Gastroenterol Res

Gastroenterology Research, ISSN 1918-2805 print, 1918-2813 online, Open Access

Article copyright, the authors; Journal compilation copyright, Gastroenterol Res and Elmer Press Inc

Journal website http://www.gastrores.org

Original Article

Volume 8, Number 6, December 2015, pages 281-290

Hepatitis C in Liver Allograft Recipients: Utility of One-Year Post-Transplantation Biopsy as an Indicator of Antiviral Therapy

Figure 2. Graft survival rate in SVR and viremic patients categorized according to fibrosis stage at 1 year post-transplant. There is a trend of worsening graft failure from stage 0 to stage 5.

Figure 3. Cumulative graft survival among patients alive at 1 year post-transplant; Kaplan-Meier analysis, comparison by log-rank test.

Figure 4. Cumulative patient survival among patients alive at 1 year post-transplant; Kaplan-Meier analysis, comparison by log-rank test.

Figure 5. Cumulative graft survival according to fibrosis stage (at 1 year post-transplant) and treatment response; Kaplan-Meier analysis, comparison by log-rank test; mean survival with confidence intervals shown. Std. error: standard error.

**Table 1.** Demographics and Baseline Clinical Features
	Mild disease (n = 116)	Severe disease (n = 136)	P value
All values are shown as mean ± SD or proportion as appropriate. Comparison by two-tailed t-test or Chi-square test as appropriate. n: number. SD: standard deviation.
Age (years)	52 ± 7	51 ± 6	0.06
Gender (male)	98 (84%)	96 (71%)	0.009
Caucasian	107 (92%)	124 (91%)	0.76
Child-Pugh status			0.14
Class A	12 (10%)	6 (4%)
Class B	69 (59%)	80 (59%)
Class C	35 (30%)	50 (37%)
Child-Pugh score	9 ± 1.8	9 ± 1.6	0.12
MELD score	16 ± 7	16 ± 8	0.87
Blood group			0.62
A	40 (34%)	56 (41%)
B	11 (9%)	14 (10%)
AB	9 (8%)	7 (5%)
O	56 (48%)	59 (43%)
Co-morbidities
Diabetes mellitus	35 (30%)	37 (27%)	0.60
Hypertension	43 (37%)	43 (32%)	0.36
BMI (kg/m²)	29 ± 5	28 ± 5	0.12
Obesity (BMI ≥ 30)	44 (38%)	43 (32%)	0.29
Renal Failure	16 (14%)	22 (16%)	0.60
Hepatocellular carcinoma	32 (28%)	37 (27%)	0.95

Table 1. Demographics and Baseline Clinical Features

Mild disease (n = 116)

Severe disease (n = 136)

P value

All values are shown as mean ± SD or proportion as appropriate. Comparison by two-tailed t-test or Chi-square test as appropriate. n: number. SD: standard deviation.

Age (years)

52 ± 7

51 ± 6

0.06

Gender (male)

98 (84%)

96 (71%)

0.009

Caucasian

107 (92%)

124 (91%)

0.76

Child-Pugh status

0.14

Class A

12 (10%)

6 (4%)

Class B

69 (59%)

80 (59%)

Class C

35 (30%)

50 (37%)

Child-Pugh score

9 ± 1.8

9 ± 1.6

0.12

MELD score

16 ± 7

16 ± 8

0.87

Blood group

0.62

40 (34%)

56 (41%)

11 (9%)

14 (10%)

9 (8%)

7 (5%)

56 (48%)

59 (43%)

Co-morbidities

Diabetes mellitus

35 (30%)

37 (27%)

0.60

Hypertension

43 (37%)

43 (32%)

0.36

BMI (kg/m²)

29 ± 5

28 ± 5

0.12

Obesity (BMI ≥ 30)

44 (38%)

43 (32%)

0.29

Renal Failure

16 (14%)

22 (16%)

0.60

Hepatocellular carcinoma

32 (28%)

