On-treatment quantitative hepatitis B e antigen predicted response to nucleos(t)ide analogues in chronic hepatitis B

Table 1 Baseline clinical characteristics of patients with chronic hepatitis B according to treatment response after 96-wk nucleos(t)ide analogues therapy

Parameters	Overall	VR (+)	VR (-)	P value	SC (+)	SC (-)	P value
n (%)	76	43 (56.6)	33 (43.4)	-	15 (19.7)	61 (80.3)	-
Gender, female/male	20/56	15/28	5/28	0.053	5/10	15/46	0.491
Age, yr	32.63 ± 9.69	32.3 ± 9.83	33.06 ± 9.63	0.738	31.87 ± 11.6	32.82 ± 9.26	0.735
HBsAg, lg IU/mL	3.95 ± 0.83	3.96 ± 0.68	3.94 ± 1.00	0.881	3.93 ± 0.60	3.96 ± 0.88	0.385
HBeAg, lg PEIU/mL	2.24 ± 1.31	2.18 ± 1.38	2.32 ± 1.22	0.679	2.36 ± 1.41	2.21 ± 1.29	0.527
anti-HBc, lg IU/mL	4.77 ± 0.46	4.82 ± 0.43	4.71 ± 0.50	0.311	4.85 ± 0.44	4.75 ± 0.47	0.464
ALT, U/L	213.73 ± 157.17	247.95 ± 150.58	169.13 ± 156.56	0.029	216.49 ± 153.18	213.05 ± 159.38	0.94
ALT strata, ≥/< 5ULN	31/45	25/18	6/27	< 0.001	9/6	22/39	0.091
HBV DNA, lg copies/mL	8.16 ± 1.34	8.06 ± 1.45	8.3 ± 1.19	0.608	8.55 ± 0.91	8.07 ± 1.41	0.324
Genotype, C/non-C	53/23	31/12	22/11	0.61	10/5	43/18	0.773

VR (+)/VR (-), with/without virological response at week 96 (virological response: HBV DNA ≤ 300 copies/mL); SC (+)/SC (-), with/without HBeAg seroconversion at week 96. HBsAg: Hepatitis B surface antigen; ALT: Alanine aminotransferase; HBV: Hepatitis B virus; VR: Virological response; SC: HBeAg seroconversion; ULN: Upper limit of normal.

Table 2 Baseline and on-treatment parameters associated with 96-wk virological response and hepatitis B e antigen seroconversion in chronic hepatitis B patients received nucleos(t)ide analogues therapy

Factors	VR				SC
	Univariate		Multivariate		Univariate		Multivariate
	OR (95%CI)	P value	OR (95%CI)	P value	OR (95%CI)	P value	OR (95%CI)	P value
Baseline
Age	0.99 (0.95-1.04)	0.734	-	-	0.99 (0.93-1.05)	0.731	-	-
Sex, female/male	3 (0.96-9.38)	0.059	3.76 (1.09-13.01)	0.037	1.53 (0.45-5.20)	0.493	-	-
HBsAg (lg IU/mL)	1.04 (0.60-1.81)	0.879	-	-	0.96 (0.49-1.88)	0.904	-	-
HBeAg (lg PEIU/mL)	0.92 (0.65-1.31)	0.633	-	-	1.1 (0.70-1.72)	0.682	-	-
Anti-HBc (lg IU/mL)	1.68 (0.62-4.59)	0.308	-	-	1.6 (0.46-5.50)	0.459	-	-
HBV DNA (lg copies/mL)	0.87 (0.62-1.24)	0.451	-	-	1.38 (0.82-2.31)	0.221	-	-
ALT (U/L)	1.004 (1.000-1.007)	0.038	-	-	1 (0.99-1.01)	0.939	-	-
ALT strata, ≥/< 5ULN	6.25 (2.14-18.26)	< 0.001	7.09 (2.32-21.67)	< 0.001	2.66 (0.84-8.46)	0.098	-	-
Genotype, C/non-C	1.29 (0.48-3.46)	0.61	-	-	0.84 (0.25-2.80)	0.773	-	-
Week 12
HBsAg (lg IU/mL)	0.83 (0.45-1.53)	0.551	-	-	0.95 (0.47-1.92)	0.882	-	-
HBsAg decline (lg IU/mL)	1.43 (0.72-2.84)	0.301	-	-	1.04 (0.46-2.35)	0.919	-	-
HBeAg (lg PEIU/mL)	0.5 (0.33-0.76)	0.001	0.62 (0.40-0.95)	0.03	0.5 (0.30-0.85)	0.011	-	-
HBeAg decline (lg PEIU/mL)	3.04 (1.55-5.98)	0.001	2.58 (1.25-5.33)	0.01	2.47 (1.46-4.16)	< 0.001	2.47 (1.46-4.16)	0.001
Anti-HBc (lg IU/mL)	1.14 (0.49-2.64)	0.764	-	-	2.56 (0.83-7.93)	0.102	-	-
Anti-HBc decline (lg IU/mL)	1.43 (0.45-4.59)	0.546	-	-	0.3 (0.06-1.51)	0.145	-	-
ALT (U/L)	0.99 (0.98-1.01)	0.221	-	-	1 (0.98-1.02)	0.876	-	-
ALT decline (U/L)	1.004 (1.00-1.01)	0.03	-	-	1 (0.99-1.01)	0.918	-	-
HBV DNA (lg copies/mL)	0.57 (0.36-0.90)	0.016	-	-	0.72 (0.42-1.25)	0.249	-	-
HBV DNA decline (lg copies/mL)	1.36 (0.90-2.03)	0.141	-	-	2.11 (1.16-3.84)	0.015	-	-
Week 24
HBsAg (lg IU/mL)	0.61 (0.31-1.21)	0.155	-	-	0.84 (0.48-1.46)	0.535	-	-
HBsAg decline (lg IU/mL)	1.79 (0.94-3.42)	0.076	-	-	1.21 (0.62-2.37)	0.571	-	-
HBeAg (lg PEIU/mL)	0.39 (0.24-0.64)	< 0.001	0.45 (0.27-0.77)	0.003	0.28 (0.14-0.58)	< 0.001	0.37 (0.17-0.81)	0.013
HBeAg decline (lg PEIU/mL)	2.37 (1.41-3.99)	0.001	2.03 (1.10-3.74)	0.024	2.8 (1.64-4.78)	< 0.001	2.02 (1.17-3.49)	0.012
Anti-HBc (lg IU/mL)	0.73 (0.33-1.63)	0.448	-	-	1.29 (0.48-3.45)	0.608	-	-
Anti-HBc decline (lg IU/mL)	3.11 (0.99-3.79)	0.053	-	-	1.11 (0.31-3.99)	0.874	-	-
ALT (U/L)	0.99 (0.98-1.01)	0.477	-	-	0.99 (0.96-1.02)	0.516	-	-
ALT decline (U/L)	1.004 (1.00-1.01)	0.031	-	-	1 (0.99-1.01)	0.822	-	-
HBV DNA (lg copies/mL)	0.55 (0.37-0.80)	0.002	-	-	0.45 (0.23-0.86)	0.016	-	-
HBV DNA decline (lg copies/mL)	1.39 (1.02-1.88)	0.035	-	-	2.39 (1.39-4.11)	0.002	-	-

