Hepatology International (2018) 12:90–93
https://doi.org/10.1007/s12072-018-9862-1 (0123456789().,-volV)(0123456789().,-volV)
EDITORIAL
Early occurrence and recurrence of hepatocellular carcinoma
in hepatitis C virus-infected patients after sustained virological
response
Tatsuo Kanda1 • Shunichi Matsuoka1 • Mitsuhiko Moriyama1
Received: 20 February 2018 / Accepted: 24 March 2018 / Published online: 4 April 2018
Ó Asian Pacific Association for the Study of the Liver 2018
Abbreviations
HCV Hepatitis C virus
HCC Hepatocellular carcinoma
DAA Direct-acting antiviral agent
SVR Sustained virological response
Introduction
Chronic hepatitis C virus (HCV) infection is one of the
major causes of liver cirrhosis and hepatocellular carci-
noma (HCC). Recently, the interferon-free combination of
direct-acting antiviral agents (DAAs) against HCV could
result in higher sustained virological response (SVR) rates
(* 95%) [1]. In the interferon era, long-term eradication
of HCV could lead to the reduction of liver-related com-
plications, including HCC [2]. In the DAA era, achieve-
ment of SVR and long-term eradication of HCV can be
expected to prevent liver-related complications, including
HCC.
SVR is important for the prevention of HCC
development
Nishiguchi et al. [3] demonstrated that interferon-a
improved liver function and that its use could be associated
with a reduction of HCC in patients with chronic HCV
infection and cirrhosis. Yoshida et al. [4] retrospectively
studied 2890 patients with chronic hepatitis C diagnosed by
liver biopsy. Among these, 490 patients did not receive
interferon treatment. Of the other 2400 interferon-treated
& Tatsuo Kanda
kandat-cib@umin.ac.jp
1
Division of Gastroenterology and Hepatology, Department of
Medicine, Nihon University School of Medicine, 30-1
Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
123
patients, SVR was, and was not achieved in 789 (32.9%)
and 1568 (65.3%) patients, respectively. In 43 patients,
response was undetermined. They observed that HCC
developed in 89 (3.7%) of 2400 interferon-treated patients
and in 59 (12.0%) of 490 untreated patients with median
follow-up after liver biopsy of 4.3 years for all 2890
patients [4]. In 337 patients with cirrhosis, HCC developed
in 33 (14.3%) of 230 interferon-treated patients and in 32
(29.9%) of 107 untreated patients. Of 2400 interferon-
treated patients, HCC developed in 10 (1.3%) of 786
patients with SVR and in 76 (4.8%) of 1568 patients
without SVR. Of 230 interferon-treated patients with cir-
rhosis, HCC developed in 1 (1.9%) of 53 patients with
SVR, whereas HCC developed in 30 (17.9%) of 168
patients without SVR [4]. They also found, by multivariate
analysis, that interferon therapy was associated with a risk
ratio for HCC of 0.516 (95% CI 0.358 to 0.742) and
especially among patients with SVR (risk ratio, 0.197 [CI
0.099 to 0.392]) [4]. Of interest, the hepatitis C antiviral
long-term treatment against cirrhosis (HALT-C) cohort
showed that maintenance peginterferon did not reduce the
incidence of HCC in HCV-positive patients with bridging
fibrosis or cirrhosis [5]. These results suggest that it is
important for the prevention of HCC to achieve SVR in all
HCV-positive patients.
SVR by interferon could reduce recurrence
in post-HCC treated patients
As postsurgical recurrence of HCC is frequent and fatal,
various adjuvant treatments including interferon should be
considered [6]. However, it is difficult to use interferon
with or without ribavirin in post-HCC surgical patients due
to their relatively poor liver function. Shiratori et al. [7]
demonstrated that interferon therapy after the ablation of
HCC by ethanol injection improves the prognosis in HCV-
positive patients with HCC. This randomized, controlled
Hepatology International (2018) 12:90–93
study included total 74 patients with compensated cirrho-
sis, 3 or fewer HCCs and lower HCV RNA loads
(\ or = 2 9 106 copies/mL): 49 patients received inter-
feron for 48 weeks, resulting in 14 with SVR and 35 with
non-SVR; and 25 patients did not receive interferon [7]. Of
interest, the rate of first recurrence of new HCC lesions was
similar in patients treated with or without interferon.
However, the rates of second or third recurrence of HCCs
seemed to be lower in the interferon group than in the
untreated group. Survival rates in patients with and without
SVR were 86 and 80% at 3 years, 78 and 65% at 5 years,
and 68 and 48% at 7 years, respectively [7]. Meta-analysis
also showed that interferon treatment after resection or
ablation of HCC could reduce the recurrence of HCC and
improve their survival [8].
Peginterferon plus ribavirin could also reduce the
occurrence and recurrence of HCC and improve the sur-
vival as well [9–11]. Huang et al. [9] observed that, after
the end of treatment, 43 (41%) of 105 patients developed
HCC recurrence, and that, of interest, 24 (56%) of these 43
patients had their recurrence within 6 months after the end
of treatment and that 33 (77%) of the patients with HCC
recurrence were of de novo pattern. These results indicated
that peginterferon plus ribavirin therapy had a limited
effect in the tertiary prevention of HCC.
