Original article
Pancreas, biliary tract, and liver
Factors Associated With Increased Risk of De Novo or Recurrent Hepatocellular Carcinoma in Patients With Cirrhosis Treated With Direct-Acting Antivirals for HCV Infection

https://doi.org/10.1016/j.cgh.2018.10.038Get rights and content

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 3-year 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).

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.

Section snippets

Patient Population

Consecutive HCV patients with cirrhosis starting DAA treatment between December 2014 and 2016 at a single hepatology center were enrolled. Exclusion criteria were Child-Pugh-Turcotte (CPT) C score, whose treatment was not reimbursed by Italian National Health System outside the liver transplant waiting list; human immunodeficiency virus coinfection; and active HCC at baseline (DAA start), whose treatment was not allowed by Italian prescription rules. Patients with baseline atypical or

Baseline Patient Characteristics

This study includes 565 HCV CPT A-B patients with cirrhosis starting DAA between December 2014 and 2016 and followed for a median of 25 (3–39) months after DAA start: 505 patients had no previous HCC history, and 60 patients had a previous HCC (Figure 1). The baseline patient characteristics are shown in Table 1. Overall, median age was 64 (28–87) years, 60% were males, and 87% had CPT score A. Among CPT A patients, 14 (2.4%) had history of previous ascites, occurring 24 (6–48) months before

Discussion

This single-center, longitudinal 3-year follow-up study, including 565 patients with cirrhosis treated with DAAs, reports rates of de novo and recurrent HCC of 2% and 13% per year, respectively. Being most HCC diagnosed in early stages, the majority of patients received curative HCC treatments. Moreover, male gender, diabetes, and liver stiffness or noninvasive markers of liver fibrosis were found to be the strongest and independent predictors of de novo HCC, whereas diabetes was the only

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Conflicts of interest These authors disclose the following: Elisabetta Degasperi received speaking and teaching fees from Gilead, MSD, BMS, and AbbVie. Roberta D’Ambrosio is on the Advisory Board at AbbVie and Gilead; received speaking and teaching fees from AbbVie, Gilead, MSD, and BMS; and received research support from Gilead. Massimo Iavarone received speaking and teaching fees from Bayer, Gilead Science, Janssen, BTG, and AbbVie; and is a consultant at BTG. Angelo Sangiovanni is on the Speaker Bureau at Bayer, Gilead Science, Janssen, BTG, AbbVie, and Novartis; and on the advisory board at Tiziana Life sciences. Alessio Aghemo has received grant and research support from Gilead and Abbvie; is on the Advisory Board at Gilead, MSD, AbbVie, Janssen, BMS, and Alfasigma; and on the Speaker Bureau at Gilead, MSD, AbbVie, Janssen, and BMS. Massimo Colombo has received grant and research support from BMS and Gilead Science; is on advisory committees at Merck, Roche, Novartis, Bayer, BMS, Gilead Science, Tibotec, Vertex, Janssen Cilag, Achillion, Lundbeck, GSK, GenSpera, AbbVie, AlfaWasserman, and Jennerex; and has received speaking and teaching fees from Tibotec, Roche, Novartis, Bayer, BMS, Gilead Science, Vertex, Merck, Janssen, Sanofi, and AbbVie. Pietro Lampertico is on the Speaker Bureau at Bristol-Myers Squibb, Roche, Gilead, GlaxoSmithKline, MSD, and Janssen.

The remaining authors disclose no conflicts.

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