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Page 8 of 12 Rutledge et al. Hepatoma Res 2019;5:31 I http://dx.doi.org/10.20517/2394-5079.2019.19

tolerate and achieve viral clearance with IFN therapy were a very well-compensated group with minimal
liver disease. Indeed, we observed that the entire IFN-treated group was significantly younger and had less
cirrhosis, less diabetes and lower Child-Pugh scores than DAA-treated patients. This echoes many of the
other previously published studies [20-23] . In our meta-analysis of hazard ratios, after adjusting for a number
of risk factors for HCC, we found that the rates of de novo HCC were lower in the DAA-treatment group
compared to IFN-treated, although this did not reach statistical significance. This finding reinforces the
hypothesis that “higher-risk” patients receive treatment with DAA agents than were treated with IFN in
the past, thus leading to selection bias. There has been particular concern about the rates of HCC recurrence
following DAA treatment, which were felt to be even more pronounced than the risk of de novo HCC [12,14,24] .
However, we found no increased risk of HCC in DAA-treated patients compared with IFN-treated patients,
and after adjusting for risk factors such as age and cirrhosis, the DAA-treated group trended towards a
lower rate of recurrent HCC, although this did not reach statistical significance.

Our meta-analysis excluded any studies with less than one year of follow-up after end-of-treatment;
[25]
this rigorous exclusion was not performed in another recent meta-analysis . We believe that helped to
mitigate any increase in rates of “early” HCC post-treatment due to sub-clinical HCC which may have
been present prior to the initiation of antiviral therapy. We also performed a sub-group analysis, whereby
HCC events occurring within six months of end-of-treatment were excluded, and we measured HCC rates
in the second-year post-treatment. Our strict exclusion criteria and subgroup analyses were designed to
mitigate surveillance bias, where patients who undergo treatment for HCV may be monitored more closely
in the months following treatment due to more frequent visits to a hepatologist and may be more likely
to undergo HCC screening with abdominal imaging. Limitations of our study include its retrospective
observational nature thus allowing for confounding variables since many of these studies were not initially
designed to compare rates of HCC, and the heterogeneous nature of the studies which had variable lengths
of follow-up, differing percentages of patients with cirrhosis and different individual DAA treatment
regimens. Furthermore, none of the studies which included both DAA-treated and IFN-treated persons
adjusted for the exact same baseline risk factors for HCC, so this limited the validity of comparing the
studies directly and deriving hazard ratios. There was minimal accounting for indication bias, which is one
of the criticisms of these studies. Finally, there was a disproportionate number of male patients included
in the meta-analysis, due to the high number of subjects in the VA studies: 64,306/93,435 DAA-treated and
50,143/72,486 IFN-treated subjects included in the meta-analysis were acquired from VA-based studies.
Given that the veteran patient population has higher rates of smoking and alcohol use than the general
population, the risk of HCC in this subgroup was likely higher which may have skewed the results (although
approximately equal proportions of DAA and IFN-treated patients were obtained from VA data).

The debate on whether or not DAAs increase the risk of HCC has been ongoing for several years now.
Initial reports from Europe first raised concern, and multiple studies confirming and refuting this theory
have since been published [12-18,26] . The immune theory and liver regeneration theory are some of the most
commonly cited theories for the perceived increase in HCC after treatment with DAA therapy. After
treatment with DAAs, the HCV virus becomes undetectable within days to weeks, far more quickly
than with IFN-based therapy. It has been suggested that clearing the hepatitis virus rapidly with fall in
antigenic load removes the immune surveillance (with CD8+ T cells for example) which protected against
[27]
the development of neoplasia . It is also thought that as the liver regenerates rapidly after viral clearance,
[28]
small sub-clinical tumors or areas of metaplasia may grow and become clinically evident .
Small case series have found that tumors are more likely to be multi-focal and tend to have a more aggressive
[29]
biology in DAA-treated individuals compared to IFN-treated or untreated subjects. Romano et al. describe
a particularly aggressive HCC pattern at diagnosis after DAA treatment. In 39% of the 27 patients treated
with DAA therapy who developed HCC, there was an infiltrative pattern or more than three nodules present