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Table 3. Risk factors for occurrence/recurrence of HCC
Author/Study design Occurrence/Recurrence Risk factors for the development of HCC
Conti et al. [14] Occurrence No associate factor
Recurrence Age, liver stiffness
Kanwal et al. [17] Occurrence non-SVR, alcohol use, non-African Americans, cirrhosis
9
Calvaruso et al. [18] Occurrence Albumin < 3.5 g/dL, platelet count < 120 × 10 /L, absence of SVR
Romano et al. [19] Occurrence Positive for HBsAg, APRI score ≥ 2.5, CPC B, treatment failure
Nagata et al. [20] Occurrence IL-28 genetic polymorphism, post-treatment WFA*M2BP
Recurrence IL-28 genetic polymorphism, post-treatment WFA*M2BP
Nahon et al. [21] Occurrence non-SVR, older age, excessive alcohol consumption, lower platelet count, high
GGT levels, HCV genotype 1
Ioannou et al. [42] Occurrence non-SVR, cirrhosis
Yoo et al. [22] Occurrence Alpha-fetoprotein level > 9.5 ng/mL
Singer et al. [23] Occurrence Older age, male gender, cirrhosis, thrombocytopenia, portal hypertension,
diabetes, tobacco use, alcoholic liver disease
Carrat et al. [24] Occurrence Untreated, non-SVR
Ide et al. [25] Occurrence Age ≥ 62 years old, male gender, FIB-4 index ≥ 4.6, and GGTP level ≥ 44 IU/L
Cabibbo et al. [34] Recurrence Main tumor size > 2.5 cm, history of prior recurrence
Nishibatake Kinoshita et al. [35] Recurrence Higher lens culinaris agglutinin-reactive fraction of alpha-fetoprotein level,
a history of multiple HCC treatments, and a shorter interval between HCC
treatment and initiation of antiviral therapy
Singal et al. [37] Recurrence No associate factor

HCC: hepatocellular carcinoma; SVR: sustained virological response; CPC: Child-Pugh Class; HCV: hepatitis C virus; IFN: interferon

[20]
The retrospective cohort study from Japan by Nagata et al. analyzed 60 patients in the IFN-based therapy
group and 83 patients in the IFN-free therapy group. The incidence of HCC recurrence after locally curative
treatment was not significantly different between IFN-based and IFN-free therapy groups by propensity
score-matched analysis (five-year incidence: 54.2% in IFN-based and 45.1% in IFN-free therapy, P = 0.54).
[35]
Nishibatake Kinoshita et al. enrolled HCC patients previously treated with radiofrequency ablation (147
patients in DAA group and 156 patients in IFN group). The rate of HCC recurrence at one and two years
was 39% and 61% in IFN group and 39% and 60% in DAA group, respectively (P = 0.43). There was also no
significant difference between the two groups after performing matching analysis (P = 0.68). To compare the
[36]
rate of HCC recurrence between the patients who received DAA and IFN-based therapies, Waziry et al.
published meta-analyses study containing 17 studies. The incidence of HCC recurrence after SVR was 9.21
per 100 person-year in DAA group and 12.16 per 100 person-year in IFN group. After adjusting analysis,
DAA treatment was not associated with HCC recurrence (Relative risk: 0.62, 95%CI: 0.11-3.45, P = 0.56). To
[37]
solve this debate firmly, a large study from USA and Canada was published by Singal et al. in 2019. In total,
793 patients with HCV-associated HCC, including 304 patients who received DAA and 489 patients without
treatment, were analyzed. HCC recurred in 42.1% patients in the DAA group and 58.9% in the untreated
group. Although DAA treatment seems to decrease the risk of HCC recurrence (HR: 0.32, 95%CI: 025-0.41),
after accounting for time-varying exposure, DAA treatment was not associated with increasing or decreasing
the risk of HCC recurrence after complete response (HR: 0.90, 95%CI: 0.70-1.16).

RISK FACTORS FOR OCCURRENCE/RECURRENCE OF HEPATOCELLULAR CARCINOMA

AFTER TREATING WITH DIRECT-ACTING ANTIVIRALS
In most of the studies on the interplay between DAA and HCC, non-SVR, advanced liver disease, and
older age were associated with risk of HCC. Table 3 contains the risk factors for development of HCC.

In a report about the early occurrence and recurrence of HCC in HCV-related cirrhosis treated with DAA,
Child-Pugh class (OR: 4.18, 95%CI: 1.17-14.8, P = 0.03) and history of HCC (OR: 12.0, 95%CI: 4.02-35.74,
P < 0.0001) were associated with HCC development. There was no significant factor in patients without
history of previous HCC, while age (OR: 0.82, 95%CI: 0.69-0.97, P = 0.02) and liver stiffness (OR: 1.19,