Page 290 - Read Online

Page 2 of 13 Harrod et al. Hepatoma Res 2019;5:28 I http://dx.doi.org/10.20517/2394-5079.2019.15
[5]
fibrotic effect of the virus undoubtedly playing a role . Involvement of a direct mutagenic mechanism in
addition to this is purely speculative at this stage, though animal and human models have demonstrated
[6-8]
a potentially increased risk of HCC development in the non-cirrhotic HCV-positive patient . Though
HCV is a RNA-virus that cannot integrate into the host genome, it produces gene products that have been
shown to have mutagenic effects in ex vivo human models, with further work in human models required to
establish how this translates to in vivo processes [9,10] .

Following HCV clearance, patients see a reduction in liver-related morbidity and death [11,12] . This has also
been shown in HCV-cirrhotic patients with successfully treated HCC, in which hepatic decompensation
has been found to be the major driver of death, highlighting the importance of preserving liver function in
[13]
this group . Understanding how HCV clearance might impact upon the pro-carcinogenic environment
remains uncertain, though this will likely become clearer as our understanding of the post-SVR liver
progresses.

The timing and duration of HCV treatment in patients with HCC is becoming increasingly important,
though guidance generally remains that we should make these decisions on a case-by-case basis. Another
consideration is the interaction between HCC and HCV treatments, particularly with the swelling tide of
HCC treatments waiting to break.

HCV TREATMENT REGIMENS
HCV evokes a strong T cell-mediated reaction in the acute phase that successfully clears the virus in 30%
of patients. In the remaining 70% of patients, multiple viral escape mechanisms - including inactivation
[14]
of pathways that induce interferon - overwhelm the immune system, resulting in chronic infection .
Endogenous interferons are part of our natural arsenal against viruses, which explains the previous
successes of exogenous interferon (IFN) in the treatment of HCV. Prior to 2011, prolonged courses of IFN
were the mainstay of treatment outside of clinical trials for those infected with HCV, with or without
concomitant ribavirin, with success rates ranging between 5%-50% depending on duration of therapy, stage
of liver disease and genotype [15-17] . The exact mechanism by which ribavirin targets HCV is not completely
[18]
understood, but is thought to have an effect on viral replication . The addition of ribavirin improved
outcomes but these regimens were poorly tolerated by many and improved alternatives were desperately
sought.

The management of HCV has transformed over the past decade, with sustained virologic response
(SVR) rates in excess of 95% following treatment with newer directly-acting antiviral agents (DAAs) .
[18]
Mechanistically, DAAs inhibit viral replication by inhibiting certain non-structural viral proteins, ultimately
resulting in viral clearance . DAA use has become more widespread and, with that, our understanding of
[19]
their interaction with other treatments will improve.

Prior to the use of DAAs, IFN-based regimens were used in certain subgroups of patients, with significant
histopathological improvements seen following successful treatment. It is more difficult to assess post-SVR
histopathological changes as we are no longer required to perform pre-treatment biopsies as we were in the
IFN-era. However, when assessing histopathology within 2 years of treatment, though there is suggestion
[20]
of fibrosis regression, persistent inflammatory activity has been observed despite the absence of the virus .

Interferon-based therapies and HCC
Historical treatment with IFN-based therapies targeted patients with little or no fibrosis; a low-risk
[21]
group in terms of HCC development . In patients with advanced fibrosis or cirrhosis that were treated
with maintenance pegylated interferon (PEG-IFN) in the HALT-C trial, it was noted that maintenance