The potential effect of HBV vaccination on off-treatment HBsAg reversion after interferon-induced HBsAg clearance

Figures & data

Figure 1. Flow chart of patient enrollment. Abbreviations: CHB, chronic hepatitis B; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; ICC, intrahepatic cholangiocarcinoma; IFN, interferon; NA, nucleoside/nucleotide analogues; w, weeks.

Table 1. Clinical characteristics of CHB patients with HBsAg clearance.

Characteristics	IFN-induced group(n = 112)	NA-induced group(n = 36)	Spontaneous group(n = 51)	P^†-value
At the time of HBsAg clearance
Age, years, median (IQR)	36.6 (32.0–42.7)	42.8 (36.3–54.1)	49.7 (40.4–57.0)	<.001
Male sex, n (%)	100 (89.3%)	23 (63.9%)	41 (80.4%)	.002
HBsAg negativity, n (%)	112 (100%)	36 (100%)	51 (100%)	1.000
HBsAb positivity, n (%)	34 (31.2%)	11 (32.4%)	19 (37.3%)	.746
HBsAb level, mIU/ml, n(%)				.433
< 10 mIU/ml	75 (68.8%)	23 (67.6%)	32 (62.7%)
10–100 mIU/ml	24 (22.0%)	6 (17.6%)	15 (29.4%)
100–1000 mIU/ml	10 (9.2%)	5 (14.7%)	3 (5.9%)
> 1000 mIU/ml	0 (0.0%)	0 (0.0%)	1 (2.0%)
HBeAg positivity, n (%)	6 (5.5%)	2 (5.9%)	0 (0.0%)	.179
HBeAb positivity, n (%)	77 (70.6%)	23 (67.6%)	48 (94.1%)	.002
Undetectable HBV DNA, n (%)	112 (100%)	36 (100%)	51 (100%)	1.000
At the end of follow-up
Duration of treatment, weeks# or years*, median (IQR)	62.0^# (48.0–107.5)	10.0* (4.3–12.0)		<0.001^¶
Follow-up time, weeks, median (IQR)	131.5 (51.8–215.8)	113.5 (66.0–229.5)	217.0 (101.0–355.0)	0.004
HBsAg reversion, n (%)	24 (21.4%)	1 (2.8%)	3 (5.9%)	0.003

Abbreviations: HBeAb, hepatitis B e antibody; HBeAg, hepatitis B e antigen; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; IFN, interferon; IQR, interquartile range; NA, nucleoside/nucleotide analogues.

Note: HBsAg level > 0.05 IU/ml, HBsAb level >10 mIU/ml, HBeAg level >1.0 S/CO and HBeAb level <1.0 S/CO were defined as positive, respectively. HBsAg reversion was defined as HBsAg level > 0.05 IU/ml after HBsAg clearance.

^†Differences of clinical characteristics among the three groups were examined using Kruskal–Wallis test for continuous variables and chi-square test or Fisher’s exact test for categorical variables.

^¶Differences of duration of treatment between the the former two groups were determined using Mann-Whitney U test.

^#Denotes weeks. * Denotes years.

Figure 2. Cumulative incidences of HBsAg reversion according to the different HBsAg clearance methods. Abbreviations: HBsAg, hepatitis B surface antigen; IFN, interferon; NA, nucleoside/nucleotide analogues.

Notes: * Represents p < .05, ** Represents p < .01, *** Represents p < .001, ns represents no significance.

Figure 3. HBV vaccination in IFN-induced group. (a) The proportion of the patients with or without HBV vaccination. (b) The proportion of the patients with sequential administration vs. simultaneous administration of IFN and HBV vaccine. (c) The proportion of the patients receiving 1 dose, 2 doses or ≥ 3 doses of HBV vaccine. (d) The proportion of the patients with diverse HBsAb levels following HBV vaccination. (e) The proportion of responders or non-responders to HBV vaccination. (f) The proportion of the patients with weak or strong response to HBV vaccination. Abbreviations: HBV, hepatitis B virus; IFN, interferon.

Notes: Simultaneous administration of IFN and HBV vaccine was defined as initiating injection of vaccine between HBsAg clearance and cessation of IFN treatment. Sequential administration was defined as initiating injection of vaccine after cessation of IFN treatment. The individual who had a HBsAb level of ≥10 mIU/ml or <10 mIU/ml after HBV vaccination was defined as responder or non-responder, respectively. Weak or strong response to HBV vaccination refers to the highest HBsAb level ≤100 mIU/ml or >100 mIU/ml after injection of vaccine, respectively.

Table 2. Clinical characteristics of the patients with or without HBV vaccination in IFN-induced HBsAg clearance group.

