Influence of nonalcoholic fatty liver disease on the therapeutic effect of nucleoside (acid) analogs for hepatitis B virus

Table 1 Baseline demographic data and clinical characteristics of chronic hepatitis B patients, n (%)/mean ± SD/95%CI

Variable	Chronic hepatitis B	Complete virologic response	Partial virologic response	t/χ2	P value
	(n = 465)	(n = 139)	(n = 326)
Gender (n = 465)				χ2 = 0.006	0.940
Male	320 (68.8)	96 (69.1)	224 (68.7)
Female	145 (31.2)	43 (30.9)	102 (31.3)
Age (years), n = 465	35.5 ± 10.5	38.1 ± 11.7	34.4 ± 9.7	t = 3.514	0.0005
HBV DNA baseline level, log10 (IU/mL), n = 465	6.1 ± 6.0	5.6 ± 1.9	6.4± 2.0	t = 3.661	0.0003
Virus shedding time (months), n = 428	9.8 ± 8.7	6.9 ± 5.8	11.2 ± 9.5	t = 4.919	< 0.0001
HBsAg baseline level, log10 (IU/mL + 1), n = 461	3.4 ± 1.0	3.0 ± 0.9	3.6 ± 1.0	t = 5.479	< 0.0001
HBeAg				χ2 = 14.57	< 0.0001
Positive	298 (64.1)	71 (51.1)	227 (69.6)
Negative	167 (35.9)	68 (48.9)	99 (30.4)
NAFLD				χ2 = 5.815	0.016
Yes	133 (28.6)	29 (20.9)	104 (31.9)
No	332 (71.4)	110 (79.1)	222 (68.1)
Leucocytes (G/L), n = 396	5.5 ± 1.7	5.4 ± 1.8	5.6 ± 1.6	t = 0.7417	0.4587
Haemoglobin (g/L), n = 396	148.2 ± 18.2	148.6 ± 17.2	147.9 ± 18.7	t = 0.3339	0.7386
Neutrophils (G/L), n = 396	3.2 ± 1.4	3.2 ± 1.4	3.3 ± 1.4	t = 0.6343	0.5263
Lymphocytes (G/L), n = 396	1.8 ± 0.6	1.8 ± 0.6	1.8 ± 0.6	t = 0.0444	0.9646
Total bilirubin log10 (μmol/L), n = 464	1.2 ± 0.2	1.2 ± 0.2	1.2 ± 0.2	t = 0.8594	0.3906
Alanine aminotransferase log10 (U/L), n = 464	1.7 ± 0.4	1.7 ± 0.4	1.7 ± 0.4	t = 0.6270	0.5310
Aspartate aminotransferase log10 (U/L), n = 464	1.6 ± 0.3	1.6 ± 0.3	1.6 ± 0.3	t = 1.432	0.1527
Albumin (g/L), n = 464	44.9 ± 3.3	44.9 ± 3.5	44.9 ± 3.2	t = 0.0135	0.9892
Uric acid (umol/L), n = 447	337.5 ± 92.8	327.7 ± 76.5	341.6 ± 98.8	t = 1.454	0.1467
Fasting glucose (mmol/L), n = 229	5.5 ± 1.1	5.6 ± 1.5	5.4 ± 0.9	t = 1.283	0.2009
Triglyceride (mmol/L), n = 264	1.4 ± 1.1	1.2 ± 0.6	1.4 ± 1.2	t = 2.056	0.0408
Total cholesterol (mmol/L), n = 264	4.5 ± 1.0	4.4 ± 1.0	4.9 ± 0.9	t = 3.694	0.0003
High-density lipoprotein (mmol/L), n = 264	1.2 ± 0.3	1.2 ± 0.3	1.1 ± 0.3	t = 1.761	0.0794
Low-density lipoprotein (mmol/L), n = 264	2.8 ± 0.9	2.82 ± 0.90	2.8 ± 0.9	t = 0.1163	0.9075
Treatment follow-up period (months), n = 465	28.3 ± 17.5	39.8 ± 16.9	22.9 ± 15.0	t = 10.52	< 0.0001
aAPRI score, n = 396	0.42 (0.28-0.81)	0.41 (0.27-0.90)	0.43 (0.29-0.81)	Z = -0.571	0.568
Low (< 0.5)	226 (57.07)	68 (58.62)	158 (56.43)	t = 0.161	0.688
Intermediate (0.5-1.5)	128 (32.32)	36 (31.03)	92 (32.86)	t = 0.125	0.724
High (> 1.5)	42 (10.61)	12 (10.35)	30 (10.71)	t = 0.012	0.913
bFibrosis-4 score, n = 395	0.93 (0.52-1.82)	1.00 (0.50-1.94)	0.89 (0.54-1.74)	Z = -0.232	0.816
Low (< 1.45)	266 (67.34)	74 (63.79)	192 (68.82)	t = 0.940	0.332
Intermediate (1.45-3.25)	82 (20.76)	22 (18.97)	60 (21.50)	t = 0.321	0.571
High (> 3.25)	47 (11.90)	20 (17.24)	27 (9.68)	t = 4.472	0.034

