Hepatic decompensation/serious adverse events in post-liver transplantation recipients on sofosbuvir for recurrent hepatitis C virus

Table 1 Details of 13 cases with hepatic decompensation/serious adverse events

Case	Rx	Genotype	Age	Sex	Years since transplant	Baseline1					1st event wk	First episode	Later episodes	Overall outcome	SVR 12(Y/N)
						Hemoglobin(g/dL)	Platelets(× 103/μL)	Albumin(g/dL)	Total bilirubin(mg/dL)	ALT(U/L)
1	SOF/RBV	13	77	F	5.0	9.3	78	2.9	0.6	33	15.4	Hospitalized for SBP	Hospitalized for SBP, ascites, anemia; jaundice, hyperkalemia	Hospitalized for fall soon after EOT, developed ICH, eventually died in hospital	Died
	24 wk2
2	SOF/RBV	2	70	M	17.0	7.9	13	3.9	4.7	15	4.3	Hospitalized for PSE	None	Transferred to Hospice, died	Died
	24 wk
3	SOF/RBV	13	37	F	1.2	8.9	143	2.9	16.9	39	2.9	Hospitalized for failure to thrive, jaundice, anemia requiring transfusion	Hospitalized for jaundice, anemia requiring transfusion, blurred vision	Completed 48 wk of treatment, never undetectable	N
	48 wk
4	SOF/RBV	3	49	M	1.9	12.4	138	4.4	0.7	43	2.0	Anemia requiring transfusion	Anemia requiring transfusion	Completed treatment	Y
	24 wk
5	SOF/RBV	13	67	M	13.2	11.8	118	3.1	2.1	72	2.9	Anemia requiring transfusion	Worsening ascites requiring increased dose of diuretics	Hemoglobin level and ascites improved after intervention; completed treatment but relapsed	N
	24 wk
6	SOF/RBV	12	56	F	1.5	13.0	152	5.0	0.7	44	2.9	Anemia requiring transfusion	None	Hemoglobin improved after transfusion; completed treatment	Y
	24 wk
7	SOF/RBV	12	70	F	7.3	12.0	127	3.6	0.4	60	4.4	Symptomatic anemia, no transfusion, treatment discontinued	None	Viral load detectable 4 mo after treatment discontinuation	N
	24 wk
8	SOF/PEG/RBV	2	65	F	6.0	12.7	85	3.6	0.3	38	6.6	Anemia requiring transfusion	Anemia requiring multiple transfusions	Completed treatment	Y
	24 wk3
9	SOF/RBV	12	60	M	9.1	11.3	94	3.6	0.8	199	5.0	Anemia requiring transfusion	Hospitalized for hyperglycemia, anemia requiring transfusion; treatment discontinued	Detectable viral load 7 wk after treatment discontinued	N
	24 wk
10	SOF/RBV	4	64	F	7.5	9.6	98	2.7	5.5	24	2.4	Anemia requiring transfusion	Hospitalized for SBP, anemia requiring transfusion, treatment discontinued	Hemoglobin improved after transfusions; viral load undetectable at treatment discontinuation; became detectable 1 mo later	N
	24 wk
11	SOF/RBV	12	49	M	2.2	15.2	113	3.9	0.6	74	5.9	Admitted for acute cholangitis after presenting with fever, jaundice, diarrhea	None	Resolution of presenting symptoms with antibiotics, biliary stent placement; completed treatment, relapsed	N
	24 wk
12	SOF/RBV	3	56	M	1.1	10.7	65	3.6	1.1	94	9.0	Hospitalized for partial SBO	Hospitalized for hyperkalemia	SBO resolved with conservative medical management	Y
	24 wk
13	SOF/RBV	13	68	M	1.7	10.7	196	1.9	2.2	24	5.0	Hospitalized, PSE, UTI	Hospitalized for recurrent PSE due to UTI	Completed treatment, +EOT response, relapsed 4 wk post-EOT	N
	24 wk

¹Baseline: indicates the most recent laboratory values prior to treatment initiation;

²SOF/RBV: Sofosbuvir/Ribavirin;

³SOF/PEG/RBV: Sofosbuvir/PEG-interferon/Ribavirin. Laboratory Reference Range: Hemoglobin (g/dL), Ref: 13.9-16.3; Platelets (× 10³/μL), Ref: 150-450; Albumin (g/dL), Ref: 3.5-4.9; Total Bilirubin (mg/dL), Ref: 0.1-1.2; ALT (U/L), Ref: 1-53. ALT: Alanine aminotransferase; SVR: Sustained virological response; SBP: Spontaneous bacterial peritonitis; EOT: End of treatment; ICH: Intracranial hemorrhage; PSE: Portosystemic encephalopathy; SBO: Small bowel obstruction; UTI: Urinary tract infection.

