Longterm impact of response to interferonbased therapy in
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 Johnson 1, 2, Emily de Groot 3, Sarah Berhane 1, Toshifumi Tada 4, Takashi Kumada 4, Hidenori Toyoda 4 1 Department of Molecular and Clinical Cancer Medicine, University of Liverpool, UK; 2 The Clatterbridge Cancer Centre NHS Foundation Trust, Clatterbridge Road, Bebington, Wirral, CH 63 4 JY, UK; 3 University of St Andrews, Fife KY 16 9 AJ; 4 Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Gifu, 503 -8052, Japan INTRODUCTION • 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 validated 2 tool (the ALBI score 1) 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 1 A) Paralleled by changes in FIB-4 and platelets (Figs 1 B & C) 15 year survival, SVR vs No-SVR (95% vs 79. 3%, p<0. 0001) (Fig 2 A) 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 2 b) 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) • • AIM Treatment response To apply the ALBI score to patients undergoing interferonbased therapy for HCV and thereby, • Examine the impact of achievement of SVR on liver function, • Assess the concurrent changes in, FIB 4 trend from baseline to HCC diagnosis according to Metavir fibrosis stage 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) - hepatic fibrosis (by FIB-4 index) Observa tion N Table 1: Baseline demographics 7 5 4 3 F 0, F 1, F 2, n=96 F 3, F 4, n=24 2 1 0 0 2 4 6 8 10 12 14 16 FIB 4 changes from start of treatment to HCC diagnosis (years) 18 20 Figure 3. FIB 4 trend from baseline to HCC diagnosis according to Metavir fibrosis stage, i. e. F 0, F 1 and F 2 as early and F 3/F 4 as late. Overall median FIB 4 figures at baseline and HCC development were 3. 28 (IQR 2. 43, t-test (between first and last observation s) Median (IQR) FIB-4 First 109 3. 46 (2. 21, 5. 15) No SVR last 109 5. 23 (3. 94, 7. 45) First 24 2. 93 (2. 59, 4. 34) SVR last 24 2. 54 (2. 09, 3. 32) Platelets First 111 13. 7 (10. 9, 17. 7) No SVR last 111 10. 5 (7. 2, 14. 4) First 24 14 (10. 7, 15. 4) SVR last 24 16. 2 (12. 3, 20. 6) *log or square root† transformation prior to undertaking tests. t-test (between firsts) t-test (between lasts) p=0. 8256* p<0. 0001* p=0. 8256* p=0. 4526* p=0. 0001* 0. 4882† p<0. 0001† 0. 4882† P=0. 0114† p<0. 0001† • Analyse survival and causes of death, and thereby -build and quantify a picture of the consequences of • Retrospective study (n=1118 ) HCV +ve patients from Ogaki Municipal Hospital, Japan • All received interferon-based therapy, 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) F 3 F 2 F 0: F 1: F 2: F 3: F 4 0: 3: 7: 2: 0 FIGURE 2: Survival by SVR status (A) all deaths (B) excluding HCC deaths 0, 00 • Mainly Genotypes 1 & 2 (56% and 44%), 5, 00 10, 00 15, 00 • All had pre-treatment histology 85%< F 2 • >95% within 1 month of starting treatment 20, 00 SVR 13. 44 2. 86 6. 33 9. 78 7. 39 9. 68 13. 67 5. 41 4. 73 Yes Yes Yes F 4 26 3. 56 Yes 89 105 62 Median (IQR) 105 (62, 138) F 4 F 3 F 4 F 0: F 1: F 2: F 3: F 4 0: 1: 3: 3: 6 48 1018 21 Median (IQR) 32 (23, 48) 6. 27 8. 50 8. 02 7. 39 (5. 41, 9. 68) 3 (23. 