1. Long-term impact of response to interferon-based therapy in patients with chronic HCV in relation to liver function, survival and cause of death
Philip Johnson1,2, Emily de Groot3, Sarah Berhane1, Toshifumi Tada4, Takashi Kumada4, Hidenori Toyoda4
1Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK;
2The Clatterbridge Cancer Centre NHS Foundation Trust, Clatterbridge Road, Bebington, Wirral, CH63 4JY, UK;
3University of St Andrews, St Andrews, Fife KY16 9AJ;
4Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Gifu, , Japan
INTRODUCTION
RESULTS
PATIENTS & METHODS 2
Achieving SVR in chronic HCV results in:
•A decrease in liver and non liver-related complications,
•Together with improvements in quality of life,
•Improvement in degree of fibrosis
We have recently developed a simple, and extensively validated2 tool (the ALBI score1) that allows quantification of liver function, based on the simple serum tests of serum albumin and bilirubin.
Clear difference in liver function according to SVR status (Fig 1A)
Paralleled by changes in FIB-4 and platelets (Figs 1B & C)
15 year survival, SVR vs No-SVR (95% vs 79.3%, p<0.0001) (Fig 2A)
Major cause of death was HCC (45.5%) (90% of cases in No-SVR)
Only 5% of deaths (6/1118, 0.6% overall) from liver failure
Little survival difference in SVR if HCC-related deaths excluded (Fig 2b)
HCC could develop in patients who were pre-cirrhotic before treatment despite SVR and over periods as short as 3 years (Fig 3 and Table 3)
Table 1: Baseline demographics
Variable
Non-SVR patients (N=459)
SVR patients (N=659)
All (N=1118)
Age at start of first treatment
58 (52, 63), n=459
55 (46, 62), n=659
57 (48, 62), n=1118
Platelets (x 104 /µL)
15.9 (12.1, 19.9)
17.8 (14.2, 22.2)
16.9 (13.4, 21.3)
Bilirubin (µmol/l)
10 (9, 14), n=459
10 (9, 14), n=659
10 (9, 14), n=1118
Albumin (g/L)
41 (38, 43), n=459
42 (40, 44), n=659
41 (39, 44), n=1118
ALBI score
-2.79 (-3.04, -2.54)
-2.91 (-3.08, -2.69)
-2.87 (-3.05, -2.65),
ALBI grade, n (%)
n=459
n=659
n=1118 1
331 (72.11)
562 (85.28)
893 (79.87) 2
127 (27.67)
97 (14.62)
224 (20.04) 3
1 (0.22)
0 (0.00)
1 (0.09)
Metavir fibrosis stage, n (%)
n=435
n=616
n=1051
51 (11.72)
94 (15.26)
145 (13.80)
217 (49.89)
336 (54.55)
553 (52.62)
104 (23.91)
146 (23.70)
250 (23.79)
57 (13.10)
37 (6.01)
94 (8.94) 4
6 (1.38)
3 (0.49)
9 (0.86)
HCC development, n (%)
112 (24.40), n=459
24 (3.64), n=659**
136 (12.16), n=1118
Cause of death
n=99
n=35
n=134
HCC
55 (55.56)
6 (17.14)
61 (45.52)
Liver failure
6 (6.06)
1 (2.86)
7 (5.22)
Other cancer
19 (19.19)
19 (54.29)
38 (28.36)
Non-cancer/other
9 (25.71)
28 (20.90)
FIB4 index
2.31 (1.51, 3.81)
1.88 (1.14, 2.84)
2.04 (1.29, 3.2)
Median and interquartile range given for all continuous variables
Figure 3. FIB4 trend from baseline to HCC diagnosis according to Metavir fibrosis stage, i.e. F0, F1 and F2 as early and F3/F4 as late. Overall median FIB4 figures at baseline and HCC development were 3.28 (IQR 2.43,
Treatment response
Observation N
Median (IQR)
t-test (between first and last observations)
t-test (between firsts)
t-test (between lasts)
FIB-4
No SVR
First
109
3.46 (2.21, 5.15)
p<0.0001*
p=0.8256*
last
5.23 (3.94, 7.45)
p=0.0001*
SVR 24
2.93 (2.59, 4.34)
p=0.4526*
2.54 (2.09, 3.32)
Platelets
111
13.7 (10.9, 17.7)
p<0.0001†
0.4882†
10.5 (7.2, 14.4)
14 (10.7, 15.4)
P=0.0114†
16.2 (12.3, 20.6)
*log or square root† transformation prior to undertaking tests.
