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Galicia-Moreno et al. Hepatoma Res 2020;6:20 I http://dx.doi.org/10.20517/2394-5079.2019.36 Page 13 of 18

of topoisomerase II [101] . Its use though is not recommended by many clinical guidelines such as AASLD or
EASLD. In Latin America, patients receiving doxorubicin with arterial embolization have a 58% survival
[5]
rate at 2 years . In patients with advanced HCC however, doxorubicin administration failed to improve
[5]
survival . The combined effects of doxorubicin and sorafenib have been studied but favorable results were
not obtained because of higher toxicity, mainly cardiotoxicity and neutropenia [102] .

Interferon
These are agents with an immunomodulatory and antiproliferative effect on tumor cells in HCC. Adjuvant
interferon (IFN) therapy has been demonstrated to reduce the recurrence of HCC, but does not improve
the survival of HCV-related HCC patients. IFN is effective in intermediate and advanced HCC patients [103] .
In terms of survival, tumor response and toxicity, IFN administration is superior to doxorubicin in patients
with HCC.

IFN has several properties including antiviral, anti-tumor, and immunomodulatory effects [104] . Three IFN
subtypes have been identified: type 1 (IFN a and b), 2 (IFN-g), and 3 (IFN-λ), but only IFN-type 1 is used in
[103]
the treatment of chronic viral hepatitis to reduce the risk of HCC in patients infected with HCV . Evidence
was first obtained from a randomized controlled trial with 90 patients where IFN treatment was effective
in decreasing the incidence of HCC [105] . In patients with HCV-related cirrhosis treated with IFN, there was
a sustained virological response (SVR) after treatment that in turn, resulted in improved clinical outcomes
including a lower risk of decompensation and HCC development [106] .

In Latin America and according to the LAASL, the preventive effect of antiviral therapy in patients with
HCV is more effective when using pegylated IFN plus ribavirin, which achieves higher SVRs. It is important
to note however, that chronic administration of low dose pegylated IFN, without achieving SVR, fails to
[5]
reduce the risk of HCC .
Direct acting antivirals
As previously mentioned, chronic HCV is the leading cause of HCC worldwide. The implementation of
in vitro replication models using sub-genomic replicons and the cell culture system of HCV enabled the
discovery and development of direct-acting antivirals (DAAs) for the treatment of chronic HCV. These
antivirals have considerably improved the sustained viral response in the treatment of all HCV genotypes,
with cure rates of more than 95% [107] . Treatment with DAAs in Latin America lagged behind Europe, Asia
and North America but results have been really good in terms of viral eradication. Nevertheless, this must
still be interpreted with caution since the number of studies in Latin America are still scarce.

In a multicenter study performed in Latin America to evaluate the association between DAAs and HCC
waitlist progression or its recurrence following liver transplantation (LT) between 2012 and 2018, 503 patients
without chronic HCV and 481 patients with chronic HCV were recruited (197, 19, 24, 180, 18, 5, 45 and 3
patients each from Argentina, Uruguay, Chile, Brazil, Mexico, Peru, Colombia and Ecuador respectively).
From these HCV patients, 327 were not treated with DAAs while 164 were. The most commonly used DAA
+
regimen was sofosbuvir/daclatasvir in 68.3% (112) of patients, followed by peritaprevir/ritonavir/ombitasvir/
dasabuvir in 12.2% (n = 20), and sofosbuvir/ledipasvir in 6.7% (n = 11). The overall SVR was 89.8% 95%CI
(81.0-97.1), which was not statistically different between patients treated before 90.6%CI (83.9-94.1) or after
transplantation 89.2%CI (80.4-94.9). While the patients were on the waiting list period, 13.4% (n = 66) of HCV
patients received DAA treatment and 86.6% (n = 425) did not. The cumulative incidence of HCC progression
was 24.2% (n = 222). Patients treated with DAAs before LT presented a similar cumulative incidence of
+
tumor waitlist progression when compared with the HCV untreated DAA group (26.2% vs. 26.9% P =
0.47); both had a similar HCC drop-out rate [12.1%CI (0.4-8.1) vs. 12.9 %CI (3.8-27.2)]. A non-significant
but numerically higher proportion of patients with pre-LT DAAs presented with extrahepatic progression