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Page 2 of 12 Rutledge et al. Hepatoma Res 2019;5:31 I http://dx.doi.org/10.20517/2394-5079.2019.19

Conclusion: We did not find evidence for increased rates of HCC in DAA-treated compared with IFN-treated patients.
Compared to those treated with IFN, older patients with additional risk factors for HCC were treated with DAAs.
This imbalance appears to explain the higher numerical incidence of HCC among DAA-treated patients.

Keywords: Humans, hepatitis C virus, liver cirrhosis, liver neoplasms, interferons

INTRODUCTION
[1]
Hepatocellular carcinoma (HCC) is the fastest rising cause of cancer-related death in the United States .
In most developed countries, chronic hepatitis C virus (HCV) infection is the leading risk factor for HCC.
Approximately half of the increase in HCC cases in the United States may be accounted for by the aging
[1]
cohort with chronic HCV infection . Though the presence of cirrhosis is an important risk factor for the
[2]
development of HCC in HCV-infected individuals, HCV itself may have pro-carcinogenic properties .
Specifically, the virus induces tumor development indirectly via inflammatory and pro-fibrotic host
responses and may also exert direct oncogenic effects upon the infected cell, via deregulation of host cell
[2]
checkpoints, oxidative stress and DNA damage .
Patients with HCV-related cirrhosis have a risk of developing HCC, estimated at 3%-5% per year . The
[3]
risk is further enhanced by alcohol misuse, diabetes mellitus, obesity and coinfection with hepatitis B or
HIV . Studies have shown that achieving sustained viral response (SVR) after interferon (IFN) treatment
[4,5]
[6-8]
reduces the risk of HCC to 0.5%-1% per year . It was originally believed that IFN reduced the risk via
antiviral as well as direct anti-tumor effects but non-sustained responders to IFN do not achieve the same
[9]
reduction in HCC risk . This may be related to the fact that IFN delays the development of HCC but does
not prevent it in the presence of persistent viremia and cirrhosis.

With the FDA approval of IFN-free regimens in 2014, it was anticipated that the risk of HCC would be
further reduced due to their high SVR achievement rates (upwards of 95% compared to approximately 56%
with pegylated-IFN and ribavirin regimens) [10,11] . Thus it was surprising when several sentinel European
reports published in 2016 raised concern for increased rates of HCC in patients treated with IFN-free
direct-acting antiviral (DAA) regimens. Most of the studies reported increased rates of HCC recurrence
but a few reported increased rates of de novo HCC. Some of these tumors were diagnosed within weeks to
months of DAA treatment and several studies observed that tumors were unusually aggressive and locally
invasive on imaging [12-15] . Later, conflicting studies were published that did not show evidence of increased
risk of HCC, with follow-up periods of up to 15 months [16-18] .

However, all the studies had significant limitations. They were observational in nature, each with small
numbers of patients. They evaluated heterogeneous populations with varying numbers of patients with
cirrhosis. The question was raised as to whether the perceived increased risk was an artifact of selection
bias, whereby older patients with more advanced liver disease and additional risk factors for HCC are being
treated with DAA than would historically been treated in the era of IFNs.

The development of a safe, efficacious and well-tolerated treatment has revolutionized the landscape of
HCV treatment. Patients treated with DAAs have been shown to have lower rates of decompensation and
model for end-stage liver disease (MELD) score progression than those not treated with DAA agents [16,19] .
Finding a correlation between DAAs and HCC development or recurrence would have major implications.
Thus, to find a more definitive answer to this question, we compared rates of HCC occurrence and
recurrence in DAA-treated persons with IFN-treated and untreated patients in a meta-analysis of all
published studies.