Clinical utility of hepatitis B surface antigen kinetics in treatment-naïve chronic hepatitis B patients during long-term entecavir therapy

Table 1 Clinical characteristics of enrolled patients, categorized by HBeAg status n (%)

Characteristics	Total (n = 211)	HBeAg-positive (n = 62)	HBeAg-negative (n = 149)	P value1
Age (yr)	50.4 ± 11.9	43.8 ± 12.2	53.2 ± 10.6	< 0.0001
Male	147 (69.7)	39 (63.0)	108 (72.5)	0.170
Treatment time (yr)	5.24 (2.00-9.62)	4.39 (2.11-9.62)	5.35 (2.00-9.58)	0.590
Cirrhosis	66 (31.3)	12 (19.4)	54 (36.2)	0.016
HCC2	32 (15.2)	5 (8.1)	27 (18.1)	0.060
HBV genotype3	101:86:2 (53.4%:45.5%:1.1%)	21:39:01	80:47:01	0.001
B:C:B + C		(34.4%:63.9%:1.6%)	(62.5%:36.7%:0.8%)
ALT (× ULN)	4.12 ± 5.88	4.42 ± 6.62	3.99 ± 5.56	0.630
HBV DNA (log IU/mL)	5.84 ± 1.70	7.24 ± 1.39	5.26 ± 1.50	< 0.0001
HBsAg (log IU/mL)	3.15 ± 0.80	3.80 ± 0.71	2.89 ± 0.67	< 0.0001

Continuous variables are expressed as mean ± SD, except treatment time, which is expressed as median (range). Categorical variables are expressed as numbers (percentages).

¹P value represents HBeAg-positive patients compared with HBeAg-negative patients;

²HCC diagnosed before or within half a year of entecavir therapy;

³HBV genotype could not be determined in 1 HBeAg-positive patient and 21 HBeAg-negative patients because of low HBV viral loads in these patients. ALT: Alanine aminotransferase; HBeAg: Hepatitis B e antigen; HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma; ULN: Upper limit of normal.

Table 2 Univariate and multivariate analyses of factors associated with virological response in HBeAg-positive patients

Factors	Univariate analysis			Multivariate analysis
	HR	95%CI	P value	HR	95%CI	P value
Sex (female vs male)	1.31	0.73-2.36	0.37	2.95	1.33-6.57	0.008
Age (yr)	1.00	0.98-1.02	0.90	0.99	0.96-1.01	0.390
Cirrhosis (yes vs no)	0.91	0.42-1.96	0.81	0.94	0.32-2.79	0.910
HBV genotype (B vs C)1	1.14	0.62-2.09	0.67	2.04	0.99-4.21	0.053
ALT (× ULN)	1.02	0.98-1.06	0.25	1.04	1.00-1.08	0.060
HBV DNA (≤ 5 vs > 5 log IU/mL)	2.72	0.96-7.68	0.06	1.78	0.46-6.90	0.400
HBsAg (< 4 vs ≥ 4 log IU/mL)	1.96	1.08-3.55	0.03	4.92	2.10-11.51	< 0.001

¹Only one HBeAg-positive patient had a mixed HBV genotype B and C infection; therefore, a genotype B + C subset was not included in this analysis. ALT: Alanine aminotransferase; CI: Confidence interval; HR: Hazard ratio; HBeAg: Hepatitis B e antigen; HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus; ULN: Upper limit of normal.

Table 3 Univariate and multivariate analyses of factors associated with virological response in HBeAg-negative non-cirrhotic patients

Factors	Univariate analysis			Multivariate analysis
	HR	95%CI	P value	HR	95%CI	P value
Sex (female vs male)	1.14	0.72-1.81	0.57	1.39	0.78-2.47	0.27
Age (yr)	0.99	0.97-1.01	0.53	0.99	0.96-1.01	0.31
HBV genotype (B vs C)1	1.17	0.70-1.93	0.55	1.34	0.79-2.30	0.28
ALT (× ULN)	1.00	0.96-1.04	0.94	0.99	0.94-1.04	0.65
HBV DNA (≤ 4 vs > 4 log IU/mL)	1.33	0.73-2.40	0.35	0.63	0.19-2.07	0.45
HBsAg (< 2.4 vs ≥ 2.4 log IU/mL)	3.95	2.19-7.12	< 0.001	3.12	1.58-6.19	0.001

¹None of the HBeAg-negative non-cirrhotic patients had a mixed HBV genotype B and C infection. ALT: Alanine aminotransferase; CI: Confidence interval; HR: Hazard ratio; HBeAg: Hepatitis B e antigen; HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus; ULN: Upper limit of normal.

