Observational Study
Copyright ©The Author(s) 2022.
World J Gastroenterol. Aug 14, 2022; 28(30): 4182-4200
Published online Aug 14, 2022. doi: 10.3748/wjg.v28.i30.4182
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 ± 13.451.4 ± 10.959.1±11.4< 0.001< 0.0010.086< 0.001
Male sex280 (45.2)277 (47.9)412 (48.1)0.5110.3510.2810.955
HCV RNA, log10 IU/mL5.89 (5.08-6.45)5.83 (4.87-6.49)6.04 (5.27-6.53)< 0.0010.9790.017< 0.001
HCV genotype< 0.001< 0.001< 0.001< 0.001
1256 (41.4)242 (41.9)491 (57.3)
2299 (48.3)323 (55.9)355 (41.4)
Others/missing64 (10.3)13 (2.2)11 (1.3)
Diagnosis status< 0.001< 0.0010.0020.058
Chronic hepatitis417 (67.4)456 (78.9)639 (74.6)
Compensated cirrhosis202 (32.6)122 (21.1)218 (25.4)
FIB-4 index< 0.001< 0.0010.142< 0.001
≤ 1.45112 (18.9)191 (33.3)164 (19.9)
1.45-3.25218 (36.8)200 (34.8)337 (40.9)
≥ 3.25263 (44.3)183 (31.9)323 (39.2)
APRI score0.150.090.0940.853
≤ 2.0480 (80.3)485 (84.1)708 (83.7)
> 2.0118 (19.7)92 (15.9)138 (16.3)
ALBI score0.0040.040.0010.313
≤ -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 smoker264 (42.9)283 (49.5)380 (44.5)0.0580.0220.5190.068
Alcohol intake< 0.001< 0.001< 0.001< 0.001
None326 (53.0)226 (39.4)419 (48.9)
Social227 (36.9)308 (53.7)229 (26.7)
Significant161 (9.9)40 (7.0)209 (24.4)
Fatty liver disease on imaging study, n = 138971 (19.3), n = 36786 (21.1), n = 408140 (22.8), n = 6140.4350.5490.2020.516
Anti-HBcIgG (+), n = 144247 (11.0), n = 42933 (8.4), n = 39164 (10.3), n = 6220.460.2250.730.33
BMI, kg/m223.4 ± 3.223.8 ± 3.023.8 ± 3.10.020.1430.021
Diabetes mellitus120 (19.4)77 (13.3)128 (14.9)0.010.0050.0240.391
Hypertension145 (23.4)107 (18.5)243 (28.4)< 0.0010.0370.034< 0.001
Cardiovascular disease16 (2.6)3 (0.5)25 (2.9)0.0060.0040.7010.001
Cerebrovascular disease17 (2.7)4 (0.7)20 (2.3)0.0260.0070.6170.017
Laboratory study
WBC, × 103/mm35.09 (4.29-6.50)5.05 (3.91-6.16)5.40 (4.40-6.61)< 0.0010.1450.164< 0.001
Hemoglobin, g/dL13.5 (12.3-14.5)13.7 (12.7-14.8)13.8 (12.7-14.8)< 0.0010.004< 0.0011
Platelet, × 103/mm3162 (118-212)174 (130-220)172 (129-215)0.2290.2360.3171
Albumin, g/dL4.2 (3.9-4.4)4.2 (4.0-4.5)4.2 (4.0-4.4)< 0.001< 0.0010.0011
Total bilirubin, mg/dL0.8 (0.5-1.0)0.7 (0.6-1.0)0.7 (0.6-1.0)0.784111
ALP, IU/L87 (68-136)79 (63-112)121 (78-250)< 0.0010.001< 0.001< 0.001
AST, IU/L50 (30-85)50 (31-83)46 (30-76)0.02610.1390.038
ALT, IU/L42 (23-80)52 (29-100)36 (22-70)< 0.0010.0130.176< 0.001
Creatinine, mg/dL0.9 (0.7-1.0)0.8 (0.7-1.0)0.8 (0.7-1.0)0.857111
PT, INR1.06 (1.01-1.12)1.03 (0.98-1.08)1.03 (0.97-1.09)< 0.001< 0.0010.0070.119
