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Page 2 of 8 Yang et al. Hepatoma Res 2020;6:31 I http://dx.doi.org/10.20517/2394-5079.2019.45

INTRODUCTION
It is estimated that 71 million people have chronic hepatitis C virus (HCV) infection, which can lead to
[1]
liver cirrhosis and hepatocellular carcinoma (HCC) . It seems reasonable that HCV eradication would
reduce the risk of HCV-related complications including HCC. Cirrhosis is the major risk factor of HCC
[2]
and about 3% patients with HCV related cirrhosis develop HCC annually . In the past decades, pegylated
interferon combined with ribavirin (PR) has been widely used for the treatment of HCV. Despite the
sustained virological response (SVR) rates associated with PR therapy not being high enough, and
[3]
relatively more adverse events reported, studies have demonstrated that interferon (IFN)-induced SVR
[4]
could reduce HCC incidence . The annual incidence of HCC is mostly less than 2% in cirrhotic patients
[5,6]
achieving SVR after IFN-based regimens .
Direct-acting antivirals (DAAs) have fundamentally changed HCV therapy because of their high efficacy
and tolerability, even in the patients with cirrhosis [7-9] . In these studies, patients with SVR showed
improvements in disease severity and mortality. In 2016, relatively high rates of HCC occurrence and
recurrence were reported after the success treatment of HCV using DAAs [10,11] . Since then, this has been a
highly controversial topic.

This review article summarizes the relevant articles focusing on the impact of DAAs on de novo occurrence
of HCC in HCV patients. We searched the MEDLINE electronic database using the search terms [“hepatitis
C” (MeSH)], (“direct-acting antivirals”), and [“hepatocellular carcinoma” (MeSH)] from the start of the
database (1996 year) until April 19, 2020. Searches were limited to human studies written in English.
Eligible study designs included retrospective or prospective observational cohort studies, randomized
controlled trials and interventional studies. Figure 1 shows the study flow chart.

STUDIES SUPPORTING HIGH RATES OF HCC OCCURRENCE AFTER DAAS TREATMENT
Table 1 summarizes the studies supporting high rates of HCC occurrence after DAAs treatment [11-14] .
[11]
Conti et al. from Italy reported that HCC was detected in 3.2 % (9/285) cirrhotic patients at 24-week
follow-up after DAAs therapy. Ravi et al. from the United States (US) reported that 9.1% (6/66 patients)
[14]
[12]
of cirrhotic patients developed HCC within six months of DAAs treatment. Studies from Portugal and
[13]
Austria also reported high rates of HCC occurrence after DAAs treatment. This data raised concerns that
DAAs may promote the development of HCC. However, these studies were underpowered because of their
retrospective design, lack of untreated or IFN controls, small sample size, and limited follow-up time.

POSSIBLE MECHANISMS OF HCC OCCURRENCE AFTER DAAS TREATMENT
There is a complex equilibrium between pro tumor factors such as HCV and inflammation and anti-tumor
factors such as the immune system. A rapid reduction in the HCV viral load by DAAs treatment might
impair immune surveillance, resulting in the development of HCC. Serti et al. reported DAAs treatment
[15]
[16]
was associated with a rapid decreased activation of natural killer cells. Meissner et al. reported that
HCV clearance by DAAs treatment was accompanied by down regulation of IFN-stimulated genes and the
levels of type II and III IFNs. The serum level of microRNA-122, a regulator of HCV replication and tumor
suppressor against HCC , decreased in patients with IFN-free therapy induced SVR . Debes et al.
[18]
[17]
[19]
reported a panel of cytokines, apoptosis markers, and growth factors with higher levels before DAAs
therapy in patients with new HCC compared with controls. Interestingly, their results suggested that the
immune background rather than DAAs mediated immune modulation would lead to HCC development.
STUDIES AGAINST HIGH RATES OF HCC DEVELOPMENT AFTER DAAS TREATMENT
From 2016, many retrospective and prospective cohort studies with larger sizes and greater follow-up
duration after DAAs therapy were published. Table 2 summarizes the studies not supporting high rates