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Nakamura et al. Hepatoma Res 2019;5:16 I http://dx.doi.org/10.20517/2394-5079.2019.06 Page 9 of 11

to patients with HCC at the initial treatment and that 39% of the patients in our study had recurrent HCC, we
concluded that DAA treatment did not induce recurrence more frequently than interferon treatment, as we found
that a history of multiple treatments for HCC before DAA therapy was an important risk factor for recurrence after
DAA therapy.

[21]
We previously reported that AFP > 10 ng/mL after RFA for HCC is a significant risk factor for recurrence .
In the present study, however, AFP elevation before DAA treatment was not extracted as a significant factor for
HCC recurrence. The discrepancy may be due to the small number of high-AFP cases in the present study due to
curative treatment and the suppression of carcinogenic potential by DAA therapy. The median AFP values before
and after DAA treatment were 8.4 ng/mL and 5.3 ng/mL, respectively, in the present study. Of note, however: the
recurrence rate was higher in patients with high AFP-L3 levels at the initiation of DAA therapy than in patients
with low AFP-L3 levels. High AFP-L3 levels are known to indicate that the HCC has a high malignant carcinogenic
[22]
potential and is associated with a poor prognosis . Although most published studies did not report the AFP-L3
levels of their patients, it is possible that case studies showing high recurrence rates after DAA included patients
with high AFP-L3 levels.

We experienced two HCC patients who showed recurrence with portal vein invasion. Considering that both
patients had a history of multiple treatments and the frequency of such a recurrence pattern was not high, it is
difficult to conclude whether or not DAA treatment was responsible for this type of recurrence. Careful observation
will be necessary in order to confirm whether or not the prevalence of such cases will increase in the future.

Our study was associated with some limitations. First, although the observation period was relatively long among
studies in which DAA therapy was administered after curative treatment of HCC, the duration was still not
sufficient to estimate the long-term survival. Second, the number of deaths was extremely small; thus, the effect of
DAA therapy on prolonging the survival could not be evaluated. In addition, some factors affecting the recurrence
of HCC, such as alcohol consumption and coexisting diabetes mellitus, have not been well studied.

In conclusion, the recurrence rate in patients treated with DAAs after curative treatment of HCC was comparable
to that before the DAA era. We also found that multiple tumors at the first HCC treatment, a history of multiple
treatments for HCC, and high AFP-L3 at the time of DAA treatment were risk factors for HCC recurrence. Given
that the incidence of recurrence after DAA therapy was non-negligible, a long-term follow-up is necessary to ensure
a long survival, especially for patients who have risk factors for recurrence.

DECLARATIONS
Acknowledgments
The authors thank Dr. Hidenori Shiraha, Dr. Fusao Ikeda, Dr. Kenji Kuwaki, Dr. Tetsuya Yasunaka, Dr. Yuki
Yasunaka, Dr. Yasuto Takeuchi, Dr. Nozomu Wada, Dr. Atsushi Oyama and Dr. Akinobu Takaki for their help in
collecting data and providing meaningful advice.

Authors’ contributions
Study concept and design: Nakamura S, Nouso K, Okada H, Tanaka M
Acquisition of data: Nakamura S, Onishi H, Fujioka S, Araki Y, Iwadou S, Kumada T, Toyoda H, Motomura K,
Kariyama K, Kobashi H, Kaneyoshi T, Ando M, Moriya A, Taniguchi H, Morimoto Y, Hagihara H
Analysis of data: Nakamura S, Nouso K
Drafting of the manuscript: Nakamura S, Nouso K
Statistical analysis: Nakamura S
Study supervision: Nouso K, Okada H, Tanaka M