Baseline and longitudinal biomarkers predict hepatocellular carcinoma in chronic hepatitis C: A cohort study

Table 1 Baseline characteristics of the study cohort

Parameter	Value
Demographics
Age (years, n = 271)	66.0 (58.0-73.0)
Sex (n = 271)
Male	115 (42.4)
Female	156 (57.6)
Follow-up time (years, n = 271)	9.4 (8.7-10.1)
Virological profile
HCV viral load (IU/mL, n = 190)	941202 (64914-2861279)
HCV genotype (n = 136)
Type 1	49 (36.0)
Type 2	48 (35.3)
Type 6	23 (16.9)
Other (mixed)	16 (11.8)
Comorbidities
Hypertension (n = 271)	139 (51.3)
Diabetes mellitus (n = 271)	86 (31.7)
Dyslipidemia (n = 271)	31 (11.4)
Disease severity
Cirrhosis (n = 270)	76 (28.0)
Baseline FIB-4 index (n = 263)
< 1.45	35 (13.3)
1.45-3.25	93 (35.4)
> 3.25	135 (51.3)

Data are presented as median (interquartile range) or n (%). HCV: Hepatitis C virus; FIB-4: Fibrosis-4.

Table 2 Cox regression analysis of hepatocellular carcinoma in relation to baseline characteristic and biomarkers

Variable	Univariate		Multivariate
	HR (95%CI)	P value	aHR (95%CI)	P value
Demographics
Sex (male)	1.51 (0.97-2.33)	0.067	1.74 (1.05-2.86)	0.03
Age (per 1-year increase)	1.03 (1.00-1.05)	0.033	1.01 (0.98-1.04)	0.559
Biomarkers
HCV RNA > 6 × 106 (IU/mL)	0.78 (0.28-2.16)	0.634	-	-
AFP ≥ 20 (ng/mL)	3.31 (1.85-5.92)	< 0.001	2.79 (1.50-5.19)	0.001
Cr ≥ 1 (mg/dL)	1.49 (0.87-2.55)	0.142	-	-
T-Bil ≥ 1 (mg/dL)	3.37 (1.85-6.15)	< 0.001	2.06 (0.89-4.75)	0.091
PT ≥ 12 (second)	1.22 (0.56-2.67)	0.621	1.36 (0.48-3.83)	0.564
Alb < 3.5 (g/dL)	1.77 (0.80-3.95)	0.16	1.22 (0.38-3.96)	0.739
Disease severity
FIB-4 score
1.45-3.25	Reference
< 1.45	0.12 (0.02-0.89)	0.039	Not estimable1
> 3.25	3.13 (1.84-5.31)	< 0.001	2.72 (1.51-4.90)	< 0.001
Comorbidities
Diabetes Mellitus	1.53 (0.98-2.39)	0.061	1.43 (0.84-2.43)	0.184
Hypertension	0.90 (0.58-1.40)	0.646	0.62 (0.37-1.06)	0.079
Dyslipidemia	0.77 (0.37-1.59)	0.475	0.71 (0.27-1.87)	0.493

¹Not estimable due to zero events (complete separation) in the fibrosis-4 < 1.45 group.

HR: Hazard ratio; aHR: Adjusted hazard ratio; 95%CI: 95% confidence interval; HCV: Hepatitis C virus; AFP: Alpha-fetoprotein; FIB-4: Fibrosis-4; Cr: Creatinine; T-Bil: Total bilirubin; PT: Prothrombin time; Alb: Albumin.

Table 3 Cox regression analysis of hepatocellular carcinoma relation to 3-years characteristic and biomarkers

Variable	Univariate		Multivariate
	HR (95%CI)	P value	aHR (95%CI)	P value
Demographics
Sex (male)	1.32 (0.81-2.15)	0.27	1.72 (0.64-4.66)	0.282
Age (per 1-year increase)	1.02 (1.00-1.05)	0.098	1.01 (0.96-1.06)	0.78
Biomarkers
AFP ≥ 20 (ng/mL)	9.27 (4.80-17.87)	< 0.001	6.74 (2.48-18.33)	< 0.001
Cr ≥ 1 (mg/dL)	1.81 (1.00-3.27)	0.049	0.92 (0.35-2.39)	0.859
T-Bil ≥ 1 (mg/dL)	2.92 (1.38-6.20)	0.005	2.57 (0.96-6.88)	0.06
PT ≥ 12 (second)	1.76 (0.69-4.47)	0.233	-	-
Alb < 3.5 (g/dL)	1.70 (0.70-4.16)	0.243	-	-
Disease severity
FIB-4 score
1.45-3.25	Reference
< 1.45	0.14 (0.02-1.06)	0.057	Not estimable1
> 3.25	2.75 (1.54-4.93)	0.001	2.30 (0.75-7.03)	0.143

¹Not estimable due to zero events (complete separation) in the fibrosis-4 < 1.45 group.

HR: Hazard ratio; aHR: Adjusted hazard ratio; 95%CI: 95% confidence interval; HCV: Hepatitis C virus; AFP: Alpha-fetoprotein; FIB-4: Fibrosis-4; Cr: Creatinine; T-Bil: Total bilirubin; PT: Prothrombin time; Alb: Albumin.

Table 4 Pair-wise comparisons between five groups of 3-year fibrosis-4 trajectories and risk of hepatocellular carcinoma

	HCC cases (n)	Incidence (%)	HR (95%CI)	P value
Stable 1.45-3.25	7/46	15.2	Reference	-
Stable < 1.45	0/21	0	0.12 (0.01-2.25)	0.157
Stable > 3.25	39/92	42.4	4.10 (1.66-10.13)	0.002
Improved	8/39	20.5	1.44 (0.47-4.40)	0.525
Worsened	9/45	20	1.39 (0.47-4.13)	0.55

Improved trajectory: Fibrosis-4 from > 3.25 to either 1.45-3.25 or < 1.45, or from 1.45-3.25 to < 1.45; Worsened trajectory: From < 1.45 to either 1.45-3.25 or > 3.25, or from 1.45-3.25 to > 3.25. HR: Hazard ratio; 95%CI: 95% confidence interval; HCC: Hepatocellular carcinoma.