Retreatment hepatitis B surface antigen clearance prediction model identifies pegylated interferon alpha candidates in chronic hepatitis B

Table 1 Characteristics of patients with hepatitis B surface antigen positive compared with patients with hepatitis B surface antigen negative after retreatment, n (%)

Characteristic	Total patients (n = 135)	HBSP (n = 107)	HBSN (n = 28)	P value
Age (years), median (Q1, Q3)	40.00 (35.00, 46.00)	40.00 (35.00, 47.00)	38.50 (35.75, 41.00)	0.311
Male	100 (74.07)	80 (74.77)	20 (71.43)	0.720
BMI (kg/m2), median (Q1, Q3)	24.70 (22.80, 26.60)	24.75 (23.02, 26.78)	24.70 (22.35,25.90)	0.388
HBV family history				0.203
No	59 (44.70)	44 (41.90)	15 (55.56)
Yes	73 (55.30)	61 (58.10)	12 (44.44)
Smoke history				0.836
No	38 (65.52)	30 (63.83)	8 (72.73)
Yes	20 (34.48)	17 (36.17)	3 (27.27)
Drink history				0.848
No	49 (84.48)	39 (82.98)	10 (90.91)
Yes	9 (15.52)	8 (17.02)	1 (9.09)
Diabetes mellitus				1.000
No	125 (94.70)	99 (94.29)	26 (96.30)
Yes	7 (5.30)	6 (5.71)	1 (3.70)
Hypertension				0.881
No	116 (87.88)	93 (88.57)	23 (85.19)
Yes	16 (12.12)	12 (11.43)	4 (14.81)
Cirrhosis				0.362
No	102 (75.56)	79 (73.83)	23 (82.14)
Yes	33 (24.44)	28 (26.17)	5 (17.86)
First circle Peg-IFNα treatment relative
Combination of NAs				< 0.001
No	8 (5.93)	2 (1.87)	6 (21.43)
Yes	127 (94.07)	105 (98.13)	22 (78.57)
Type of NAs				0.001
No	8 (5.93)	2 (1.87)	6 (21.43)
ETV	29 (21.48)	27 (25.23)	2 (7.14)
TDF	49 (36.29)	39 (36.45)	10 (35.72)
TAF	40 (29.63)	32 (29.91)	8 (28.57)
Combine	9 (6.67)	7 (6.54)	2 (7.14)
Baseline HBsAg level of initial treatment (log10 IU/mL), median (Q1, Q3)	3.23 (2.84, 3.59)	3.32 (2.98, 3.71)	2.92 (2.30, 3.18)	< 0.001
HBsAg level at week 12 of initial treatment (log10 IU/mL), median (Q1, Q3)	3.03 (2.35, 3.39)	3.14 (2.67, 3.49)	1.83 (0.87, 2.75)	< 0.001
HBsAg level at end of initial treatment (log10 IU/mL), median (Q1, Q3)	2.55 (1.44, 3.16)	2.72 (1.82, 3.30)	0.93 (0.30, 1.87)	< 0.001
HBsAg decline at week 12 of initial treatment (log10 IU/mL), median (Q1, Q3)	0.21 (0.07, 0.62)	0.15 (0.03, 0.36)	0.84 (0.32, 1.19)	< 0.001
HBsAg decline at end of initial treatment (log10 IU/mL), median (Q1, Q3)	0.65 (0.30, 1.42)	0.50 (0.28, 0.93)	1.64 (0.72, 1.97)	< 0.001
HBsAg decline at end of initial treatment (%), median (Q1, Q3)	0.78 (0.05, 0.96)	0.69 (0.46, 0.88)	0.98 (0.81, 0.99)	< 0.001
