Predictors of hepatocellular carcinoma recurrence associated with the use of direct-acting antiviral agent therapy for hepatitis C virus after curative treatment: A prospective multicenter cohort study.

Masahito Nakano,Shuichi Matsumoto,Hironori Koga,Satoshi Miuma,Yoko Yoshimaru,Yuichiro Eguchi,Satoshi Oeda,Takuji Torimura,Ryoko Kuromatsu,Tatsuya Ide,Shotaro Sakisaka,Hiroshi Yatsuhashi,Seiichi Mawatari,Satoru Hashimoto,Yutaka Sasaki,Akio Ido,Tetsuo Sohda,Makoto Nakamuta,Yuichi Honma,Masaru Harada,Satoshi Shakado,Yuko Takami,Tatsuji Maeshiro,Masataka Seike,Nobito Higuchi,Kenji Nagata,Kazuwa Nakao

doi:10.1002/cam4.2061

Abstract

BackgroundPrevious studies have suggested an association between the use of direct‐acting antiviral agents (DAAs) for treating hepatitis C virus (HCV) infection and the resulting decrease in the incidence of hepatocellular carcinoma (HCC); however, it is unclear whether DAAs prevent the recurrence of HCC after curative treatment for HCC. This study aimed to prospectively investigate HCC recurrence and its predictors after curative treatment for HCC.MethodsA total of 3012 patients with chronic HCV infection, with or without cirrhosis, who were treated with DAAs were enrolled between January 1, 2015 and January 31, 2017 as per the institutional review board approved study protocol at 15 institutions, including 10 university hospitals and five high‐volume centers in the Kyusyu area of Japan. Of the 3012 patients, 459 patients who had HCC but were cured with surgery or ablation therapy (curative treatment) before the use of DAAs were included in the analysis.ResultsDuring a mean follow‐up period of 29.4 months, 217 (47.2%) patients developed HCC recurrence. The median time to recurrence was 34.0 months, and the 1‐, 2‐, and 3‐year cumulative HCC recurrence rates were 27.1%, 43.4%, and 50.8%, respectively. The risk factors for HCC recurrence were the α‐fetoprotein (AFP) level before DAA therapy (P = 0.0047) and the number of curative treatments for HCC before DAA therapy (P < 0.0001).ConclusionsA high AFP level and multiple occurrences of HCC before DAA therapy are associated with a high risk for HCC recurrence after curative treatment. Follow‐up after DAA therapy should include special attention to the abovementioned risk factors.

Highlights

We focused on the identification of predictors for hepatocellular carcinoma (HCC) recurrence after direct‐acting antiviral agents (DAAs) therapy in the 459 patients with precured HCC, while the remaining 2553 patients were subjected to an independent analysis (Figure 1), because the characteristics of the two populations, and the risk factors for HCC development were shown to be significantly
Based on the univariate analysis, sex, platelet count, AFP level, aminotransferase to platelet count ratio index (APRI), FIB‐4 index, the presence of cirrhosis, and number of curative treatments for HCC before the DAA therapy were identified as factors that were significantly associated with HCC recurrence after the DAA therapy
The IFN‐based treatment is often difficult to perform in patients with hepatitis C virus (HCV) infection because of the associated adverse events, such as high fever, general fatigue, loss of appetite, and platelet count reduction, especially in the elderly patients and patients with cirrhosis, with a low platelet count

Summary

| INTRODUCTION

Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma (HCC).[1,2] HCC is a frequent consequence of HCV‐related cirrhosis, with an annual incidence of 1%‐8%.3 In addition, HCV infection may promote carcinogenesis; its eradication will directly decrease the risk of developing HCC.[4,5] With the recent development of interferon (IFN)‐free direct‐acting antiviral agents (DAAs), high rates of sustained virological response (SVR) have been achieved in patients with chronic HCV infection.[6,7,8]. In this cohort study, we recruited 3012 patients with chronic HCV infection, with or without cirrhosis, who were treated with DAAs between January 1, 2015 and January 31, 2017. Age before DAA therapy (y) Sex (male/female) AST level before DAA therapy (IU/L) ALT level before DAA therapy (IU/L) GGTP level before DAA therapy (IU/L) Platelet count before DAA therapy (×104/μL) AFP level before DAA therapy (ng/mL) APRI before DAA therapy FIB‐4 index before DAA therapy Geno/serotype (1/2/1+2/unknown) Habitual alcohol intake (presence/absence/ unknown) Diabetes mellitus (presence/absence/unknown) Fatty liver (presence/absence/unknown) Cirrhosis (presence/absence/unknown) Number of curative treatments for HCC before DAA therapy (1/2/3 or more/unknown). All statistical analyses were performed using the JMP pro 13 software (SAS Institute, Cary, NC)

| RESULTS

| DISCUSSION

Findings

CONFLICTS OF INTEREST