Table 2 Baseline characteristics of cases and controls

	Categorical: n (%)			P value1
	Continuous: median (IQR)
	Total	Case (n = 13)	Controls (n = 29)
Demographics and clinical characteristics
Age (yr)	60 (56-65)	64 (56-68)	60 (57-64)	0.97
Gender, female	14 (33)	6 (46)	8 (28)	0.15
Race, black	4 (9)	1 (7)	3 (10)	1.00
Ethnicity, Hispanic	9 (21)	1 (7)	8 (28)	0.23
Weight (lbs)	163 (146-182)	155 (122-168)	170 (147-193)	0.04
BMI (kg/m2)	26.4 (22.6-28.7)	25.6 (21.6-27.8)	26.7 (24.6-29.0)	0.12
Years since Transplant	5.4 (2.1–8.8)	4.98 (1.7-7.5)	5.6 (2.7-8.8)	0.52
Comorbidities
Hepatocellular Carcinoma	16 (38)	5 (38)	11 (38)	1.00
Diabetes	21 (50)	6 (46)	15 (52)	1.00
Hypertension	27 (64)	9 (69)	18 (62)	0.74
Depression	5 (12)	1 (8)	4 (14)	1.00
Liver disease severity
Cirrhosis	8 (19)	3 (23)	5 (17)	0.69
FIB-4	4.81 (3.00-7.02)	6.57 (3.12-8.94)	4.49 (2.78-6.71)	0.24
FIB-4, ≥ 3.25	28 (67)	9 (69)	19 (65)	1.00
Treatment naïve	9 (21)	3 (23)	6 (21)	1.00
Treatment Regimen
SOF/RBV	38 (90)	12 (92)	26 (90)	1.00
SOF/PEG/RBV	4 (10)	1 (8)	3 (10)	1.00
Genotype
1	31 (74)	8 (62)	23 (79)	0.27
2	3 (7)	2 (15)	1 (3)	0.22
3	5 (12)	2 (15)	3 (10)	0.64
4	2 (5)	1 (8)	1 (3)	0.53
Labs
Hemoglobin (g/dL) (Ref: 13.9-16.3 g/dL)	12.7 (10.8-14.2)	11.3 (9.6-12.4)	12.9 (12.2-14.5)	0.01
Platelets (× 103/μL) (Ref: 150-450 × 103/μL)	117 (82-148)	113 (85-138)	121 (81-150)	0.21
HCV viral load (log10) (IU/mL) (Ref: 15-108 IU/mL)	6.53 (6.27-6.72)	6.59 (6.07-6.70)	6.53 (6.32-6.76)	0.81
Serum creatinine (mg/dL) (Ref: 0.70-1.40 mg/dL)	1.44 (1.10-1.72)	1.60 (1.33-1.86)	1.23 (1.04-1.60)	0.06
eGFR (mL/min per 1.73 m2 Albumin, g/dL) (Ref: 3.5-4.9 g/dL)	49 (41-67)	42 (32-49)	56 (44-70)	0.01
	3.8 (3.5-4.1)	3.6 (2.9-3.9)	3.8 (3.6-4.1)	0.23
ALT (U/L) (Ref: 1-53 U/L)	59 (39-82)	43 (33-72)	65 (42-89)	0.15
AST (U/L) (Ref: 1-50 U/L)	62 (49-92)	61 (53-77)	64 (41-93)	0.95
INR	1.0 (1.0-1.2)	1.0 (0.9-1.3)	1.0 (1.0-1.1)	0.852
Total bilirubin (mg/dL) (Ref: 0.1-1.2 mg/dL)	0.7 (0.5-1.1)	0.8 (0.6-2.2)	0.7 (0.5-1.0)	0.10
Alpha fetoprotein (ng/mL) (Ref: 0.0-9.0 ng/mL)	5.0 (3.1-9.2)	5.0 (3.5-12.1)	5.0 (3.0-8.2)	0.40

¹Student t test unless noted otherwise;

²Mann-Whitney. BMI: Body mass index; SOF: Sofosbuvir; RBV: Ribavirin; PEG: Pegylated interferon; eGFR: Estimated glomerular filtration rate; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; INR: International normalized ratio.

