Dynamics of cytokines predicts risk of hepatocellular carcinoma among chronic hepatitis C patients after viral eradication

Table 1 Baseline demographics of study subjects

Group	Total	DAA	IFN	P value (DAA vs IFN)
n	100	50	50
Age (yr)	63.8 ± 7.2	64.9 ± 7.9	62.6 ± 6.3	0.100
Sex, n (%)
Female	66 (66.0)	38 (76.0)	28 (56.0)	0.057
Male	34 (34.0)	12 (24.0)	22 (44.0)
HCV genotype, n (%)
1	65 (65.0)	37 (74.0)	28 (56.0)	0.098
2	23 (23.0)	10 (20.0)	13 (26.0)
Mixed	12 (12.0)	3 (6.0)	9 (18.0)
HCV RNA (log IU/mL)	2.47 ± 0.89	2.67 ± 0.84	2.28 ± 0.91	0.027
FIB-4	6.14 ± 3.28	6.55 ± 3.69	5.73 ± 2.80	0.213
AFP (ng/mL)	26.3 ± 56.7	28.8 ± 74.0	23.6 ± 29.3	0.662
Platelet (k/μL)	119.8 ± 34.7	115.2 ± 35.9	124.4 ± 33.2	0.186
AST (IU/L)	136.9 ± 79.9	115.2 ± 64.7	158.7 ± 87.9	0.006
ALT (IU/L)	177.5 ± 138.4	127.9 ± 83.9	227.0 ± 163.2	2.7 × 10-4
γ-GT (IU/L)	67.6 ± 48.8	57.2 ± 42.6	76.7 ± 52.4	0.053
Cholesterol (mg/dL)	161.6 ± 34.8	158.6 ± 37.1	165.2 ± 32.0	0.388
Triglyceride (mg/dL)	97.7 ± 41.4	99.2 ± 40.5	96.0 ± 42.8	0.722
HDL (mg/dL)	47.0 ± 13.3	49.0 ± 11.6	44.1 ± 15.1	0.107
LDL (mg/dL)	90.6 ± 26.4	86.0 ± 24.4	97.2 ± 28.1	0.068
Cr (mg/dL)	0.79 ± 0.24	0.77 ± 0.27	0.82 ± 0.20	0.222
HbA1c (%)	5.8 ± 1.2	5.5 ± 0.7	6.0 ± 1.5	0.016
BMI (kg/m2)	24.4 ± 4.7	24.0 ± 6.0	24.8 ± 2.9	0.381

DAA: Direct-acting antiviral agent; IFN: Interferon; HCV: Hepatitis C virus; FIB-4: Fibrosis-4 index; AFP: Alpha-fetoprotein; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; γ-GT: γ-glutamyltransferase; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; Cr: Creatinine; HbA1c: Hemoglobin A1c; BMI: Body mass index.

Table 2 Factors associated with the onset of hepatocellular carcinoma: Univariate and multivariate Cox regression models

Variables	Univariate Cox regression		Multivariate Cox regression
	Crude HR (95%CI)	P value	Adjusted HR (95%CI)	Adjusted P value
Age (yr)	1.07 (0.98-1.18)	0.149	-	-
Sex (male vs female)	3.19 (0.96-10.65)	0.059	-	-
HCV genotype	1.00 (0.47-2.13)	0.995	-	-
HCV RNA (log IU/mL)	0.68 (0.37-1.25)	0.213	-	-
FIB-4	1.13 (0.98-1.31)	0.089	-	-
FIB-4 (≥ 9 vs < 9)	4.04 (1.27-12.86)	0.018	-	-
Platelet (k/μL)	0.99 (0.98-1.01)	0.408	-	-
AFP (ng/mL)	1.00 (1.00-1.01)	0.308	-	-
HbA1c (%)	1.28 (1.01-1.62)	0.041	-	-
HbA1c (≥ 7 vs < 7%)	5.38 (1.38-20.99)	0.015	-	-
BMI (kg/m2)	1.00 (0.83-1.20)	0.993	-	-
Treatment (DAA vs IFN)	0.66 (0.07-6.15)	0.713	-	-
TNF-α (pg/mL)
Pre-Tx TNF-α ≥ 18	5.15 (1.57-16.87)	0.007	-	-
Post-Tx TNF-α ≥ 6	0.79 (0.25-2.46)	0.683	-	-
ΔTNF-α ≤ -5.7	11.07 (2.27-53.87)	0.003	11.54 (2.27-58.72)	0.003
TWEAK (pg/mL)
Pre-Tx TWEAK ≥ 500	2.18 (0.64-7.39)	0.213	-	-
Post-Tx TWEAK ≥ 600	0.80 (0.20-3.11)	0.744	-	-
ΔTWEAK ≤ -70	4.01 (1.20-13.40)	0.024	-	-

The forward stepwise multivariate Cox regression model was adjusted by age, sex, hepatitis C virus (HCV) genotypes, HCV RNA, Fibrosis-4 index (FIB-4), platelet, alpha-fetoprotein, hemoglobin A1c, body mass index, treatment, tumor necrosis factor-α and tumor necrosis factor-like weak inducer of apoptosis (pretreatment, posttreatment, Δ). The cut-off value for each cytokine and FIB-4 was determined by Youden index of receiver operating characteristic curve. Δ = (posttreatment cytokine level) - (pretreatment cytokine level). DAA: Direct-acting antiviral agent; IFN: Interferon; HCV: Hepatitis C virus; FIB-4: Fibrosis-4 index; AFP: Alpha-fetoprotein; HbA1c: Hemoglobin A1c; BMI: Body mass index; HCV: Hepatitis C virus; TNF-α: tumor necrosis factor-α; TWEAK: TNF-like weak inducer of apoptosis; Pre-Tx: Pretreatment; Post-Tx: Posttreatment; HR: Hazard ratio; CI: Confidence interval.