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.

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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, 503-8052, 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 E-mail: philip.johnson@liverpool.ac.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.