37 (27%)

0.95

**Table 2.** Baseline Laboratory Features
	Mild disease (n = 116)	Severe disease (n = 136)	P value
All values are shown as mean ± SD or proportion as appropriate. Comparison by two-tailed t-test or Chi-square test as appropriate. n = 209. n = 238; data unavailable in 14 patients (mild disease: 5, severe disease: 9). Cytomegalovirus antibody (positive: > 4 IU/L). **Epstein-Barr viral capsid antigen antibody (positive: > 20 IU/L); n = 243. n: number. SD: standard deviation; IU: international units.
Hemoglobin (g/dL)	12.0 ± 2.1	11.7 ± 2.1	0.20
WBC (× 10³/L)	5.0 ± 2.7	5.9 ± 4.0	0.04
Platelets (× 10³/L)	67 ± 40	74 ± 50	0.25
Bilirubin (mg/dL)	4.1 ± 6.2	4.6 ± 7.4	0.55
ALT (IU/L)	131 ± 411	152 ± 420	0.69
AST (IU/L)	334 ± 1926	255 ± 914	0.67
ALP (IU/L)	166 ± 106	164 ± 88	0.87
γGTP (IU/L)	97 ± 116	95 ± 97	0.89
Albumin (g/dL)	2.9 ± 0.5	2.8 ± 0.6	0.29
INR	1.4 ± 0.4	1.4 ± 0.5	0.95
Creatinine (mg/dL)	1.3 ± 1.3	1.4 ± 1.4	0.77
HCV RNA (× 10⁶ IU/mL)*	1.02 ± 3.4	2.0 ± 6.4	0.16
HCV genotype 1**	89 (81%)	111 (87%)	0.22
Anti-CMV, IgG (IU/L)	105 ± 122	102 ± 126	0.86
Anti-CMV, IgG-positive***	81 (70%)	81 (60%)	0.09
Anti-EBV, IgG (IU/L)	251 ± 222	242 ± 196	0.75
Anti-EBV, IgG-positive****	79 (71%)	101 (77%)	0.24

Table 2. Baseline Laboratory Features

Mild disease (n = 116)

Severe disease (n = 136)

P value

All values are shown as mean ± SD or proportion as appropriate. Comparison by two-tailed t-test or Chi-square test as appropriate. *n = 209. **n = 238; data unavailable in 14 patients (mild disease: 5, severe disease: 9). ***Cytomegalovirus antibody (positive: > 4 IU/L). ****Epstein-Barr viral capsid antigen antibody (positive: > 20 IU/L); n = 243. n: number. SD: standard deviation; IU: international units.

Hemoglobin (g/dL)

12.0 ± 2.1

11.7 ± 2.1

0.20

WBC (× 10³/L)

5.0 ± 2.7

5.9 ± 4.0

0.04

Platelets (× 10³/L)

67 ± 40

74 ± 50

0.25

Bilirubin (mg/dL)

4.1 ± 6.2

4.6 ± 7.4

0.55

ALT (IU/L)

131 ± 411

152 ± 420

0.69

AST (IU/L)

334 ± 1926

255 ± 914

0.67

ALP (IU/L)

166 ± 106

164 ± 88

0.87

γGTP (IU/L)

97 ± 116

95 ± 97

0.89

Albumin (g/dL)

2.9 ± 0.5

2.8 ± 0.6

0.29

INR

1.4 ± 0.4

1.4 ± 0.5

0.95

Creatinine (mg/dL)

1.3 ± 1.3

1.4 ± 1.4

0.77

HCV RNA (× 10⁶ IU/mL)*

1.02 ± 3.4

2.0 ± 6.4

0.16

HCV genotype 1**

89 (81%)

111 (87%)

0.22

Anti-CMV, IgG (IU/L)

105 ± 122

102 ± 126

0.86

Anti-CMV, IgG-positive***

81 (70%)

81 (60%)

