Page 85 - Read Online

Page 4 of 8 Pazgan-Simon. Hepatoma Res 2020;6:17 I http://dx.doi.org/10.20517/2394-5079.2019.52

AASLD pointed out that patients with cirrhosis and HCC have lower SVR rates than those with cirrhosis
without HCC. Longer regimens may improve treatment response. Patients with compensated cirrhosis
should be treated with sofosbuvir/ledipasvir or sofosbuvir/velpatasvir (with ribavirin) for 12 weeks. In those
[8,9]
with decompensated cirrhosis and HCC, the above treatment regimen should be extended to 24 weeks .
GLOBAL HEALTH SECTOR STRATEGY ON VIRAL HEPATITIS
In 2016, the WHO published the global health sector strategy on viral hepatitis which aims at reducing viral
hepatitis-related mortality. The strategy aims to identify 80% of HCV and HBV infected patients and start
treatment in 80% of them, to minimise the risk of infection during blood transfusion and phlebotomy, as
well as to ensure access to sterile injecting equipment for people who inject drugs by 2030. Available, easy-
to-administer treatments increase the chances to effectively implement this strategy in relation to HCV
infection. Many countries, such as Georgia and Australia, have already approached the targets set by the
WHO for 2030.

CARCINOGENESIS IN PATIENTS AFTER DAA TREATMENT - MOLECULAR ASPECTS
As the HCV does not embed in human genome, it does not exert a direct carcinogenic effect.

There is a number of hypotheses to explain the development of primary liver cancer after DAA treatment.
The first of them assumes that DAA causes rapid virus clearance, which results in immune dysfunction,
cytokine activation, dysregulation of apoptosis and reactive oxygen species which, in turn, stimulate
[9]
angiogenesis directly involved in tumour growth .

DAA treatment is associated with rapid viral clearance and modulating antiviral immunity in favour of
promoting oncogenesis. DAAs change the risk of HCC by facilitating restoration of innate immunity,
downregulation of interferone II and III genes and their receptors, as well as reducing the mi-R-122 levels,
[10]
which promotes proliferation .
The evidence seems to indicate that carcinogenesis after DAA therapy is associated with HCV-induced
imbalance between life- and apoptosis-promoting factors.

Viral clearance is associated with expression of a number of apoptosis-regulating genes, such as TP53, FAS,
TGF, VEGF, which trigger tumour development and spread. Furthermore, other genes, such as HGF, ROS
and FGF stimulate and upregulate angiogenesis.

In the case of antiviral drug resistance, natural killer (NK) cell dysfunction leads to virus proliferation and
reduced expression of interferon genes, disrupting natural defence mechanisms. Decreased interferon gamma
levels stimulates carcinogenesis, while impaired interferon gene expression results in HCC development.

Another hypothesis postulates that carcinogenesis occurs in response to cytotoxic cell silencing caused
by transient immunosuppression during viral clearance. As NKG2D expression on NK cells plummets in
response to DAA treatment, HCC develops.

The immune markers present at baseline, which are associated with a higher risk of HCC, include the TNF
alpha, which is constantly secreted in patients with HCC, unlike cancer-free patients, in whom TNF alpha
suppression has been shown [Table 2].

HCC OCCURRENCE IN PATIENTS TREATED WITH DAA
In 2016 and 2017, shortly after the first DAA approval, first reports of post-SVR development of HCC in
patients with cirrhosis treated with DAA were published [Table 3]. However, the study groups in these