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 5, October 2015, pages 237-246

Slower Fibrosis Progression Among Liver Transplant Recipients With Sustained Virological Response After Hepatitis C Treatment

Figure 3. Plots R² by treatment type. This shows increasing trend in percentage of R² for a non-linear cubic model fit from “no treatment” to “SVR treatment”. This indicates favorable improvement in time dependent fibrosis scores, and this was most evident with SVR.

**Table 1.** Literature Review [12-21]
Author	Year	Country	N	Study design	CG	FU	Pre-treatment fibrosis	Effect on fibrosis: SVR	Effect on fibrosis: NR	Effect on fibrosis: control	P value
N: number of patients; NS: not significant; *: number of patients evaluated histologically; CG: control group; NR: non-responders; SVR: sustained virological response; FU: follow-up.
Tame et al [15]	2013	Italy	35*	Prospective	N	40	Metavir 2/4	(n = 9) 32% improved, 68% unchanged, 0% worsened	(n = 19) 38% improved, 66% unchanged, 16% worsened	(n = 7) 70% improved, 50% unchanged, 50% worsened	0.05
Belli et al [12]	2012	Italy	69*	RCT	Y	36	Ishaq-Knodell ≤ 3/6	(n = 15) 20% worsening	(n = 21) 47.6% worsening	(n = 36) 50% worsening	0.04
Carrion et al [16]	2007	Spain	81	RCT	Y	6	Metavir 2/4	(n = 18) 50% improved, 50% stable, 0% worse	(n = 36) 6% improved, 36% stable, 58% worse	(n = 27) 4% improved, 26% stable, 70% worse	0.009
Bizollon et al [13]	2007	France	25*	Prospective	Y	6	Unknown	(n = 8) 100% improved, 0% stable, 0% worse	(n = 17) 65% improved, 35% stable, 0% worse	(n = 21) 5% improved, 19% stable, 76% worse	Significant; P value not presented
Oton et al [17]	2006	Spain	15*	Retrospective	N	6	Ishaq-Knodell ≥ 1/6	(n = 7) mean score pre-treatment: 2.4/6, mean score post-treatment: 2.6/6	(n = 8) mean score pre-treatment: 2.7/6, mean score post-treatment: 3.7/6		NS
Fernandez et al [18]	2006	Spain	16*	Prospective	N	6	Scheuer Fibrosis score	(n = 7) mean score pre-treatment: 1.5/4, mean score post-treatment: 1.1/4	(n = 9) mean score pre-treatment: 2.4/6, mean score post-treatment: 2.8/6		NS
Barenguer et al [19]	2009	Spain	47*	Retrospective	N	12	HAI fibrosis stage 0 - 4	No change and improvement 46%	No change and improvement 44%		NS
Stravitz et al [21]	2004	USA	23	Retrospective	N	23		(n = 11) mean score pre-treatment: 1.9/4, mean score post-treatment: 1.5/4	(n = 12) mean score pre-treatment: 2.5/4, mean score post-treatment: 2.7/4		NS
Abdelmalek et al [20]	2004	USA	26*	Retrospective	N	24 - 60	Not known	At year 2 FU, 27% improved, 38% unchanged, 35% worsened, At year 3-5 FU, 67% improved, 13% unchanged, 20% worsened.			0.05
Bahra et al [14]	2007	Germany	28	Prospective	N	36	1.8	(n = 28) 18% improved, 60% unchanged, 21% worsened. Mean fibrosis stage at 1, 3 and 5 years: 2.0, 2.1 and 1.4 respectively.			NS

Table 1. Literature Review [12-21]

Author

Year

Country

Study design

Pre-treatment fibrosis

Effect on fibrosis: SVR

Effect on fibrosis: NR

Effect on fibrosis: control

P value

N: number of patients; NS: not significant; *: number of patients evaluated histologically; CG: control group; NR: non-responders; SVR: sustained virological response; FU: follow-up.

