Changes in characteristics of patients with hepatitis C virus-related cirrhosis from the beginning of the interferon-free era

Table 1 Baseline characteristics of 3577 patients with cirrhosis treated with interferon-free regimens

Parameter	2015-2016	2017	2018	2019	2020	2021
Number of patients	1199	827	573	438	199	341
Gender, females/males, n (%)	600 (50)/599 (50)	401 (48.5)/426 (51.5)	251 (43.8)/322 (56.2)	164 (37.4)/274 (62.6)	71 (35.7)/128 (64.3)	140 (41.1)/201 (58.9)
Age (yr), mean ± SD; min-max	58.6 ± 11.8; 21-97	59.4 ± 12.0; 22-87	58.2 ± 13.8; 21-89	55.2 ± 13.2; 26-91	54.6 ± 12.1; 28-83	56.6 ± 12.6; 25-86
Females	62.2 ± 10.8; 25-91	62.1 ± 11; 25-85	61.8 ± 14.2; 21-89	60.3 ± 12.8; 30-91	59.4 ± 12.2; 29-83	60.5 ± 12.3; 25-85
Males	55.1 ± 11.8; 21-97	56.8 ± 12.3; 22-87	55.4 ± 12.8; 27-88	52.1 ± 12.5; 26-89	51.9 ± 11.2; 28-80	53.9 ± 12.1; 30-86
Median (Q1, Q3)	60 (52, 67)	60 (52, 67)	59 (48, 68)	56 (45, 63)	55 (45, 63)	57 (47, 65)
Females, median (Q1, Q3)	63 (57, 69)	62 (56, 70)	62 (54, 73)	61 (52.5, 68)	60 (52, 68)	61 (53, 68.5)
Males, median (Q1, Q3)	57 (47, 63)	57 (48, 65)	56 (45, 64)	51 (42, 61)	52 (44, 60)	52 (44, 63)
BMI, mean ± SD; min-max	27.3 ± 4.5; 13.4-49.4	27.5 ± 4.8; 14.2-45.5	27.1 ± 4.7; 21-89	27.7 ± 5.2; 17-52.5	27.9 ± 5.6; 16-57.4	27.5 ± 4.9; 15.6-50
Comorbidities, n (%)
Any comorbidity	921 (76.8)	682 (82.5)	431 (75.2)	303 (69.2)	141 (70.9)	252 (73.9)
Hypertension	582 (48.5)	384 (46.4)	279 (48.7)	179 (40.9)	72 (36.2)	158 (46.3)
Diabetes	263 (21.9)	212 (25.6)	120 (20.9)	76 (17.4)	44 (22.1)	136 (27)
Renal disease	48 (4)	39 (4.7)	20 (3.5)	10 (2.3)	9 (4.5)	12 (3.5)
Autoimmune diseases	29 (2.4)	14 (1.7)	8 (1.4)	9 (2.1)	2 (1)	3 (0.9)
Non-HCC tumors	20 (1.7)	15 (1.8)	12 (2.1)	12 (2.7)	6 (3)	15 (4.4)
Other	628 (52.4)	560 (67.7)	352 (61.4)	208 (47.5)	147 (73.9)	179 (52.5)
Concomitant medications, n (%)	879 (73.3)	635 (76.8)	431 (75.2)	305 (69.6)	138 (69.3)	245 (71.8)
ALT IU/L, mean ± SD	97.3 ± 66.2	96.4 ± 69.9	96 ± 85	107.1 ± 91.7	114.5 ± 103.8	115.9 ± 101.2
Bilirubin mg/dL, mean ± SD	1.2 ± 0.9	1 ± 0.7	1.1 ± 0.9	1.1 ± 0.9	1.1 ± 1.6	1.1 ± 0.9
Albumin g/dL, mean ± SD	5.8 ± 12.8	3.8 ± 0.5	3.8 ± 0.5	3.9 ± 0.5	3.8 ± 0.5	3.9 ± 0.6
Creatinine mg/dL, mean ± SD	1.1 ± 3.8	0.8 ± 0.5	0.9 ± 0.5	0.9 ± 0.7	0.9 ± 0.3	0.9 ± 0.7
Hemoglobin g/dL, mean ± SD	14.1 ± 1.8	14.1 ± 1.8	14 ± 1.8	14.1 ± 1.9	14.2 ± 1.8	13.9 ± 1.9
Platelets, × 1000/μL, mean ± SD	118.7 ± 61.6	136.1 ± 67.9	135 ± 70	136.5 ± 61.9	145.8 ± 87.6	145.6 ± 76.9
HCV RNA × 106 IU/mL, mean ± SD	1.6 ± 4.6	2.5 ± 6.4	2 ± 4.8	3.3 ± 24	1.7 ± 2.6	2 ± 3.2