HBsAg: Hepatitis B surface antigen; HBeAg: Hepatitis B e antigen; Anti-HBc: Hepatitis B core antibody; ALT: Alanine aminotransferase; HBV: Hepatitis B virus; VR: Virological response (HBV DNA ≤ 300 copies/mL); SC: HBeAg seroconversion; ULN: Upper limit of normal.

Table 3 Predictive value of hepatitis B e antigen titer as well as its declined value at week 12 and 24 for virological response after 96-wk nucleos(t)ide analogues therapy

Factors	ROC		Sensitivity (95%CI)	Specificity (95%CI)	PPV (95%CI)	NPV (95%CI)
	AUROC (95%CI)	P value
Week 12
HBeAg < 0.8 lg PEIU/mL	0.733 (0.617-0.849)	0.001	0.63 (0.48-0.78)	0.81 (0.67-0.96)	0.82 (0.68-0.96)	0.62 (0.47-0.77)
HBeAg decline > 0.84 lg PEIU/mL	0.709 (0.590-0.827)	0.002	0.65 (0.50-0.80)	0.75 (0.59-0.91)	0.78 (0.64-0.92)	0.62 (0.46-0.78)
Combined the above	0.812 (0.687-0.936)	< 0.001	0.71 (0.54-0.89)	0.91 (0.78-1.00)	0.91 (0.78-1.00)	0.71 (0.54-0.89)
Week 24
HBeAg < 1.3 lg PEIU/mL	0.788 (0.683-0.892)	< 0.001	0.88 (0.78-0.98)	0.64 (0.46-0.81)	0.76 (0.63-0.88)	0.81 (0.65-0.97)
HBeAg decline > 1.6 lg PEIU/mL	0.736 (0.620-0.851)	< 0.001	0.55 (0.39-0.70)	0.94 (0.85-1.00)	0.92 (0.81-1.00)	0.62 (0.48-0.76)
Combined the above	0.923 (0.838-1.000)	< 0.001	0.85 (0.70-0.99)	1	1	0.83 (0.66-0.99)

HBeAg: Hepatitis B e antigen; VR: Virological response (HBV DNA ≤ 300 copies/mL); AUROC: Area under the receiver operating characteristic curve; PPV: Positive predictive value; NPV: Negative predictive value.

Table 4 Predictive value of hepatitis B e antigen titer as well as its declined value at week 12 and 24 for hepatitis B e antigen seroconversion after 96-wk nucleos(t)ide analogues therapy

Factors	ROC		Sensitivity (95%CI)	Specificity (95%CI)	PPV (95%CI)	NPV (95%CI)
	AUROC (95%CI)	P value
Week 12
HBeAg decline > 1.8 lg PEIU/mL	0.767 (0.623-0.911)	0.001	0.6 (0.32-0.88)	0.87 (0.78-0.96)	0.53 (0.26-0.79)	0.9 (0.82-0.98)
Week 24
HBeAg < -0.5 lg PEIU/mL	0.828 (0.712-0.944)	< 0.001	0.67 (0.40-0.94)	0.92 (0.84-0.99)	0.67 (0.40-0.94)	0.92 (0.84-0.99)
HBeAg decline > 2.2 lg PEIU/mL	0.814 (0.676-0.953)	< 0.001	0.73 (0.48-0.99)	0.9 (0.82-0.98)	0.65 (0.39-0.90)	0.93 (0.86-1.00)
Combined the above	0.928 (0.791-1.000)	< 0.001	0.88 (0.58-1.00)	0.98 (0.94-1.00)	0.88 (0.58-1.00)	0.98 (0.94-1.00)

HBeAg: Hepatitis B e antigen; SC: HBeAg seroconversion; AUROC: Area under the receiver operating characteristic curve; PPV: Positive predictive value; NPV: Negative predictive value.