Best therapy for the easiest to treat hepatitis C virus genotype 1b-infected patients

Table 1 Baseline characteristics of 11385 genotype 1b-infected patients treated with interferon-free regimens

Parameter	GT1b patients, n = 11385
Sex, female/male, n (%)	6085 (53.4)/5300 (46.6)
Age in yr, mean ± SD; min-max	53 ± 14.8; 17-97
Females	54.8 ± 15.1; 18-92
Males	51 ± 14.3; 17-97
BMI, kg/m2 mean ± SD; min-max	26.3 ± 4.5; 13.2-57.4
Comorbidities, n (%)
Any comorbidity	7280 (63.9)
Hypertension	4013 (35.2)
Diabetes	1447 (12.7)
Renal disease	470 (4.1)
Autoimmune diseases	251 (2.2)
Non-HCC tumors	237 (2.1)
Other	5330 (46.8)
Concomitant medications, n (%)	6842 (60.1)
Liver fibrosis n(%)
F0	237 (2.1)
F1	4440 (39)
F2	2135 (18.8)
F3	1587 (13.9)
F4	2768 (24.3)
No data	218 (1.9)
HCC history, n (%)	175 (1.5)
OLTx history, n (%)	122 (1.1)
HBV coinfection (HBsAg+), n (%)	106 (0.9)
HIV coinfection, n (%)	359 (3.1)
ALT IU/L, mean ± SD	75.8 ± 65.5
Bilirubin mg/dL, mean ± SD	0.8 ± 0.9
Albumin g/dL, mean ± SD	4.3 ± 3.2
Creatinine mg/dL, mean ± SD	0.9 ± 1.8
Hemoglobin g/dL, mean ± SD	14.4 ± 1.8
Platelets × 1000/μL, mean ± SD	195.3 ± 77.8
HCV RNA × 106 IU/mL, mean ± SD	2.1 ± 4.7

ALT: Alanine transaminase; BMI: Body mass index; F: Fibrosis; GT: Genotype; HBsAg+: Hepatitis B surface antigen; HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus; HIV: Human immunodeficiency virus; IFN: Interferon; OLTx: Orthotopic liver transplantation; SD: Standard deviation.

Table 2 Genotype 1b-infected patients with liver cirrhosis treated with direct-acting antivirals

Parameter	GT1b patients, n = 2768
History of hepatic decompensation, n (%)
Ascites	322 (11.6)
Encephalopathy	87 (3.1)
Documented esophageal varices, n (%)	860 (31)
Hepatic decompensation at baseline, n (%)
Ascites - moderate responded to diuretics and tense	164 (5.9)
Encephalopathy	72 (0.3)
Child-Pugh, n (%)
B	362 (13.1)
C	20 (0.1)
No data	223 (8.1)

GT: Genotype.

Table 3 Treatment characteristics of genotype 1b-infected patients treated with direct-acting antiviral

Parameter	GT1b patients, n = 11385
History of previous therapy
Treatment-naïve	8497 (74.6)
Non-responder	949 (8.3)
Relapser	831 (7.3)
Discontinuation due to safety reason	338 (3)
Unknown type of response	728 (6.4)
No data	42 (0.4)
Previous treatment regimen in treatment-experienced, n = 2846
IFN ± RBV	149 (5.2)
PegIFN ± RBV	2080 (73.1)
IFN + RBV + DAA	438 (15.4)
DAA	155 (5.4)
No data	24 (0.9)
Genotype-specific treatment regimens
ASV + DCV	135 (1.2)
LDV/SOF ± RBV	2652 (23.3)
OBV/PTV/r + DSV ± RBV	3685 (32.4)
GZR/EBR ± RBV	2270 (19.9)
Other (SOF ± SMV ± DCV ± RBV, SMV ± DCV ± RBV)	16 (0.1)
Pangenotypic regimens
GLE/PIB	1684 (14.8)
GLE/PIB + SOF + RBV	3 (< 0.1)
SOF/VEL ± RBV	931 (8.2)
VOX/VEL/SOF	9 (0.1)

