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Harrod et al. Hepatoma Res 2019;5:28 I http://dx.doi.org/10.20517/2394-5079.2019.15 Page 7 of 13

Figure 2. Advantages and disadvantages of treating HCV prior to or post-liver transplantation [33,35]

[35]
therefore pose a disadvantage in terms of wait-list time, thus allowing potential for tumour progression .
[35]
This is particularly relevant in locations with high volumes of HCV-positive liver donors [Figure 2].
In addition to the potential impact on HCC outcomes, an impact on HCV outcomes has been
demonstrated in patients receiving DAA therapy pre- vs. post-transplant [Figure 2]. One recent large
retrospective study demonstrated a difference in SVR rates between pre- and post-transplant treated
[34]
patients, with the latter seeing improved clearance . In terms of liver transplantation, there are certainly
advantages and disadvantages of treating HCV prior to HCC [Figure 2], which should be considered on an
individual basis.

The evidence to date offers a compelling argument for considering treatment of the HCC before treatment
of HCV. These findings require further data in order to make concrete recommendations in terms of HCV
treatment timing, and each case should still be reviewed on an individual basis.

DAAs and systemic therapies
There is a paucity of data regarding concomitant use of DAAs and the systemic agents used in advanced
HCC. Sorafenib was the breakthrough targeted therapy first used in the treatment of advanced HCC
and although its effect on median overall survival does not extend life expectancy beyond one year, it is
yet to be superseded a decade after the seminal SHARP trial [56-58] . Sorafenib is a multi-kinase inhibitor
[59]
with a potent inhibitory effect on c-Raf . NS5a - a non-structural protein produced by HCV that is
[60]
integral in viral replication - has been shown to bind to cRaf and, studied in vitro, inhibition of cRaf
by sorafenib effectively blocks HCV replication . Multiple other mechanisms of sorafenib inhibition of
[59]
HCV replication, such as alteration of the viral entry step, the production of viral particles and Claudin-1
downregulation, have been demonstrated [61-63] . Though the antiviral effect of sorafenib in human studies
to date have been disappointing, this association has not yet been excluded [56,64,65] . Interestingly, Sorafenib
has been shown to provide a greater benefit in overall survival in HCV patients when compared to other
[66]
aetiologies of liver disease . Newer drugs including lenvatinib, a multi-kinase inhibitor, in the front-line
and regorafinib, cabozantinib (both multi-kinase inhibitors) and ramucirumab (an antiVEGFR mAb) in
[67]
the second-line have been incorporated into new guidelines and are now increasing in use , but their
potential interactions with DAA regimens have been explored still less.

As many trials for the new DAA regimens excluded patients with HCC, there is a little data on the
[68]
interaction between targeted therapies and DAAs . One small case series noted that there were no