Hepatocellular carcinoma, decompensation, and mortality based on hepatitis C treatment: A prospective cohort study

Table 1 Baseline characteristics of the entire hepatitis C virus cohort according to the treatment

Variable, n (%)	Untreated group (n = 619)	IBT group (n = 578)	DAA group (n = 857)	P value (3 Gr.)	P value (U vs I)	P value (U vs D)	P value (I vs D)
Age (yr)	60.4 ± 13.4	51.4 ± 10.9	59.1±11.4	< 0.001	< 0.001	0.086	< 0.001
Male sex	280 (45.2)	277 (47.9)	412 (48.1)	0.511	0.351	0.281	0.955
HCV RNA, log10 IU/mL	5.89 (5.08-6.45)	5.83 (4.87-6.49)	6.04 (5.27-6.53)	< 0.001	0.979	0.017	< 0.001
HCV genotype				< 0.001	< 0.001	< 0.001	< 0.001
1	256 (41.4)	242 (41.9)	491 (57.3)
2	299 (48.3)	323 (55.9)	355 (41.4)
Others/missing	64 (10.3)	13 (2.2)	11 (1.3)
Diagnosis status				< 0.001	< 0.001	0.002	0.058
Chronic hepatitis	417 (67.4)	456 (78.9)	639 (74.6)
Compensated cirrhosis	202 (32.6)	122 (21.1)	218 (25.4)
FIB-4 index				< 0.001	< 0.001	0.142	< 0.001
≤ 1.45	112 (18.9)	191 (33.3)	164 (19.9)
1.45-3.25	218 (36.8)	200 (34.8)	337 (40.9)
≥ 3.25	263 (44.3)	183 (31.9)	323 (39.2)
APRI score				0.15	0.09	0.094	0.853
≤ 2.0	480 (80.3)	485 (84.1)	708 (83.7)
> 2.0	118 (19.7)	92 (15.9)	138 (16.3)
ALBI score				0.004	0.04	0.001	0.313
≤ -2.60 (Grade 1)	446 (73.0)	450 (78.1)	674 (80.3)
> -2.60 (Grade 2 or 3)	165 (27.0)	126 (21.9)	165 (19.7)
Ever smoker	264 (42.9)	283 (49.5)	380 (44.5)	0.058	0.022	0.519	0.068
Alcohol intake				< 0.001	< 0.001	< 0.001	< 0.001
None	326 (53.0)	226 (39.4)	419 (48.9)
Social	227 (36.9)	308 (53.7)	229 (26.7)
Significant1	61 (9.9)	40 (7.0)	209 (24.4)
Fatty liver disease on imaging study, n = 1389	71 (19.3), n = 367	86 (21.1), n = 408	140 (22.8), n = 614	0.435	0.549	0.202	0.516
Anti-HBcIgG (+), n = 1442	47 (11.0), n = 429	33 (8.4), n = 391	64 (10.3), n = 622	0.46	0.225	0.73	0.33
BMI, kg/m2	23.4 ± 3.2	23.8 ± 3.0	23.8 ± 3.1	0.02	0.143	0.02	1
Diabetes mellitus	120 (19.4)	77 (13.3)	128 (14.9)	0.01	0.005	0.024	0.391
Hypertension	145 (23.4)	107 (18.5)	243 (28.4)	< 0.001	0.037	0.034	< 0.001
Cardiovascular disease	16 (2.6)	3 (0.5)	25 (2.9)	0.006	0.004	0.701	0.001
Cerebrovascular disease	17 (2.7)	4 (0.7)	20 (2.3)	0.026	0.007	0.617	0.017
Laboratory study
WBC, × 103/mm3	5.09 (4.29-6.50)	5.05 (3.91-6.16)	5.40 (4.40-6.61)	< 0.001	0.145	0.164	< 0.001
Hemoglobin, g/dL	13.5 (12.3-14.5)	13.7 (12.7-14.8)	13.8 (12.7-14.8)	< 0.001	0.004	< 0.001	1
Platelet, × 103/mm3	162 (118-212)	174 (130-220)	172 (129-215)	0.229	0.236	0.317	1
Albumin, g/dL	4.2 (3.9-4.4)	4.2 (4.0-4.5)	4.2 (4.0-4.4)	< 0.001	< 0.001	0.001	1
Total bilirubin, mg/dL	0.8 (0.5-1.0)	0.7 (0.6-1.0)	0.7 (0.6-1.0)	0.784	1	1	1
ALP, IU/L	87 (68-136)	79 (63-112)	121 (78-250)	< 0.001	0.001	< 0.001	< 0.001
AST, IU/L	50 (30-85)	50 (31-83)	46 (30-76)	0.026	1	0.139	0.038
ALT, IU/L	42 (23-80)	52 (29-100)	36 (22-70)	< 0.001	0.013	0.176	< 0.001
Creatinine, mg/dL	0.9 (0.7-1.0)	0.8 (0.7-1.0)	0.8 (0.7-1.0)	0.857	1	1	1
PT, INR	1.06 (1.01-1.12)	1.03 (0.98-1.08)	1.03 (0.97-1.09)	< 0.001	< 0.001	0.007	0.119
AFP, ng/dL	4.3 (2.5-9.7)	3.5 (2.3-7.1)	3.8 (2.4-6.6)	0.868	1	1	1
Cohort entry time				< 0.001	< 0.001	< 0.001	< 0.001
January 2007–June 2015	488 (78.8)	561 (97.1)	49 (5.7)
July 2015–June 2019	131 (21.2)	17 (2.9)	808 (94.3)
SVR rate	-	67.5 (451/668)	95.3 (817/857)	-	-	< 0.001	-
Follow-up duration (yr)	5.6 (3.4-8.2)	7.9 (6.1-9.7)	3.5 (2.0-5.5)	< 0.001	< 0.001	< 0.001	< 0.001

