Factors Associated With Increased Risk of De Novo or Recurrent Hepatocellular Carcinoma in Patients With Cirrhosis Treated With Direct-Acting Antivirals for HCV Infection

Abstract

BACKGROUND & AIMS:Patients with cirrhosis and hepatitis C virus (HCV) infection treated with direct-acting antivirals (DAAs) are still at risk for developing hepatocellular carcinoma (HCC). We aimed to identify features of de novo or recurrent HCCs in these patients, and factors associated with HCC development, in a large cohort of patients with cirrhosis who received treatment with DAAs. METHODS:In a retrospective study, we collected data from 565 patients with cirrhosis (median age, 64 years; range, 28-87 years; 60% male, 49% infected with HCV genotype 1; median liver stiffness measurement [LSM], 19.1 kPa; 87% Child-Pugh-Turcotte score A) treated with DAAs at a single center in Italy, from December 2014 through 2016. Cirrhosis was defined based on clinical features, histologic factors (METAVIR F4), or LSM >11.9 kPa. Patients were assessed (complete blood analysis and HCV-RNA quantification) every 4 weeks during treatment; at weeks 4, 12, and 24 afterward; and at 6-month intervals thereafter. HCC surveillance was performed by ultrasound or CT scans every 3-6 months, based on history of HCC. Non-invasive markers of fibrosis, such as ratio of aspartate aminotransferase to platelets, fibrosis-4 (FIB-4) score, and LSMs were assessed. RESULTS:During a median 25 months of follow up (range, 3-39 months), HCC developed in 28/505 patients without a history of HCC (de novo HCC); the 3-year estimated cumulative probability for HCC was 6% (95% CI, 4%-9%). Of patients with de novo HCC, 75% had a single tumor and 82% of these were Barcelona liver cancer stage 0-A; the median level of alpha-fetoprotein was 6 ng/mL (range, 1.0-9240 ng/mL). Male sex (hazard ratio [HR], 6.17; 95% CI, 1.44-26.47; P [ .01), diabetes (HR, 2.52; 95% CI, 1.08-5.87; P [ .03), LSM (HR, 1.03; 95% CI, 1.01-1.06; P [ .01), and FIB-4 score (HR, 1.08; 95% CI, 1.01-1.14; P [ .01) were independently associated with de novo HCC. HCC developed in 20/60 patients with a history of HCC (HCC recurrence); the 3year cumulative probability for recurrence was 43% (95% CI, 20%-61%). In the 20 patients with HCC recurrence, 11 had a single tumor and 90% were Child-Pugh-Turcotte score A. Diabetes was independently associated with HCC recurrence (HR, 4.12; 95% CI, 1.55-10.93; P [ .004).Abbreviations used in this paper: CONCLUSIONS:In a large, single-center cohort of consecutive patients with cirrhosis and who received DAA treatment for HCV infection, most liver tumors were identified at early stages. Male sex, diabetes, and non-invasive markers of liver fibrosis can be used to identify patients at increased risk for HCC following DAAs therapy.

Risk of Hepatocellular Carcinoma after HCV Clearance by Direct-Acting Antivirals Treatment Predictive Factors and Role of Epigenetics

“…Degasperi et al [ 102 ] showed similar results in a retrospective study on 505 cirrhotic patients DAAs treated, demonstrating that a baseline LS > 30 kPa was an independent predictor of de novo HCC, being that the 3-year estimated incidence of de novo HCC was 20% in patients with LSM > 30 kPa versus 5% in patients with LSM ≤ 30 kPa ( p = 0.0003). Recently, in a population of 640 HIV/HCV co-infected patients followed for a median period of 31.6 months post-SVR by DAAs, with the aim of verifying the incidence of HCC, it was shown that none of the 374 patients with LS < 14 kPa at baseline developed HCC [ 103 ].…”

“…Several studies have shown that the male sex, diabetes and elevated serum alpha-fetoprotein levels before and after DAAs treatment are significant predictors of the onset or recurrence of HCC [ 34 , 39 , 66 , 67 , 102 ].…”

Liver steatosis is a major predictor of poor outcomes in chronic hepatitis C patients with sustained virological response

“…In a recent study of 565 cirrhotic patients from Italy that were followed for a median period of 25 months, both type 2 DM and high LSM were associated with de novo occurrence of HCC during follow‐up . Nonetheless, baseline LS was not reported in this study and its cohort had an immanent bias because all the patients were cirrhotic at baseline.…”

Postsustained Virological Response Management in Hepatitis C Patients

“…Calvaruso et al 31 on the other hand found that low albumin and reduced baseline platelet levels were associated with increased HCC incidence. Lastly Degasperi et al, 32 found male sex and diabetes to be independent predictors of HCC incidence in 565 cirrhotic patients treated with DAAs and followed up for a median time of 25 months after starting antiviral therapy. Host genetic factors may also be involved in HCC development.…”