Direct-acting antiviral agents

do not increase the incidence

of hepatocellular carcinoma
development:
a prospective, multicenter
study

Ide, T. et al

By : dr. Frihastina Siti Khadijah

Supervisor :
BACKGROUND
 BACKGROUND
It has recently
Chronic hepatitis C
virus (HCV) been reported
infection is a major that the HCV SVR
cause of liver induced by DAA
cirrhosis and treatment
hepatocellular reduced the
carcinoma (HCC) OBJECTIVE incidence of HCC

To clarify whether
DAAs have a
favorable effect on
Recently, IFN-free suppressing the
development of However, increases
direct-acting antiviral
agents (DAAs) have HCC in unexpected early
been developed, occurrence or
resulting in high rates recurrence of HCC
of sustained virological after HCV
response (SVR) in elimination by
patients with HCV DAAs have also
been reported
PATIENTS AND METHOD
 Method

This study prospectively investigated the

incidence and risk factors for HCC
development after DAA therapy between
January 1st 2015 and January 31th 2017, in
a large multicenter cohort in the Kyushu area
of Japan.
 Research Flow Chart
patients
identification :
•Serotype of HCV Patients were
Chronic hepatitis Follow up
•Presence of treated
C patients with occurance of
cirrhosis with DAAs and
or without HCC every six
•Habitual alcohol achieved a SVR
cirrhosis month until
intake at 12 weeks
36th month
•Presence of (SVR12)
Fatty liver
Radiologic and •Presence type-2
laboratory test : DM
•Ultrasonography
•AST, ALT, GGTP, Statistical
AFP, FIB-4 index The fibrosis-4 (FIB-4) index = AST [IU/L] × age [years] / Analysis
platelet count [109/L] × ALT [IU/L]1/2
• AST to platelet
count ratio index
(APRI) APRI)= AST [IU/L] / (upper limit of normal AST [IU/L])
× 100/platelet count (109/L).

Exclusion criteria :Patients who had HCC,

Exclude if meet hepatitis B virus surface antigen, or other forms
exclusion criteria of liver diseases prior to DAA treatment
 Statistical analysis
Cox proportional
• Estimate the hazard ratios for
hazard regression
model risk factors

Kaplan–Meier • Determine the cumulative

method incidence

log-rank tests • Differences between groups

P < 0,05 means statistically significant

RESULT
 Baseline characteristics of all patients
2552
A total 2552
patients were
included in this
study

One third of the

patients had
cirrhosis.
Cumulative Incidence
•Among 255 patients,
70 patients (2.7%)
developed HCC.

•The 12th, 24th , and

36th month cumulative
HCC incidence was
1.3%, 2.9%, and 4.9%,
respectively

•The interval between

starting DAA treatment
and the diagnosis of
HCC was 13.9 ± 8.5
months.
Baseline characteristics of Patient who
developed HCC
The cumulative HCC incidence
stratified by cirrhosis status

The 12th, 24th, and

36th month incidences
were 2.5%, 5.2%, and
10.0% in patients with
cirrhosis and 0.9%,
2.1%, and 2.9% in
patients without
cirrhosis, respectively
 Risk Factor Associated with the Development of HCC
Univariate analysis
identified patient age,
sex, AST, ALT, GGTP,
Platelet count, AFP, APRI,
FIB-4 index, diabetes
mellitus, and cirrhosis as
factors significantly
associated with HCC

According to the
multivariate analysis,
sex (male), age, FIB-4
index, and GGTP were
independent factors
significantly associated
with HCC

From ROC analysis, age

≥62 years old, FIB-4 index
≥4.6, and GGTP level ≥44
IU/L were identified as
cutoff values.
Cumulative incidence of HCC by patient with risk factor

Patients with 4
risk factors
have a higher
incidence than
patients with 3
or 2 or no risk
factors
 Time of HHC diagnosis from DAA treatment initiation
and the maximum HCC diameter at diagnosis

• Five patients had HCC

diameters greater than
2.0 cm, developed HCC
within 6-12 months,
• There was no
relationship between
the time and diameter
(p = 0.74).
Five cases with large HCC that developed within
six months after the start of DAA treatment
DISCUSSION
Comparison of Incidence

In Japanese patients, the Although compared against

natural incidence rate of a different treatment era,
HCC was 1.8% in patients our incidence (0.9% in
with chronic hepatitis and chronic hepatitis and 2.5%
7.1% in those with cirrhosis. in cirrhosis) was not higher.
Comparison with Other Study

Recently, Calvaruso et al.

reported that SVR by DAA
treatment reduced the
incidence of HCC in a large
This is consistent
prospective study of
with the findings of
patients with cirrhosis.
this study (2.5%
and 5.2%,
They reported that HCC
respectively).
developed in 2.1% of
patients with Child–Pugh
class A disease after SVR at
one year, which increased
to 5.7% at two years.
 Comparison with Other Studies
• Nakao et al. reported six • We also focused on five
patients who developed cases with large HCC that
rapidly growing HCC after developed within six
DAA treatment, with a months after the start of
DAA treatment.
moderate pathological
degree of tumor • However, our cases had
high AFP levels before DAA
differentiation in all six treatment and the AFP
patients. levels increased even after
starting DAA treatment.
Our cases also had
advanced liver fibrosis,
based on the FIB-4 index,
Risk factor of HCC Occurance from this
study

Male These risk factors have been

previously reported in patients
treated with IFN-based therapy

Old Age
Risk Factor Wang et al, suggested that
GGTP was associated with DNA
High GGTP damage, genomic instability,
and genetic mutation by
increasing the uptake of iron,
leading to the progression of
High FIB-4 HCC
Weakness Our Study

Accurate comparison of
HCC occurrence rates
requires comparison with
the rate in patients not
receiving treatment;

however, it is not
ethically possible to
conduct such a study.
CONCLUSION
 The results of this However, HCC
prospective study development still occurs.
suggested that achieving Careful follow-up is
SVR by DAA treatment important in patients with
reduces the incidence of risk factors.
HCC

Old age, male sex, high Patients with large and early
serum GGTP level, and tumor occurrence did not
receive sufficient diagnostic
high FIB-4 index were
imaging. We recommend
important risk factors to enhanced abdominal CT or MRI
predict the occurrence of before treatment with DAAs is
HCC. initiated.
TERIMA KASIH