¹Significant alcohol intake is defined as weekly ≥ 210 g for men and ≥ 140 g for women.

Data were presented as mean ± SD, median (interquartile range), or n (%). AFP: Alpha-feto protein; ALBI: Albumin-bilirubin; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; APRI: Aspartate aminotransferase to platelet ratio index; AST: Aspartate aminotransferase; BMI: Body mass index; DAA: Direct acting antivirals; FIB-4: Fibrosis-4; HCV: Hepatitis C virus; IBT: Interferon-based therapy; INR: International normalized ratio; PT: Prothrombin time; WBC: White blood cell.

Table 2 Annual incidence rates of hepatocellular carcinoma, decompensation and death/transplantation according to treatment exposure and the presence of cirrhosis

	Group	PY	No. of events	No./100 PY (95%CI)	HR (95%CI)	P value
Entire cohort	Hepatocellular carcinoma
	Untreated group	3285.4	65	1.98 (1.56-2.52)	Reference	-
	IBT group	3888.9	23	0.59 (0.39-0.89)	0.31 (0.19-0.49)	< 0.001
	DAA group	2158.0	25	1.16 (0.78-1.71)	0.59 (0.37-0.95)	0.029
	Decompensation
	Untreated group	3333.6	54	1.62 (1.24-2.11)	Reference	-
	IBT group	3950.1	10	0.25 (0.14-0.47)	0.15 (0.07-0.29)	< 0.001
	DAA group	2178.7	5	0.23 (0.10-0.55)	0.16 (0.06-0.39)	< 0.001
	Death or transplantation
	Untreated group	4438.3	148	3.33 (2.85-3.91)	Reference	-
	IBT group	4850.1	42	0.87 (0.64-1.18)	0.22 (0.16-0.31)	< 0.001
	DAA group	2467.2	16	0.65 (0.40-1.06)	0.30 (0.17-0.51)	< 0.001
No cirrhosis	Hepatocellular carcinoma
	Untreated group	2364.6	15	0.63 (0.38-1.05)	Reference	-
	IBT group	2971.8	6	0.20 (0.09-0.45)	0.30 (0.11-0.77)	0.012
	DAA group	1569.4	8	0.51 (0.26-1.02)	0.90 (0.37-2.18)	0.812
	Decompensation
	Untreated group	2369.9	6	0.25 (0.11-0.56)	Reference	-
	IBT group	2992.3	1	0.03 (0.00-0.24)	0.09 (0.01-0.74)	0.026
	DAA group	1573.4	0	0.00	0.00	N/A
	Death or transplantation
	Untreated group	3176.3	63	1.98 (4.15-7.12)	Reference	-
	IBT group	3712.3	22	0.59 (0.39-0.90)	0.26 (0.16-0.42)	< 0.001
	DAA group	1784.6	7	0.39 (0.19-0.82)	0.33 (0.15-0.75)	0.008
Cirrhosis	Hepatocellular carcinoma
	Untreated group	919.9	50	5.44 (4.15-7.12)	Reference	-
	IBT group	917.1	17	1.85 (1.16-2.97)	0.35 (0.20-0.61)	< 0.001
	DAA group	588.6	17	2.89 (1.81-4.61)	0.53 (0.30-0.92)	0.025
	Decompensation
	Untreated group	962.8	48	4.99 (3.78-6.57)	Reference	-
	IBT group	957.7	9	0.84 (0.49-1.80)	0.18 (0.09-0.37)	< 0.001
	DAA group	606.3	5	0.82 (0.34-1.97)	0.17 (0.07-0.44)	< 0.001
	Death or transplantation
	Untreated group	1262.1	85	6.73 (5.48-8.27)	Reference	-
	IBT group	1137.8	20	1.76 (1.14-2.71)	0.21 (0.13-0.35)	< 0.001
	DAA group	682.6	9	1.32 (0.69-2.52)	0.28 (0.14-0.56)	< 0.001

A Cox proportional hazards model was used to determine hazards ratios and P values. CI: Confidence interval; DAA: Direct acting antivirals; HR: Hazard ratio; IBT: Interferon-based therapy; N/A: Not applicable; PY: Person-year.

Table 3 Multivariate time-varying Cox regression analysis for hepatocellular carcinoma and death/transplantation in entire cohort