^aAspartate aminotransferase to platelet ratio index score = [(aspartate aminotransferase (U/L)/upper limit of normal)/platelet (10⁹/L)] × 100

^bFibrosis-4 score = [Age (years) × aspartate aminotransferase (U/L)]/[platelet (10⁹/L) × square root alanine aminotransferase (U/L)]

APRI: Aspartate aminotransferase-to-platelet ratio index; HBsAg: Hepatitis B surface antigen; HBeAg: Hepatitis B e antigen; NAFLD: Nonalcoholic fatty liver disease.

Table 2 Logistic regression analysis of risk factors for partial virological response to antiviral therapy of chronic hepatitis B

Variable	Univariate analysis			Multivariate analysis model I			Multivariate analysis model II			Multivariate analysis model III
	β	OR (95%CI)	P value	β	OR (95%CI)	P value	β	OR (95%CI)	P value	β	OR (95%CI)	P value
Age (years)	-0.033	0.968 (0.949-0.986)	0.001	-0.013	0.987 (0.965-1.009)	0.253	-0.004	0.996 (0.971-1.021)	0.746	-0.003	0.997 (0.973-1.023)	0.842
HBV DNA baseline level, log10 (IU/mL)	0.183	1.201 (1.086-1.328)	< 0.001	0.017	1.017 (0.886-1.168)	0.809	0.011	1.011 (0.87-1-176)	0.884	0.008	1.008 (0.867-1.173)	0.913
Virus shedding time (months)	0.063	1.065 (1.033-1.097)	< 0.001	0.033	1.033 (1.001-1.067)	0.046	0.038	1.039 (1.002-1.078)	0.039	0.039	1.04 (1.002-1.078)	0.037
HBeAg positive (vs negative)	0.787	2.196 (1.461-3.302)	< 0.001	-0.18	0.836 (0.468-1.492)	0.544	-0.06	0.942 (0.501-1.773)	0.853	-0.083	0.92 (0.488-1.736)	0.797
HBsAg baseline level, log10 (IU/mL+1)	0.624	1.866 (1.5-2.322)	< 0.001	0.507	1.661 (1.254-2.2)	< 0.001	0.517	1.677 (1.237-2.273)	0.001	0.52	1.682 (1.239-2.282)	0.001
NAFLD (vs non-NAFLD)	0.575	1.777 (1.11-2.845)	0.017	0.583	1.792 (1.068-3.006)	0.027	0.92	2.508 (1.368-4.6)	0.003	0.9	2.459 (1.34-4.514)	0.004
APRI score	-0.069	0.934 (0.836-1.043)	0.224				-0.052	0.949 (0.853-1.056)	0.34
FIB-4 score	-0.041	0.96 (0.92-1.002)	0.061							-0.023	0.977 (0.939-1.016)	0.247

HBV DNA: Hepatitis B virus deoxyribonucleic acid; NAFLD: Nonalcoholic fatty liver disease; HBsAg: Hepatitis B surface antigen; HBeAg: Hepatitis B e antigen; APRI: Aspartate aminotransferase-to-platelet ratio index; FIB-4: Fibrosis-4 index; OR: Odds ratio.

Table 3 Baseline demographic data and clinical features of high viral load chronic hepatitis B combined with nonalcoholic fatty liver disease, n (%)/mean ± SD