Ryu et al. [12] also examined the effects of SVR by
interferon therapy before HCC occurrence on recurrence
and survival after curative surgical microwave ablation.
This retrospective study included 518 HCV-associated
HCC patients: 34 patients with SVR before HCC occur-
rence and 484 control patients without SVR before or after
surgery. They found that survival rates of patients with and
without SVR were 100 and 94.8% at 1 year, 100 and
74.6% at 3 years, 95.8 and 50.7% at 5 years, and 80.4 and
23.4% at 10 years, respectively [12]. They also found that
the recurrence-free survival rates were significantly higher
in patients with SVR by interferon therapy before HCC
occurrence.
Will DAAs have the same effects
for secondary prevention as interferon
treatment?
Interferon-including regimens have been effective for only
HCV-positive patients with a mild stage of cirrhosis and
interleukin 28B (IL28B) major type [13]. Interferon-free
combination of DAAs could be used in HCV-positive
patients even if they have decompensated cirrhosis [14], as
well as aged patients. We also reported that the occurrence
of HCC was not a rare event during and immediately after
peginterferon with ribavirin therapy in HCV-positive
patients because HCV-associated HCC patients were
91
getting progressively older than before in Japan [15].
Clinicians should regularly check for the possible occur-
rence or recurrence of HCC during or after antiviral
treatments even in patients with SVR.
According to these reasons, DAAs could be used in
patients after surgery for HCC. Will DAAs have the same
effects for secondary prevention as interferon treatment?
There are several articles debating this issue [16–21].
Although Reig et al. [16] observed a high rate of HCC
recurrence after DAA treatment in patients with prior HCC,
almost studies demonstrated that SVR was associated with
a reduction in the risk of HCC among patients treated with
DAAs and that DAA treatment did not promote HCC
[17–19]. Meta-analyses including a total of 41 studies
(n = 13,875 patients) demonstrated that there was no dif-
ferent HCC occurrence or recurrence following SVR
between DAA and interferon-based treatment [18]. A
recent prospective population study demonstrated that,
among patients with advanced hepatitis C (fibrosis
stage =[F3) receiving DAAs, the risk of ‘‘de novo’’ HCC
during the first year is not higher, and might be lower, than
that of untreated patients and that early HCC appearance
may reflect pre-existing, microscopic, or undetectable tu-
mors [20].
Ryu et al. [12] also demonstrated that patients with HCC
occurring more than 5 years after achieving SVR by
interferon had longer recurrence-free survival, supporting
the fact that DAA-induced SVR does not seem to reduce
occurrence in patients with HCV-associated cirrhosis and
recurrence in patients previously treated for HCC in the
short term [22]. Ioannou et al. [19] also reported DAA-
induced SVR is associated with a 71% reduction in HCC
risk, although they diagnosed HCC at least 180 days after
the initiation of antiviral treatment. SVR by peginterferon
and ribavirin could not prevent early HCC recurrence
within 6 months after the end of treatment in some patients
[9], although there are contrary opinions [21, 23]. SVR
achieved by peginterferon and ribavirin markedly
improved survival in intermediate stage HCC patients
receiving transarterial chemoembolization (TACE) [24].
This effect of SVR should be addressed since some patients
with intermediate stage HCC were not considered to
receive antiviral treatment for their assumption to be
shorter survival.
Conclusion
Although interferon-free regimens could result in higher
SVR rates in HCV patients even with advanced liver
fibrosis and after HCC surgery, this treatment may also
affect hepatic immunity and activity [25–27]. These regi-
mens might also have an effect on tumor immunity, which
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is especially important for short-term occurrence and
recurrence. Recently, it was reported that the levels of
cytokines in serum before DAA treatment correlate with
the later development of HCC [28]. Debes et al. [28]
investigated 13 patients who developed HCC within
18 months after DAA treatment and 10 patients who did
not develop HCC, and they evaluated their serum cytokines
before, during and after DAA treatment. They concluded
that a set of immune markers could predict HCC devel-
opment following DAA treatment in HCV-positive patients
[28]. Further studies will be needed regarding this issue.
Both short-term and long-term incidences of HCC during
and after interferon-free combinations of DAA therapy
should be focused upon in clinical practice.
Funding This work was partially supported by JSPS KAKENHI
[Grant number 17K09404] and Japan Agency for Medical Research
and Development (AMED) [Grant Number JP16jk0210014].
Compliance with ethical standards
Conflict of interest Dr. Tatsuo Kanda received research grants from
Merck Sharp and Dohme (MSD), Chugai Pharm and AbbVie. The
founding sponsors played no role in the study design, data collection,
analyses, interpretation, writing of the manuscript, or in the decision
to publish the results. Shunichi Matsuoka and Mitsuhiko Moriyama
have declared that there are no conflicts of interest.
Ethical approval This article does not contain any studies with human
participants or animals performed by any of authors.
Informed consent Not necessary, see above.
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