1. Early occurrence of hepatocellular carcinoma
in patients with HCV cirrhosis treated with
direct acting antivirals
Vincenza Calvaruso*, Giuseppe Cabibbo ,Irene Cacciola, Salvatore Petta, Salvatore Madonia, Alessandro Bellia, Fabio Tinè, Marco Distefano, Lydia Giannitrapani, Tullio Prestileo, Giovanni Mazzola, Antonio Davì, Licia Larocca, Annalisa Ardiri, Antonio Digiacomo, Maria Gussio, Luigi Guarneri, Alfonso Averna, Carmelo Iacobello, Antonio Magro, Ignazio Scalici, Fabio Cartabellotta, Francesca Savalli, Maurizio Russello, Gaetano Scifo, Giovanni Squadrito, Calogero Cammà, Giovanni Raimondo, Antonio Craxì, Vito Di Marco
RESIST-HCV (Rete Sicilia Selezione Terapia – HCV), Sicily, Italy
*Gastroenterologia & Epatologia, DIBIMIS, University of Palermo, Italy

2. Background
In patients with cirrhosis, HCV clearance on IFN-based regimens reduces the risk of liver decompensation and of hepatocellular carcinoma (HCC) and hence affects death rates. Oral direct acting antivirals (DAAs) can eradicate HCV in most patients with chronic HCV infection regardless of genotype and stage of liver disease. While a reduction of deaths due to improved liver function is uniformly reported in patients with advanced cirrhosis treated with DAAs, data on the risk and modality of HCC occurrence in this setting are discordant.

3. Aims of the study
To evaluate the early occurrence of HCC in a prospective cohort of patients with HCV cirrhosis and no previous diagnosis of HCC, treated with DAAs
To analyze the risk factors associated with HCC occurrence
To assess the clinical presentation of HCC according to viral response pattern to DAAs

4. The RESIST-HCV network
RESIST-HCV (Rete Sicilia Selezione Terapia–HCV) is a web-based network which includes all patients with HCV liver disease treated with DAAs since March 2015 by 22 centers in Sicily (5.1 million inhabitants)

5. Patients and Methods
All consecutive patients with HCV cirrhosis included in RESIST-HCV, a regional database covering all DAA treatments in Sicily.
The diagnosis of cirrhosis included at least one of the following criteria:
previous liver biopsy with a stage 4 of fibrosis by METAVIR,
esophageal and/or gastric varices,
Fibroscan > 12 kPa,
platelets < 100 x 109/L.

6. Patients and Methods
Patients were treated with DAAs regimens according to the AIFA priority criteria and AISF guidelines.
HCC surveillance was performed by US every 6 months before, during and after antiviral treatment.
When a liver focal lesion was identified by US, HCC was confirmed by imaging (CT or/and MR) and/or biopsy
Patients with a previous diagnosis of HCC, with previous OLT or on a OLT waiting list were excluded.
Patient who withdrew from therapy and those not evaluable for SVR were not assessed for outcomes.

7. Flow-chart of the RESIST – HCV cohort
2,877 patients with cirrhotic
who started DAAs
between March 2015 and July 2016
273 (9.5%) patients excluded
185 with previous HCC
55 with previous OLT
33 on waiting list for OLT
138 (4.8%) patients not evaluated
21 death (4 liver related and liver unrelated)
19 stopped therapy for AEs
30 drop-outs
68 no SVR data available
2,466 (85.7%) patients
evaluated for HCC occurrence