IFN: Interferon; SD: Standard deviation; BMI: Body mass index; HCC: Hepatocellular carcinoma; ALT: Alanine transaminase; HCV RNA: Ribonucleic acid of hepatitis C virus.

Table 2 Characteristics of liver disease in six-time intervals

Parameter	2015-2016	2017	2018	2019	2020	2021
Number of patients	1199	827	573	438	199	341
GT, n (%)
1	17 (1.4)	22 (2.7)	15 (2.6)	7 (1.6)	1 (0.5)	7 (2.1)
1a	21 (1.8)	17 (2.1)	10 (1.7)	10 (2.3)	9 (4.5)	8 (2.3)
1b	1070 (89.2)	652 (78.8)	420 (73.3)	291 (66.4)	125 (62.8)	247 (72.4)
2	0	0	1 (0.2)	3 (0.7)	0	3 (0.9)
3	56 (4.7)	103 (12.4)	109 (19.0)	111 (25.3)	60 (30.2)	63 (18.5)
4	35 (2.9)	33 (4.0)	17 (3)	16 (3.7)	4 (2)	13 (3.8)
5	0	0	0	0	0	0
6	0	0	1 (0.2)	0	0	0
Child-Pugh class, n (%)
A	1033 (86.2)	724 (87.6)	521 (90.9)	397 (90.7)	176 (88.4)	285 (83.6)
B	118 (9.8)	77 (9.3)	47 (8.2)	36 (8.2)	18 (9.1)	49 (14.3)
C	9 (0.7)	1 (0.1)	2 (0.4)	1 (0.2)	1 (0.5)	3 (0.9)
No data	39 (3.3)	25 (3.0)	3 (0.5)	4 (0.9)	4 (2.0)	4 (1.2)
MELD score, n (%)
< 15	1072 (89.4)	757 (91.5)	529 (92.3)	414 (94.5)	188 (94.5)	319 (93.5)
15-18	45 (3.8)	28 (3.4)	29 (5.1)	12 (2.8)	3 (1.5)	14 (4.1)
19-20	11 (0.9)	12 (1.5)	5 (0.9)	4 (0.9)	2 (1)	4 (1.2)
> 20	13 (1.1)	4 (0.5)	7 (1.2)	3 (0.7)	2 (1)	2 (0.6)
No data	58 (4.8)	26 (3.1)	3 (0.5)	5 (1.1)	4 (2)	2 (0.6)
History of hepatic decompensation, n (%)
Ascites	124 (10.3)	65 (7.8)	64 (11.2)	26 (5.9)	15 (7.5)	47 (13.8)
Encephalopathy	33 (2.8)	15 (1.8)	19 (3.3)	4 (0.9)	2 (1)	7 (2.1)
Documented esophageal varices, n (%)	375 (31.3)	202 (24.4)	127 (22.2)	85 (19.4)	38 (19.1)	58 (17)
Hepatic decompensation at baseline, n (%)
Moderate ascites-responded to diuretics	47 (3.9)	30 (3.6)	29 (5.1)	22 (5)	10 (5)	29 (8.5)
Tense ascites-not responded to diuretics	3 (0.3)	0	2 (0.3)	0	0	3 (0.9)
Encephalopathy	30 (2.5)	13 (1.6)	7 (1.2)	7 (1.6)	2 (1)	9 (2.6)
HCC history, n (%)	57 (4.8)	30 (3.6)	19 (3.3)	15 (3.4)	7 (3.5)	19 (5.6)
OLTx history, n (%)	23 (1.9)	4 (0.5)	1 (0.2)	1 (0.2)	0	1 (0.3)
HBV coinfection (HBsAg+), n (%)	12 (1)	12 (1.5)	12 (2.1)	8 (1.8)	3 (1.5)	6 (1.8)
HIV coinfection, n (%)	13 (1.1)	16 (1.9)	16 (2.8)	28 (6.4)	9 (4.5)	10 (2.9)

