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*Service d’Hépatologie Hôpital Jean Verdier Bondy – Université Paris 13

Profiling of routine serum parameters and APP evolution in cirrhosis following HCV eradication for stratification of HCC risk: a trajectory clustering analysis from the ANRS CO12 CirVir cohort. Pierre Nahon * , Richard Layese, Valérie Bourcier , Carole Cagnot,

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*Service d’Hépatologie Hôpital Jean Verdier Bondy – Université Paris 13

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  1. Profiling of routine serum parameters and APP evolution in cirrhosis following HCV eradication for stratification of HCC risk: a trajectory clustering analysis from the ANRS CO12 CirVir cohort Pierre Nahon* , Richard Layese, Valérie Bourcier, Carole Cagnot, Patrick Marcellin, Dominique Guyader, Stanislas Pol, Dominique Larrey, Françoise Roudot-Thoraval, Etienne Audureau, and ANRS CO12 CirVir group *Service d’Hépatologie Hôpital Jean Verdier Bondy – Université Paris 13

  2. Financial Disclosures Honoraria or consultation fees: Abbvie, Astra-Zeneca, Bayer, Bristol-Myers Squibb, Gilead Sciences, IPSEN

  3. CirVir CO12 Identifying residual risk of HCC following HCV eradication in compensated cirrhosis:Machine learningapproaches (decisiontreeanalysis) N=836 JCO, in revision

  4. Longitudinal and sequentialassessment of biologicalparameters for early HCC detection Are routine serumparametersestimatingliverfunction Or inflammation and AFP levelscorrelatedwith HCC development? What influence in case of control of the cause of liverdisease ?

  5. Objectives of the study Based on the analysis of protocol-drivencollected data from a national prospective cohortcovering INF and DAA therapeuticeras In patients withcompensated HCV-relatedcirrhosisincluded in HCC surveillance programs and baseline active viral replication : To identify specific longitudinal profiles of routine serum parameters (RSP) and AFP evolution before and after HCV eradication in patients with cirrhosis which could be associated with higher risk of HCC occurrence.

  6. The ANRS CO12 CirVir prospective cohort: inclusion criteria - design DESIGN • Prospective multicentrestudy (35French hospitals) • Visits: every 6 months(HCC screening) • Biobanks: at inclusion and everyyear Inclusions n=1822 FOLLOW-UP Median: 67.5 months December 2016End point March 2006 June 2012 Biopsy-proven Child-Pugh A cirrhosis HCV- or HBV-related cirrhosis Anti-HCV+ or HBsAg+ Absence of previous decompensation or HCC Trinchet JC, et al. Hepatology 2015, Ganne et al, Hepatology 2016, Nahon et al, Gut 2017, Nahon et al, Gastroenterology 2017 and 2018

  7. Statisticalanalysis SVR … … Serum AFP and RSP (ALT, AST, GGT, PT, albumin, bilirubin, platelets) were assessed every 6 months. For the present analysis, only patients with at least 3 available AFP and RSP sequential measurements were included • Population #1: No/before SVR • Patients who did not achieve SVR • OR period before achievement of SVR • Population #2: After SVR • Period after achievement of SVR Trajectory analysis was based on a k-means approach for clustering individuals with similar trajectories of AFP and RSP over time.

  8. HCV-infected patients N=1429 Flow-chart • N=106 excluded • N=69 Incorrect inclusion criteria • N=6 Withdrawal of consent • N=31 HCV/HBV co-infection Considered patients N=1323 • N=606 excluded • N=258 achieved SVR before inclusion • N=348 with <3 sequentialmeasurements on AFP/RSP Included patients N=717 Population #1 No SVR/before SVR N=717 Population #2 After SVR N=413 (57.6%)

  9. Baseline characteristics

  10. « Inflammatory » and high AFP levels (n=190, 26%) Cluster A Population #1 No SVR/before SVR, N=717 3 clusters Cluster B « Liverfailure » (n=198, 28%) Cluster C Least impaired values (n=329, 46%) AST ALT AFP GGT

