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Page 4 of 8 Lee et al. Hepatoma Res 2020;6:21 I http://dx.doi.org/10.20517/2394-5079.2019.44

[61]
North America (304 received DAA therapy vs. 489 received no HCV therapy) published by Singal et al.
showed no association between DAA therapy and HCC recurrence (HR = 0.90; 95%CI: 0.70-1.16).

[62]
Dang et al. reported a 60%-70% improvement in 5-year all-cause and liver-related mortality in HCV-
[14]
related HCC patients after DAAs with SVR, compared to patients untreated for HCV. Singal et al.
hypothesized that, by decreasing HCV viral load and slowing or preventing liver decompensation, DAA
therapy could reduce the risk for late HCC recurrence.

ACTIVE HCC EFFECT ON SVR, AND TIMING OF DIRECT-ACTING ANTIVIRAL THERAPY
Lower HCV SVR rates were reported in the presence of HCC [63-69] . It is speculated that the low HCV SVR
rates were due to altered inflammatory state in the tumor microenvironment, DAA uptake into hepatocyte,
resistant profiles in the context of HCC, immune escape mechanism, HCC reservoir, and penetration of
DAAs to HCV-infected HCC tissue [63,69] .

[70]
Although Ahmed et al. showed that pre-liver transplant HCV treatment with DAAs provided great
outcomes and the most cost-effective management for CHC patients with HCC or decompensated cirrhosis
while waiting for liver transplant in the US, a study on US veterans with HCV observed an SVR rate of 74.4%
[64]
in patients who received DAAs during active HCC compared to 91.1% in patients without HCC . Deferring
DAA therapy until six months after completion of either liver resection or ablation is recommended in HCC
[14]
patients who are eligible for curative HCC treatment .
[71]
Radhakrishnan et al. using HCV-TARGET database demonstrated a 50% reduced SVR in HCV patients
with HCC, but SVR was not different among patients who received complete, partial, or no treatment at all.

Median wait time, availability of hepatitis C-positive organ, and severity of liver decompensation are
the determinants of timing of DAA therapy in HCV-associated HCC patients who are on the liver
transplantation (LT) list. DAA therapy for patients awaiting LT is usually deferred until after transplant so
[14]
patients will be eligible to receive an HCV positive donor .
Reduced liver-related deaths on LT waiting list and decreased progression of liver disease from post-
transplant HCV reinfection by DAA have been observed [72,73] . Some patients treated by DAAs with SVR
while awaiting LT had sufficient improvement in liver function to receive other curative therapies or forego
[76]
transplant [73-75] . Although Yang et al. suggested DAAs might be associated with a higher rate of HCC
recurrence post-LT in a small group of patients, Emamaullee and colleagues demonstrated that HCV
eradication pre-LT did not impact rates of delisting for HCC progression or rates of HCC recurrence post-
[77]
LT in a larger retrospective study .

DAA THERAPY IN PATIENTS WITH UNTREATED ADVANCED HCC
Limited data are available regarding the use of DAAs in hepatitis C patients with untreated advanced HCC.
A theoretical benefit from DAAs in this setting is that it may improve liver decompensation and allow
continued HCC therapy. Tumor burden, life expectancy, and patient preference need to be considered for
[14]
DAA therapy since it is palliative .
SUMMARY
Highly potent DAAs in recent years have revolutionized hepatitis C treatment and have high SVR rate
exceeding 90%. Numerous studies have shown that DAA-induced SVR reduces risk of hepatitis C-associated
HCC. Although recent research demonstrated no increased risk of HCC in HCV patients after DAA
with SVR, the HCV-TARGET database and other resources, such as DAA manufacturers’ database and