GT: Genotype; MELD: Model for end-stage liver disease; HCC: Hepatocellular carcinoma; OLTx: Orthotopic liver transplantation; HBV: Hepatitis B virus; HBsAg+: Hepatitis B surface antigen; HIV: Human immunodeficiency virus.

Table 3 Treatment characteristics in six-time intervals

Parameter	2015-2016	2017	2018	2019	2020	2021
Number of patients	1199	827	573	438	199	341
History of previous therapy
Treatment-naïve	543 (45.3)	532 (64.3)	470 (82.0)	385 (87.9)	171 (86)	318 (93.2)
Nonresponder	290 (24.2)	103 (12.5)	23 (4.0)	7 (1.6)	6 (3)	11 (3.2)
Relapser	173 (14.4)	72 (8.7)	49 (8.5)	35 (8)	17 (8.5)	6 (1.8)
Discontinuation due to safety reason	71 (5.9)	40 (4.8)	14 (2.5)	4 (0.9)	1 (0.5)	3 (0.9)
Unknown type of response	120 (10.0)	76 (9.2)	14 (2.5)	7 (1.6)	2 (1)	3 (0.9)
No data	2 (0.2)	4 (0.5)	3 (0.5)	0	2 (1)	0
Number of patients with treatment failure	n = 654	n = 291	n = 100	n = 53	n = 26	n = 23
IFN ± RBV	64 (9.8)	36 (12.4)	2 (2)	0	0	0
PegIFN ± RBV	390 (59.6)	197 (67.7)	48 (48)	14 (26.4)	9 (34.6)	9 (39.1)
PegIFN + RBV + DAA	196 (30)	47 (16.1)	10 (10)	3 (5.7)	0	0
IFN-free	4 (0.6)	11 (3.8)	39 (39)	35 (66)	17 (65.4)	14 (60.9)
No data	0	0	1 (1)	1 (1.9)	0	0
Current treatment regimen
Genotype-specific treatment regimens
ASV + DCV	42 (3.5)	13 (1.6)	0	0	0	0
LDV/(SOF ± RBV)	350 (29.2)	283 (34.2)	154 (26.9)	16 (3.7)	5 (2.5)	4 (1.2)
OBV/PTV/(r ± DSV ± RBV)	745 (62.1)	327 (39.5)	32 (5.6)	0	0	1 (0.3)
GZR/(EBR ± RBV)	0	97 (11.7)	205 (35.8)	76 (17.3)	16 (8)	15 (4.4)
Other	62 (5.2)	104 (12.6)	19 (3.3)	0	0	0
SOF ± SMV ± DCV ± RBV, SMV ± DCV ± RBV
Pangenotypic regimens
GLE/PIB	0	1 (0.1)	59 (10.3)	178 (40.6)	99 (49.8)	117 (34.3)
GLE/(PIB + SOF + RBV)	0	0	0	2 (0.5)	0	0
SOF/(VEL ± RBV)	0	2 (0.3)	104 (18.1)	166 (37.9)	79 (39.7)	195 (57.2)
VOX/VEL/SOF	0	0	0	0	0	9 (2.6)
Current-RBV-containing therapies	855 (71.3)	360 (43.5)	163 (28.4)	44 (10)	12 (6)	23 (6.7)

