Liver decompensation predicts ribavirin overexposure in hepatitis C virus patients treated with direct-acting antivirals

Table 1 Subjects’ baseline characteristics

Characteristics	Overall (n = 68)	Child pugh A (n = 54)	Child pugh B (n = 14)	P value
Age (yr), mean ± SD	55 ± 8.6	55.2 ± 9.5	54.6 ± 5	0.8
Male, n (%)	52 (76.5)	43 (79.6)	9 (64.3)	0.2
White race, n (%)	66 (97.1)	53 (98.1)	13 (92.9)	0.3
HIV infection, n (%)	39 (57.4)	29 (53.7)	10 (71.4)	0.2
HBsAg positive, n (%)	1 (1.5)	1 (1.9)	0	-
History of HCC, n (%)	6 (8.8)	4 (7.4)	2 (14.3)	0.6
HCV treatment experienced, n (%)	43 (63.2)	33 (61.1)	10 (71.4)	0.5
Liver stiffness (kPa), median (IQR)	21.4 (15.9-34.4)	21.2 (15.6-33.1)	31.1 (17.8-54.3)	0.1
HCV genotype, n (%)				0.7
1a	23 (33.8)	18 (33.3)	5 (35.7)
1b	11 (16.2)	9 (16.7)	2 (14.3)
2	6 (8.8)	6 (11.1)	-
3	22 (32.4)	17 (31.5)	5 (35.7)
4	6 (8.8)	4 (7.4)	2 (14.3)
Weight (kg), mean ± SD	73 ± 14.1	73.2 ± 15.3	72.1 ± 8.5	0.7
Hb baseline (g/L), mean ± SD	143 ± 18	146 ± 16	129 ± 17	0.002
Bilirubin (mg/L), median (IQR)	9.5 (5.6-19)	4.7 (2.8-8.2)	7.7 (5.3-16)	< 0.001
Creatinine (mg/L), mean ± SD	8 ± 1.3	8.2 ± 1.5	7.5 ± 0.8	0.011
eGFR (mL/min per 1.73 m2), median (IQR)	101 (90-109)	99 (88-105)	102 (98-107)	0.3
HCV-RNA baseline (IU/mL)	933559 (25667-2128936)	1228876 (410822-2940050)	246455 (126308-712307)	0.007
1DAAs regimen, n (%)				0.2
SOF, n (%)	6 (8.8)	6 (11.1)	-
SOF + DCV, n (%)	29 (42.6)	21 (38.9)	8 (57.1)
SOF + SMP, n (%)	1 (1.5)	-	1 (7.1)
DCV + SMP, n (%)	4 (5.9)	3 (5.6)	1 (7.1)
SOF + LDV, n (%)	12 (17.6)	11 (20.4)	1 (7.1)
OBV/PTV/r + DSV, n (%)	12 (17.6)	9 (16.7)	3 (21.4)
OBV/PTV/r, n (%)	4 (5.9)	4 (7.4)	-

¹All regimens are intended in association with ribavirin. HCC: Hepatocellular carcinoma; eGFR: Estimated glomerular filtration rate; DAAs: Direct-acting antivirals; SOF: Sofosbuvir; DCV: Daclatasvir; SMP: Simeprevir; LDV: Ledipasvir; OBV: Ombitasvir; PTV: Paritaprevir; R: Ritonavir; DSV: Dasabuvir.

Table 2 Ribavirin dosages and plasma levels (C_trough) and haemoglobin loss over the course of treatment

Parameters	Overall (n = 68)	Child pugh A (n = 54)	Child pugh B (n = 14)	P value
RBV (mg/kg pre die), mean ± SD	14.4 ± 1.7	14.4 ± 1.36	14.9 ± 1.6	0.3
1RBV week 1 (ng/L) median (IQR)	9105 (6130-1310)	8750 (5700-11680)	14050 (9010-22280)	0.007
1RBV week 2 (ng/L) median (IQR)	15000 (11600-27680)	14150 (11150-20000)	23550 (17200-28930)	0.001
2RBV week 4 (ng/L) median (IQR)	18300 (12900-27680 )	17850 (12200-26500)	26250 (17700-35130)	0.024
3RBV week 8 (ng/L) median (IQR)	23100 (17050-31000)	21500 (16100-27950)	33000 (19800-41380)	0.0034
Mean RBV 1, 2, 4 wk, (ng/L) median (IQR)	14240 (10770-19450)	13280 (10480-18200)	19600 (14670-26870)	0.005
Mean RBV 1, 2, 4, 8 wk, (ng/L) median (IQR)	16490 (12220-21750)	15135 (11850-19830)	21700 (15090-29280)	0.006
Mean RBV, full treatment duration (ng/L), mean ± SD	18079 ± 6609	17528 ± 6020	20327 ± 7700	0.2
RBV dosage reduction, n (%)	37 (54.4)	27 (50)	10 (71.4)	0.2
Weeks before reduction, median (IQR)	6.1 (4-9.8)	5 (4-9.7)	7 (4-10)	0.6
Hb loss week 4 (g/L), mean ± SD	19.6 ± 1.8	19 ± 13	21 ± 32	0.54
Hb loss week 8 (g/L), mean ± SD	21 ± 19	20 ± 13	25 ± 35	0.34

¹Data for 68 subjects;

²Data for 62 subjects;

³Data for 95 subjects;

⁴Analysis of covariance of Hb at week 4 and haemoglobin (Hb) at week 8, adjusted for baseline Hb levels. RBV: Ribavirin; Hb: Haemoglobin; IQR: Interquartile range.

Table 3 Baseline predictors of average plasmatic Ribavirin levels in the first 8 wk of therapy

	Univariate analysis			Multivariate analysis
	β value	95%CI	P value	β value	95%CI	P value
Baseline ribavirin dosage (mg/kg)	205	77; 332	0.002	161	36; 286	0.013
IFN-experienced	97	-303; 497	0.6
Male gender	-539	-975; -103	0.016	-349	-765; 68	0.099
Age (yr)	13	-9; 34	0.3
White race	424	-714; 1563	0.5
Bilirubin (mg/L)	870	-920; 2670	3
Creatinine (mg/L)	-2890	-16830; 11040	7
Child-Pugh class	232	66; 399	0.007	192	35; 348	0.017
Liver stiffness (kPa)	-1.6	-14; 11	0.8
HIV infection	76	-314; 466	0.7

IFN: Interferon; HIV: Human immunodeficiency virus.