profiling of routine serum parameters and app evolution in … · 2019-10-28 · financial...
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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
*Service d’Hépatologie
Hôpital Jean Verdier
Bondy – Université Paris 13
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
Financial Disclosures
• Honoraria or consultation fees: Abbvie, Astra-Zeneca, Bayer,
Bristol-Myers Squibb, Gilead Sciences, IPSEN
Identifying residual risk of HCC following HCV eradication in compensated
cirrhosis: Machine learning approaches (decision tree analysis)
CirVir CO12
JCO, in revision
N=836
Longitudinal and sequential assessment of biological
parameters for early HCC detection
Are routine serum parameters estimating liver functionOr inflammation and AFP levels correlated with HCC development?
What influence in case of control of the cause of liver disease ?
Objectives of the study
In patients with compensated HCV-related cirrhosis included in HCC surveillance programsand 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.
Based on the analysis of protocol-driven collected data from a nationalprospective cohort covering INF and DAA therapeutic eras
The ANRS CO12 CirVir prospective cohort:
inclusion criteria - design
Inclusions
n=1822
FOLLOW-UP
Median: 67.5 months
March
2006
June
2012
December
2016End point
DESIGN
• 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
• Prospective multicentre study (35 French hospitals)
• Visits: every 6 months (HCC screening)
• Biobanks: at inclusion and every year
Statistical analysis
• 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.
SVR
…
…
Flow-chart
N=106 excluded
• N=69 Incorrect inclusion criteria
• N=6 Withdrawal of consent
• N=31 HCV/HBV co-infection
N=606 excluded
• N=258 achieved SVR before inclusion
• N=348 with <3 sequential measurements on AFP/RSP
Population #1 No SVR/before SVR
N=717
Population #2 After SVR
N=413 (57.6%)
HCV-infected patientsN=1429
Considered patients
N=1323
Included patients
N=717
Baseline characteristicsBaseline characteristics (N=717)
Gender, males 440 (61.4%)
Age, years 57.1 (±10.5)
HCV Genotype 1 522 (74.3%)
Body Mass Index, kg/m² Mean (±SD) 26.4 (±5.0)
Normal weight <25 272 (42.0%)
Overweight [25-30[ 260 (40.2%)
Obesity ≥30 115 (17.8%)
Past excessive alcohol intake 222 (32.1%)
Diabetes 143 (19.9%)
Dyslipidaemia 42 (5.9%)
Hypertension 197 (27.5%)
Oesophageal varices 199 (33.7%)
Creatinine, µmol/L 72.9 (±31.1)
eGFR 99.2 (±25.9)
Total bilirubin, µmol/L 15.0 (±8.4)
AST IU/L 86.4 (±56.1)
xN 2.4 (±1.6)
ALT IU/L 101.6 (±79.4)
xN 2.4 (±1.9)
GGT IU/L 154.2 (±159.4)
xN 3.3 (±3.6)
Alkaline phosphatase IU/L 119.2 (±70.7)
xN 0.9 (±0.4)
Serum albumin, g/L 40.5 (±4.7)
Alpha-foetoprotein, ng/mL 15.5 (±29.9)
Platelet count, 10^3/mm3 131.4 (±56.6)
Prothrombin t ime (%) 86.4 (±12.5)
3 clusters Population #1 No SVR/before SVR, N=717
« Inflammatory » and high AFP levels (n=190, 26%)
« Liver failure » (n=198, 28%)
Least impaired values (n=329, 46%)
Cluster A
Cluster B
Cluster C
ALT AST
AFPGGT
3 clusters Population #1 No SVR/before SVR, N=717
« Inflammatory » and high AFP levels (n=190, 26%)
« Liver failure » (n=198, 28%)
Least impaired values (n=329, 46%)
Cluster A
Cluster B
Cluster C
PT PLATELETS
BILIRUBINALBUMIN
Influence of pre-SVR clusters on HCC riskTotal HCC=142 (19.8%)
Cluster CCluster BCluster A
P<0.001
« Inflammatory » and high AFP
levels (n=190, 26%)
« Liver failure »
(n=198, 28%)