Tame et al [15]

2013

Italy

35*

Prospective

Metavir 2/4

(n = 9)
32% improved, 68% unchanged, 0% worsened

(n = 19)
38% improved, 66% unchanged, 16% worsened

(n = 7)
70% improved, 50% unchanged, 50% worsened

0.05

Belli et al [12]

2012

Italy

69*

RCT

Ishaq-Knodell ≤ 3/6

(n = 15)
20% worsening

(n = 21)
47.6% worsening

(n = 36)
50% worsening

0.04

Carrion et al [16]

2007

Spain

RCT

Metavir 2/4

(n = 18)
50% improved, 50% stable, 0% worse

(n = 36)
6% improved, 36% stable, 58% worse

(n = 27)
4% improved, 26% stable, 70% worse

0.009

Bizollon et al [13]

2007

France

25*

Prospective

Unknown

(n = 8)
100% improved, 0% stable, 0% worse

(n = 17)
65% improved, 35% stable, 0% worse

(n = 21)
5% improved, 19% stable, 76% worse

Significant; P value not presented

Oton et al [17]

2006

Spain

15*

Retrospective

Ishaq-Knodell ≥ 1/6

(n = 7)
mean score pre-treatment: 2.4/6,
mean score post-treatment: 2.6/6

(n = 8)
mean score pre-treatment: 2.7/6,
mean score post-treatment: 3.7/6

Fernandez et al [18]

2006

Spain

16*

Prospective

Scheuer Fibrosis score

(n = 7)
mean score pre-treatment: 1.5/4,
mean score post-treatment: 1.1/4

(n = 9)
mean score pre-treatment: 2.4/6,
mean score post-treatment: 2.8/6

Barenguer et al [19]

2009

Spain

47*

Retrospective

HAI fibrosis stage 0 - 4

No change and improvement 46%

No change and improvement 44%

Stravitz et al [21]

2004

USA

Retrospective

(n = 11)
mean score pre-treatment: 1.9/4,
mean score post-treatment: 1.5/4

(n = 12)
mean score pre-treatment: 2.5/4,
mean score post-treatment: 2.7/4

Abdelmalek et al [20]

2004

USA

26*

Retrospective

24 - 60

Not known

At year 2 FU, 27% improved, 38% unchanged, 35% worsened, At year 3-5 FU, 67% improved, 13% unchanged, 20% worsened.

0.05

Bahra et al [14]

2007

Germany

Prospective

1.8

(n = 28)
18% improved, 60% unchanged, 21% worsened.
Mean fibrosis stage at 1, 3 and 5 years: 2.0, 2.1 and 1.4 respectively.

**Table 2.** Clinical Characteristics of Patients Prior to Anti-HCV Therapy
Features	Study cohort (n = 167)	Control group (n = 27)	Treatment group (n = 140)	P value
n: number of patients; NHBD: non-heart beating donor; MELD: model for end-stage liver disease; CTP: Child-Turcotte-Pugh.
Patient age, mean ± SD	49.4 ± 7.7	48.6 ± 9.09	49.5 ± 7.4	NS
Patient ≥ 65, % (n)	2.4 (4)	3.7 (1)	2.1 (3)	NS
Gender male, % (n)	78.4 (131)	74.1 (20)	79.3 (111)	NS
Race white, % (n)	89.8 (150)	88.9 (15)	90 (126)	NS
Non-Hispanic, %	95.8 (160)	88.9 (24)	90 (126)	NS
Donor age, mean ± SD	40.6 ± 17.3	41.1 ± 18.8	40.5 ± 17.1	NS
Donor age, % > 50	31.7 (53)	29.6 (8)	32.1 (45)	NS
Donor gender, % male	55.7 (53)	55.6 (15)	55.7 (78)	NS
Donor ethnic, % white	85 (142)	81.5 (22)	85.7 (120)	NS
Donor ethnic, % non-Hispanic	83.8 (140)	77.8 (21)	85 (119)	NS
Donor NHBD, % (n)	6.3 (4)	00(00)	7.7 (4)	NS
MELD score, mean ± SD	16.4 ± 7.1	18.2 ± 7.9	16 ± 6.9	NS
Child-Pugh score, mean ± SD	7.8 ± 1.58	7.9 ± 1.5	7.8 ± 1.5	NS
Cold ischemia time, h ± SD	11.5 ± 3.5	12.9 ± 3.9	11.3 ± 3.4	NS
Warm ischemia time, min ± SD	34.8 ± 21.1	28.5 ± 24.0	36 ± 20.4	NS
Induction therapy, % (n)	16.8 (28)	14.8 (4)	17.1 (24)	NS
Received steroids, % (n)	81.6 (129)	87 (20)	80.7 (109)	NS