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

Table 4 The overall treatment effectiveness and according to treatment regimens in relation to different risk factors among the studied patients (per protocol analysis)

Parameter	Whole population	Females	Males	F4	T-ex	History of hepatic decompensation	≥ 70-year-old	eGFR ≤ 60 mL/min	Obese1	HIV+
All regimens	10903/11112 (98.1)	5891/5969 (98.7)	5012/5143 (97.5)	2590/2678 (96.7)	2726/2795 (97.5)	319/336 (94.9)	1490/1509 (98.7)	281/284 (98.9)	1880/1923 (97.8)	327/341 (95.9)
ASV + DCV	119/132 (90.2)	72/79 (91.1)	47/53 (88.7)	47/55 (85.5)	40/47 (85.1)	0/1 (0)	22/24 (91.7)	5/5 (100)	26/28 (92.9)	1/1 (100)
LDV/SOF ± RBV	2534/2582 (98.1)	1381/1398 (98.8)	1153/1184 (97.4)	679/707 (96)	680/696 (97.7)	173/181 (95.6)	386/389 (99.2)	67/67 (100)	446/459 (97.2)	103/107 (96.3)
OBV/PTV/r + DSV ± RBV	3563/3627 (98.2)	1949/1973 (98.8)	1614/1654 (97.6)	969/992 (97.7)	1490/1516 (98.3)	72/74 (97.3)	397/403 (98.5)	80/82 (97.6)	602/611 (98.5)	26/28 (92.9)
GZR/EBR ± RBV	2179/2216 (98.3)	1201/1215 (98.8)	978/1001 (97.7)	362/372 (97.3)	291/297 (98)	19/20 (95)	397/401 (99)	87/88 (98.9)	380/389 (97.7)	48/48 (100)
GLE/PIB	1625/1643 (98.9)	869/874 (99.4)	756/769 (98.3)	264/268 (98.5)	112/114 (98.2)	12/12 (100)	147/150 (98)	24/24 (100)	267/267 (100)	72/76 (94.7)
GLE/PIB + SOF + RBV	3/3 (100)	1/1 (100)	2/2 (100)	1/1 (100)	3/3 (100)	-	-	-	1/1 (100)	-
SOF/VEL ± RBV	857/884 (96.9)	409/419 (97.6)	448/465 (96.3)	260/275 (94.5)	91/101 (90.1)	40/44 (90.9)	138/139 (99.3)	16/16 (100)	158/167 (94.6)	74/78 (94.9)
VOX/VEL/SOF	9/9 (100)	2/2 (100)	7/7 (100)	3/3 (100)	7/7 (100)	-	3/3 (100)	-	-	3/3 (100)

¹Body mass index > 30 kg/m².

Data are presented as number/total number of patients (percentage). ASV: Asunaprevir; DCV: Daclatasvir; DSV: Dasabuvir; EBR: Elbasvir; eGFR: Estimated glomerular filtration rate; F: Fibrosis; GLE: Glecaprevir; GZR: Grazoprevir; HIV: Human immunodeficiency virus; LDV: Ledipasvir; OBV: Ombitasvir; PIB: Pibrentasvir; PP: Per protocol; PTV/r: Paritaprevir; RBV: Ribavirin; SOF: Sofosbuvir; SVR: Sustained virological response; T-ex: Treatment-experience; VEL: Velpatasvir; VOX: Voxilaprevir.