Least impaired values
(n=329, 46%)
Cluster A
Cluster B
Cluster C
HC
C c
um
ula
tive
in
cid
en
ce
Time (months)
Population #1 No SVR/before SVR, N=717
Population #1 No SVR/before SVR, N=717
« Inflammatory » and high AFP levels (n=190, 26%, HCC=25.3%)
« Liver failure » (n=198, 28%, HCC=26.8%)
Least impaired values (n=329, 46%, HCC=12.5%)
Cluster A
Cluster B
Cluster C
Cluster C Cluster B Cluster A
N=329 N=198 N=190
Mean (±SD) Mean (±SD) Mean (±SD) p-values
Gender, males 212 (65.2%) 113 (56.5%) 115 (59.9%) 0.121
Age, years 56.6 (±10.7) 59.5 (±10.7) 55.3 (±9.4) 0.0003
HCC occurrence (%) 41 (12.5%) 53 (26.8%) 48 (25.3%) <0.0001
Death (%) 44 (13.4%) 41 (20.7%) 62 (32.6%) <0.0001
Past excessive alcohol intake 108 (34.1%) 55 (28.6%) 59 (32.4%) 0.444
Body Mass Index, kg/m² 25.9 (±4.9) 27.1 (±5.3) 26.5 (±4.6) 0.039
Diabetes 56 (17.2%) 45 (22.5%) 42 (21.9%) 0.251
Dyslipidaemia 22 (6.8%) 8 (4.0%) 12 (6.3%) 0.408
Hypertension 73 (22.5%) 64 (32.0%) 60 (31.3%) 0.023
Oesophageal varices 51 (20.4%) 95 (54.3%) 53 (32.1%) <0.0001
HCV Genotype 1 236 (73.8%) 150 (76.5%) 136 (72.7%) 0.835
AS
AT
(U
LN
)G
GT
(UL
N)
Population #2 After SVR, N=413
Elevated biochemical parameters (n=95, 23.0%, HCC=13.7%)
Persisting liver impairment (n=109, 26.4%, HCC=15.6%)
Least impaired values (n=228, 55.2%, HCC=7.5%)Cluster A
Cluster B
Cluster C
AF
P
AST ALT
AFPGGT
TP
(%
)
BIL
IRU
BIN
(U
LN
)
Population #2 After SVR, N=413
Elevated biochemical parameters (n=95, 23.0%, HCC=13.7%)
Persisting liver impairment (n=109, 26.4%, HCC=15.6%)
Least impaired values (n=228, 55.2%, HCC=7.5%)Cluster A
Cluster B
Cluster C
PT PLATELETS
BILIRUBINALBUMIN
Population #2 After SVR, N=413
Elevated biochemical parameters
(n=95, 23.0%, HCC=13.7%)
Persisting liver impairment
(n=109, 26.4%, HCC=15.6%)
Least impaired values
(n=228, 55.2%, HCC=7.5%)Cluster A
Cluster B
Cluster C
HC
C c
um
ula
tive
in
cid
en
ce
Time (months)
Influence of pre-SVR clusters on HCC riskTotal HCC=47 (11.4%)
Population #2 After SVR, N=413
Elevated biochemical parameters (n=95, 23.0%, HCC=13.7%)
Persisting liver impairment (n=109, 26.4%, HCC=15.6%)
Least impaired values (n=228, 55.2%, HCC=7.5%)Cluster A
Cluster B
Cluster C
Cluster A Cluster B Cluster C
N=228 N=109 N=95
Mean (±SD) Mean (±SD) Mean (±SD) p-values
Gender, males 137 (63.4%) 75 (65.8%) 50 (60.2%) 0.727
Age, years 54.6 (±9.1) 57.6 (±9.5) 53.0 (±8.4) 0.001
HCC occurrence 17 (7.5%) 17 (15.6%) 13 (13.7%) 0.026
Death 8 (3.7%) 6 (5.3%) 4 (4.8%) 0.783
Past excessive alcohol intake 73 (34.8%) 33 (29.2%) 23 (29.1%) 0.486
Body Mass Index, kg/m² 25.9 (±4.9) 26.7 (±4.5) 26.4 (±4.3) 0.322
Diabetes 33 (15.3%) 19 (16.7%) 13 (15.7%) 0.947
Dyslipidaemia 19 (8.8%) 5 (4.4%) 2 (2.4%) 0.077
Hypertension 52 (24.1%) 33 (28.9%) 15 (18.1%) 0.212
Oesophageal varices 23 (13.8%) 45 (45.5%) 14 (22.2%) <0.0001
HCV Genotype 1 138 (65.4%) 92 (82.1%) 57 (70.4%) 0.009
Treatedtoo late? ?
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 approach also highlighted that these 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.
• 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
Aix-en-
Provenc
e
Marseille
Nice
St
Laurent-
du-Var
Montpellier
Toulouse
Bordeaux
Pessac
Clermont-
Ferrand
Lyon
Grenoble
Besançon
Nancy
Reims
Lille
AmiensRouen
Rennes
Caen
Tours
Poitiers
Angers
Le Mans Ile-de-France
(n= 11)
35 centres
ANRS CO12 CirVir group
Trinchet JC, et al. Hepatology 2015;62:737–50. ANRS, Agence Nationale de Recherches sur le Sida et les hépatites