Variable	Hepatocellular carcinoma		Decompensation		Death/transplantation
	aHR (95%CI)	P value	aHR (95%CI)	P value	aHR (95%CI)	P value
Model 1
Untreated group	Reference	-	Reference	-	Reference	-
IBT group	0.47 (0.28-0.80)	0.005	0.16 (0.08-0.33)	< 0.001	0.28 (0.18-0.43)	< 0.001
DAA group	0.58 (0.35-0.96)	0.035	0.12 (0.03-0.33)	< 0.001	0.19 (0.10-0.35)	< 0.001
Age, yr	1.06 (1.03-1.08)	< 0.001	1.00 (0.98-1.03)	0.805	1.05 (1.03-1.06)	< 0.001
Male sex	2.50 (1.37-4.55)	0.003	-	-	1.70 (1.24-2.33)	< 0.001
HCV genotype			-	-	-	-
2	Reference	-
1	2.25 (1.45-3.48)	< 0.001
Others/unknown	1.72 (0.66-4.48)	0.266
Cirrhosis	3.81 (2.38-6.10)	< 0.001	9.26 (4.03-21.03)	< 0.001	1.88 (1.34-2.64)	< 0.001
Ever smoker	1.47 (0.82-2.66)	0.192	-	-	-	-
Alcohol consumption			-	-	-	-
None	Reference	-
Social	1.20 (0.73-1.98)	0.473
Significant	2.20 (1.14-4.24)	0.027
BMI, kg/m2	-	-	-	-	0.94 (0.89-0.99)	0.019
Diabetes mellitus	0.96 (0.59-1.56)	0.872	-	-	1.12 (0.77-1.62)	0.563
Albumin, g/dL	0.71 (0.44-1.15)	0.162	0.35 (0.20-0.63)	< 0.001	0.36 (0.25-0.51)	< 0.001
Total bilirubin, mg/dL	0.95 (0.80-1.12)	0.568	1.03 (0.98-1.08)	0.264	-	-
PT, INR	2.66 (1.13-6.24)	0.025	3.32 (1.08-10.19)	0.036	2.34 (1.06-5.16)	0.034
AFP, log10 ng/dL	2.12 (1.48-3.05)	< 0.001	1.54 (0.95-2.51)	0.08	1.29 (0.94-1.77)	0.112
Model 2
Untreated or no SVR	Reference	-	Reference	-	Reference	-
SVR	0.41 (0.26-0.65)	< 0.001	0.10 (0.04-0.29)	< 0.001	0.26 (0.17-0.39)	< 0.001
Age, yr	1.06 (1.04- 1.08)	< 0.001	1.02 (0.99-1.04)	0.152	1.06 (1.04-1.07)	< 0.001
Male sex	2.50 (1.38-4.54)	0.003	-	-	1.68 (1.23-2.30)	0.001
HCV genotype			-	-	-	-
2	Reference	-
1	2.25 (1.45-3.48)	< 0.001
Others/unknown	1.57 (0.60-4.09)	0.359
Cirrhosis	3.75 (2.35-6.01)	< 0.001	7.54 (3.32-17.15)	< 0.001	1.72 (1.23-2.41)	0.002
Ever smoker	1.53 (0.85-2.75)	0.156	-	-	-	-
Alcohol consumption			-	-	-	-
None	Reference	-
Social	1.24 (0.75-2.04)	0.397
Significant	2.69 (1.40-5.16)	0.003
BMI, kg/m2	-	-	-	-	0.94 (0.89-0.99)	0.024
Diabetes mellitus	0.99 (0.61-1.61)	0.959	-	-	1.10 (0.76-1.60)	0.612
Albumin, g/dL	0.76 (0.47-1.20)	0.238	0.42 (0.24-0.71)	0.001	0.42 (0.30-0.60)	< 0.001
Total bilirubin, mg/dL	0.96 (0.81-1.13)	0.624	1.03 (0.99-1.08)	0.156	-	-
PT, INR	2.53 (1.02-6.28)	0.044	4.42 (1.48-13.20)	0.008	2.69 (1.22-5.92)	0.014
AFP, log10 ng/dL	2.10 (1.46-3.02)	< 0.001	1.48 (0.90-2.44)	0.12	1.17 (0.86-1.60)	0.32

Total number of patients, 2197; number of hepatocellular carcinomas, 113; number of deaths, 202; number of transplantations, 4; number of decompensations, 69. AFP: Alpha-feto protein; aHR: Adjusted hazard ratio; BMI: Body mass index; CI: Confidence interval; DAA: Direct acting antivirals; HCV: Hepatitis C virus; IBT: Interferon-based therapy; PT: Prothrombin time; SVR: Sustained virologic response.

Table 4 Comparison of characteristics and outcomes between the interferon-based treatment-sustained virologic response and direct-acting antivirals-sustained virologic response groups: Unadjusted and propensity score matching groups

