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Page 4 of 14 Russo et al. Hepatoma Res 2018;4:25 I http://dx.doi.org/10.20517/2394-5079.2018.52

DAA AND HCC: JUST FICTION?
On the other hand, other published articles did not confirm the higher occurrence or recurrence of HCC
in patients treated with IFN-free, DAA-based therapy. Strong evidence against this assumption was given
by three French prospective multicentre studies by the Agency for Research on AIDS and Viral Hepatitis
(ANRS in the French acronym) cohorts of DAA-treated HCV-infected patients treated with curative HCC
[21]
therapies . In detail, the rates of recurrence in the ARNS CO22 HEPATHER cohort (including 189 DAA+
and 78 DAA- patients) were 0.73/100 and 0.66/100 person-months respectively in the DAA+ and the DAA-
group. In the ARNS CO12 CirVir cohort, the rates were 1.11/100 in 13 DAA+ and 1.73/100 person-months in
66 DAA-. Finally, the ARNS CO23 CUPILT cohort of HCC liver transplant recipients, successively treated
with IFN-free antiviral therapy, showed a recurrence rate of 2% (7/314 patients). Notwithstanding the large
number of patients that were analysed in these studies, no increase in the risk of HCC recurrence after
antiviral therapy was detected in any of the cohorts. The recurrence rates did not differ between treated and
[22]
untreated patients. A sharp criticism towards the ANRS study design was made by Kolly and Dufour
stating that it artificially decreased the rate of HCC recurrence in untreated patients. The ARNS collaborative
group argued, as a defence of the accuracy of the design of the study, that treatment was considered as
time-dependent variable and that patients who underwent treatment were considered part of the untreated
[23]
group until the therapy started . A study in an English cohort, including more than 400 treated patients,
[24]
supported the French findings. Also, Cheung et al. , after a follow-up of 12 months, revealed a reduction
in HCC rates after HCV eradication in DAA-treated patients. The preliminary data of another prospective
observational study of patients with liver cancer and HCV infection treated with DAAs, show no HCC
[25]
recurrence after curative treatment in a median follow-up of 12 months . Furthermore, the study by
[26]
Zavaglia et al. did not confirm the alarming findings of Reig and Conti: amongst the 31 patients they
followed, they only observed 1 case of liver cancer, with a median follow-up of 8 months. The longer interval
between complete HCC curative treatment and antiviral therapy (median 19 months in Zavaglia’s experience
vs. 11 months in Reig’s study) could partly explain the contrasting results. It appears that, the longer the
interval between tumor eradication and antiviral therapy initiation, the lower the risk that residual tumoral
[26]
cells are still present at the beginning of DAA treatment , and this is highly conceivable.
[27]
Cabibbo et al. in a prospective study of 143 patients with previously successfully treated HCC, then treated
with DAAs, showed 6-, 12- and 18-month recurrence rates of 12%, 26% and 29.1% respectively; in this group
of patients, the authors found comparable results to those observed in DAA-unexposed patients. Previous
history of HCC recurrence (HR: 2.22; 95%CI: 1.02-4.83; P = 0.043) and tumor size (HR: 2.73; 95%CI: 1.23-
6.06; P < 0.014) were the two independent risk factors for HCC early recurrence that could be used to stratify
[28]
the risk of HCC recurrence. A large amount of data was analysed by Waziry et al. in a meta-analysis
and meta-regression analysis based on 41 studies: no evidence of increased HCC occurrence or recurrence
risk after DAA therapy vs. INF-based therapy was found. HCV eradication was confirmed to decrease
HCC risk in patients who achieved SVR, whereas older age, advanced cirrhosis and worse patient baseline
characteristics in DAA-treated population were independent predictors of HCC development and provide
an explanation of the apparently higher risk (3.1 vs. 1.1/100 per years). Another study was conducted by
[29]
Ioannou et al. on a large cohort of HCV infected cirrhotic patients from the Veterans Affairs national
healthcare system, treated with IFN regimen alone, DAA regimen or INF+DAAs, during a 6.1 years mean
follow-up. A 71% HCC occurrence risk reduction was associated with DAAs-induced SVR compared to
treatment failure, but the reduction was similar, irrespective of how SVR was achieved (DAA-only AHR: 0.29;
95%CI: 0.23-0.37; DAA + INF AHR: 0.48; 95%CI: 0.32-0.73; IFN-only: 0.32; 95%CI: 0.28-0.37). Maan and
[30]
Feld are also amongst the authors supporting the association between SVR achievement and HCC risk
reduction due to the analysis of a retrospective study on cohorts of veterans treated with DAAs. In a study
[31]
by Kobayashi et al. , 77 patients treated with DAAs, who achieved SVR, were compared to 528 patients who
underwent viral eradication with Peg-IFN/RBV during a median follow-up of 4 years. Amongst DAA-treated
patients, 2.6% developed liver cancer, while the 3- and 5-year cumulative HCC development rates were 1.30%