AFP, ng/dL4.3 (2.5-9.7)3.5 (2.3-7.1)3.8 (2.4-6.6)0.868111
Cohort entry time< 0.001< 0.001< 0.001< 0.001
January 2007–June 2015488 (78.8)561 (97.1)49 (5.7)
July 2015–June 2019131 (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
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 cohortHepatocellular carcinoma
Untreated group3285.4651.98 (1.56-2.52)Reference-
IBT group3888.9230.59 (0.39-0.89)0.31 (0.19-0.49)< 0.001
DAA group2158.0251.16 (0.78-1.71)0.59 (0.37-0.95)0.029
Decompensation
Untreated group3333.6541.62 (1.24-2.11)Reference-
IBT group3950.1100.25 (0.14-0.47)0.15 (0.07-0.29)< 0.001
DAA group2178.750.23 (0.10-0.55)0.16 (0.06-0.39)< 0.001
Death or transplantation
Untreated group4438.31483.33 (2.85-3.91)Reference-
IBT group4850.1420.87 (0.64-1.18)0.22 (0.16-0.31)< 0.001
DAA group2467.2160.65 (0.40-1.06)0.30 (0.17-0.51)< 0.001
No cirrhosisHepatocellular carcinoma
Untreated group2364.6150.63 (0.38-1.05) Reference-
IBT group2971.860.20 (0.09-0.45)0.30 (0.11-0.77)0.012
DAA group1569.480.51 (0.26-1.02)0.90 (0.37-2.18)0.812
Decompensation
Untreated group2369.960.25 (0.11-0.56)Reference-
IBT group2992.310.03 (0.00-0.24)0.09 (0.01-0.74)0.026
DAA group1573.400.000.00N/A
Death or transplantation
Untreated group3176.3631.98 (4.15-7.12)Reference-
IBT group3712.3220.59 (0.39-0.90)0.26 (0.16-0.42)< 0.001
DAA group1784.670.39 (0.19-0.82)0.33 (0.15-0.75)0.008
CirrhosisHepatocellular carcinoma
Untreated group919.9505.44 (4.15-7.12)Reference-
IBT group917.1171.85 (1.16-2.97)0.35 (0.20-0.61)< 0.001
DAA group588.6172.89 (1.81-4.61)0.53 (0.30-0.92)0.025
Decompensation
Untreated group962.8484.99 (3.78-6.57)Reference-
IBT group957.790.84 (0.49-1.80)0.18 (0.09-0.37)< 0.001
DAA group606.350.82 (0.34-1.97)0.17 (0.07-0.44)< 0.001
Death or transplantation
Untreated group1262.1856.73 (5.48-8.27)Reference-
IBT group1137.8201.76 (1.14-2.71)0.21 (0.13-0.35)< 0.001
DAA group682.691.32 (0.69-2.52)0.28 (0.14-0.56)< 0.001
Table 3 Multivariate time-varying Cox regression analysis for hepatocellular carcinoma and death/transplantation in entire cohort
VariableHepatocellular carcinoma
Decompensation
Death/transplantation
aHR (95%CI)
P value
aHR (95%CI)
P value
aHR (95%CI)
P value
Model 1
Untreated groupReference-Reference-Reference-
IBT group 0.47 (0.28-0.80)0.0050.16 (0.08-0.33)< 0.0010.28 (0.18-0.43)< 0.001
DAA group0.58 (0.35-0.96)0.0350.12 (0.03-0.33)< 0.0010.19 (0.10-0.35)< 0.001
Age, yr1.06 (1.03-1.08)< 0.0011.00 (0.98-1.03)0.8051.05 (1.03-1.06)< 0.001
Male sex2.50 (1.37-4.55)0.003--1.70 (1.24-2.33)< 0.001
HCV genotype----
2Reference-