Variable	Before adjustment				PS matched
	IBT-SVR group (n = 451)	DAA-SVR group (n = 817)	P value	SMD	IBT-SVR group (n = 213)	DAA-SVR group (n = 213)	P value	SMD
Age, yr	51.0 ± 10.6	59.1 ± 11.4	< 0.001	0.741	53.9 ± 9.8	53.7 ± 11.4	0.823	0.022
Male sex	209 (46.3)	394 (48.2)	0.52	0.036	102 (47.9)	97 (45.5)	0.627	0.047
HCV RNA, xlog10 IU/mL	5.72 (4.77-6.37)	6.04 (5.26-6.52)	< 0.001	0.278	5.84 (4.91-6.53)	6.07 (5.21-6.50)	0.439	0.073
HCV genotype			< 0.001	0.406			0.731	0.058
1	167 (37.0)	464 (56.8)			95 (44.6)	101 (47.4)
2	278 (61.6)	342 (41.9)			116 (54.5)	111 (52.1)
Others	6 (1.3)	11 (1.3)			2 (0.9)	1 (0.5)
Entry-to-treat, year	0 (0-0.3)	0.2 (0-2.1)	< 0.001	0.654	0.1 (0-0.4)	0.1 (0-0.4)	0.78	0.125
Diagnosis status			0.001	0.192			0.901	0.012
Chronic hepatitis	373 (82.7)	612 (74.9)			174 (81.7)	173 (81.2)
Compensated cirrhosis	78 (17.3)	205 (25.1)			39 (18.3)	40 (18.8)
FIB-4 index			< 0.001	0.294			0.363	0.071
≤ 1.45	156 (34.8)	156 (19.9)			69 (32.7)	59 (29.1)
1.45–3.25	155 (34.6)	326 (41.6)			74 (35.1)	85 (41.9)
≥ 3.25	137 (30.6)	302 (38.5)			68 (32.2)	59 (29.1)
APRI score			0.562	0.096			0.108	0.048
< 2.0	383 (85.1)	676 (83.9)			186 (87.7)	170 (82.1)
≥ 2.0	67 (14.9)	130 (16.1)			26 (12.3)	37 (17.9)
ALBI score			0.958	0.044			0.339	0.054
≤ -2.60 (Grade 1)	360 (80.0)	639 (79.9)			172 (81.1)	172 (82.7)
> -2.60 (Grade 2 or 3)	90 (20.0)	161 (20.1)			40 (18.9)	36 (16.3)
Ever smoker	228 (50.8)	15 (37.5)	0.045	0.162	95 (44.6)	93 (43.7)	0.527	0.019
Alcohol intake			< 0.001	0.669			0.816	0.058
None	171 (38.0)	19 (47.5)			98 (46.0)	104 (48.8)
Social	245 (54.4)	13 (32.5)			88 (41.3)	85 (39.9)
Significant1	34 (7.6)	8 (20.0)			27 (12.7)	24 (11.3)
