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Page 4 of 9 Yoo et al. Hepatoma Res 2020;6:9 I http://dx.doi.org/10.20517/2394-5079.2019.49

propensity score-matched analysis (three-year incidence: 3.3% in IFN-based therapy and 1.4% in IFN-free
[21]
therapy; P = 0.49). In a study from France, Nahon et al. . published a report about the incidence of HCC
after DAA for HCV in patients with cirrhosis included in surveillance programs The retrospective cohort
study included 1270 patients with biopsy-proven cirrhosis and classified into DAA group (n = 336), SVR-IFN
group (n = 495), and non-SVR group (n = 439). The three-year cumulative incidences of HCC were 5.9% in
the DAA group, 3.1% in the SVR-IFN group, and 12.7% in the non-SVR group (HR: 2.03, 95%CI: 1.07-3.84,
P = 0.03 for the DAA group vs. the SVR-IFN group). However, under propensity score matched analysis,
there was no significant increase in risk of HCC for DAA use (HR: 0.89, 95%CI: 0.46-1.73, P = 0.735). The
DAA group was older, and had a higher rate of diabetes or portal hypertension than SVR-IFN group. These
features suggested that a more advanced liver disease, older age, and higher rates of comorbidities favor liver
[22]
carcinogenesis. Yoo et al. published similar comparative data of de novo HCC occurrence in DAA group
and IFN group. The cumulative incidence of HCC occurrence was not different between DAA group and
[23]
IFN group (P = 0.827). In USA, Singer et al. analyzed 30,138 patients receiving DAA treatment, 137,502
patients without any treatment, and 12,948 patients receiving IFN treatment. This study revealed that DAA
treatment was associated with a reduced risk of HCC compared to IFN treatment after performing inverse
probability of treatment weighting (adjusted HR: 0.69, 95%CI: 0.59-0.81).

[25]
[24]
In 2019, the debate on the interplay between DAA and HCC continued, and Carrat et al. and Ide et al.
published prospective cohort studies. In the former study in France, 7344 patients with DAA treatment,
[24]
and 2551 patients without treatment were enrolled . DAA treatment seems to increase the risk of HCC
(HR: 2.77, 95%CI: 2.07-3.71). However, after adjustment for variables, DAA treatment was associated with a
decrease in HCC (adjusted HR: 0.66, 95%CI: 0.46-0.91) and all-cause mortality (adjusted HR: 0.48, 95%CI:
[25]
0.33-0.70). A prospective study from Japan by Ide et al. enrolled 2552 patients who were treated with
DAAs and achieved a SVR. The three-year cumulative incidence of HCC was 4.9% in all patients, 10.0% in
patients with cirrhosis, and 2.9% in patients without cirrhosis. They concluded that DAAs do not increase
the risk of HCC occurrence after achieving SVR.

THE INTERPLAY BETWEEN DIRECT-ACTING ANTIVIRALS AND RECURRENCE OF

HEPATOCELLULAR CARCINOMA
HCC is treated with curative treatment or non-curative interventions according to tumor stage, liver
function, and performance status. After curative treatment such as surgical resection for HCC, the risk of
recurrence is 60%-70% at five years [26,27] . Several studies have shown that adjuvant IFN therapy after curative
treatment can reduce the recurrence rate of HCC [28-32] .

The papers published on the HCC recurrence after DAA treatment are organized in Table 2. Despite
[13]
expectations that achieving SVR after DAA treatment will reduce the recurrence of HCC, Reig et al.
reported an unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing
DAA therapy in 2016. The study included 58 patients with prior history of treated HCC with complete
response who lacked “non-characterized nodules”. They reported unexpected high recurrence rate of
[14]
27.6% and median time from DAA start to recurrence was 3.5 months (range 1.1-8 months). Conti et al.
published another similar report about early recurrence of HCC. In this retrospective cohort study, the
recurrence rate of HCC after completing DAA therapy was 28.81% (17 of 59 patients, 95%CI: 17.76-42.07)
during the 24-week post-treatment evaluation. Fifty-nine patients with a history of previous HCC included
11 patients who received transarterial chemoembolization”. This term has only been mentioned once for
previous HCC. The study indicated that patients previously treated for HCC still have a high risk of tumor
recurrence.

Opposite opinions to the previous paper were subsequently published. One prospective study used three
[33]
French multicenter ANRS cohorts . The DAA group and untreated group were analyzed and the rate