Naïve hepatitis B e antigen-negative chronic hepatitis B patients are at risk of carotid atherosclerosis: A prospective study

Table 1 Baseline characteristics of included subjects and comparison between infected and non-infected subjects and among patients infected by hepatitis B virus according to the phase of the infection (chronic hepatitis B vs inactive carriers)

	Controls	Chronic hepatitis B	Inactive carriers
	n = 201	n = 49	n = 152	P value1	P value2
Age, yr	48.1 ± 10.2	48.4 ± 12.0	46.5 ± 13.4	0.29	0.28
Male sex (%)	103 (51.2)	31 (64.6)	84 (54.9)	0.13	0.16
Race (%)				< 0.001	0.48
Caucasian	186 (92.5)	35 (72.9)	102 (66.7)
Asian	2 (1.0)	6 (12.5)	11 (7.2)
African	0 (0)	6 (12.5)	28 (18.3)
Hispanic	13 (6.5)	1 (2.1)	12 (7.8)
Cardiovascular risk factors (%)
Tobacco exposure	74 (36.8)	15 (31.3)	45 (29.6)	0.09	0.48
Alcohol intake3	70 (34.8)	11 (22.9)	23 (15.4)	< 0.001	0.17
Hypertension	40 (19.9)	11 (22.9)	27 (17.8)	0.46	0.28
Diabetes	4 (2.0)	4 (8.3)	6 (3.9)	0.08	0.2
Dyslipidemia	46 (22.9)	3 (6.3)	31 (20.4)	0.08	0.02
Central obesity	52 (25.9)	10 (20.8)	27 (17.9)	0.04	0.4
BMI, kg/m2	25.3 ± 3.6	26.0 ± 3.9	25.2 ± 4.0	0.76	0.22
Liver cirrhosis (%)	0 (0)	12 (24.4)	0 (0)	< 0.001	< 0.001
ALT, IU/mL	22.6 ± 12.7	59.7 ± 48.6	25.6 ± 16.7	< 0.001	< 0.001
GGT, IU/mL	30.4 ± 30.9	60.7 ± 87.9	31.5 ± 63.3	0.24	< 0.001
LDL, mg/dL4	131.9 ± 38.3	116.9 ± 30.7	118.1 ± 32.6	0.002	0.82
Triglycerides, mg/dL	108.0 ± 56.7	96.4 ± 46.3	106.8 ± 59.1	0.54	0.26
C-reactive protein, mg/dL5	0.29 ± 0.42	0.84 ± 1.90	1.00 ± 9.00	0.42	0.88
HOMA index5	2.05 ± 1.84	4.20 ± 3.50	3.40 ± 3.90	< 0.001	0.18
HBsAg, logIU/mL	-	3.6 ± 0.8	2.9 ± 1.2	-	0.001
HBV DNA, logIU/mL	-	4.4 ± 1.8	2.4 ± 1.1	-	< 0.001
Transient elastography, kPa	4.5 ± 1.4	11.3 ± 10.9	5.5 ± 2.4	< 0.001	< 0.001
CAP, dB/m	246.5 ± 54.5	227.4 ± 55.0	227.2 ± 56.2	0.001	0.98

Data are expressed as the median (interquartile range) or as the n (%).

¹Comparison between hepatitis B virus-infected and non-infected controls.

²Comparison between patients with chronic hepatitis B and inactive carriers.

³Significant alcohol intake was defined as > 30 g per day for men and > 20 g per day for women.

⁴These data were available in 132 non-infected subjects.

⁵This data was available in 83 non-infected subjects. ALT: Alanine transaminase; CAP: Control attenuation parameter; GGT: Gamma glutamyltransferase; HBV: Hepatitis B virus; HBsAg: Hepatitis B surface antigen; BMI: Body mass index; LDL: Low-density lipoprotein; HOMA: Homeostasis model assessment.