Characteristics	NAFLD	Non-NAFLD	t/χ2	P value
	(n = 40)	(n = 80)
Gender			χ2 = 8.450	0.004
Male	37 (92.5)	53 (66.3)
Female	3 (7.5)	27 (33.7)
Age (years)	29.5 ± 5.6	31.0 ± 7.1	t = 1.161	0.2480
HBV DNA baseline level, log10 (IU/mL)	8.1 ± 0.5	8.0 ± 0.5	t = 0.3877	0.6990
Virus shedding time (months)	16.8 ± 6.1	13.0 ± 6.8	t = 3.003	0.0033
Virology breakthrough time (months)	6.8 ± 5.6	10.9 ± 11.5	t = 1.378	0.1735
HBsAg baseline level, log10 (IU/mL)	4.4 ± 0.6	4.2 ± 0.7	t = 1.252	0.2148
Antiviral therapy			t = 1.985	0.371
ETV	4 (10.0)	15 (18.8)	t = 1.532	0.216
TDF	12 (30.0)	26 (32.5)	t = 0.077	0.781
ETV and TDF	24 (60.0)	39 (48.7)	t = 1.353	0.245
low-level viremia	30 (75.0)	49 (61.3)	t = 2.241	0.134
Virological response			χ2 = 8.750	0.003
Complete virologic response	5 (12.5)	31 (38.8)
Partial virologic response	35 (87.5)	49 (61.2)
Serological response (HBsAg)			χ2 = 0.0000	1.000
Yes	1 (2.5)	2 (2.5)
No	39 (97.5)	78 (97.5)
Serological response (HBeAg)			χ2 = 3.116	0.078
Yes	1 (2.5)	12 (15.0)
No	39 (97.5)	68 (85.0)
Leucocytes, (G/L)	6.4 ± 2.1	5.5 ± 1.6	t = 2.414	0.0175
Erythrocyte, (T/L)	5.2 ± 0.4	4.9 ± 0.5	t = 3.308	0.0013
Platelets, (G/L)	228.5 ± 51.2	200.4 ± 54.2	t = 2.489	0.0144
Haemoglobin, (G/L)	155.4 ± 16.6	146.5 ± 16.7	t = 2.533	0.0128
Neutrophils, (G/L)	3.8 ± 1.8	3.1 ± 1.3	t = 2.232	0.0278
Lymphocytes, (G/L)	2.0 ± 0.5	1.9 ± 0.5	t = 1.277	0.2043
Total bilirubin, log10 (μmol/L)	1.2 ± 0.2	1.2 ± 0.2	t = 0.2773	0.7820
≤ 19	29 (72.5)	54 (67.5)	t = 0.313	0.576
> 19	11 (27.5)	26 (32.5)
Alanine aminotransferase, log10 (U/L)	1.7 ± 0.3	1.9 ± 0.5	t = 1.814	0.0722
≤ 35	6 (15.0)	17 (21.3)	t = 0.672	0.412
> 35	34 (85.0)	63 (78.7)
Aspartate aminotransferase, log10 (U/L)	1.5 ± 0.2	1.7 ± 0.4	t = 2.545	0.0122
≤ 40	21 (52.5)	29 (36.3)	t = 2.897	0.089
> 40	19 (47.5)	51 (63.7)
APRI score	0.5 ± 0.4	0.8 ± 0.6	t = 2.639	0.0096
Fibrosis-4 score	0.7 ± 0.4	1.0 ± 0.6	t = 2.631	0.0098
Total protein, (g/L)	75.6 ± 5.8	74.3 ± 5.1	t = 1.336	0.1841
Albumin, (g/L)	45.7 ± 2.4	43.7 ± 3.4	t = 3.414	0.0009
Globulin, (g/L)	29.9 ± 5.2	30.6 ± 4.3	t = 0.7613	0.4480
Urea nitrogen, (mmol/L)	4.6 ± 1.3	4.2 ± 1.2	t = 1.599	0.1125
Creatinine, (μmol/L)	76.3 ± 7.5	71.1 ± 11.2	t = 2.542	0.0124
Uric acid, (μmol/L)	413.7 ± 95.7	314.0 ± 86.8	t = 5.546	< 0.0001
Fasting glucose, (mmol/L)	5.3 ± 0.5	5.8 ± 2.4	t = 0.8360	0.4074
Triglyceride, (mmol/L)	1.6 ± 1.6	1.0 ± 0.5	t = 2.085	0.0418
Total cholesterol, (mmol/L)	4.5 ± 0.8	4.2 ± 0.9	t = 1.328	0.1897
High-density lipoprotein, (mmol/L)	1.0 ± 0.2	1.2 ± 0.3	t = 1.886	0.0647
Low-density lipoprotein, (mmol/L)	2.9 ± 0.7	2.5 ± 0.8	t = 1.768	0.0827
Treatment follow-up period, (months)	33.8 ± 16.8	35.1 ± 17.8	t = 0.3550	0.7233

NAFLD: Nonalcoholic fatty liver disease; ETV: Entecavir; TDF: Tenofovir disoproxil fumarate; HBV DNA: Hepatitis B virus deoxyribonucleic acid; HBsAg: Hepatitis B surface antigen; HBeAg: Hepatitis B e antigen; APRI: Aspartate aminotransferase-to-platelet ratio index.