Table 2. Clinical Characteristics of Patients Prior to Anti-HCV Therapy

Features

Study cohort (n = 167)

Control group (n = 27)

Treatment group (n = 140)

P value

n: number of patients; NHBD: non-heart beating donor; MELD: model for end-stage liver disease; CTP: Child-Turcotte-Pugh.

Patient age, mean ± SD

49.4 ± 7.7

48.6 ± 9.09

49.5 ± 7.4

Patient ≥ 65, % (n)

2.4 (4)

3.7 (1)

2.1 (3)

Gender male, % (n)

78.4 (131)

74.1 (20)

79.3 (111)

Race white, % (n)

89.8 (150)

88.9 (15)

90 (126)

Non-Hispanic, %

95.8 (160)

88.9 (24)

90 (126)

Donor age, mean ± SD

40.6 ± 17.3

41.1 ± 18.8

40.5 ± 17.1

Donor age, % > 50

31.7 (53)

29.6 (8)

32.1 (45)

Donor gender, % male

55.7 (53)

55.6 (15)

55.7 (78)

Donor ethnic, % white

85 (142)

81.5 (22)

85.7 (120)

Donor ethnic, % non-Hispanic

83.8 (140)

77.8 (21)

85 (119)

Donor NHBD, % (n)

6.3 (4)

00(00)

7.7 (4)

MELD score, mean ± SD

16.4 ± 7.1

18.2 ± 7.9

16 ± 6.9

Child-Pugh score, mean ± SD

7.8 ± 1.58

7.9 ± 1.5

7.8 ± 1.5

Cold ischemia time, h ± SD

11.5 ± 3.5

12.9 ± 3.9

11.3 ± 3.4

Warm ischemia time, min ± SD

34.8 ± 21.1

28.5 ± 24.0

36 ± 20.4

Induction therapy, % (n)

16.8 (28)

14.8 (4)

17.1 (24)

Received steroids, % (n)

81.6 (129)

87 (20)

80.7 (109)

**Table 3.** Anti-HCV Treatment Course
Clinical features	Control (n = 27)	Treatment (n = 140)	P value
SD: standard deviation; ALT; alanine aminotransferase; AST: aspartate aminotransferase; ALP: alkaline phosphatase; MHAI: modified histologic activity index.
Bilirubin pre-treatment, mg/dL	0.91	0.61	1.29	1.92	NS
Bilirubin at initiation, mg/dL	2.86	6.07	1.61	3.47	NS
Bilirubin at follow-up, mg/dL	5.49	9.14	3.77	8.53	NS
ALT pre-treatment, IU/dL	121.56	122.84	96.89	103.40	NS
AST pre-treatment, IU/dL	99.11	115.61	90.09	130.42	NS
AST/ALT pre-treatment	0.89	0.51	0.92	0.42	NS
ALP pre-treatment, IU/dL	275.73	311.36	171.11	190.02	NS
Cholestasis index	2.29	2.46	2.21	1.95	NS
Creatinine pre-treatment, mg/dL	1.35	0.51	1.26	0.42	NS
Time from transplant to pre-treatment biopsy, years	0.99	1.46	0.90	1.05	NS
MHAI grade 0 - 18 pre-treatment	5.20	1.86	4.93	2.78	NS
Fibrosis stage 0 - 6 pre-treatment	1.11	1.31	1.34	1.46	NS
Time from transplant to treatment, years			0.98	1.06	NS
Treatment duration, years			1.62	1.16	NS
Time from transplant to follow-up biopsy, years	3.29	2.31	3.97	2.89	NS