8. Baseline clinical and virological features of 2,466 patients with HCV cirrhosis treated with DAAs
Variables
2,466 patients
Age (years, mean, SD)
65.4 ± 10.7
Gender ( males, %)
1,406 (57.0%)
ALT (IU/L, mean, SD)
88.6 ± 60.6
Platelets (x 109/L)
129.4 ± 65.4
INR (mean, SD)
1.1. ± 0.2
Bilirubin (mg/dL, mean,SD)
1.1 ± 0.6
Albumin (g/dL, mean, SD)
3.8 ± 0.5
HCV genotype 1b 1a 2 3 4
other
1,762 (71.5)
204 (8.3)
227 (9.2)
168 (6.8)
100 (4.1)
5 (0.2)
Child-Pugh score A B
2,229 (90.4)
237 (9.6)
MELD score (mean, SD)
8.2 ± 2.5
Presence of esophageal varices* (%)
867/1,668 (52)
Diabetes (%)
728 (29.5)
Previous IFN-based therapy
Naive (%)
Experienced (%)
1100 (45.6)
1,366 (55.4)
* 1668 patients with endoscopy

9. SVR12 according to Child Pugh class

10. Cumulative incidence of HCC by Kaplan-Meier analysis
Median follow-up since starting DAAs: 14 months (range 2-22)
No SVR
Rate of HCC occurrence (%)
Overall
SVR
Overall HCC occurrence
Time
Events, N. (%)
Cumulative incidence
(Kaplan – Meier estimates x 100)
6 months
24 (1.0)
1.0%
12 months
59 (2.4)
2.7%
18 months
73 (2.9)
4.4%
24 months
78 (3.1)
7.4%

11. HCC occurrence
Number of de novo HCCs observed during follow-up: (3.16%)
Mean time-lag from DAAs exposure to HCC occurrence (months): 10 (2-22)
HCC occurrence during DAAs: (11.5%)
after DAAs: (88.5%)
HCC staging: BCLC A: (76.9%)
BCLC B: (10.3%)
BCLC C: (12.8%)
Milan In (76.9%)
Milan out (23.1%)

12. HCC features and time of occurrence
Milan in Milan out
p = 0.365
p < 0.001 %
1/9

13. Cumulative incidence of HCC according to Child-Pugh class and SVR status
No SVR- CP B
p <
Rate of HCC occurrence (%)
No SVR- CP A
SVR- CP B
SVR- CP A

14. Risk factors for HCC occurrence by Cox multivariate model
Multivariate Cox’s regression HR
HR (95% CI) p
Albumin (mg/dl): ≥ 3.5
< 3.5
1.82
0.011
Platelets (x103/dL) ≥ 120
< 120
3.83
< 0.001
SVR 12
No SVR 12
3.29
Bilirubina si in univariata ma no in multi perché related with SVR.
HCC in diabete  18/536
HCC in diabete no 40/1365 p 0.6
Screened variables : age, gender, bilirubin, albumin, INR, PLT, diabetes, duration of DAA regimens, SVR 12

15. HCC occurrence according to risk factors in 2,466 patients
SVR: 2,368 patients (95.2%)
No SVR: 118 patients (4.8%)
Unfavorable factors:
No SVR 12
Albumin < 3.5 g/dl
PLT < 120 x 103 /dL
Rate of HCC occurrence (%)
N.PTS (%) 1,020 (41.3) (39.0) (14.9) (1.6) (1.8) (1.4)

16. HCC occurrence according to risk factors: predicted cumulative incidence
No SVR
Alb - PLT -
No SVR
Alb + or PLT +
probability of HCC occurrence (%)
16.8%
9.1%
5.3%
2.8%
2.6%
0.8%
SVR
Alb - PLT -
Diamo un significato clinico ai risulti del nostro modello.
SVR Alb + or PLT+
No SVR
Alb+ PLT+
SVR
Alb+ PLT+

17. Conclusions
In patients with HCV cirrhosis, HCC occurred after starting DAAs in 2.7 % of those with SVR and in 11.8 of those without.
Factors affecting the likelihood of occurrence of HCC were the stage of liver disease and lack of SVR. Risk profiling at the individual patient level was scarcely reliable.
These data extend the favourable experience of HCC risk reduction with IFN-based regimens to the setting of patients with advanced cirrhosis. The risk of HCC after SVR remains however proportional to the stage of liver disease.
HCC occurring in patients not responding to DAAs has a more aggressive clinical presentation.