Table 4 Univariate and multivariate analyses of factors associated with HBeAg seroclearance in HBeAg-positive patients

Factors	Univariate analysis			Multivariate analysis
	HR	95%CI	P value	HR	95%CI	P value
Sex (female vs male)	0.74	0.36-1.54	0.43	1.14	0.49-2.67	0.76
Age (yr)	1.00	0.98-1.03	0.81	0.99	0.95-1.02	0.42
Cirrhosis (yes no)	1.42	0.64-3.15	0.39	0.71	0.24-2.07	0.53
HBV genotype (B vs C)1	1.17	0.57-2.39	0.67	2.04	0.90-4.62	0.09
ALT (× ULN)	1.02	0.96-1.09	0.51	1.04	0.98-1.09	0.17
HBV DNA (≤ 5 vs > 5 log IU/mL)	2.10	0.64-6.93	0.22	3.40	0.83-13.87	0.09
HBsAg (< 4 vs ≥ 4 log IU/mL)	3.32	1.49-7.43	0.003	5.74	2.19-15.00	< 0.001

¹Only one HBeAg-positive patient had a mixed HBV genotype B and C infection; therefore, a genotype B + C subset was not included in this analysis. ALT: Alanine aminotransferase; CI: Confidence interval; HR: Hazard ratio; HBeAg: Hepatitis B e antigen; HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus; ULN: Upper limit of normal.

Table 5 Univariate and multivariate analyses of factors associated with HBeAg seroconversion in HBeAg-positive patients

Factors	Univariate analysis			Multivariate analysis
	HR	95%CI	P value	HR	95%CI	P value
Sex (female vs male)	0.70	0.29-1.72	0.440	1.02	0.35-2.97	0.970
Age (yr)	0.99	0.95-1.02	0.440	0.98	0.94-1.02	0.310
Cirrhosis (yes vs no)	0.93	0.31-2.75	0.890	0.57	0.15-2.16	0.410
HBV genotype (B vs C)1	0.86	0.35-2.13	0.750	1.49	0.52-4.26	0.450
ALT (× ULN)	1.03	0.96-1.10	0.390	1.05	0.99-1.11	0.120
HBV DNA (≤ 5 vs > 5 log IU/mL)	3.16	0.93-10.76	0.070	4.15	1.05-16.44	0.043
HBsAg (< 4 vs ≥ 4 log IU/mL)	3.05	1.12-8.28	0.029	5.05	1.58-16.14	0.006

¹Only one HBeAg-positive patient had a mixed HBV genotype B and C infection; therefore, a genotype B + C subset was not included in this analysis. ALT: Alanine aminotransferase; CI: Confidence interval; HR: Hazard ratio; HBeAg, hepatitis B e antigen; HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus; ULN: Upper limit of normal.

Table 6 Univariate and multivariate analyses of factors associated with new hepatocellular carcinoma development

Factors		Univariate analysis			Multivariate analysis
		HR	95%CI	P value	HR	95%CI	P value
Sex (female vs male)		0.42	0.09-1.90	0.26	0.31	0.05-1.94	0.21
Age (yr)		1.08	1.03-1.13	0.001	1.05	0.99-1.12	0.12
HBeAg (positive vs negative)		0.44	0.10-1.97	0.28	0.91	0.14-6.00	0.92
Cirrhosis (yes vs no)		11.32	3.11-41.24	< 0.001	13.02	2.00-84.99	0.007
HBV genotype (B vs C)1		0.58	0.18-1.90	0.37	0.63	0.12-3.28	0.58
ALT (× ULN)		1.02	0.95-1.09	0.55	1.06	0.97-1.16	0.20
HBV DNA (log IU/mL)		0.90	0.66-1.22	0.48	1.06	0.59-1.91	0.84
HBsAg (log IU/mL)		0.80	0.41-1.55	0.51	0.98	0.29-3.36	0.97

¹Only two patients (one HBeAg-positive and one HBeAg-negative cirrhotic) had mixed HBV genotype B and C infection; therefore, a genotype B + C subset was not included in this analysis. ALT: Alanine aminotransferase; CI: Confidence interval; HR: Hazard ratio; HBeAg: Hepatitis B e antigen; HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma; ULN: Upper limit of normal.