AIM
To apply the ALBI score to patients undergoing interferon- based therapy for HCV and thereby,
•Examine the impact of achievement of SVR on liver function,
•Assess the concurrent changes in,
- hepatic fibrosis (by FIB-4 index)
- portal hypertension/fibrosis (by platelet count)
•Analyse survival and causes of death, and thereby
-build and quantify a picture of the consequences of SVR
Percentage survival (95% CI)
Status
At 5 years
At 10 years
At 15 years
At 20 years
At 25 years
No SVR
97.71 (95.78, 98.76)
89.48 (85.84, 92.23)
79.25 (73.97, 83.57)
66.13 (59.25, 72.13)
51.83 (41.80, 60.94)
SVR
98.81 (97.51, 99.43)
96.43 (94.25, 97.79)
93.15 (89.72, 95.46)
89.00 (84.21, 92.41)
84.77 (77.11, 90.03)
CONCLUSION
Function and fibrosis improve in parallel after SVR and changes over time can be readily quantitated
Improvement in survival associated with SVR is largely attributable to a decreased incidence of HCC
HCC can develop from pre-cirrhotic fibrosis in a small number of years.
Table 2: FIB-4 and platelets at first and last observations of HCC patients according to SVR status
At Baseline (start of IFN treatment)
At HCC diagnosis/resection
Time in between (years)
SVR
Metavir fibrosis stage
ALT (U/L) F1 46 23
13.44
Yes F3 83 F4
2.86
144 F2 29
6.33
156 32
9.78
138 45
7.39
118 74
9.68
151 57
13.67
120 33
5.41 21 12
4.73 26
3.56 89 48
6.27
105
1018
8.50 62
8.02
F0:F1:F2:F3:F4
0 : 3 : 7 : 2 : 0
Median (IQR) 105 (62, 138)
0 : 1 : 3 : 3 : 6
Median (IQR) 32 (23, 48)
7.39 (5.41, 9.68)
3 (23.1%) < 5 years
N=13
ACKNOWLEDGEMENTS
None
PATIENTS & METHODS 1
Percentage survival (95% CI)
Status
At 5 years
At 10 years
At 15 years
At 20 years
At 25 years
No SVR
98.43 (96.53, 99.29)
93.31 (89.87, 95.61)
87.96 (83.04, 91.53)
82.22 (75.64, 87.16)
75.23 (66.58, 81.94)
SVR
98.97 (97.73, 99.54)
97.32 (95.37, 98.45)
94.33 (91.01, 96.44)
90.65 (85.96, 93.83)
86.33 (78.53, 91.45)
REFERENCES
Retrospective study (n=1118 ) HCV +ve patients from
Ogaki Municipal Hospital, Japan
All received interferon-based therapy,
Mainly Genotypes 1 & 2 (56% and 44%),
SVR = 59%, no SVR=41%
Median follow-up =11.1 years range (1-26)
All had pre-treatment histology 85%< F2
>95% within 1 month of starting treatment
1. Johnson PJ, et al., J Clin Oncol 2015;33:550-8.
2. Pinato DJ et al., Journal of Hepatology 2016of Hepatology (2016)of Hepatology (2016)
FIGURE 2: Survival by SVR status (A) all deaths (B) excluding HCC deaths
Table 3. Fibrosis stage, assessed histologically, before treatment and at time of HCC development/resection in patient achieving SVR
DISCLOSURES
None
CONTACT INFORMATION
Correspondence to:
Philip Johnson
Department of Molecular and Clinical Cancer Medicine,
University of Liverpool, Liverpool L69 3GA, UK
FIGURE 1: Changes in (A) ALBI, (B) FIB-4 and (C) platelets over time from baseline, according to SVR status.
Curves significantly differ from start of treatment for both ALBI and FIB4, whereas statistically significant differences emerged at 3 months (from baseline) for platelets.