Table 3 Unadjusted logistic regression analysis of factors associated with hepatic decompensation/serious adverse events

	Unadjusted
	OR	95%CI	P value
Demographics and clinical characteristics
Age (yr)	1.00	0.92-1.09	0.97
Gender, female	2.13	0.47-9.72	0.40
Race, black	0.73	0.01-9.98	1.00
Ethnicity, Hispanic	0.22	0.01-2.07	0.30
Weight (lbs)	0.98	0.95-1.00	0.06
BMI (kg/m2)	0.87	0.73-1.04	0.13
Years since transplant	0.96	0.83-1.10	0.52
Comorbidities
Hepatocellular carcinoma	1.02	0.21-4.78	1.00
Diabetes	0.80	0.17-3.58	1.00
Hypertension	1.40	0.29-7.76	0.91
Depression	0.54	0.01-6.05	1.00
Liver disease severity
Cirrhosis	1.42	0.19-9.49	0.96
FIB-4	1.07	0.95-1.20	0.29
FIB-4, ≥ 3.25	1.17	0.25-6.70	1.00
Treatment naïve	1.14	0.15-6.77	1.00
Treatment Regimen
SOF/RBV	REF	REF	REF
SOF/PEG/RBV	0.86	0.11-3.19	1.00
Genotype
1	REF	REF	REF
2	6.25	0.26-477.66	0.39
3	1.90	0.13-18.36	0.86
4	2.75	0.03-228.51	0.95
Labs
Hemoglobin (g/dL)	0.61	0.40-0.88	< 0.01
(Ref: 13.9-16.3 g/dL)
Platelets (× 103/μL)	0.99	0.98-1.00	0.26
(Ref: 150-450 × 103/μL)
HCV viral load [log10 (IU/mL)]	0.90	0.38-2.44	0.82
(Ref: 15-108 IU/mL)
Serum creatinine (mg/dL)	2.27	0.88-8.82	0.09
(Ref: 0.70-1.40 mg/dL)
eGFR (mL/min per 1.73 m2)	0.95	0.90-0.99	0.01
Albumin (g/dL)	0.45	0.13-1.32	0.15
(Ref: 3.5-4.9 g/dL)
ALT (U/L)	0.99	0.97-1.00	0.19
(Ref: 1-53 U/L)
AST (U/L)	1.00	0.99-1.00	0.54
(Ref: 1-50 U/L)
INR	1.27	1.12-1.14	0.22
Total bilirubin (mg/dL)	2.43	1.17-8.65	< 0.01
(Ref: 0.1-1.2 mg/dL)
Alpha fetoprotein (ng/mL)	0.25	0.99-1.11	0.15
(Ref: 0.0-9.0 ng/mL)

BMI: Body mass index; SOF: Sofosbuvir; RBV: Ribavirin; PEG: Pegylated interferon; eGFR: Estimated glomerular filtration rate; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; INR: International normalized ratio.

Table 4 Unadjusted sensitivity analysis of factors associated with serious adverse events

