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The impact of direct-acting antivirals on early tumor recurrence after radiofrequency ablation in hepatitis C-related hepatocellular carcinoma
  Jnl of Hepatology Aug 2016
To the Editor
We read with interest the article by Reig et al. reporting unexpected early tumor recurrence in patients with hepatitis C virus-related hepatocellular carcinoma (HCC) undergoing interferon-free direct-acting antivirals (DAAs) [1. Even though the administration of DAAs in hepatitis C-infected patients after curative treatment of HCC is currently approved in Japan, the effects of DAAs on recurrence and overall survival are not yet fully understood. Therefore, we conducted this retrospective study to investigate the impact of DAAs on early tumor recurrence after curative therapy for hepatitis C-related HCC.
The study by Reig et al. is not without limitations. Firstly, patients who were treated with different treatment modalities were included, and there was no comparable control. Moreover, the interval between HCC treatment and the initiation of DAA therapy was long (median, 11.2 months; interquartile range, 3.6-23.2 months). Therefore, in this study, the initial treatment modalities were limited to radiofrequency ablation (RFA) and, individuals who had been treated with interferon (IFN)-based therapy after HCC treatment and those who had not undergone antiviral therapy after HCC treatment were included as historical controls. The interval between HCC treatment and the start of antiviral therapy was limited to less than 2 years to minimize selection bias.
From January 1999 to December 2015, a total of 1,191 patients were treated with RFA for initial hepatitis C-related HCC in our hospital. Among these, 27 patients had started DAA treatment within 2 years of completing radical RFA for initial hepatitis C-related HCC (DAA group), 38 patients had been treated with IFN-based therapy (IFN group), and 861 patients who did not undergo antiviral therapy after HCC treatment were included in the control group. The early tumor recurrence rate (< 3 years) among the three groups was compared using the Kaplan-Meier method, and risk factors for early recurrence were evaluated using the Cox proportional hazards model. The follow-up period ended on June 30, 2016.
The baseline characteristics of the patients are shown in Table 1. At the time of analysis, 26 patients were evaluable for sustained virological response (SVR)12 weeks after the end of DAA therapy; 22 patients (85%) achieved SVR12, and 13 patients (34%) achieved SVR 12 in the IFN group. The median interval between HCC treatment and the start of antiviral therapy was 5.8 months (range, 0.5-21 months) in the DAA group and 5.4 months (range, 0.5-19 months) in the IFN group. During a median observation period of 1.3 years in the DAA group, no patients died, and eight patients developed early tumor recurrence, all cases being intrahepatic tumors. In the IFN group, 4 patients died, 1 was lost to follow-up, and 26 developed tumor recurrence. In the control group, 186 patients died, and 553 developed tumor recurrence within 3 years. The cumulative recurrence rates at 1 and 2 years were 21.1% and 29.8%, respectively, in the DAA group, 26.3% and 52.9%, respectively, in the IFN group, and 30.5% and 61.0%, respectively, in the control group (Fig. 1). In a univariate analysis, multiple tumors (hazard ratio [HR] 1.33, p < 0.001), tumor size > 2 cm (HR 1.52, p < 0.001), alpha-fetoprotein protein level (AFP) ⩾ 100 ng/mL (HR 1.53, p < 0.001), lens culinaris agglutinin reactive fraction of AFP (AFP-L3) ⩾ 15% (HR 1.51, p < 0.001), des-γ-carboxy prothrombin level ⩾ 100 mAU/mL (HR 1.4, p = 0.003), and Child-Pugh class A (HR 0.74, p = 0.002) were significantly associated with early tumor recurrence. After adjusting for these significant risk factors, the use of DAA was not significantly associated with early tumor recurrence (DAA group vs. control: HR 0.57, p = 0.12; DAA group vs. IFN group: HR 0.65, p = 0.28). Multiple tumors (HR 1.33, p < 0.001), tumor size > 2 cm (HR 1.46, p < 0.001), AFP level ⩾ 100 ng/mL (HR 1.41, p = 0.001), and Child-Pugh class A (HR 0.79, p = 0.01) remained independent predictors of early tumor recurrence in a multivariate analysis.
Our data suggest that the rate of early tumor recurrence in those receiving DAA therapy was not higher than that in the IFN or control groups. The recurrence rate in the control group seemed higher compared with previously reported data from our institution [2 because of the inclusion of only hepatitis C-related HCC patients and the exclusion of patients treated with antiviral therapy after HCC treatment. A higher rate of recurrence was not observed in the DAA group compared with the control or IFN group, although IFN was previously reported to improve recurrence-free survival [3. In a multivariate analysis, tumor stage and high AFP levels, rather than the use of DAA, were strongly associated with early recurrence, which are related to tumor dissemination. An unexpected high frequency and unexpected aggressive recurrence were not observed in the current study.
In this preliminary analysis, DAA use did not affect early HCC recurrence adversely. Thus, ongoing clinical practice should not be changed. Large-scale randomized clinical trials are needed to resolve this issue; however, these may be associated with ethical issues

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