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Rutledge et al. Hepatoma Res 2019;5:31 I http://dx.doi.org/10.20517/2394-5079.2019.19 Page 7 of 12

Figure 4. Rates of recurrent HCC by treatment group and SVR status. Colored bars represent rates of recurrent HCC by SVR status, with
95%CIs depicted by the capped vertical black lines. Rates of recurrent HCC were as follows: DAA group, overall: 16.76/100py (95%CI:
10.75, 22.91), SVR: 18.17/100py (95%CI: 3.84, 33.58) and non-SVR: 44.16/100py, (95%CI: 0.006, 90.35). IFN group, overall: 14.31/100py
(95%CI: 10.17, 19.16), SVR: 11.01/100py (95%CI: 4.85, 17.63), non-SVR: 16.89/100py (95%CI: 10.05, 24.02). Untreated group:
25.69/100py (95% CI: 14.44,37.27). “Overall” group included some patients not included in SVR or non-SVR groups. SVR: sustained viral
response; HCC: HCC: hepatocellular carcinoma; CI: confidence interval; IFN: interferon; DAA: direct-acting antiviral

Study Name
CO22 HEPATHER
CO12 CirVir
Huang et al.
lkeda et al.1997
Virgoleux et al.

Figure 5. Adjusted hazards ratio of risk of recurrent HCC in DAA- vs. IFN-treated populations. The multivariate-adjusted hazard ratio
of each individual study is represented by the blue square with the size of the square being proportional to the n of the study. The thin
horizontal grey bars represent the 95%CI of each study and the thick vertical blue line marks where the HR is equal to 1. The red diamond
with the dashed vertical red line is the overall adjusted HR, which was 0.59 (95%CI: 0.24, 1.03) for recurrent HCC in the DAA population
compared to the IFN-treated population. IFN: interferon; DAA: direct-acting antiviral; HCC: hepatocellular carcinoma

14.62/100py, (95%CI: 8.94, 20.52). Again, when we take the second-year rates post-treatment, we saw
similar recurrence rates [DAA group: 6.66/100py (95%CI: 1.96, 12.11) and IFN group: 5.35/100py, (95%CI:
0.54, 11.06)]. Our additional meta-analysis of the five studies with multivariate analyses found that the
unadjusted HR of recurrence in DAA vs. IFN-treated groups was 0.59 (95%CI: 0.11, 1.14) and after adjusting
for age, gender, baseline AFP, ethnicity and Child-Pugh score, the HR was 0.59 (95%CI: 0.24, 1.03) [Figure 5].

DISCUSSION
Our study is the largest meta-analysis to evaluate the risk of HCC after treatment with DAA therapy
published to date. The results demonstrate that the risk of de novo HCC is similar between IFN- and DAA-
treated cohorts. In the sub-group analysis by SVR, non-SVR IFN and non-SVR DAA groups had similar
rates of de novo HCC, although the confidence interval for the DAA cohort was wide because of the very
small numbers who did not achieve SVR. Those who achieved SVR with IFN had a significantly lower rate
of HCC occurrence than the DAA-treated SVR group. We postulate that this is because patients who could