HBeAg				0.542
Negative	98 (73.13)	77 (71.96)	21 (77.78)
Positive	36 (26.87)	30 (28.04)	6 (22.22)
HBV DNA (log10 IU/mL), median (Q1, Q3)	-3.00 (-3.00, 3.17)	-3.00 (-3.00, 3.04)	2 .00 (-3.00, 3.39)	0.323
ALT (U/L), median (Q1, Q3)	25.50 (19.00, 42.50)	25.00 (17.00, 40.00)	31.70 (19.00, 45.00)	0.277
AST (U/L), median (Q1, Q3)	22.50 (18.00, 29.00)	22.00 (18.00, 29.00)	24.00 (18.00, 29.00)	0.878
GGT (U/L), median (Q1, Q3)	24.00 (17.00, 38.75)	24.00 (16.25, 39.75)	24.00 (17.00, 35.00)	0.928
TBIL (μmol/L), median (Q1, Q3)	16.40 (13.00, 21.63)	16.85 (13.28, 22.02)	15.25 (11.38,17.70)	0.064
ALB (g/L), median (Q1, Q3)	48.40 (46.75, 49.95)	48.15 (46.55, 50.00)	48.90 (47.80, 49.80)	0.319
PLT (109/L), median (Q1, Q3)	194.00 (164.25, 236.25)	197.00 (166.00, 238.00)	189.00 (165.00, 212.00)	0.445
AFP (IU/mL), median (Q1, Q3)	2.68 (1.89, 4.58)	2.76 (1.89, 4.63)	2.51 (2.10, 4.25)	0.637
LSM (kPa), median (Q1, Q3)	7.60 (6.00, 9.80)	7.70 (6.17, 9.80)	6.46 (5.65, 9.20)	0.184
CAP (dB/m), median (Q1, Q3)	249.00 (231.00, 276.20)	256.00 (232.00, 278.00)	239.00 (228.75, 254.25)	0.037
Second circle Peg-IFNα treatment relative
HBsAg level at retreatment baseline (log10 IU/mL), median (Q1, Q3)	2.53 (1.67, 3.12)	2.81 (2.02, 3.31)	0.89 (-0.28, 2.31)	< 0.001
Rebound magnitude of HBsAg at retreatment baseline compared to end of initial treatment (log10 IU/mL), median (Q1, Q3)	0.00 (-0.14, 0.19)	0.00 (-0.10, 0.16)	-0.03 (-0.54, 0.32)	0.433
Rebound magnitude of HBsAg at retreatment baseline compared to end of initial treatment (%), median (Q1, Q3)	0.00 (-0.06, 0.07)	0.00 (-0.04, 0.07)	-0.15 (-0.96, 0.08)	0.027
Rebound magnitude of HBsAg at retreatment baseline compared to baseline of initial treatment (%), median (Q1, Q3)	-0.20 (-0.43, -0.09)	-0.17 (-0.29, -0.08)	-0.63 (-1.10, -0.30)	< 0.001
The interval weeks between the two treatments (weeks), median (Q1, Q3)	23.40 (15.00, 39.85)	20.70 (15.00, 32.95)	36.40 (16.20, 86.17)	0.015
1st Peg-IFN treatment course (weeks), median (Q1, Q3)	48.00 (36.00, 58.70)	48.00 (36.00, 55.35)	39.40 (27.65, 51.50)	0.824
2nd Peg-IFN treatment course (weeks), median (Q1, Q3)	28.00 (21.25, 44.75)	26.05 (19.02, 43.30)	30.00 (19.55, 47.00)	0.016
Total follow-up time (weeks), median (Q1, Q3)	147.60 (126.30, 182.05)	155.10 (131.60, 182.05)	134.95 (116.75, 178.78)	0.181