IFN: Interferon; RBV: Ribavirin; PegIFN: Pegylated interferon; DAA: Direct-acting antivirals; ASV: Asunaprevir; DCV: Daclatasvir; LDV: Ledipasvir; SOF: Sofosbuvir; OBV: Ombitasvir; PTV/r: Paritaprevir; DSV: Dasabuvir; GZR: Grazoprevir; EBR: Elbasvir; SMV: Simeprevir; GLE: Glecaprevir; PIB: Pibrentasvir; VEL: Velpatasvir; VOX: Voxilaprevir.

Table 4 Treatment effectiveness according to regimen, calculated as per protocol analysis

Regimen	SVR PP, n (%)
All regimens	3271/3442 (95)
OBV/PTV/(r ± DSV ± RBV)	1052/1076 (97.8)
LDV/(SOF ± RBV)	748/778 (96.1)
GZR/(EBR ± RBV)	387/398 (97.2)
VEL/(SOF ± RBV)	477/521 (91.6)
GLE/PIB	420/435 (96.6)
GLE/PIB/(SOF + RBV)	2/2 (100)
ASV + DCV	47/55 (85.5)
SOF + DCV ± RBV	21/21 (100)
SOF + RBV	105/144 (72.9)
SOF + SMV ± RBV	5/5 (100)
VOX/VEL/SOF	7/7 (100)

PP: Per protocol; SVR: Sustained virological response; OBV: Ombitasvir; PTV/r: Paritaprevir; DSV: Dasabuvir; RBV: Ribavirin; LDV: Ledipasvir; SOF: Sofosbuvir; GZR: Grazoprevir; EBR: Elbasvir; VEL: Velpatasvir; GLE: Glecaprevir; PIB: Pibrentasvir; ASV: Asunaprevir; DCV: Daclatasvir; SMV: Simeprevir; VOX: Voxilaprevir.

Table 5 Comparison of responders and virological non-responders to antiviral therapy