0.09

Anti-EBV, IgG (IU/L)

251 ± 222

242 ± 196

0.75

Anti-EBV, IgG-positive****

79 (71%)

101 (77%)

0.24

**Table 3.** Donor Features
	Mild disease (n = 116)	Severe disease (n = 136)	P value
All values are shown as mean ± SD or proportion as appropriate. Comparison by two-tailed t-test or Chi-square test as appropriate. n = 247. n = 243. **n = 245. n: number. SD: standard deviation; anti-HCV: antibody to hepatitis C virus; anti-HBc: antibody to hepatitis B core antigen; CMV: cytomegalovirus.
Age (years)	41 ± 17	45 ± 16	0.026
Males	68 (59%)	78 (57%)	0.84
Caucasian	96 (83%)	120 (88%)	0.21
Living donor	9 (8%)	14 (10%)	0.49
Anti-HCV positive*	13 (11%)	22 (17%)	0.25
Anti-HBc positive**	13 (12%)	14 (11%)	0.86
Anti-CMV IgG positive***	70 (63%)	82 (61%)	0.76
Donor biopsy	61 (53%)	82 (60%)	0.22
Blood group			0.83
A	39 (34%)	52 (38%)
B	13 (11%)	13 (10%)
AB	7 (6%)	6 (4%)
O	57 (49%)	65 (48%)
Donor recipient mismatch
Gender	48 (41%)	58 (43%)	0.84
Racial	24 (21%)	26 (19%)	0.75
ABO blood group	5 (4%)	7 (5%)	0.76

Table 3. Donor Features

Mild disease (n = 116)

Severe disease (n = 136)

P value

All values are shown as mean ± SD or proportion as appropriate. Comparison by two-tailed t-test or Chi-square test as appropriate. *n = 247. **n = 243. ***n = 245. n: number. SD: standard deviation; anti-HCV: antibody to hepatitis C virus; anti-HBc: antibody to hepatitis B core antigen; CMV: cytomegalovirus.

Age (years)

41 ± 17

45 ± 16

0.026

Males

68 (59%)

78 (57%)

0.84

Caucasian

96 (83%)

120 (88%)

0.21

Living donor

9 (8%)

14 (10%)

0.49

Anti-HCV positive*

13 (11%)

22 (17%)

0.25

Anti-HBc positive**

13 (12%)

14 (11%)

0.86

Anti-CMV IgG positive***

70 (63%)

82 (61%)

0.76

Donor biopsy

61 (53%)

82 (60%)

0.22

Blood group

0.83

39 (34%)

52 (38%)

13 (11%)

13 (10%)

7 (6%)

6 (4%)

57 (49%)

65 (48%)

Donor recipient mismatch

Gender

48 (41%)

58 (43%)

0.84

Racial

24 (21%)

26 (19%)

0.75

ABO blood group

5 (4%)

7 (5%)

0.76

**Table 4.** Operative Features
	Mild disease (n = 116)	Severe disease (n = 136)	P value
All values are shown as mean ± SD or proportion as appropriate. Comparison by two-tailed t-test or Chi-square test as appropriate. *n = 246. n: number. SD: standard deviation.
Cold ischemia time (h)	9.8 ± 3.4	9.9 ± 3.9	0.82
Warm ischemia time (min)	34 ± 11	33 ± 10	0.24
Red cell transfusion (unit)*	7.5 ± 6.7	8.5 ± 7.5	0.28
Platelets (unit)	6.2 ± 8.1	7.7 ± 9.4	0.20
Fresh frozen plasma (unit)*	6.4 ± 6.6	7.6 ± 7.3	0.20
Piggyback graft placement	98 (84%)	117 (86%)	0.73
Duct-duct anastomosis	110 (95%)	129 (95%)	1.0
T-tube placement	77 (66%)	96 (71%)	0.47
Veno-venous bypass	81 (70%)	94 (69%)	0.90
Length of stay post-transplant (days)	19 ± 19	21 ± 23	0.64

Table 4. Operative Features

Mild disease (n = 116)

Severe disease (n = 136)

P value

All values are shown as mean ± SD or proportion as appropriate. Comparison by two-tailed t-test or Chi-square test as appropriate. *n = 246. n: number. SD: standard deviation.

