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Page 6 of 9 Moghe et al. Hepatoma Res 2018;4:36 I http://dx.doi.org/10.20517/2394-5079.2018.54

radiologic tumor recurrence. Those results implied that DAA therapy increased the recurrence rate of treated
HCC. In another study of 344 cirrhotic patients without HCC (59 with treated HCC and complete response)
who received DAA, 91% achieved SVR . During a follow-up period of 24 weeks, 26 (8%) were noted to
[39]
have HCC - 17/59 (29%) with previous HCC and 9/285 (3%) without previously diagnosed HCC. The rate
of HCC recurrence was higher compared to historical controls. In a retrospective study of HCV patients
with cirrhosis and treatment with DAA, the development of de novo HCC was examined . De novo HCC
[40]
was noted in 9% of the patients during or within 6 months of DAA therapy with new indeterminate lesions
in another 3%. The authors concluded that as this rate exceeded the previously reported rate of 3% within
6 months of completing treatment, DAA appeared to increase the risk of de novo HCC development. In
contrast, an analysis of data from three French prospective multicenter cohorts did not show an increased
risk of HCC recurrence following DAA therapy . The cohorts included more than 6000 patients treated
[41]
with DAA. Among patients with previously treated HCC, the rate of HCC recurrence was similar in patients
who received DAA vs. those who did not receive DAA.

More recently, two large retrospective studies provided more definitive evidence of the effect of SVR induced
by DAA on the development of HCC. In a study of 22,500 patients treated with DAA at any of the 129 US
Veterans Health Administration (VHA) hospitals, 39% were noted to have cirrhosis . New HCCs were
[42]
noted in 271 patients including 183 with SVR. Overall, annual HCC incidence was 1.19/100 person-years
with significant reduced risk of HCC among patients with SVR compared to those without SVR (0.9 vs.
3.45/100 person-years). Although, patients with cirrhosis had the highest annual incidence of HCC after
SVR (1.82 vs. 0.34 in patients without cirrhosis), the protective effect of SVR was similar among patients with
or without cirrhosis. The second study was conducted by our group at Veterans Affairs Healthcare System
Pittsburgh using the “Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES)” database
that is populated with a wide range of clinical information pertaining to veterans seropositive for HCV .
[43]
We identified 17,836 patients without prior HCC - 3534 received interferon-based therapy, 5734 received
DAA and 8468 patients constituted the control untreated group. SVR was achieved by 67% of the interferon
treated group and 96% of the DAA treated group. Among patients with cirrhosis who achieved SVR, HCC-
free survival was similar in the interferon treated and DAA treated groups. Both groups had improved HCC-
free survival compared to the untreated group. The two studies established that DAA induced SVR reduced
the risk of HCC development; however, absolute HCC risk remained high among patients with cirrhosis.

The divergence of conclusions reached in the studies is intriguing. Earlier reports of increased HCC
recurrence and de novo HCC following DAA induced viral clearance were based on smaller cohorts which
were likely affected by selection bias. The reported increase in HCC was explained on the basis of changes in
hepatic microenvironment. It was postulated that rapid viral clearance induced by DAA stunned immune
surveillance that was characteristic of chronic hepatitis C. The resulting disruption in immunomodulation
allowed niches of dormant neoplastic cells to proliferate unchecked. A direct effect of DAA on cancer
cell growth was also proposed . In contradistinction to those studies, the two VHA studies reported
[44]
beneficial effects of DAA induced SVR. Despite the limitations of retrospective design, the considerable
size of the study cohorts provided a more definitive evidence of the beneficial effect of DAA induced SVR
on development of HCC.

SUMMARY
Patients with advanced hepatic fibrosis or cirrhosis due to hepatitis C are at considerable risk of HCC. Viral
clearance induced by interferons was noted to effect significant risk reduction for HCC development. In
contrast, an increase in de novo HCC and HCC recurrence was reported following SVR achieved with DAA.
More recently, two large studies provided convincing evidence for the beneficial effect of DAA induced SVR