12.25 (1.45-3.48)< 0.001
Others/unknown1.72 (0.66-4.48)0.266
Cirrhosis3.81 (2.38-6.10)< 0.0019.26 (4.03-21.03)< 0.0011.88 (1.34-2.64)< 0.001
Ever smoker1.47 (0.82-2.66)0.192----
Alcohol consumption----
NoneReference-
Social1.20 (0.73-1.98)0.473
Significant2.20 (1.14-4.24)0.027
BMI, kg/m2----0.94 (0.89-0.99)0.019
Diabetes mellitus0.96 (0.59-1.56)0.872--1.12 (0.77-1.62)0.563
Albumin, g/dL0.71 (0.44-1.15)0.1620.35 (0.20-0.63)< 0.0010.36 (0.25-0.51)< 0.001
Total bilirubin, mg/dL0.95 (0.80-1.12)0.5681.03 (0.98-1.08)0.264--
PT, INR2.66 (1.13-6.24)0.0253.32 (1.08-10.19)0.0362.34 (1.06-5.16)0.034
AFP, log10 ng/dL2.12 (1.48-3.05)< 0.0011.54 (0.95-2.51)0.081.29 (0.94-1.77)0.112
Model 2
Untreated or no SVRReference-Reference-Reference-
SVR0.41 (0.26-0.65)< 0.0010.10 (0.04-0.29)< 0.0010.26 (0.17-0.39)< 0.001
Age, yr1.06 (1.04- 1.08)< 0.0011.02 (0.99-1.04)0.1521.06 (1.04-1.07)< 0.001
Male sex2.50 (1.38-4.54)0.003--1.68 (1.23-2.30)0.001
HCV genotype----
2Reference-
12.25 (1.45-3.48)< 0.001
Others/unknown1.57 (0.60-4.09)0.359
Cirrhosis3.75 (2.35-6.01)< 0.0017.54 (3.32-17.15)< 0.0011.72 (1.23-2.41)0.002
Ever smoker1.53 (0.85-2.75)0.156----
Alcohol consumption----
NoneReference-
Social1.24 (0.75-2.04)0.397
Significant2.69 (1.40-5.16)0.003
BMI, kg/m2----0.94 (0.89-0.99)0.024
Diabetes mellitus0.99 (0.61-1.61)0.959--1.10 (0.76-1.60)0.612
Albumin, g/dL0.76 (0.47-1.20)0.2380.42 (0.24-0.71)0.0010.42 (0.30-0.60)< 0.001
Total bilirubin, mg/dL0.96 (0.81-1.13)0.6241.03 (0.99-1.08)0.156--
PT, INR2.53 (1.02-6.28)0.0444.42 (1.48-13.20)0.0082.69 (1.22-5.92)0.014
AFP, log10 ng/dL2.10 (1.46-3.02)< 0.0011.48 (0.90-2.44)0.121.17 (0.86-1.60)0.32
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, yr51.0 ± 10.659.1 ± 11.4< 0.0010.74153.9 ± 9.853.7 ± 11.40.8230.022
Male sex209 (46.3)394 (48.2)0.520.036102 (47.9)97 (45.5)0.6270.047
HCV RNA, xlog10 IU/mL5.72 (4.77-6.37)6.04 (5.26-6.52)< 0.0010.2785.84 (4.91-6.53)6.07 (5.21-6.50)0.4390.073
HCV genotype< 0.0010.4060.7310.058
1167 (37.0)464 (56.8)95 (44.6)101 (47.4)
2278 (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, year0 (0-0.3)0.2 (0-2.1)< 0.0010.6540.1 (0-0.4)0.1 (0-0.4)0.780.125
Diagnosis status0.0010.1920.9010.012
Chronic hepatitis373 (82.7)612 (74.9)174 (81.7)173 (81.2)
Compensated cirrhosis78 (17.3)205 (25.1)39 (18.3)40 (18.8)
FIB-4 index< 0.0010.2940.3630.071
≤ 1.45156 (34.8)156 (19.9)69 (32.7)59 (29.1)
1.45–3.25155 (34.6)326 (41.6)74 (35.1)85 (41.9)
≥ 3.25137 (30.6)302 (38.5)68 (32.2)59 (29.1)
APRI score0.5620.0960.1080.048
< 2.0383 (85.1)676 (83.9)186 (87.7)170 (82.1)
