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Page 8 of 10 Iliescu et al. Hepatoma Res 2018;4:3 I http://dx.doi.org/10.20517/2394-5079.2017.48

In our study, the occurrence of HCC in patients treated with DAAs was noted during therapy, as well as at
the end and also three months after completing it. Older age, comorbidities, advanced fibrosis are all factors
that should be taken into consideration when analyzing the increased risk of developing HCC. The mean
age of the participants included in our study was 60.29 ± 11.19 years, and more than 60% of them had an F4
degree of fibrosis, which may justify the occurrence of HCC in these cases. The risk of HCC development in
patients with compensated cirrhosis in our study group is consistent with literature data . However, in spite
[3]
of the HCC occurrence, SVR was achieved in all the patients that continued antiviral therapy.

It is worth mentioning that, while the alpha interferon based regimens activate natural killer (NK) cells, the
DAAs rapidly decrease the levels of HCV RNA, thus leading to a blockage in NK cells activation . This way,
[21]
the protective effect of the inflammatory mechanisms is lost and liver regeneration as well as carcinogenesis
may appear . There is also evidence showing an elevated level of vascular endothelial growth factor after
[22]
[23]
the initiation of IFN-free treatment .
Given the fact that most of the HCC cases found in our study were detected in the first month of therapy,
the hypothesis that the tumors were already there, before starting the DAA treatment, simply becoming
radiologically detectable after initiating the therapy, should be taken into consideration.

The imaging of HCC is complicated and may have limitations, especially in the early stages, as the tumor has
a variety of radiologic appearances and may coexist with regeneration and dysplastic nodules in the cirrhotic
liver. In patients with HCC diagnosed during or at the end of DAA therapy, it is most likely that the tumors
were already there, mainly due to their dimensions at the time of diagnosis. However, this only emphasizes
the importance of ultrasound and AFP follow-up, even during antiviral therapy. In this case, we do not
consider that the initial evaluation of these patients should have included a mandatory CT scan, as it has not
been proven to be cost-effective; also, a hypothetical mandatory imagistic evaluation would not be CT scan,
but liver MRI, with further increases of the imbalance cost-effectiveness. In patients diagnosed with HCC
after achieving SVR, it is most likely that the tumors developed during or after antiviral therapy. They were
of small dimensions and all presented the infiltrative pattern previously discussed.

Therefore, we recommend the usage of a combination of ultrasound and serum AFP as a primary surveillance
method for HCC, especially in cirrhotic patients. If abnormalities are detected by these methods, further
exploration by CT and MRI is required.

In conclusion, the use of DAAs is not associated with a decrease in the development of HCC. Therefore,
the screening for HCC should not be stopped after achievement of SVR, as IFN-free treatments cure the
viral infection, not the liver disease itself. Patients who develop HCC after antiviral treatment need to be
evaluated by MRI in order to detect the extension of the disease as these tumors are more often infiltrative.
More studies should be undoubtedly performed, before determining the association between DAA therapy
and HCC development.

DECLARATIONS
Authors’ contributions
Concept and design: Iliescu EL, Mercan-Stanciu A, Toma L
Data acquisition: Mercan-Stanciu A, Toma L, Rusie D
Data analysis: Iliescu EL, Ioanitescu ES, Dumitru R
Manuscript preparation: Iliescu EL, Mercan-Stanciu A, Toma L
Critical revision and finalizing of the manuscript: Iliescu EL