HBSP: Hepatitis B surface antigen positive; HBSN: Hepatitis B surface antigen negative; BMI: Body mass index; HBV: Hepatitis B virus; Peg-IFNα: Pegylated interferon alpha; NAs: Nucleoside analogs; ETV: Entecavir; TDF: Tenofovir disoproxil fumarate; TAF: Tenofovir alafenamide fumarate tablets; HBsAg: Hepatitis B surface antigen; HBeAg: Hepatitis B envelope antigen; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma-glutamyl transferase; TBIL: Total bilirubin; ALB: Albumin; PLT: Platelet; AFP: Alpha-fetoprotein; LSM: Liver stiffness measurement; CAP: Controlled attenuation parameter.

Table 2 Univariate Cox regression, least absolute shrinkage and selection operator regression, and multivariate Cox regression analysis of factors associated with hepatitis B surface antigen seroclearance in patients with chronic hepatitis B receiving pegylated interferon alpha-2b retreatment

Characteristic	Univariable		LASSO	Multivariable
	HR (95%CI)	P value		HR (95%CI)	P value
Age (years)	0.979 (0.931-1.030)	0.406
Gender
Male	1
Female	1.185 (0.522-2.690)	0.685
BMI (kg/m2)	0.945 (0.837-1.067)	0.363
HBV family history
No	1
Yes	0.642 (0.301-1.373)	0.254
Smoke history
No	1
Yes	0.785 (0.208-2.968)	0.722
Drink history
No	1
Yes	0.562 (0.072-4.393)	0.583
Diabetes mellitus
No	1
Yes	0.742 (0.100-5.482)	0.770
Hypertension
No	1
Yes	1.444 (0.497-4.194)	0.499
Cirrhosis
No	1
Yes	0.662 (0.252-1.742)	0.404
First circle Peg-IFNα treatment relative
Combination of NAs			Yes		0.022
No	1			1
Yes	0.159 (0.064-0.394)	< 0.001		0.276 (0.092-0.833)
Type of NAs
No	1
ETV	0.056 (0.011-0.280)	< 0.001
TDF	0.198 (0.072-0.546)	0.002
TAF	0.188 (0.065-0.544)	0.002
Combine	0.187 (0.038-0.933)	0.041
1st Peg-IFNα treatment course (weeks)	1.011 (0.986-1.037)	0.394
Baseline HBsAg level of initial treatment (log10 IU/mL)	0.472 (0.324-0.686)	< 0.001
HBsAg level at week 12 of initial treatment (log10 IU/mL)	0.433 (0.329-0.569)	< 0.001
HBsAg level at end of initial treatment (log10 IU/mL)	0.474 (0.377-0.594)	< 0.001	Yes	1.024 (0.641-1.638)	0.920
HBsAg decline at week 12 of initial treatment (log10 IU/mL)	4.043 (2.576-6.343)	< 0.001	Yes	1.113 (0.578-2.142)	0.310
HBsAg decline at end of initial treatment (log10 IU/mL)	2.450 (1.748-3.434)	< 0.001	Yes	2.050 (1.108-3.793)	0.028
HBsAg decline at end of initial treatment (%)	27.448 (3.286-29.246)	0.002
HBeAg
Negative	1
Positive	0.706 (0.285-1.749)	0.452
HBV DNA (log10 IU/mL)	1.047 (0.954-1.148)	0.333
ALT (U/L)	1.001 (0.999-1.003)	0.266
AST (U/L)	0.997 (0.989-1.005)	0.501
GGT (U/L)	1.000 (0.994-1.006)	0.965
TBIL (μmol/L)	0.989 (0.941-1.040)	0.670
ALB (g/L)	1.063 (0.921-1.227)	0.405
PLT (109/L)	0.998 (0.990-1.006)	0.643
AFP (ng/mL)	0.966 (0.885-1.055)	0.441
LSM (kPa)	0.919 (0.798-1.059)	0.244
CAP (dB/m)	0.994 (0.987-1.001)	0.109
The interval weeks between the two treatments (weeks)	1.010 (1.006-1.014)	< 0.001	Yes	1.013 (1.008-1.018)	< 0.001
Second circle Peg-IFNα treatment relative
HBsAg level at retreatment baseline (log10 IU/mL)	0.440 (0.353-0.549)	< 0.001	Yes	0.571 (0.410-0.795)	0.001
Rebound magnitude of HBsAg at retreatment baseline compared to end of initial treatment (log10 IU/mL)	0.757 (0.658-0.872)	< 0.001
Rebound magnitude of HBsAg at retreatment baseline compared to end of initial treatment (%)	0.682 (0.448-1.037)	0.073
Rebound magnitude of HBsAg at retreatment baseline compared to baseline of initial treatment (%)	0.179 (0.107-0.300)	< 0.001
Model parameter			λ = 0.054

LASSO: Least absolute shrinkage and selection operator; HR: Hazard ratio; CI: Confidence interval; BMI: Body mass index; HBV: Hepatitis B virus; Peg-IFNα: Pegylated interferon alpha; NAs: Nucleoside analogs; ETV: Entecavir; TDF: Tenofovir disoproxil fumarate; TAF: Tenofovir alafenamide fumarate tablets; HBsAg: Hepatitis B surface antigen; HBeAg: Hepatitis B envelope antigen; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma-glutamyl transferase; TBIL: Total bilirubin; ALB: Albumin; PLT: Platelet; AFP: Alpha-fetoprotein; LSM: Liver stiffness measurement; CAP: Controlled attenuation parameter.