Cold ischemia time (h)

9.8 ± 3.4

9.9 ± 3.9

0.82

Warm ischemia time (min)

34 ± 11

33 ± 10

0.24

Red cell transfusion (unit)*

7.5 ± 6.7

8.5 ± 7.5

0.28

Platelets (unit)

6.2 ± 8.1

7.7 ± 9.4

0.20

Fresh frozen plasma (unit)*

6.4 ± 6.6

7.6 ± 7.3

0.20

Piggyback graft placement

98 (84%)

117 (86%)

0.73

Duct-duct anastomosis

110 (95%)

129 (95%)

1.0

T-tube placement

77 (66%)

96 (71%)

0.47

Veno-venous bypass

81 (70%)

94 (69%)

0.90

Length of stay post-transplant (days)

19 ± 19

21 ± 23

0.64

**Table 5.** Immunosuppression and Antiviral Therapy
	Mild disease (n = 116)	Severe disease (n = 136)	P value
All values are shown as mean ± SD or proportion as appropriate. Comparison by two-tailed t-test or Chi-square test as appropriate. n: number. SD: standard deviation. Perioperative with either antithymocyte globulin or alemtuzumab. During the first post-operative year and hydrocortisone equivalent. **Post-transplant treatment with pegylated interferon-α2b or pegylated interferon-α2a with ribavirin.
Corticosteroids	107 (92%)	121 (89%)	0.38
Anti-T cell antibody*	10 (9%)	27 (20%)	0.012
Mycophenolate mofetil	29 (25%)	33 (24%)	0.89
Sirolimus	1 (1%)	4 (3%)	0.24
Acute rejection	33 (28%)	60 (44%)	0.01
Acute rejection episodes	0.4 ± 0.7	0.6 ± 0.8	0.034
ACR: steroid boluses	29 (25%)	50 (37%)	0.045
Chronic rejection	4 (3%)	9 (7%)	0.26
Cumulative steroid dose (g)**	154 ± 780	214 ± 781	0.54
Cumulative tacrolimus dose (mg/year)	467 ± 577	686 ± 996	0.038
Interferon therapy***	79 (68%)	99 (73%)	0.41
Interferon responders	28 (24%)	31 (23%)	0.8

Table 5. Immunosuppression and Antiviral Therapy

Mild disease (n = 116)

Severe disease (n = 136)

P value

All values are shown as mean ± SD or proportion as appropriate. Comparison by two-tailed t-test or Chi-square test as appropriate. n: number. SD: standard deviation. *Perioperative with either antithymocyte globulin or alemtuzumab. **During the first post-operative year and hydrocortisone equivalent. ***Post-transplant treatment with pegylated interferon-α2b or pegylated interferon-α2a with ribavirin.

Corticosteroids

107 (92%)

121 (89%)

0.38

Anti-T cell antibody*

10 (9%)

27 (20%)

0.012

Mycophenolate mofetil

29 (25%)

33 (24%)

0.89

Sirolimus

1 (1%)

4 (3%)

0.24

Acute rejection

33 (28%)

60 (44%)

0.01

Acute rejection episodes

0.4 ± 0.7

0.6 ± 0.8

0.034

ACR: steroid boluses

29 (25%)

50 (37%)

0.045

Chronic rejection

4 (3%)

9 (7%)

0.26

Cumulative steroid dose (g)**

154 ± 780

214 ± 781

0.54

Cumulative tacrolimus dose (mg/year)

467 ± 577

686 ± 996

0.038

Interferon therapy***

79 (68%)

99 (73%)