Table 5 The comparison of virological responders and non-responders to direct-acting antiviral therapy

Parameter	Responders, n = 10903	Non-responders, n = 209	P value
Sex, females/males, n (%)	5891 (54)/5012 (46)	78 (37.3)/131 (62.7)	< 0.001
Age in yr, mean ± SD; min-max	52.9 ± 14.8; 17-97	53.4 ± 13; 25-84	0.69
BMI, kg/m2 mean ± SD; min-max	26.3 ± 4.5; 13.2-57.4	27 ± 4.6; 15.4-48	0.005
Genotype-specific treatment regimens, n (%)
ASV + DCV	119 (1.1)	13 (6.2)	< 0.001
LDV/SOF ± RBV	2534 (23.2)	48 (22.9)	0.99
OBV/PTV/r + DSV ± RBV	3563 (32.6)	64 (30.7)	0.58
GZR/EBR ± RBV	2179 (20)	37 (17.7)	0.46
Other (SOF ± SMV ± DCV ± RBV, SMV ± DCV ± RBV)	14 (0.1)	2 (1)	0.03
Pangenotypic regimens, n (%)
GLE/PIB	1625 (14.9)	18 (8.6)	0.01
GLE/PIB + SOF + RBV	3 (< 0.1)	0	0.06
SOF/VEL ± RBV	857 (7.8)	27 (12.9)	0.01
VOX/VEL/SOF	9 (0.2)	0	0.42
Regimen, n (%)			0.65
Genotype-specific	8409 (77.1)	164 (80.5)
Pangenotypic	2494 (22.9)	45 (21.5)
Comorbidities, n (%)
Any comorbidity	6958 (63.8)	138 (65.7)	0.55
Hypertension	3842 (35.2)	75 (35.7)	0.90
Diabetes	1369 (12.6)	24 (11.4)	0.72
Renal disease	446 (4.1)	7 (3.3)	0.71
Autoimmune diseases	240 (2.2)	4 (1.9)	0.96
Non-HCC tumors	214 (2)	6 (2.9)	0.49
Other	5085 (46.6)	106 (50.5)	0.27
Concomitant medications, n (%)	6517 (59.8)	141 (67.5)	0.03
Liver fibrosis, n (%)
F0	229 (2.1)	2 (1)	0.37
F1	4308 (39.5)	50 (23.9)	< 0.001
F2	2054 (18.8)	38 (18.2)	0.88
F3	1522 (14)	25 (12)	0.47
F4	2590 (23.8)	88 (42.1)	< 0.001
No data	200 (1.8)	6 (2.9)	0.40
History of previous therapy, n (%)
Treatment-naïve	8138 (74.6)	140 (67)	0.01
Non-responder	908 (8.3)	24 (11.5)	0.13
Relapser	803 (7.4)	21 (10)	0.18
Discontinuation due to safety reason	320 (2.9)	9 (4.3)	0.34
Unknown type of response	695 (6.4)	15 (7.2)	0.74
No data	39 (0.4)	0	0.78
Previous DAA treatment	120 (1.2)	18 (9)	< 0.001
History of hepatic decompensation, n (%)
Ascites	286 (2.6)	14 (6.7)	< 0.001
Encephalopathy	75 (0.7)	7 (3.3)	< 0.001
Documented esophageal varices, n (%)	778 (7.1)	38 (18.2)	< 0.001
Hepatic decompensation at baseline, n (%)
Ascites	136 (1.3)	10 (4.8)	< 0.001
Encephalopathy	58 (0.5)	6 (2.9)	< 0.001
HCC history, n (%)	150 (1.4)	8 (3.8)	0.01
OLTx history, n (%)	117 (1.1)	2 (0.9)	0.86
Child-Pugh, n (%)
B	306 (2.8)	23 (11)	< 0.001
C	15 (0.1)	0	0.67
HBV coinfection (HBsAg+), n (%)	102 (0.9)	2 (0.9)	0.74
HIV coinfection, n (%)	327 (3)	14 (6.7)	0.004
ALT IU/L, mean ± SD	75.6 ± 65.3	85.5 ± 71.1	0.005
Bilirubin mg/dL, mean ± SD	0.8 ± 0.8	1 ± 0.7	< 0.001
Albumin g/dL, mean ± SD	4.3 ± 3.3	4.1 ± 2.8	< 0.001
Creatinine mg/dL, mean ± SD	0.9 ± 1.9	0.8 ± 0.2	0.93
Hemoglobin g/dL, mean ± SD	14.4 ± 1.8	14.3 ± 1.9	0.71
Platelets, × 1000/μL, mean ± SD	196.5 ± 77.4	160.6 ± 73.3	< 0.001
HCV RNA × 106 IU/mL, mean ± SD	2.1 ± 4.8	2.2 ± 2.8	0.02

