Increased Risk for Hepatocellular Carcinoma Persists Up to 10 Years After HCV Eradication in Patients With Baseline Cirrhosis or High FIB-4 Scores

Abstract

Background & aims: It is unclear if hepatocellular carcinoma (HCC) risk declines over time after hepatitis C virus (HCV) eradication. We analyzed changes in HCC annual incidence over time following HCV eradication and identified dynamic markers of HCC risk.

Methods: We identified 48,135 patients who initiated HCV antiviral treatment from 2000 through 2015 and achieved a sustained virologic response (SVR) in the Veterans Health Administration (29,033 treated with direct-acting antiviral [DAA] agents and 19,102 treated with interferon-based regimens). Patients were followed after treatment until February 14, 2019 (average 5.4 years), during which 1509 incident HCCs were identified.

Results: Among patients with cirrhosis before treatment with DAAs (n = 9784), those with pre-SVR fibrosis-4 (FIB-4) scores ≥3.25 had a higher annual incidence of HCC (3.66%/year) than those with FIB-4 scores <3.25 (1.16%/year) (adjusted hazard ratio 2.14; 95% confidence interval 1.66-2.75). In DAA-treated patients with cirrhosis and FIB-4 scores ≥3.25, annual HCC risk decreased from 3.8%/year in the first year after SVR to 2.4%/year by the fourth year (P=.01). In interferon-treated patients with FIB-4 scores ≥3.25, annual HCC risk remained above 2%/year, even 10 years after SVR. A decrease in FIB-4 scores from ≥3.25 pre-SVR to <3.25 post-SVR was associated with an approximately 50% lower risk of HCC, but the absolute annual risk remained above 2%/year. Patients without cirrhosis before treatment (n = 38,351) had a low risk of HCC, except for those with pre-SVR FIB-4 scores ≥3.25 (HCC risk 1.22%/year) and post-SVR FIB-4 scores ≥3.25 (HCC risk 2.39%/year); risk remained high for many years after SVR.

Conclusions: Patients with cirrhosis before an SVR to treatment for HCV infection continue to have a high risk for HCC (>2%/year) for many years, even if their FIB-4 score decreases, and should continue surveillance. Patients without cirrhosis but with FIB-4 scores ≥3.25 have a high enough risk to merit HCC surveillance, especially if FIB-4 remains ≥3.25 post-SVR.

Keywords: Liver Cancer; Long-Term Outcome; Population; Prognostic Factor.

Figure 1.

Cumulative HCC incidence curves following SVR, stratified by cirrhosis versus no cirrhosis and by high FIB-4 (≥3.25) versus low FIB-4 (<3.25) a. IFN-treated patients b. DAA-treated patients p-value <0.001 comparing FIB-4 ≥3.25 to <3.25 groups

Figure 2.

Annual HCC incidence after SVR in patients according to treatment type and FIB-4 score in a. Patients with pre-treatment cirrhosis b. Patients without pre-treatment cirrhosis

Figure 3.. HCC incidence in patients after SVR according to change in FIB-4 score from pre-treatment to within one year after SVR, presented separately for patients with pre-treatment cirrhosis (A-D) or without pre-treatment cirrhosis (E-H)

Panels A and E show that a drop in FIB-4 score from ≥3.25 pre-treatment to <3.25 within one year after SVR identifies patients with lower HCC incidence than those with a FIB-4 score ≥3.25 both pre-treatment and after SVR, both in patients with (A) and without (E) pretreatment cirrhosis Panels B and F show that an increase in FIB-4 score from <3.25 pre-treatment to ≥3.25 within one year after SVR identifies patients with higher HCC incidence that those with FIB-4 <3.25 both pre-treatment and after SVR, both in patients with (B) and without (F) pretreatment cirrhosis. However, the absolute risk in patients without pre-treatment cirrhosis is very low. Panels C and D (patients with pre-treatment cirrhosis) and G and H (patients without pretreatment cirrhosis) demonstrate how HCC risk varies according to pre and post-treatment FIB-4 in DAA-treated and IFN-treated patients