≥ 2.067 (14.9)130 (16.1)26 (12.3)37 (17.9)
ALBI score0.9580.0440.3390.054
≤ -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 smoker228 (50.8)15 (37.5)0.0450.16295 (44.6)93 (43.7)0.5270.019
Alcohol intake< 0.0010.6690.8160.058
None171 (38.0)19 (47.5)98 (46.0)104 (48.8)
Social245 (54.4)13 (32.5)88 (41.3)85 (39.9)
Significant134 (7.6)8 (20.0)27 (12.7)24 (11.3)
Fatty liver disease on imaging study77 (22.8), n = 337131 (22.4), n = 5860.8630.03934 (24.3)35 (24.8)0.9170.013
Anti-HBc IgG positivity25 (8.6), n = 29062 (10.5), n = 5920.3860.06212 (7.8)15 (9.7)0.5460.062
BMI, kg/m223.7 ± 3.023.9 ± 3.10.4290.04723.9 ± 2.923.9 ± 3.40.9830.005
Diabetes mellitus61 (13.6)122 (14.9)0.4950.04926 (12.2)22 (10.3)0.540.055
Hypertension80 (17.7)236 (28.9)< 0.0010.26745 (21.1)44 (20.7)0.9050.012
Cardiovascular disease3 (0.7)24 (2.9)0.0070.1622 (0.9)3 (1.4)0.3150.058
Cerebrovascular disease2 (0.4)19 (2.3)0.0120.1721 (0.5)3 (1.4)0.3150.141
Laboratory study
WBC, × 103/mm34.99 (3.90-6.10)5.40 (4.40-6.63)< 0.0010.2970.245.26 (4.25-6.35)5.35 (4.50-6.52)0.7870.027
Hemoglobin, g/dL13.6 (12.6-14.9)13.8 (12.8-14.8)0.2180.06113.9 (12.8-14.9)13.9 (12.8-14.9)0.9160.01
PLT, × 103/mm3177 (136-220)173 (130-216)0.1780.055176 (136-222)180 (139-219)0.4010.083
Albumin, g/dL4.2 (4.0-4.5)4.2 (4.0-4.4)0.6640.0824.3 (4.0-4.5)4.3 (4.0-4.5)0.7340.031
Total bilirubin, mg/dL0.7 (0.6-1.0)0.7 (0.6-1.0)< 0.0010.0720.8 (0.6-1.0)0.7 (0.6-1.0)0.850.009
ALP, IU/L80 (63-113)122 (78-250)0.0120.61290 (65-126)96 (72-183)0.5240.072
AST, IU/L50 (30-86)46 (30-76)< 0.0010.15650 (32-83)42 (27-85)0.8990.012
ALT, IU/L54 (29-105)36 (22-70)0.7560.29749 (29-85)37 (21-91)0.9150.009
Creatinine, mg/dL0.8 (0.7-1.0)0.8 (0.7-1.0)0.020.090.8 (0.7-1.0)0.8 (0.7-0.9)0.1760.069
PT, INR1.03 (0.98-1.08)1.04 (0.99-1.10)0.4340.1111.03 (0.98-1.08)1.04 (0.87-1.09)0.670.038
AFP, ng/dL3.3 (2.3-6.3)3.8 (2.3-6.5)0.1425.8 (4.9-6.5)6.1 (5.2-6.5)0.2780.034
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 groupReference-Reference-
DAA-SVR group2.03 (0.76-5.43)0.161.38 (0.55-3.49)0.494
Age, yr1.05 (1.01-1.10)0.025--
Male sex2.89 (0.97-8.61)0.057--
HCV genotype-
2Reference-
13.02 (1.18-7.68)0.021
Cirrhosis3.18 (1.33-7.68)0.0092.97 (1.42-6.20)0.004
Ever smoker0.72 (0.26-1.99)0.545--
Alcohol consumption--
NoneReference-
Social2.62 (0.92-7.60)0.072
Significant2.51 (0.71-8.82)0.152
BMI, kg/m2----
Diabetes mellitus1.03 (0.42-2.52)0.9522.16 (0.98-4.78)0.057
Albumin, g/dL0.53 (0.19-1.49)0.228--
Total bilirubin, mg/dL----
PT, INR4.12 (0.89-19.17)0.0715.27 (1.01-27.53)0.049
AFP, log10 ng/dL1.07 (0.49-2.34)0.858--