0.41

Interferon responders

28 (24%)

31 (23%)

0.8

**Table 6.** Predictors of Disease Severity at 1 Year Post-Transplant
Variables included	B ± SE	Odds ratio	95% CI	P value
Logistic regression analysis. R² = 0.07 (Hosmer & Lemeshow), 0.09 (Cox & Snell), 0.12 (Nagelkerke). Model χ² =24.1, P < 0.001. B: coefficient of regression. SE: standard error; CI: confidence interval.
Recipient age	-0.055 ± 0.02	0.95	0.91 - 0.98	0.007
Female gender	0.96 ± 0.34	2.6	1.33 - 5.07	0.005
Donor age	0.02 ± 0.01	1.02	1.0 - 1.04	0.021
Anti-T cell antibody	0.85 ± 0.41	0.43	0.19 - 0.95	0.037
Constant	2.7 ± 1.12	14.88		0.016

Table 6. Predictors of Disease Severity at 1 Year Post-Transplant

Variables included

B ± SE

Odds ratio

95% CI

P value

Logistic regression analysis. R² = 0.07 (Hosmer & Lemeshow), 0.09 (Cox & Snell), 0.12 (Nagelkerke). Model χ² =24.1, P < 0.001. B: coefficient of regression. SE: standard error; CI: confidence interval.

Recipient age

-0.055 ± 0.02

0.95

0.91 - 0.98

0.007

Female gender

0.96 ± 0.34

2.6

1.33 - 5.07

0.005

Donor age

0.02 ± 0.01

1.02

1.0 - 1.04

0.021

Anti-T cell antibody

0.85 ± 0.41

0.43

0.19 - 0.95

0.037

Constant

2.7 ± 1.12

14.88

0.016

**Table 7.** Prediction of Graft Failure Beyond First Post-Transplant Year
Variable	B ± SE	Hazard ratio	P value
Cox proportional hazards analysis. B: coefficient of regression. SE: standard error.
Fibrosis stage 5/6	1.24 ± 0.51	3.46	0.016
Fibrosis stage 3/4	0.81 ± 0.32	2.25	0.011
Fibrosis stage 2	0.54 ± 0.36	1.71	0.133
Recipient age	0.01 ± 0.02	1.01	0.649
Female gender	-0.13 ± 0.32	0.88	0.690
Donor age	0.03 ± 0.01	1.03	0.0007
Anti-T cell antibody	0.32 ± 0.30	1.38	0.285

Table 7. Prediction of Graft Failure Beyond First Post-Transplant Year

Variable

B ± SE

Hazard ratio

P value

Cox proportional hazards analysis. B: coefficient of regression. SE: standard error.

Fibrosis stage 5/6

1.24 ± 0.51

3.46

0.016

Fibrosis stage 3/4

0.81 ± 0.32

2.25

0.011

Fibrosis stage 2

0.54 ± 0.36

1.71

0.133

Recipient age

0.01 ± 0.02

1.01

0.649

Female gender

-0.13 ± 0.32

0.88

0.690

Donor age

0.03 ± 0.01

1.03

0.0007

Anti-T cell antibody

0.32 ± 0.30

1.38

0.285

**Table 8.** Allograft Failure Risk Based on Treatment Status
	P value	HR	95.0% CI HR
CI: confidence interval; HR: hazard ratio.
Mild disease viremic	0.001
Mild disease SVR	0.026	0.103	0.014	0.761
Severe disease viremic	0.007	2.050	1.218	3.451
Severe disease SVR	0.419	0.721	0.326	1.594

Table 8. Allograft Failure Risk Based on Treatment Status

P value

95.0% CI HR

Lower

Upper

CI: confidence interval; HR: hazard ratio.

Mild disease viremic

0.001

Mild disease SVR

0.026

0.103

0.014

0.761

Severe disease viremic

0.007

2.050

1.218

3.451

Severe disease SVR

0.419

0.721

0.326

1.594