.541 (95% CI: 0.421–0.661). The cut-off value of the HBeAg decline level at week 12 for predicting the HBsAg response at week 48 was 552.055 S/CO, the sensitivity was 73.00%, the specificity was 50.80%, and the AUC was 0.576 (95% CI: 0.459–0.693).
Univariate analysis OR 95% CI P value HBsAg (log10 IU/mL) 1.318 0.574−3.028 0.515 HBV DNA (log10 IU/mL) 0.564 0.315−1.012 0.055 HBeAg (S/CO) 1.001 1.000−1.002 0.196 ALT (U/L) 0.999 0.997−1.001 0.606 AST (U/L) 0.999 0.996−1.002 0.435 TBil (µmol/L) 0.967 0.905−1.032 0.312 ALB (g/L) 0.985 0.876−1.017 0.801 Flt3-L (pg/mL) 1.004 0.997−1.010 0.278 IFN-α2 (pg/mL) 1.002 0.999−1.006 0.252 IFN-γ (pg/mL) 1.001 0.998−1, 004 0.574 IL-10 (pg/mL) 0.997 0.986−1.007 0.527 IL-17A (pg/mL) 1.002 0.996−1.008 0.544 IL-6 (pg/mL) 1.005 0.993−1.017 0.398 TNF-α (pg/mL) 1.180 0.788−1.769 0.422 TGF-β1 (pg/mL) 1.000 1.000 0.488 TGF-β2 (pg/mL) 1.003 1.000−1.006 0.022 TGF-β3 (pg/mL) 1.006 0.994−1.018 0.353 HBsAg decreased in
12 weeks (log10 IU/mL)0.827 0.439−1.559 0.557 HBeAg decreased in
12 weeks (S/CO)1.000 0.999−1.001 0.683 HBsAg decreased in
24 weeks (log10 IU/mL)0.725 0.387−1.360 0.317 HBeAg decreased in
24 weeks (S/CO)1.000 0.998−1.001 0.684 Multivariate analysis
(3 months)HBsAg (log10 IU/mL) 568.906 13.255−
24417.7630.001 HBeAg (S/CO) 0.991 0.985−0.998 0.007 ALB (g/L) 1.786 1.152−2.769 0.010 HBsAg decreased in
12 weeks (log10 IU/mL)0.135 0.021−0.887 0.037 HBeAg decreased in
12 weeks (S/CO)1.006 1.001−1.011 0.029 Multivariate analysis
(6 months)HBsAg (log10 IU/mL) 194.862 6.559−
5789.3900.002 ALB (g/L) 1.618 1.061−2.468 0.026 Note. ALT, glutamic-pyruvic transaminase. AST, glutamic oxalacetic transaminase. TBil, total bilirubin. ALB, albumin. Table 4. Logistic regression analysis of predictors of an HBsAg decline ≥ 1 log10 IU/mL at week 48 after IFN treatment
Univariate analysis indicated that the baseline median TGF-β2 (OR = 1.003, 95% CI: 1.000–1.006, P = 0.022) was associated with an HBsAg decline < 1 log10 IU/mL at week 48. At week 12, the median HBsAg (OR = 568.906, 95% CI: 13.255–24417.763, P = 0.001), HBeAg (OR = 0.991, 95% CI: 0.985–0.998, P = 0.007), ALB (OR = 1.786, 95% CI: 1.152–2.769, P = 0.01), the 12-week decline in HBsAg (OR = 0.135, 95% CI: 0.021–0.887, P = 0.037), and the 12-week decline in HBeAg (OR = 1.006, 95% CI: 1.001–1.011, P = 0.029) were independently associated with an HBsAg decrease < 1 log10 IU/mL at week 48. At week 24, the median HBsAg (OR = 194.862, 95% CI: 6.559–5789.390, P = 0.002) and ALB levels (OR = 1.39, 95% CI: 6.559–5789.39.618, 95% CI: 1.061–2.468, P = 0.026) were significantly associated with a decrease < 1 log10 in HBsAg at week 48. The cut-off value of the HBsAg level at week 24 for predicting the HBsAg response at week 48 was 3.01 log10 IU/mL, the sensitivity was 100.00%, the specificity was 85.50%, and the AUC was 0.933 (95% CI: 0.882–0.985).
There was no statistically significant difference in cytokines between patients with and without HBsAg response during treatment (P > 0.013); thus, the predictive value of cytokines could not be further analyzed.
Cytokine Profiles and Virological Marker Monitoring during 48 Weeks Peginterferon Alfa Treatment for HBeAg-Positive Chronic Hepatitis B
doi: 10.3967/bes2022.042
- Received Date: 2021-08-27
- Accepted Date: 2021-11-30
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Key words:
- Chronic hepatitis B /
- Cytokine /
- Peginterferon /
- HBsAg /
- HBeAg
Abstract:
Citation: | LI Ming Hui, SUN Fang Fang, CHEN Feng Xin, ZENG Zhan, LIN Yan Jie, BI Xiao Yue, YANG Liu, DENG Wen, JIANG Ting Ting, HUANG Rong Hai, YI Wei, XIE Yao. Cytokine Profiles and Virological Marker Monitoring during 48 Weeks Peginterferon Alfa Treatment for HBeAg-Positive Chronic Hepatitis B[J]. Biomedical and Environmental Sciences, 2022, 35(4): 312-321. doi: 10.3967/bes2022.042 |