Fatty liver disease on imaging study	77 (22.8), n = 337	131 (22.4), n = 586	0.863	0.039	34 (24.3)	35 (24.8)	0.917	0.013
Anti-HBc IgG positivity	25 (8.6), n = 290	62 (10.5), n = 592	0.386	0.062	12 (7.8)	15 (9.7)	0.546	0.062
BMI, kg/m2	23.7 ± 3.0	23.9 ± 3.1	0.429	0.047	23.9 ± 2.9	23.9 ± 3.4	0.983	0.005
Diabetes mellitus	61 (13.6)	122 (14.9)	0.495	0.049	26 (12.2)	22 (10.3)	0.54	0.055
Hypertension	80 (17.7)	236 (28.9)	< 0.001	0.267	45 (21.1)	44 (20.7)	0.905	0.012
Cardiovascular disease	3 (0.7)	24 (2.9)	0.007	0.162	2 (0.9)	3 (1.4)	0.315	0.058
Cerebrovascular disease	2 (0.4)	19 (2.3)	0.012	0.172	1 (0.5)	3 (1.4)	0.315	0.141
Laboratory study
WBC, × 103/mm3	4.99 (3.90-6.10)	5.40 (4.40-6.63)	< 0.0010.297	0.24	5.26 (4.25-6.35)	5.35 (4.50-6.52)	0.787	0.027
Hemoglobin, g/dL	13.6 (12.6-14.9)	13.8 (12.8-14.8)	0.218	0.061	13.9 (12.8-14.9)	13.9 (12.8-14.9)	0.916	0.01
PLT, × 103/mm3	177 (136-220)	173 (130-216)	0.178	0.055	176 (136-222)	180 (139-219)	0.401	0.083
Albumin, g/dL	4.2 (4.0-4.5)	4.2 (4.0-4.4)	0.664	0.082	4.3 (4.0-4.5)	4.3 (4.0-4.5)	0.734	0.031
Total bilirubin, mg/dL	0.7 (0.6-1.0)	0.7 (0.6-1.0)	< 0.001	0.072	0.8 (0.6-1.0)	0.7 (0.6-1.0)	0.85	0.009
ALP, IU/L	80 (63-113)	122 (78-250)	0.012	0.612	90 (65-126)	96 (72-183)	0.524	0.072
AST, IU/L	50 (30-86)	46 (30-76)	< 0.001	0.156	50 (32-83)	42 (27-85)	0.899	0.012
ALT, IU/L	54 (29-105)	36 (22-70)	0.756	0.297	49 (29-85)	37 (21-91)	0.915	0.009
Creatinine, mg/dL	0.8 (0.7-1.0)	0.8 (0.7-1.0)	0.02	0.09	0.8 (0.7-1.0)	0.8 (0.7-0.9)	0.176	0.069
PT, INR	1.03 (0.98-1.08)	1.04 (0.99-1.10)	0.434	0.111	1.03 (0.98-1.08)	1.04 (0.87-1.09)	0.67	0.038
AFP, ng/dL	3.3 (2.3-6.3)	3.8 (2.3-6.5)		0.142	5.8 (4.9-6.5)	6.1 (5.2-6.5)	0.278	0.034