Table 2 Factors associated with the presence of carotid plaques and subclinical atherosclerosis

	Subclinical atherosclerosis			Carotid plaques
	Univariate analysis	Multivariate analysis		Univariate analysis	Multivariate analysis
		OR (95%CI)	P value		OR (95%CI)	P value
Age, years	< 0.001			< 0.001
Age > 50 years	< 0.001	1.45 (1.24-1.48)	< 0.001	< 0.001	1.43 (1.21-1.44)	< 0.001
Male sex	0.004		0.336	0.003		0.212
Central obesity	0.008		0.073	0.007		0.141
Tobacco exposure	0.003		0.081	0.002		0.187
Alcohol intake1	0.109		-	0.073		0.929
Arterial hypertension	< 0.001		0.949	< 0.001		0.690
Diabetes mellitus	0.004	1.13 (1.03-1.59)	0.028	0.01		0.082
Dyslipidemia	0.001			< 0.001		0.095
Chronic hepatitis B	0.001	1.23 (1.11-1.41)	< 0.001	0.016	1.18 (1.06-1.34)	0.004
Transient elastography, kPa	0.01		0.090	0.073		0.438
Transient elastography > 5.7 kPa	0.008			0.048
CAP, dB/m	< 0.001		0.989	< 0.001		0.577
CAP > 238 dB/m	< 0.001			< 0.001
AST, IU/mL	0.115		-	0.152		-
AST > 27 IU/mL	0.102			0.131
GGT, IU/mL	< 0.001		0.067	0.001		0.947
GGT > 36 IU/mL	< 0.001			0.001
Triglycerides, mg/dL	0.011		0.059	0.018		0.957
Triglycerides > 106 mg/dL	0.009			0.009
LDL, mg/dL	0.651		-	0.180		-
HOMA index	0.038		0.073	0.278		0.105
HOMA index > 1.2	0.150			0.489
HOMA index > 3	0.002			0.018

Data are given as mean ± SD or as n (%).

¹Significant alcohol intake was defined as > 30 g per day for male and > 20 g per day for female. At the multivariate logistic regression model only patients with available data for all the variables were included. The cut-off for inclusion was a P value < 0.10 in the univariate model. AST: Aspartate transaminase; CAP: Control attenuation parameter; GGT: Gamma glutamyltransferase; CI: Confidence interval; OR: Odds ratio; HOMA: Homeostasis model assessment; LDL: Low-density lipoprotein.

Table 3 Factors associated with the presence of carotid plaques in a propensity score matched by age, sex and main cardiovascular risk factors

	Groups of study			Univariate analysis	Multivariate analysis
	Chronic hepatitis B, n = 49	Inactive carriers, n = 49	Controls, n = 49	P value	OR (95%CI)	P value
Age, yr	48.4 ± 12.0	48.7 ± 13.0	47.1 ± 11.3	0.78
Age > 50 yr (%)	25 (51.0)	24 (49.0)	23 (46.9)	0.92	1.30 (1.12-1.50)	0.01
Male sex (%)	31 (64.6)	31 (63.3)	31 (63.3)	1		0.72
Caucasian race (%)	35 (72.9)	32 (65.3)	38 (77.6)	0.41		-
Cardiovascular risk factors (%)
Tobacco exposure	15 (31.3)	13 (26.5)	16 (32.7)	0.80		0.71
Hypertension	11 (22.9)	10 (20.4)	11 (22.4)	0.96		0.40
Diabetes	4 (8.3)	5 (10.2)	3 (6.1)	0.76		0.57
Dyslipidemia	3 (6.3)	3 (6.1)	5 (10.2)	0.68		0.54
Central obesity	10 (20.8)	10 (20.4)	10 (20.4)	1		0.06
BMI, kg/m2	26.0 ± 3.9	26.3 ± 4.9	26.4 ± 3.8	0.90		0.16
ALT, IU/mL	48.6 ± 9.4	26.9 ± 9.4	25.2 ± 9.6	< 0.001		0.08
GGT, IU/mL	60.7 ± 87.9	42.7 ± 106.0	37.7 ± 50.9	0.45		0.07
LDL, mg/dL1	116.9 ± 30.7	120.3 ± 32.6	112.7 ± 35.3	0.72		0.87
Triglycerides, mg/dL	96.4 ± 46.3	99.0 ± 57.5	115.3 ± 77.1	0.30		0.41
HOMA index2	4.2 ± 3.5	4.7 ± 5.8	2.6 ± 2.6	0.14		0.40
Transient elastography, kPa	11.3 ± 10.9	5.7 ± 3.0	5.0 ± 7.9	< 0.001		0.80
CAP, dB/m	227.4 ± 55.0	232.1 ± 48.6	251.5 ± 62.8	0.095		0.49
Chronic hepatitis B state (%)	49 (100)	0 (0)	0 (0)	< 0.001	1.26 (1.09-1.47)	0.03

¹Only available for 34 controls.