  11. « Inflammatory » and high AFP levels (n=190, 26%) Cluster A Population #1 No SVR/before SVR, N=717 3 clusters Cluster B « Liverfailure » (n=198, 28%) Cluster C Least impaired values (n=329, 46%) PT PLATELETS BILIRUBIN ALBUMIN

  12. Influence of pre-SVR clusters on HCC risk Total HCC=142 (19.8%) Population #1 No SVR/before SVR, N=717 Cluster C Cluster B Cluster A P<0.001 « Inflammatory » and high AFP levels (n=190, 26%) Cluster A HCC cumulative incidence Cluster B « Liverfailure » (n=198, 28%) Cluster C Least impaired values (n=329, 46%) Time (months)

  13. « Inflammatory » and high AFP levels (n=190, 26%, HCC=25.3%) Cluster A Population #1 No SVR/before SVR, N=717 Cluster B « Liverfailure » (n=198, 28%, HCC=26.8%) Cluster C Least impaired values (n=329, 46%, HCC=12.5%)

  14. Cluster A Least impaired values (n=228, 55.2%, HCC=7.5%) Population #2 After SVR, N=413 Cluster B Persistingliverimpairment (n=109, 26.4%, HCC=15.6%) Cluster C Elevatedbiochemicalparameters (n=95, 23.0%, HCC=13.7%) AST ASAT (ULN) ALT GGT (ULN) AFP GGT AFP

  15. Cluster A Least impaired values (n=228, 55.2%, HCC=7.5%) Population #2 After SVR, N=413 Cluster B Persistingliverimpairment (n=109, 26.4%, HCC=15.6%) Cluster C Elevatedbiochemicalparameters (n=95, 23.0%, HCC=13.7%) TP (%) PT PLATELETS BILIRUBIN (ULN) BILIRUBIN ALBUMIN

  16. Influence of pre-SVR clusters on HCC risk Total HCC=47 (11.4%) Population #2 After SVR, N=413 Cluster B Persistingliverimpairment (n=109, 26.4%, HCC=15.6%) HCC cumulative incidence Cluster C Elevatedbiochemicalparameters (n=95, 23.0%, HCC=13.7%) Cluster A Least impaired values (n=228, 55.2%, HCC=7.5%) Time (months)

  17. Cluster A Least impaired values (n=228, 55.2%, HCC=7.5%) Population #2 After SVR, N=413 Cluster B Persistingliverimpairment (n=109, 26.4%, HCC=15.6%) Cluster C Elevatedbiochemicalparameters (n=95, 23.0%, HCC=13.7%) Treated toolate? ?

  18. Conclusions This exploratory descriptive approach underlines that liver function impairment (“liver failure cluster”) or elevated biochemical parameters (“inflammatory cluster”) in HCV cirrhosis define two different profiles representing more than 50% of compensated patients in whom the risk of HCC is increased. This clustering approachalsohighlightedthatthese 2 profiles can persist despite SVR, and define subgroups of patients with an increased residual risk of HCC These analyses based on novel statistical approaches suggest that 1) HCC surveillance could be refined and improved according to the longitudinal monitoring of these routine parameters over time, 2) these clustering approaches could be enriched by the incorporation of novel circulating biomarkers useful for HCC early detection.

  19. ANRS CO12 CirVir group 35 centres • Centres: Aix en Provence, Amiens, Angers, Besançon, Bicêtre, Bobigny, Bondy, Bordeaux, Caen, Clermont-Ferrand, Clichy, Créteil, Grenoble, Le Mans, Lille, Lyon, Marseille, Nancy, Nice, Paris-Cochin, Paris Institut Montsouris, Paris Pitié Salpêtrière, Paris-St Antoine, Paris-Tenon, Pessac, Reims, Rouen, Rennes, St Laurent du Var, Suresnes, Toulouse, Tours Lille Amiens Rouen Reims Caen Rennes Nancy Ile-de-France (n= 11) Le Mans Angers Tours Besançon Poitiers Lyon Clermont- Ferrand ANRS, Agence Nationale de Recherches sur le Sida et les hépatites Trinchet JC, et al. Hepatology 2015;62:737–50. Bordeaux Grenoble Pessac Aix-en- Provence Nice Toulouse St Laurent- du-Var Montpellier Marseille

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