Parameter	Responders (n = 3271)	Non-responders (n = 171)	P value
Gender, females/males, n (%)	1539 (47)/1732 (53)	42 (24.6)/129 (75.4)	< 0.0001
Age (yr), mean ± SD; min-max	58.0 ± 12.6; 21-97	55.0 ± 10.5; 29-84	0.0002
Females	61.6 ± 11.8; 21-91	59.9 ± 10.6; 35-81	0.3173
Males	54.8 ± 12.4; 21-97	53.4 ± 10; 29-84	0.1045
BMI, mean ± SD; min-max	27.4 ± 5.0; 13.4-57.4	28.7 ± 4.6; 16-47.5	0.0001
Current treatment regimen
Genotype-specific treatment regimens
ASV + DCV	47 (1.4)	8 (4.7)	0.0001
LDV/(SOF ± RBV)	748 (22.9)	30 (17.5)	0.1047
OBV/PTV/(r ± DSV ± RBV)	1052 (32.2)	24 (14)	< 0.0001
GZR/(EBR ± RBV)	387 (11.8)	11 (6.4)	0.0314
Pangenotypic regimens
GLE/PIB	420 (12.8)	15 (8.8)	0.1186
GLE/(PIB + SOF + RBV)	2 (0.1)	0	0.7464
SOF/(VEL ± RBV)	477 (14.6)	44 (25.7)	0.0001
VOX/VEL/SOF	7 (0.2)	0	0.5448
GT, n (%)			< 0.0001
1	63 (1.9)	2 (1.2)
1a	70 (2.2)	1 (0.6)
1b	2624 (80.2)	89 (52.0)
3	397 (12.1)	76 (44.4)
4	110 (3.4)	3 (1.8)
Other	7 (0.2)	0
Comorbidities, n (%)
Any comorbidity	2498 (76.4)	131 (4)	0.9425
Hypertension	1533 (46.9)	66 (2)	0.0345
Diabetes	731 (22.3)	46 (1.4)	0.1651
Renal disease	124 (3.8)	8 (0.2)	0.5558
Autoimmune diseases	63 (1.9)	0	0.0670
Non-HCC tumors	68 (2.1)	6 (0.2)	0.1963
Other	1783 (54.5)	96 (2.9)	0.6762
Concomitant medications, n (%)	2389 (73.0)	136 (79.5)	0.0610
Treatment experienced	1039 (31.8)	69 (40.4)	0.0208
History of hepatic decompensation, n (%)
Ascites	297 (9.0)	21 (12.2)	0.1588
Encephalopathy	65 (2.0)	7 (4.1)	0.0606
Documented esophageal varices, n (%)	780 (23.8)	64 (37.4)	0.0001
Hepatic decompensation at baseline, n (%)	173 (5.3)	18 (10.5)	0.0035
HCC history, n (%)	117 (3.6)	9 (5.3)	0.2523
OLTx history, n (%)	28 (0.9)	1 (0.6)	0.7052
Child-Pugh class, n (%)
B or C	296 (9)	29 (17)	0.0006
HBV coinfection (HBsAg+), n (%)	50 (1.5)	2 (1.2)	0.7075
HIV coinfection, n (%)	79 (2.4)	6 (3.5)	0.3690
ALT IU/L, mean ± SD	101.2 ± 80.8	106.9 ± 82.0	0.3385
Bilirubin mg/dL, mean ± SD	1.1 ± 0.9	1.2 ± 0.7	< 0.0001
Albumin g/dL, mean ± SD	4.5 ± 7.7	3.9 ± 3.1	0.0002
Creatinine mg/dL, mean ± SD	0.9 ± 2.3	0.8 ± 0.2	0.8562
Hemoglobin g/dL, mean ± SD	14.1 ± 1.8	13.9 ± 1.8	0.1319
Platelets, × 1000/μL, mean ± SD	132.6 ± 66.8	109.2 ± 59.4	< 0.0001
HCV RNA × 106 IU/ml, mean ± SD	2.2 ± 10.0	2.0 ± 2.9	0.1123

SD: Standard deviation; BMI: Body mass index; ASV: Asunaprevir; DCV: Daclatasvir; LDV: Ledipasvir; SOF: Sofosbuvir; RBV: Ribavirin; OBV: Ombitasvir; PTV/r: Paritaprevir; DSV: Dasabuvir; GZR: Grazoprevir; EBR: Elbasvir; GLE: Glecaprevir; PIB: Pibrentasvir; VEL: Velpatasvir; VOX: Voxilaprevir; GT: Genotype; HCC: Hepatocellular carcinoma; OLTx: Orthotopic liver transplantation; HBV: Hepatitis B virus; HBsAg: Hepatitis B surface antigen; HIV: Human immunodeficiency virus; ALT: Alanine transaminase; HCV RNA: Ribonucleic acid of hepatitis C virus.

Table 6 Logistic multiple regression results on association between selected parameters significant in univariate analysis and non-response to antiviral treatment

Parameter	OR	95%CI	P value
Age ≥ 75 yr	0.81	0.38-1.72	0.5915
Obesity (BMI ≥ 30 kg/m2)	1.15	0.80-1.66	0.4473
Male gender	2.28	1.57-3.29	< 0.0001
Platelets < 100000/μL	1.37	0.98-1.93	0.0694
GT1b	1.54	0.66-3.59	0.3145
GT3	6.40	2.69-15.22	< 0.0001
Bilirubin > 3 mg/dL	0.29	0.08-1.00	0.0506
Albumin < 2.8 g/dL	0.98	0.44-2.20	0.966
Documented esophageal varices	1.43	1.00-2.06	0.052
Hepatic decompensation at baseline	1.49	0.76-2.91	0.2496
Hypertension	0.93	0.67-1.30	0.6783
Child-Pugh, B or C	1.80	0.95-3.42	0.0716
SOF/(VEL ± RBV)	1.13	0.76-1.69	0.541
GZR/(EBR ± RBV)	0.91	0.46-1.80	0.7951
OBV/PTV/(r ± DSV ± RBV)	0.58	0.35-0.95	0.0319
Treatment experienced	1.66	1.18-2.33	0.0039

