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Page 8 of 13 Harrod et al. Hepatoma Res 2019;5:28 I http://dx.doi.org/10.20517/2394-5079.2019.15

deleterious effects in combining ombitasvir/paritaprevir/ritonavir and dasabuvir, either in terms of anti-
[69]
neoplastic effect or SVR rate , but more studies are required to assess these interactions.

DAAs and immunotherapy
Though markedly different pathological processes are involved in chronic hepatitis C and the development
of HCC, there are some similarities between the two when considering the role of the immune system,
[70]
with T cell exhaustion implicated in both . CD8+ T cells are integral in targeting and destroying both
tumour cells and cells infected with HCV. T cell exhaustion exists to protect from tissue damage due to
persistent and overzealous immunological response to antigens and is driven by upregulation of negative
co-stimulatory pathways. With these pathways in action, key T cell effector processes are disrupted, they
[70]
become tolerant of antigenic stimuli and ultimately apoptose . T cell exhaustion is particularly efficient in
T cells that are activated in the liver, causing the immunotolerant state required in an organ that encounters
many antigenic threats. Chronic inflammation and development of cancer have both been shown to be
associated with T cell exhaustion. These negative co-stimulatory pathways are multiple, including PD1,
CTLA4, Tim3 and LAG3 - targets that are under scrutiny for potential new pharmacological options in the
treatment of HCC. Inhibition of these targets aims to unlock the potential of these T cells to reinvigorate
the immune cells. Though PD1 inhibitors in particular are now commonly associated with the treatment of
HCC, they have also been trialled in the treatment of HCV in the past, with some success . More studies
[71]
assessing the impact of anti-PD1 immunotherapy on active HCV infection are required to fully understand
its role in viral response. Multiple ongoing clinical trials using anti-PD1 antibodies are currently allowing
patients with untreated HCV to enrol, which may go some way to answering this question. Nivolumab, a
[72]
human monoclonal IgG4 antibody against PD1, is showing promise as a treatment in advanced HCC .
It has also been trialled in chronic HCV infection, showing a persistent suppression of HCV RNA in a
subgroup of patients . Pembrolizumab, another anti-PD1 monoclonal antibody, has also recently been
[71]
granted accelerated FDA approval for the treatment of advanced HCC, with promising results in the
Keynote-224 study .
[73]
In addition to the impact of immunotherapy treatment of HCC on DAA treatment of HCV, we must also
consider the opposite, as there is growing research showing the impact of DAAs on immune cells both
within the liver and peripherally [74,75] . From this, we might extrapolate that this in turn may impact on the
immune surveillance in this population, thus may affect HCC treatment outcomes. Currently the clinical
impact of the immune environment and altered immune surveillance is not clear, but insight into these
[74]
processes in the post-DAA liver is improving, which may be crucial in how we shape our treatment .

Increased research into the immune environment in the post-DAA treated liver is vital to understand the
potential impact viral clearance may have on HCC treatment response and vice versa. The effect of HCC-
targeted immunotherapy on DAA treatment of HCV is not well-studied, but it would be interesting to see
the impact on HCV treatment, and vice versa, be it synergistic, deleterious or non-existent.

Timing of HCV treatment in advanced HCC
As previously discussed, timing of HCV treatment when considering curative options has been the
source of some controversy, as the decreased efficacy of DAAs seen in the context of HCC offers a
compelling argument for treating HCV after treatment of the tumour. In advanced HCC, the chance of
cure is marginal and so delaying treatment of HCV for this reason is not practical. In patients where life-
expectancy is significantly limited, the risk vs benefit of treating HCV at all must be considered. AASLD
guidance recommends that patients with limited life expectancy within 12 months are unlikely to benefit
[76]
from HCV eradication and therefore palliative measures should take precedence in this setting . This
will include patients with decompensated liver disease and advanced hepatocellular carcinoma. For those
with a better prognosis, HCV eradication prior to sorafenib treatment of HCC may prolong post-progression