¹Significant alcohol intake is defined as weekly alcohol consumption ≥ 210 g for men and ≥ 140 g for women.

Data were presented as mean ± SD, median (interquartile range), or n (%). AFP: Alpha-feto protein; ALBI: Albumin-bilirubin; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; APRI: Aspartate aminotransferase to platelet ratio index; AST: Aspartate aminotransferase; BMI: Body mass index; DAA: Direct acting antivirals; FIB-4: Fibrosis-4; HCV: Hepatitis C virus; IBT: Interferon-based therapy; MELD: Model for end-stage liver disease; PLT: Platelet; PT: Prothrombin time; WBC: White blood cell; SVR: Sustained virologic response.

Table 5 Multivariate Cox regression analysis for hepatocellular carcinoma and death/transplantation among the sustained virologic response cohort

Variable	Hepatocellular carcinoma		Death/transplantation
	aHR (95%CI)	P value	aHR (95%CI)	P value
IBT-SVR group	Reference	-	Reference	-
DAA-SVR group	2.03 (0.76-5.43)	0.16	1.38 (0.55-3.49)	0.494
Age, yr	1.05 (1.01-1.10)	0.025	-	-
Male sex	2.89 (0.97-8.61)	0.057	-	-
HCV genotype			-	–
2	Reference	-
1	3.02 (1.18-7.68)	0.021
Cirrhosis	3.18 (1.33-7.68)	0.009	2.97 (1.42-6.20)	0.004
Ever smoker	0.72 (0.26-1.99)	0.545	-	-
Alcohol consumption			-	-
None	Reference	-
Social	2.62 (0.92-7.60)	0.072
Significant	2.51 (0.71-8.82)	0.152
BMI, kg/m2	-	-	-	-
Diabetes mellitus	1.03 (0.42-2.52)	0.952	2.16 (0.98-4.78)	0.057
Albumin, g/dL	0.53 (0.19-1.49)	0.228	-	-
Total bilirubin, mg/dL	-	-	-	-
PT, INR	4.12 (0.89-19.17)	0.071	5.27 (1.01-27.53)	0.049
AFP, log10 ng/dL	1.07 (0.49-2.34)	0.858	-	-

Total number of patients, 1250; number of hepatocellular carcinomas, 30; number of deaths, 7; number of transplantations, 3. AFP: Alpha-feto protein; aHR: Adjusted hazard ratio; BMI: Body mass index; CI: Confidence interval; DAA: Direct acting antivirals; HCV: Hepatitis C virus; IBT: Interferon-based therapy; PT: Prothrombin time; SVR: Sustained virologic response.