Page 291 - Read Online

Harrod et al. Hepatoma Res 2019;5:28 I http://dx.doi.org/10.20517/2394-5079.2019.15 Page 3 of 13

therapy did not reduce the risk of HCC development [22,23] , though this and other studies have shown that
reduction of HCV RNA correlated to a reduction in HCC risk, which reduced further still in cases of
HCV eradication [23-26] . Further to this, IFN-based treatment may decrease the HCC recurrence rate in
[17]
successfully treated HCC patients following curative therapy . A speculative link has been drawn between
the inhibitory effect of IFN on HCC proliferation, which may have an additional impact on HCC outcomes
to the antiviral effect of IFN [17,27] .

Current HCC treatment guidance is widely dictated by the Barcelona Clinic Liver Cancer (BCLC) criteria,
which stratifies liver cancer cases into stages based on tumour burden, liver disease and performance
[28]
status, allocating treatments accordingly . Curative treatments include resection, locoregional therapy
(LRT) or liver transplantation for those that fall within Milan criteria. Outside of this, palliative LRTs,
targeted systemic therapies or immunotherapy are the recommendation in advanced HCC.

Some work has been done to assess the role of IFN as an adjuvant agent in post-resection cases, with
promising early results in terms of mortality [29-32] . In the DAA era, the use of IFN-based regimens has
declined drastically and so, even in the absence of evidence for a similar role for DAAs, using IFN in this
context is unlikely to be recommended. Some debate continues over timing of HCV treatment in this
subset of patients; these medications are in their infancy and many questions remain that may take time to
address.

DAAs and HCC
DAAs have revolutionised HCV treatment with SVR rates exceeding 95%. In the presence of HCC, SVR rates
[33]
are lower at 60%-90% , the reasons for which are current sources of speculation [Figure 1] [33-35] . Certainly, the
tumour microenvironment expertly creates multiple mechanisms of immune escape in order to survive and
so it stands to reason that HCV-infected cells within the tumour may evade antiviral treatment in the same
vein. In addition to this, it has been proposed that penetration of DAAs to the HCV-infected HCC tissue
is suboptimal, not only due to altered architecture but also as tumour blood supply is from the hepatic
arterial branches as opposed to the portal venous system [Figure 1]. As original trials for newer DAAs
[35]
often exclude patients with HCC from their eligibility criteria, data on this cohort is limited. Subsequent
data has shown a decrease in SVR rates, though how this might shape our treatment regimens - be it
duration or drug combination - is not yet clear.

Some of the discordance between studies may be due to the fact that some of the studies that have shown
association between active HCC and lower SVRs included DAA regimens with sub-optimal combinations
(e.g., SOF/RBV). It will be important to assess SVR rates in this population with the new generation of
DAAs.

DAA regimen adaptations for HCV in the context of HCC
Recent data on efficacy of DAAs in patients that have concurrent HCC suggests that SVR rates are lower
than those in the absence of HCC [35-40] . This includes both patients that respond and then relapse, as well
as primary non-responders. It is, therefore, unclear whether these lower SVR rates are due to inadequate
duration of therapy, treatment resistance or a combination thereof [Figure 1]. With this in mind, further
trials are required to guide our treatment approach in this cohort of patients, be it prolonged courses of
DAA therapy or treatment combinations.

HCC post-DAA treatment
Some initial concerns regarding allegedly high rates of HCC after DAA-induced SVR compared with
IFN-induced SVR have caused controversy . This could be explained by altered immune surveillance
[41]
in the post-DAA liver environment, which may alter T cell responses and therefore have an impact on