ALT: Alanine transaminase; ASV: Asunaprevir; BMI: Body mass index; DAA: Direct-acting antiviral; DSV: Dasabuvir; DCV: Daclatasvir; EBR: Elbasvir; F: Fibrosis; GLE: Glecaprevir; GZR: Grazoprevir; HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus; HIV: Human immunodeficiency virus; LDV: Ledipasvir; OBV: Ombitasvir; OLTx: Orthotopic liver transplantation; PIB: Pibrentasvir; PTV/r: Paritaprevir; RBV: Ribavirin; SD: Standard deviation; SOF: Sofosbuvir; SMV: Simeprevir; VEL: Velpatasvir; VOX: Voxilaprevir.

Table 6 Factors associated with virologic response in logistic regression model in studied hepatitis C virus-genotype 1b population

Effect	Effect measure	Wald stat	OR	-95%CI of OR	+95%CI of OR	Pvalue
Intercept		10.742	24.208	3.600	162.775	0.001
Sex	Female	10.075	1.668	1.216	2.289	0.002
HIV-coinfection	Yes	9.278	0.393	0.216	0.717	0.002
Platelets × 1000/μL	Per 1 U increase	7.619	1.004	1.001	1.006	0.006
Decompensation at baseline	No	4.359	2.423	1.056	5.559	0.037
HCC	Yes	3.733	0.459	0.208	1.011	0.053
BMI kg/m2	Per 1 U increase	3.154	0.971	0.940	1.003	0.076
Treatment-experience	No	0.972	1.180	0.849	1.639	0.324
Albumins g/dL	Per 1 U increase	0.822	1.027	0.970	1.088	0.365
Bilirubin mg/dL	Per 1 U increase	0.294	0.963	0.839	1.104	0.588
Fibrosis	1	0.020	0.902	0.217	3.749	0.888
Fibrosis	2	0.255	0.690	0.164	2.911	0.614
Fibrosis	3	0.054	0.840	0.194	3.639	0.816
Fibrosis	4	0.547	0.580	0.137	2.460	0.460
ALT IU/mL	Per 1 U increase	0.053	1.000	0.998	1.002	0.818
History of decompensation	No	0.010	1.039	0.500	2.160	0.918

ALT: Alanine transaminase; BMI: Body mass index; CI: Confidence interval; GT: Genotype; HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus; HIV: Human immunodeficiency virus; M: Male; OR: Odds ratio.

Table 7 Safety of antiviral therapy in genotype 1b-infected patients according to treatment regimens

