Page 280 - Read Online

Russo et al. Hepatoma Res 2018;4:25 I http://dx.doi.org/10.20517/2394-5079.2018.52 Page 9 of 14

A study showed a high risk of HCC recurrence in patients treated with DAAs before liver transplantation (LT)
(5 of 18 patients, 28%) compared to untreated (6 of 63 patients, 9.5%). However, the difference did not reach
[38]
statistical significance because of the small number of patients enrolled , a series definitely too limited to
provide any information.

[39]
Belli et al. published data from a European study, investigating the probability of delisting after DAA
treatment. In this study the cumulative incidences of inactivation and delisting at 60 weeks were 33% and
[40]
19.2% respectively. In another recent study published by Pascasio et al. , 238 patients treated with DAAs
while awaiting LT were enrolled, and 24% of the patients with decompensated cirrhosis were delisted after a
median follow-up period of 50 weeks, as a result of clinical improvement, which appeared to remain stable
in most patients. Indeed, only 9% of the patients were delisted because of HCC progression and the rate of
microvascular invasion was 11%, similar to what reported in previous studies. Although these data do not
indicate an increase in HCC progression, the lack of untreated patients as a control group is a limitation.
As a consequence, the use of DAA therapy in HCC patients awaiting LT cannot be strongly recommended.
As far as SVR is concerned, in the above-mentioned study SVR rates were similar in patients with and
without HCC (87% vs. 84%, P = 0,560), and amongst patients with HCC there were no significant differences
regarding tumor characteristics or BCLC staging comparing those with or without SVR.

In a recent retrospective study, conducted at the Padua Liver Transplant Centre, we investigated whether
patients, listed for HCC and treated with DAAs, have an increased rate of tumor progression and
consequently drop out from waiting list. Two groups (including 23 patients each) were evaluated, who
underwent DAA therapy while awaiting LT or not. The two groups did not show any significant difference
in terms of dropout rate, during a median follow-up of 10 and 7 months. Interestingly, a significantly lower
probability of being transplanted was detected in the group of treated patients in comparison with the
untreated, suggesting an improvement of liver function. With regard to post-LT recurrence of HCC, similar
rates were found in the two groups (12.5% in DAA-treated vs. 8.3% in untreated group), suggesting that the
risk of tumor recurrence was not higher in patients treated with DAA pre-LT than in those treated post-LT.
[41]
Furthermore, liver explant histopathological analysis revealed similar HCC patterns in the 2 groups .

DAA AND HCC: HISTOLOGICAL PATTERN
[10]
Reig et al. in their pivotal study also expressed concern about the histological pattern of HCC recurrence
[42]
in patients treated with DAA therapy. In agreement with Reig’s study, Romano et al. demonstrated that
about 30% of HCC presented with an infiltrative and/or multifocal pattern in a multi-centre cohort of
cirrhotic patients treated with DAAs, even though their data on HCC incidence were in contrast with Reig’s
results. The more aggressive pattern of HCC was seen somehow more frequently (54.6%) in patients without
SVR compared to those with SVR (12.1%) in which the single nodule pattern prevailed (69.7%).

[43]
Nakao et al. also investigated the pattern of HCC recurrence and de novo development, reporting six
cases of de novo HCC out of 242 patients. All of the patients had been submitted to DAAs treatment, and
all showed SVR. In all six cases HCC was pathologically diagnosed, allowing inferences about tumor
characteristics and kinetics. All tumours were single nodules, moderately differentiated and rapidly growing,
the authors were therefore led to hypothesize that HCC carcinogenesis after DAA therapy occurs in a non-
conventional, multi-step manner.

DAA AND HCC: ONLY IMMUNOLOGICAL ISSUE?
It is recognized that the immune system plays a key role in modulating tumour development, but a report
[44]
by Debes et al. attempted to distinguish the immuno-related changes by measuring 22 different soluble
immune mediators in patients who developed HCC (both de novo and recurrent) after HCV treatment