OR: Odds ratio; CI: Confidence interval; BMI: Body mass index; GT: Genotype; SOF: Sofosbuvir; VEL: Velpatasvir; RBV: Ribavirin; GZR: Grazoprevir; EBR: Elbasvir; OBV: Ombitasvir; PTV/r: Paritaprevir; DSV: Dasabuvir.

Table 7 Safety of antiviral therapy in six-time intervals

Parameter	2015-2016	2017	2018	2019	2020	2021
Number of patients	1199	827	573	438	199	341
Treatment course, n (%)
According to schedule	1073 (89.5)	776 (93.8)	538 (93.9)	428 (97.7)	196 (98.5)	334 (97.9)
Therapy modification	71 (5.9)	21 (2.6)	26 (4.5)	2 (0.5)	0	0
Therapy discontinuation	44 (3.7)	19 (2.3)	9 (1.6)	5 (1.1)	1 (0.5)	6 (1.8)
No data	11 (0.9)	11 (1.3)	0	3 (0.7)	2 (1.0)	1 (0.3)
Patients with at least one AE, n (%)	500 (41.7)	212 (25.6)	139 (24.3)	80 (18.3)	36 (18.1)	66 (19.4)
Serious adverse events, n (%)	48 (4)	11 (1.3)	16 (2.8)	7 (1.6)	4 (2)	3 (0.9)
AEs leading to treatment discontinuation, n (%)	35 (2.9)	16 (1.9)	4 (0.7)	2 (0.5)	1 (0.5)	1 (0.3)
Most common AEs (≥ 2%), n (%)
Weakness/fatigue	242 (20.2)	78 (9.4)	59 (10.3)	28 (6.4)	13 (6.5)	16 (4.7)
Anemia	63 (5.3)	36 (4.4)	17 (3)	2 (0.5)	0	2 (0.6)
Sleep disorders	52 (4.3)	20 (2.4)	20 (3.5)	4 (0.9)	6 (3)	6 (1.8)
Nausea	32 (2.7)	14 (1.7)	3 (0.5)	1 (0.2)	5 (2.5)	6 (1.8)
Abdominal pain	21 (1.8)	7 (0.8)	4 (0.7)	12 (2.7)	5 (2.5)	8 (2.3)
Headaches	50 (4.2)	14 (1.7)	11 (1.9)	7 (1.2)	3 (0.5)	8 (2.3)
Myalgia/arthralgia	18 (1.5)	18 (2.2)	9 (1.6)	6 (1.4)	6 (3)	8 (2.3)
Pruritis	71 (5.9)	19 (2.3)	10 (1.7)	10 (2.3)	7 (3.5)	7 (2.1)
Skin lesions	26 (2.2)	14 (1.7)	7 (1.2)	5 (1.1)	2 (1)	4 (1.2)
Bilirubin, > ULN	44 (3.7)	30 (3.6)	3 (0.5)	3 (0.7)	0	0
AEs of particular interest
Ascites	30 (2.5)	23 (2.8)	12 (2.1)	6 (1.4)	0	13 (3.8)
Hepatic encephalopathy	28 (2.3)	12 (1.5)	6 (1.0)	2 (0.5)	1 (0.5)	6 (1.8)
Gastrointestinal bleeding	9 (0.8)	4 (0.5)	5 (0.9)	1 (0.2)	1 (0.5)	0
Death, n (%)	13 (1.1)	10 (1.2)	10 (1.7)	3 (0.7)	2 (1.0)	7 (2.1)

AE: Adverse event; ULN: Upper limit of normal.