Characteristics	Without HBV vaccination (n = 36)	With HBV vaccination (n = 72)	p*-value
Status at the time of HBsAg clearance
Age, years, median (IQR)	36.5 (31.0–42.8)	37.0 (33.0–43.8)	.559
Male sex, n (%)	32 (88.9%)	64 (88.9%)	1.000
HBsAb level, mIU/ml, n (%)			.435
< 10 mIU/ml	21 (61.8%)	50 (70.4%)
10–100 mIU/ml	8 (23.5%)	16 (22.5%)
100–1000 mIU/ml	5(14.7%)	5 (7.0%)
> 1000 mIU/ml	0 (0.0%)	0 (0.0%)
HBeAg positivity, n (%)	2 (5.9%)	4 (5.6%)	1.000
HBeAb positivity, n (%)	24 (70.6%)	50 (70.4%)	.986
Undetectable HBV DNA, n (%)	36 (100%)	72 (100%)	1.000
Status at the end of IFN treatment
HBsAb level, mIU/ml, n (%)			.594
< 10 mIU/ml	11 (30.6%)	17 (23.6%)
10–100 mIU/ml	11 (30.6%)	20 (27.8%)
100–1000 mIU/ml	11 (30.6%)	31(43.1%)
> 1000 mIU/ml	3 (8.3%)	4 (5.6%)
HBeAg positivity, n (%)	0 (0.0%)	0 (0.0%)	1.000
HBeAb positivity, n (%)	25 (69.4%)	52 (72.2%)	.764
Undetectable HBV DNA, n (%)	36 (100%)	72(100%)	1.000
Therapeutic regimen, n (%)			.011
IFN+NA	22 (61.1%)	60 (83.3%)
IFN only	14 (38.9%)	12 (16.7%)
Duration of IFN treatment, weeks, median (IQR)	68.0 (48.0–115.3)	61.0 (48.0–103.3)	.646
Duration of IFN consolidation treatment, weeks, median (IQR)	17.5 (4.5–31.0)	26.0 (16.0–35.8)	.008
Follow-up time, weeks, median (IQR)	132.0 (64.5–208.8)	116.5 (48.3–206.8)	.616

Abbreviations: HBeAb, hepatitis B e antibody; HBeAg, hepatitis B e antigen; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; IFN, interferon; IQR, interquartile range; NA, nucleoside/nucleotide analogues.

Note: HBsAg level > 0.05 IU/ml, HBsAb level >10 mIU/ml, HBeAg level >1.0 S/CO and HBeAb level <1.0 S/CO were defined as positive, respectively.

*Differences of clinical characteristics between the two groups were determined using Mann-Whitney U test for continuous variables and chi-square test or Fisher’s exact test for categorical variables.

Figure 4. Cumulative incidences of HBsAg reversion in IFN-induced group according to HBV vaccination. (a) The patients without HBV vaccination vs. with HBV vaccination. (b) The patients without HBV vaccination vs. responders to vaccination vs. non-responders to vaccination in the entire IFN-induced group. (c) The patients without HBV vaccination vs. with weak response to vaccination vs. with strong response to vaccination in the entire IFN-induced group. (d) The patients without HBV vaccination vs. with weak response to vaccination vs. with strong response to vaccination in individuals receiving sequential administration of IFN and HBV vaccine. Abbreviations: HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; IFN, interferon.

Notes: The individual who had a HBsAb level of ≥10 mIU/ml or <10 mIU/ml after HBV vaccination was defined as responder or non-responder, respectively. Weak or strong response to HBV vaccination refers to the highest HBsAb level ≤100 mIU/ml or >100 mIU/ml after injection of vaccine, respectively. Sequential administration was defined as initiating injection of vaccine after cessation of IFN treatment. * represents p < .05, ** represents p < .01, *** represents p < .001, ns represents no significance.

Table 3. Cox regression analysis of factors associated with the off-treatment HBsAg reversion in IFN-induced HBsAg clearance group.

Characteristics	Univariate Cox regression		Multivariate Cox regression
	HR (95% CI)	p-value	HR (95% CI)	p-value
Age, years
>37 vs. ≤37	0.506 (0.216–1.183)	.116	-	-
Sex
Male vs. female	0.801 (0.238–2.695)	.720	-	-
Therapeutic regimen
IFN+NA vs. IFN only	1.335 (0.498–3.581)	.566	-	-
Duration of IFN treatment, weeks
>62 vs. ≤62	1.294 (0.573–2.922)	.535	-	-
Duration of IFN consolidation treatment, weeks
>24 vs. ≤24	0.518 (0.222–1.212)	.129	-	-
HBV vaccination
Vaccinated vs. unvaccinated	0.876 (0.383–2.002)	.753	-	-
Weak response to vaccination vs. unvaccinated	2.448 (1.029–5.823)	.043	2.448 (1.029–5.823)	.043
Strong response to vaccination vs. unvaccinated	0.246 (0.066–0.907)	.035	0.246 (0.066–0.907)	.035

Abbreviations: CI, confidence interval; HR, hazard ratio; IFN, interferon; NA, nucleoside/nucleotide analogues.

Note: HBsAg reversion was defined as HBsAg level >0.05 IU/ml after HBsAg clearance. Weak or strong response to HBV vaccination refers to the highest HBsAb level ≤100 mIU/ml or > 100 mIU/ml after injection of vaccine, respectively. Continuous variables in the Cox regression model were converted to dichotomous variables based on median values.

Figure 5. A new decision-making roadmap proposed to evaluate the risk of HBsAg reversion in CHB patients achieving HBsAg clearance by the different methods and to illustrate the application of HBV vaccine in reducing HBsAg reversion. Abbreviations: CHB, chronic hepatitis B; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; IFN, interferon; NA, nucleoside/nucleotide analogues.