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Nakamura et al. Hepatoma Res 2019;5:16 I http://dx.doi.org/10.20517/2394-5079.2019.06 Page 7 of 11

Figure 3. Recurrence in patients treated with DAAs after curative treatment for HCC according to the number of previous HCC
treatments. The recurrence rates increased as the number of previous HCC treatments increased (P < 0.0001, log-rank test). HCC:
hepatocellular carcinoma; DAA: direct-acting antiviral; Tx: treatment

Table 5. Hepatocellular carcinoma status at the time of recurrence after direct-acting antiviral therapy
The final HCC Tx before DAA
Hepatectomy RFA
Number of patients with recurrence 32 103
Non-SVR 4 (12.5%) 8 (7.8%)
Maximum tumor diameter (mm) 13 (10-17) 13 (10-17)
Tumor number (1/2/3/≥ 4) 21 (65.6%)/8 (25.0%)/1 (3.1%)/2 (6.3%) 70 (68.0%)/19 (18.4%)/6 (5.8%)/8 (7.8%)
Extrahepatic metastasis (positive) 0 (0%) 3 (2.9%)
Vascular invasion (positive) 1 (3.1%) 1 (1.0%)
AFP (ng/mL) 4.9 (3.1-7.1) 6.4 (4.3-11.2)
DCP (mAU/mL) 20 (13-27) 24 (18-41)
AFP-L3 (%) 0 (0-4.9) 0.5 (0-6.7)
The values indicate the median (interquartile range) unless otherwise noted; AFP: alpha-fetoprotein; AFP-L3: lens culinaris
agglutinin-reactive alpha-fetoprotein; DCP: des-gamma-carboxy prothrombin; HCC: hepatocellular carcinoma; Tx: treatment; DAA:
direct-acting antiviral

The treatment methods for HCC after DAA therapy were as follows: RFA (n = 83, 61.4%), hepatectomy (n = 14,
10.4%), TACE (n = 22, 16.3%), radiation therapy (n = 3, 2.2%) and particle beam, percutaneous ethanol injection,
hepatic arterial infusion, systemic chemotherapy and best supportive care (n = 1 each).

DISCUSSION
In the present study, we found that the 1- and 3-year recurrence rates of curatively treated HCC patients who
received DAA therapy were 18.3% and 55.4%, respectively. In contrast, the 3-year overall survival rate was
extremely high (95.4%). In addition, we revealed that the factors associated with recurrence were multiple tumors
at the first HCC treatment, a history of multiple treatments for HCC and AFP-L3 ≥ 10% at the initiation of DAA
therapy.

Table 6 summarizes the published data on HCC recurrence after DAA administration in patients with an HCC
treatment history. The unexpectedly high rate of HCC recurrence reported by the Spanish group raised a number
[4]
of concerns and prompted a great deal of discussion . According to the original paper, 3 patients died, and 16 of
55 patients (27.6%) developed HCC recurrence after a median follow-up period of 5.7 months. However, that group