²Only available for 25 non-infected controls. ALT: Alanine transaminase; CAP: Control attenuation parameter; GGT: Gamma glutamyltransferase; BMI: Body mass index; LDL: Low-density lipoprotein; CI: Confidence interval; OR: Odds ratio; HOMA: Homeostasis model assessment.

Table 4 Baseline characteristics and analyses of factors associated with the presence of subclinical atherosclerosis of patients with hepatitis B virus infection

	Subclinical atherosclerosis	No subclinical atherosclerosis	Univariate analysis	Multivariate analysis		Adjusted multivariate analysis
	n = 49	n = 152	P value	OR (95%CI)	P value	OR (95%CI)	P value
Age, yr	57 (53.5-62.0)	42 (33.0-52.0)	< 0.001	1.10 (1.06-1.16)	< 0.001	1.19 (1.12-1.25)	< 0.001
Age > 50 yr (%)	45 (91.8)	46 (30.3)	< 0.001	21.9 (6.7-71.8)	< 0.001
Male sex (%)	31 (63.3)	84 (55.3)	0.207	-	-
BMI, kg/m2	70.0 (64-77)	69.5 (62-80)	0.261	-	-
Central obesity (%)	13 (26.5)	24 (16.0)	0.079	-	0.298		0.356
Tobacco exposure (%)	22 (44.9)	38 (25.2)	0.008	-	0.208		0.920
Alcohol intake1 (%)	14 (28.5)	20 (13.5)	0.016	-	0.876		0.092
Arterial hypertension (%)	18 (36.7)	20 (13.2)	0.001	-	0.789		0.419
Diabetes mellitus (%)	5 (10.2)	5 (3.3)	0.067	-	0.994		0.457
Dyslipidemia (%)	16 (32.6)	18 (11.9)	0.001	-	0.876		0.786
Chronic hepatitis B (%)	20 (40.8)	28 (18.4)	0.002	3.35 (1.20-9.10)	0.017	1.89 (1.75-2.04)	< 0.001
Liver cirrhosis (%)	5 (10.2)	7 (4.6)	0.138	-	-
ALT, IU/mL	29 (22.0-43.5)	24 (17.0-34.0)	0.310	-	--
ALT > ULN (%)	10 (20.4)	22 (14.5)	0.220	-	-
GGT, IU/mL	31 (18.0-62.5)	20 (16.0-28.0)	< 0.001	-	0.120
GGT > ULN (%)	16 (32.7)	8 (5.3)	< 0.001	5.90 (1.60-21.40)	0.007	1.27 (1.19-1.36)	< 0.001
HbA1c, %	5.5 (5.3-5.8)	5.4 (5.1-5.6)	0.004	-	0.78		0.551
HbA1c ≥ 6% (%)	7 (14.6)	6 (4.1)	0.018	-	-
HOMA index	3.3 (2.2-6.0)	2.4 (1.7-3.6)	0.038	-			0.054
HOMA index > 3 (%)	22 (45.8)	51 (34.2)	0.102	-	-
HBsAg, logIU/mL	3.2 (2.5-3.6)	3.3 (2.4-4.0)	0.321	-	-
HBV DNA, logIU/mL	3.1(2.4-3.8)	2.9 (2.3-3.5)	0.533	-	-
Transient elastography, kPa	6.2(4.2-10.3)	5.2 (4.2-6.9)	0.059	--	0.327	1.01 (1.00-1.01)	< 0.001
CAP, dB/m	246 (210.0-289.0)	213 (185.0-261.5)	0.004	--	0.220	1.000 (1.000-1.001)	0.006
CAP > 227 dB/m (%)	29 (67.4)	51 (38.3)	0.001	--	0.172

Data are given as mean ± SD or as n (%).

¹Significant alcohol intake was defined as > 30 g per day for male and > 20 g per day for female.At the multivariate logistic regression model only patients with available data for all the variables were included (n = 250). The cut-off for inclusion was a P value < 0.10 in the univariate model. ALT: Alanine transaminase; BMI: Body mass index; HBV: Hepatitis B virus; CI: Confidence interval; CAP: control attenuation parameter; HbA1c: Hemoglobin A1c; GGT: Gamma glutamyltransferase; OR: Odds ratio; ULN: Upper limit of normality; HOMA: Homeostasis model assessment; HBsAg: Hepatitis B surface antigen.