Page 117 - Read Online

Zanetto et al. Hepatoma Res 2018;4:70 I http://dx.doi.org/10.20517/2394-5079.2018.102 Page 7 of 16

[50]
[51]
Conversely, Kozbial et al. and Cardoso et al. reported their experiences, from Austria and Portugal re-
spectively, of an unexpectedly high incidence of HCC, which however remained isolated reports. Addition-
ally, the whole cohorts’ baseline characteristics were unavailable and patients with F3 fibrosis were included,
making it impossible to compare these results with other studies.

After the initial rush to report on small populations with short follow-ups, some longer-term studies on
larger cohorts have begun to emerge. One recent study using real-world data found DAA-based HCV treat-
ment unassociated with any increased risk of incident liver cancer. This risk even seemed to be lower than
in either untreated or IFN-treated patients, suggesting that the benefits of DAA treatment will become more
[52]
apparent with time. In the study by Singer et al. , after adjusting for gender, age and disease stage, DAA
treatment was associated with a significantly lower risk of liver cancer by comparison with no treatment (ad-
justed hazard ratio (HR) = 0.84, 95% CI: 0.73-0.96), or IFN-based treatment in the pre-DAA era (HR = 0.69,
[53]
95% CI: 0.59-0.81). Using the Electronically Retrieved Cohort of HCV-Infected Veterans database, Li et al.
found that, among the cirrhotics with a SVR, neither the HCC incidence rate nor HCC-free survival differed
significantly between the DAA and IFN groups (P = 0.78; and log-rank, P = 0.17). Both treated groups had a
significantly lower probability of developing HCC than the untreated group (log-rank, P = 0.0004).

In short, though extremely heterogeneous, the above-mentioned studies seem to suggest (with the exception
of a few isolated cases) that, regardless of how it is achieved, a SVR lowers the likelihood of HCC, albeit to a
different degree depending on the stage of liver disease. Once a SVR has been achieved, it seems that comor-
bidities and lifestyle begin to have a major role, and should therefore be taken into account.

[21]
Taking another perspective, Cucchetti et al. estimated the influence of DAA regimens on patient mortality
using a Markov model. They found DAA-based antiviral treatment associated to a drastic reduction in mor-
tality unrelated to cancer before any onset of HCC, with only a slight increment in the HCC occurrence rate.
The 20-year mortality due to causes other than HCC dropped by 21.9% in patients without varices, and by
27.5% in those with varices. Thus, assuming the cancer risk remains unchanged, the larger number of survi-
vors generated a longer lifetime risk of developing HCC.

HCC RECURRENCE
DAAs vs. no treatment
[35]
The first warning came from a Spanish multicenter study showing a high rate of HCC recurrence in com-
pensated cirrhotic patients considered to be in oncological remission after undergoing resection (34.5%),
ablation (55.2%), and trans arterial chemoembolization (10.3%), and receiving DAA treatment, with a me-
dian follow-up of 5.7 months. This finding was supported by the same authors’ comparisons of HCC recur-
rence rates, after surgical resection in one prospective study (in which HCC recurrence rates at 4 months
were 13.5% in high-risk patients, and 3.8% in low-risk cases), and after ablation in another prospective series
(unpublished data) (2.45% at 4 months and 27.6% at 12 months), as well as in the double-blind, placebo-
[54]
controlled STORM trial . Interestingly, the highest rate of recurrence (41.17%) was seen in patients with a
short interval (< 4 months) between HCC treatment and latest imaging assessment of complete response. In
[55]
this regard, Cammà et al. analyzed the data in the Reig study, and showed that the probability of HCC re-
currence during the first 6 months after starting DAAs was twice as high for patients with a shorter interval
between their HCC treatment and their latest assessment of complete response compared with patients with
longer intervals (< 15%). This may mean that the high early tumor recurrence rate described by Reig and co-
workers was driven largely by individual cases, including those initially observed, initiated on DAAs shortly
after being treated for HCC.

[35]
The paper by Reig et al. was not the only one to suggest that particular attention should be paid to manag-
[37]
ing patients with HCC receiving DAA treatment. Conti et al. confirmed that DAA-induced HCV eradica-