	OR	95%CI	P value
Demographics and clinical characteristics
Age, yr	0.99	0.91-1.08	0.79
Gender, female	2.73	0.54-18.42	0.28
Race, black	0.44	< 0.01-2.76	0.49
Ethnicity, Hispanic	0.26	< 0.01-2.37	0.39
Weight, lbs	0.97	0.94-0.99	0.02
BMI, kg/m2	0.85	0.69-1.02	0.08
Years since transplant	0.98	0.85-1.12	0.75
Comorbidities
Hepatocellular carcinoma	1.21	0.24-6.04	1.00
Diabetes	1.01	0.22-4.74	1.00
Hypertension	1.15	0.23-6.45	1.00
Depression	0.6	0.01-7.16	1.00
Liver disease severity
Cirrhosis	0.8	0.07-5.68	1.00
FIB-4	1.08	0.94-1.22	0.28
FIB-4, ≥ 3.25	0.99	0.20-5.55	1.00
Treatment naïve	1.33	0.18-8.56	1.00
Treatment Regimen
SOF/RBV	REF	REF	REF
SOF/PEG/RBV	0.91	0.12-3.46	1.00
Genotype
1	REF	REF	REF
2	8.47	0.30-744.15	0.31
3	2.27	0.16-31.69	0.72
4	3.03	0.04-256.92	0.90
Labs
Hemoglobin (g/dL)	0.63	0.36-0.95	0.02
(Ref: 13.9-16.3 g/dL)
Platelets (× 103/μL)	0.99	0.98-1.00	0.14
(Ref: 150-450 × 103/μL)
HCV viral load [log10 (IU/mL)]	1.03	0.41-2.60	0.95
(Ref: 15-108 IU/mL)
Serum creatinine (mg/dL)	2.02	0.81-5.91	0.14
(Ref: 0.70-1.40 mg/dL)
eGFR (mL/min per 1.73 m2)	0.95	0.91-0.99	0.03
Albumin (g/dL)	0.76	0.26-2.31	0.63
(Ref: 3.5-4.9 g/dL)
ALT (U/L)	0.99	0.98-1.00	0.43
(Ref: 1-53 U/L)
AST (U/L)	0.99	0.99-1.01	0.78
(Ref: 1-50 U/L)
INR	2.93	0.35-29.0	0.36
Total bilirubin (mg/dL)	1.94	1.05-4.69	0.02
(Ref: 0.1-1.2 mg/dL)
Alpha fetoprotein (ng/mL)	1.04	0.99-1.12	0.16
(Ref: 0.0-9.0 ng/mL)

BMI: Body mass index; SOF: Sofosbuvir; RBV: Ribavirin; PEG: Pegylated interferon; eGFR: Estimated glomerular filtration rate; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; INR: International normalized ratio.

Table 5 Unadjusted sensitivity analysis for factors associated with hepatic decompensation

	OR	95%CI	P value
Demographics and clinical characteristics
Age (yr)	1.03	0.92-1.16	0.67
Gender, female	2.23	0.26-19.54	0.63
Race, black	2.2	0.04-35.75	0.94
Ethnicity, Hispanic	0.39	< 0.01-2.30	0.41
Weight (lbs)	0.99	0.96-1.02	0.37
BMI (kg/m2)	0.94	0.75-1.16	0.61
Years since Transplant	0.96	0.79-1.15	0.63
Comorbidities
Hepatocellular Carcinoma	0.28	0.01-2.94	0.49
Diabetes	2.21	0.28-27.69	0.66
Hypertension	3.22	0.30-173.80	0.57
Depression	0.86	< 0.01-5.35	0.90
Liver disease severity
Cirrhosis	5.41	0.61-56.98	0.14
FIB-4	1.11	0.94-1.31	0.24
FIB-4, ≥ 3.25	2.81	0.26-151.24	0.67
Treatment naïve	4.85	0.50-58.79	0.21
Treatment Regimen
SOF/RBV	REF	REF	REF
SOF/PEG/RBV	< 0.01	< 0.01-> 99.99	0.97
Genotype
1	REF	REF	REF
2	4.67	0.32-68.03	0.26
3	2.33	0.19-28.25	0.51
4	9.33	0.46-190.63	0.15
Labs
Hemoglobin (g/dL)	0.17	0.04-0.75	0.02
(Ref: 13.9-16.3 g/dL)
Platelets (× 103/μL)	0.99	0.97-1.01	0.29
(Ref: 150-450 × 103/μL)
HCV viral load [log10 (IU/mL)]	0.79	0.29-2.18	0.65
(Ref: 15-108 IU/mL)
Serum creatinine (mg/dL)	3.12	0.99-9.77	0.05
(Ref: 0.70-1.40 mg/dL)
eGFR (mL/min per 1.73 m2)	0.92	0.86-0.99	0.02
Albumin (g/dL)	0.13	0.02-0.58	< 0.01
(Ref: 3.5-4.9 g/dL)
ALT (U/L)	0.96	0.90-0.99	0.03
(Ref: 1-53 U/L)
AST (U/L)	0.99	0.98-1.01	0.70
(Ref: 1-50 U/L)
INR	1.59	1.09-2.97	< 0.01
Total bilirubin (mg/dL)	5.65	0.99-32.34	0.05
(Ref: 0.1-1.2 mg/dL)
Alpha fetoprotein (ng/mL)	1.03	0.98-1.08	0.27
(Ref: 0.0-9.0 ng/mL)

BMI: Body mass index; SOF: Sofosbuvir; RBV: Ribavirin; PEG: Pegylated interferon; eGFR: Estimated glomerular filtration rate; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; INR: International normalized ratio.