Table 3. Anti-HCV Treatment Course

Clinical features

Control (n = 27)

Treatment (n = 140)

P value

Mean

SD: standard deviation; ALT; alanine aminotransferase; AST: aspartate aminotransferase; ALP: alkaline phosphatase; MHAI: modified histologic activity index.

Bilirubin pre-treatment, mg/dL

0.91

0.61

1.29

1.92

Bilirubin at initiation, mg/dL

2.86

6.07

1.61

3.47

Bilirubin at follow-up, mg/dL

5.49

9.14

3.77

8.53

ALT pre-treatment, IU/dL

121.56

122.84

96.89

103.40

AST pre-treatment, IU/dL

99.11

115.61

90.09

130.42

AST/ALT pre-treatment

0.89

0.51

0.92

0.42

ALP pre-treatment, IU/dL

275.73

311.36

171.11

190.02

Cholestasis index

2.29

2.46

2.21

1.95

Creatinine pre-treatment, mg/dL

1.35

0.51

1.26

0.42

Time from transplant to pre-treatment biopsy, years

0.99

1.46

0.90

1.05

MHAI grade 0 - 18 pre-treatment

5.20

1.86

4.93

2.78

Fibrosis stage 0 - 6 pre-treatment

1.11

1.31

1.34

1.46

Time from transplant to treatment, years

0.98

1.06

Treatment duration, years

1.62

1.16

Time from transplant to follow-up biopsy, years

3.29

2.31

3.97

2.89

**Table 4.** Fibrosis Analysis
	Control group	Non-responders	Relapsers	SVR	P value
LT: liver transplantation.
Time interval between LT and initiation of treatment, years		0.89	1.17	1.01	NS
Time interval between LT and first liver biopsy, years	1.03	0.81	1.06	0.96	NS
Time interval between LT and second liver biopsy, years	3.40	4.12	3.47	2.92	NS
Time interval between first and second liver biopsy, years	2.37	3.32	2.40	3.00	Ns
Mean fibrosis change between two biopsies	2.04	2.11	1.57	1.37	0.08
Mean fibrosis stage change per year	1.02	0.63	0.65	0.45	0.08
Direction of change in fibrosis					NS
Regression, % (n)	7.4 (2)	7.4 (6)	6.2 (2)	11.1 (3)
No change, % (n)	18.5 (5)	22.2 (18)	18.8 (6)	18.5 (5)
Progression, % (n)	74.1 (20)	70.4 (57)	75 (24)	70.4 (19)

Table 4. Fibrosis Analysis

Control group

Non-responders

Relapsers

SVR

P value

LT: liver transplantation.

Time interval between LT and initiation of treatment, years

0.89

1.17

1.01

Time interval between LT and first liver biopsy, years

1.03

0.81

1.06

0.96

Time interval between LT and second liver biopsy, years

3.40

4.12

3.47

2.92

Time interval between first and second liver biopsy, years

2.37

3.32

2.40

3.00

Mean fibrosis change between two biopsies

2.04

2.11

1.57

1.37

0.08

Mean fibrosis stage change per year

1.02

0.63

0.65

0.45

0.08

Direction of change in fibrosis

Regression, % (n)

7.4 (2)

7.4 (6)

6.2 (2)

11.1 (3)

No change, % (n)

18.5 (5)

22.2 (18)

18.8 (6)

18.5 (5)

Progression, % (n)

74.1 (20)

70.4 (57)

75 (24)

70.4 (19)