ASSOCIAZIONE TRA SCORE GENETICO GRS E RISCHIO DI EPATOCARCINOMA IN PAZIENTI CON CIRROSI HCV TRATTATI CON FARMACI ANTIVIRALI DIRETTI

Background and aim: Several single nucleotide polymorphisms (SNPs) have been associated with hepatocellular carcinoma (HCC) in hepatitis C virus (HCV) cirrhotics, however their role in patients cured by direct-acting antivirals (DAA) is still undefined. We assessed the association between a genetic risk score (GRS) based on the combination of 4 SNPs (PNPLA3 rs738409, MBOAT7 rs641738, TM6SF2 rs5842926 and GCKR rs1260326) and HCC in a cohort of DAA-treated patients. Methods: Consecutive HCV cirrhotics receiving DAA between December 2014-2016 in a single Center were genotyped for the 4 SNPs. Cirrhosis was defined histologically or non-invasively (Liver stiffness measurement [LSM] ≥12 kPa). HCC was diagnosed and staged according to international recommendations. Results: 509 patients were analyzed: median age 64 (28-87) years, 58% males, LSM 19.4 (12.0-75.0) kPa, 87% Child-Pugh score A (CPT) A, 11% with previous HCC history. Genotypes distribution was as follows: PNPLA3 CC (46%), CG (41%) GG (13%); MBOAT7 CC (29%), CT (49%), TT (22%); TM6SF2 CC (91%), CT (8%), TT (1%); GCKR CC (26%), CT (48%), TT (26%). Median GRS score in the overall population was 0.3 (0-1.1). Patients’ demography and clinical features were similar across SNPs genotypes. Following antiviral treatment, 491 (96%) patients achieved viral eradication. During a median follow-up of 43 (3-57) months from DAA start, HCC developed in 36/452 (8%) patients without a history of HCC (de novo HCC), 4-year estimated cumulative probability of HCC being 9% (95% CI 7-12%). Male sex (Hazard Ratio [HR] 2.54; 95% CI 1.15-5.63; p=0.02), diabetes (HR 2.39; 95% CI 1.20-4.74; p=0.01), albumin (HR 0.35; 95% CI 0.19-0.64; p=0.001) and GRS score >0.6 (HR 2.30; 95% CI 1.03-5.11; p=0.04) were independently associated with de novo HCC. Indeed, 4-year cumulative rates of de novo HCC resulted 6% (95% CI 1-10%) vs. 12% (95% CI 8-16%) in males vs. females (p=0.01); 17% (95% CI 9-24%) vs. 7% (95% CI 5-10%) in diabetic vs. non-diabetic (p=0.001); 21% (95% 10-34%) vs. 7% (95% CI 4-11%) in patients with albumin ≤ or >3.5 g/dl (p<0.001) and 16% (95% CI 8-28%) vs. 7% (95% CI 5-11%) in patients with a GRS score > or ≤0.6 (p=0.01), respectively. Main tumor features did not significantly differ according to the 4 SNPs genotypes. By combining independent risk factors for HCC, 4-year cumulative incidence resulted 20% (95% CI 12-28%) vs. 5% (95% CI 3-7%) in patients with or without two different risk factors, respectively (p<0.0001). HCC developed in 28/57 (49%) patients with a previous HCC history, corresponding to a 4-year cumulative HCC recurrence of 49% (95% CI 27-63%). At multivariate analysis, only diabetes (HR 2.77, 95% CI 1.15-6.67; p=0.02) was independently associated with recurrent HCC, while GRS score was not significant. Indeed, 4-year cumulative incidence of HCC resulted 88% (95% CI 64-100%) vs. 40% (95% CI 25-55%) in diabetic vs. non-diabetic patients, respectively (p=0.002). Conclusions: In a large, single-center cohort of consecutive HCV patients with cirrhosis who received DAA treatment, a genetic risk score was independently associated with de novo HCC, together with clinical predictors (male sex, diabetes, albumin values). Combination of clinical and genetic predictors could allow a better HCC risk stratification in HCV cirrhotic patients after viral cure, in order to develop personalized HCC surveillance programs.