Parameter	GT1b patients, n = 11385	ASV + DCV, n = 135	LDV/SOF ± RBV, n = 2652	OBV/PTV/r + DSV ± RBV, n = 3685	GZR/EBR ± RBV, n = 2270	GLE/PIB, n = 1684	GLE/PIB + SOF + RBV, n = 3	SOF/VEL ± RBV, n = 931	VOX/VEL/SOF, n = 9
Therapy course, n (%)
According to schedule	11031 (96.9)	130 (96.3)	2549 (96.1)	3513 (95.3)	2245 (98.9)	1666 (98.9)	3 (100)	900 (96.7)	9 (100)
Discontinuation	134 (1.2)	5 (3.7)	27 (1)	60 (1.6)	18 (0.8)	8 (0.5)	0	16 (1.7)	0
Modification	151 (1.3)	0	62 (2.4)	76 (2.1)	1 (< 0.1)	3 (0.2)	0	9 (1)	0
No data	69 (0.6)	0	14 (0.5)	36 (1)	6 (0.3)	7 (0.4)	0	6 (0.6)	0
Patients with at least one AE, n (%)	2167 (19)	49 (36.3)	518 (19.5)	911 (24.7)	362 (15.9)	184 (10.9)	1 (33.3)	133 (14.3)	0
Serious adverse events, n (%)	123 (1.1)	7 (5.2)	27 (1)	59 (1.6)	11 (0.5)	5 (0.3)	0	14 (1.5)	0
AEs leading to treatment discontinuation, n (%)	82 (0.7)	2 (1.5)	20 (0.8)	47 (1.3)	7 (0.3)	4 (0.2)	0	2 (0.2)	0
Most common AEs (≥ 1%), n (%)
Weakness/fatigue	1073 (9.4)	20 (14.8)	409 (15.4)	395 (10.7)	141 (6.2)	57 (3.4)	0	46 (4.9)	0
Anemia	142 (1.2)	1 (0.7)	65 (2.5)	55 (1.5)	9 (0.4)	1 (0.1)	1 (33.3)	5 (0.5)	0
Sleep disorders	214 (1.9)	4 (3)	49 (1.8)	95 (2.6)	29 (1.3)	25 (1.5)	0	12 (1.3)	0
Skin lesions	106 (0.9)	6 (4.4)	24 (0.9)	41 (1.1)	10 (0.4)	13 (0.8)	0	12 (1.3)	0
Itchy skin	205 (1.8)	0	31 (1.2)	135 (3.7)	6 (0.3)	27 (1.6)	0	5 (0.5)	0
Diarrhea	83 (0.7)	4 (3)	20 (0.8)	32 (0.9)	17 (0.7)	4 (0.2)	0	6 (0.6)	0
Nausea	136 (1.2)	4 (3)	29 (1.1)	50 (1.4)	25 (1.1)	20 (1.2)	0	8 (0.9)	0
Headaches	306 (2.7)	5 (3.7)	87 (3.3)	95 (2.6)	60 (2.6)	45 (2.7)	0	13 (1.4)	0
Myalgia/arthralgia	166 (1.5)	5 (3.7)	27 (1)	65 (1.8)	45 (2)	13 (0.8)	0	11 (1.2)	0
Abdominal pain	159 (1.4)	10 (7.4)	27 (1)	45 (1.2)	41 (1.8)	22 (1.3)	0	14 (1.5)	0
Loss of appetite	52 (0.5)	3 (2.2)	6 (0.2)	24 (0.7)	9 (0.4)	4 (0.2)	0	6 (0.6)	0
AEs of particular interest (cirrhotics), n (%)	n = 2768	n = 55	n = 737	n = 1019	n = 380	n = 278	n = 1	n = 290	n = 3
Ascites	60 (2.2)	0	31 (4.2)	21 (2.1)	2 (0.5)	0	0	6 (2.1)	0
Encephalopathy	44 (1.6)	0	22 (3)	16 (1.6)	1 (0.3)	2 (0.7)	0	3 (1)	0
Gastrointestinal bleeding	16 (0.6)	0	10 (1.4)	4 (0.4)	0	0	0	2 (0.7)	0
Death, n (%)	64 (0.6)	0	19 (0.7)	18 (0.5)	9 (0.4)	5 (0.3)	0	13 (1.4)	0

AE: Adverse event; ASV: Asunaprevir; DCV: Daclatasvir; DSV: Dasabuvir; EBR: Elbasvir; GLE: Glecaprevir; GT: Genotype; GZR: Grazoprevir; LDV: Ledipasvir; OBV: Ombitasvir; PIB: Pibrentasvir; PTV/r: Paritaprevir; RBV: Ribavirin; SOF: Sofosbuvir; VEL: Velpatasvir; VOX: Voxilaprevir.