1%) < 5 years Yes Yes 2. Improvement in survival associated with SVR is largely attributable to a decreased incidence of HCC 3. HCC can develop from pre-cirrhotic fibrosis in a small number of years. ACKNOWLEDGEMENTS None REFERENCES 1. Johnson PJ, et al. , J Clin Oncol 2015; 33: 550 -8. 2. Pinato DJ et al. , Journal of Hepatology 2016 of Hepatology (2016)of N=13 Hepatology (2016) 20 None 4 -2, 4 FIB 4 ALBI score -2, 2 FIB 4_SVR FIB 4_no. SVR 5 ALBI_SVR ALBI_no. SVR -2, 6 3 15 1 -3, 2 0 Years after treatment 0, 00 CONTACT INFORMATION 10 2 -3 DISCLOSURES 25 6 25, 00 -2 -2, 8 • Median follow-up =11. 1 years range (1 -26) Function and fibrosis improve in parallel after SVR and changes over time can be readily quantitated Table 3. Fibrosis stage, assessed histologically, before treatment and at time of HCC development/resection in patient achieving SVR -1, 8 • SVR = 59%, no SVR=41% Time in between (years) 32 Platelets PATIENTS & METHODS 1 Percentage survival (95% CI) At HCC diagnosis/resection Metavir fibrosis stage ALT (U/L) F 1 23 F 4 23 F 2 29 F 4 32 F 3 45 F 3 74 F 4 57 F 2 33 F 2 12 PLT_SVR PLT_no. SVR 5 5, 00 10, 00 57 (48, 62), n=1118 16. 9 (13. 4, 21. 3) 10 (9, 14), n=1118 41 (39, 44), n=1118 -2. 87 (-3. 05, -2. 65), n=1118 893 (79. 87) 224 (20. 04) 1 (0. 09) n=1051 145 (13. 80) 553 (52. 62) 250 (23. 79) 94 (8. 94) 9 (0. 86) 136 (12. 16), n=1118 n=134 61 (45. 52) 7 (5. 22) 38 (28. 36) 28 (20. 90) 2. 04 (1. 29, 3. 2) 1. Table 2: FIB-4 and platelets at first and last observations of HCC patients according to SVR status At Baseline (start of IFN treatment) Metavir fibrosis stage ALT (U/L) F 1 46 F 3 83 F 1 144 F 2 156 F 2 138 F 2 118 F 2 151 F 2 120 F 1 21 All (N=1118) CONCLUSION p<0. 0001† - portal hypertension/fibrosis (by platelet count) SVR Non-SVR patients Variable (N=459) (N=659) Age at start of first treatment 58 (52, 63), n=459 55 (46, 62), n=659 Platelets (x 104 /µL) 15. 9 (12. 1, 19. 9) 17. 8 (14. 2, 22. 2) Bilirubin (µmol/l) 10 (9, 14), n=459 10 (9, 14), n=659 Albumin (g/L) 41 (38, 43), n=459 42 (40, 44), n=659 ALBI score -2. 79 (-3. 04, -2. 54) -2. 91 (-3. 08, -2. 69) ALBI grade, n (%) n=459 n=659 1 331 (72. 11) 562 (85. 28) 2 127 (27. 67) 97 (14. 62) 3 1 (0. 22) 0 (0. 00) Metavir fibrosis stage, n (%) n=435 n=616 0 51 (11. 72) 94 (15. 26) 1 217 (49. 89) 336 (54. 55) 2 104 (23. 91) 146 (23. 70) 3 57 (13. 10) 37 (6. 01) 4 6 (1. 38) 3 (0. 49) HCC development, n (%) 112 (24. 40), n=459 24 (3. 64), n=659** Cause of death n=99 n=35 HCC 55 (55. 56) 6 (17. 14) Liver failure 6 (6. 06) 1 (2. 86) Other cancer 19 (19. 19) 19 (54. 29) Non-cancer/other 19 (19. 19) 9 (25. 71) FIB 4 index 2. 31 (1. 51, 3. 81) 1. 88 (1. 14, 2. 84) Median and interquartile range given for all continuous variables 6 FIB 4 Achieving SVR in chronic HCV results in: PATIENTS & METHODS 2 RESULTS 15, 00 Years after treatment 20, 00 25, 00 0 0, 00 5, 00 10, 00 15, 00 Years after treatment 20, 00 25, 00 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 FIB 4, whereas statistically significant differences emerged at 3 months (from baseline) for platelets. Correspondence to: Philip Johnson Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L 69 3 GA, UK E-mail: philip. johnson@liverpool. ac. uk
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