Direct-acting Antivirals Reduce the Risk of Tumour Progression of Hepatocellular Carcinoma After Curative Treatment

Hiroko Ikenaga; Sawako Uchida-Kobayashi; Akihiro Tamori; Naoshi Odagiri; Kanako Yoshida; Kohei Kotani; Hiroyuki Motoyama; Ritsuzo Kozuka; Etsushi Kawamura; Atsushi Hagihara; Hideki Fujii; Masaru Enomoto; Norifumi Kawada

Disclosures

J Viral Hepat. 2022;29(1):52-59. 

In This Article

Results

Patient Characteristics

We identified 558 patients with HCV-related HCC diagnosed for the first time. After adjusting for the inclusion and exclusion criteria, 165 patients were included in the analysis. After curative treatment for HCC, 72 patients received DAA therapy (DAA-treated group) and 93 patients did not (untreated group). Baseline characteristics are listed in Table 1. The median age was 72 years (interquartile range [IQR], 67–77), and 96 patients (58.2%) were men. Surgical resection for HCC was performed in 32.1% of patients. Patients in the DAA-treated group had lower FIB-4 index (p = .001) and ALBI score (p = .03), higher platelet level (p = .003) and were more likely to undergo surgical resection (p < .001). Most patients (84.2%) had genotype 1 HCV infection.

The median follow-up period was 27.2 (IQR 11.0–49.4) months: 21.2 (IQR 7.7–43.7) months in the untreated group and 39.4 (IQR 20.9–58.9) months in the DAA-treated group. The median time from the HCC treatment to the initiation of DAA therapy was 8.0 (IQR, 5.4–30.8) months, wherein 33.3% were treated within 6 months, 29.2% were treated within 6–12 months, 9.7% were treated within 1–2 years, and 27.8% were treated for more than 2 years after HCC treatment.

Tumour Progression

We recorded 47 incidences of tumour progression in the untreated group and nine in the DAA-treated group. Among them, 29 (51.8%) involved more than 4 nodules in the liver, 13 (23.2%) were due to portal invasion, 8 (14.3%) were due to extrahepatic metastasis, and 6 (10.7%) were due to deterioration of hepatic reserve. A total of 22 (39.3%) cases were detected at first recurrence, 17 (30.4%) were at second recurrence, and 17 (30.4%) had more than three recurrences. The one-year, 3-year- and 5-year tumour progression rates were 7.1%, 35.7% and 54.5%, respectively, in the untreated group and 5.9%, 9.2% and 17.1%, respectively, in the DAA-treated group (Figure 2A). The annual incidence rate of recurrence was 14.0% in the untreated group and 4.1% in the DAA-treated group (Table 2).

Figure 2.

Cumulative incidence of tumour progression (A) and liver-related mortality (B) by Kaplan-Meier analysis. Tumour progression was defined as when HCC in Barcelona Clinic Liver Cancer (BCLC) stage 0/A progressed to BCLC stage B–D

Liver-related Mortality

A total of 31 and 3 liver-related deaths were detected in the untreated and DAA-treated groups, respectively. The 1-year, 3-year and 5-year liver-related mortality rates were 0.7%, 13.7% and 40.2%, respectively, in the untreated group and 1.5%, 3.5% and 10.0%, respectively, in the DAA-treated group (Figure 2B). The annual incidence of liver-related death was 6.42% in the untreated group and 1.05% in the DAA-treated group (Table 2).

Recurrence at new Foci

A total of 67 and 29 recurrences at new foci were detected in the untreated and DAA-treated groups, respectively. In the untreated group and the DAA-treated group, 48/67 (71.6%) and 24/29 (82.8%) recurrences at new foci were detected as BCLC stage 0/A. The 6-month, 1-year and 2-year recurrence at new foci probabilities were 4.0%, 21.4% and 42.9%, respectively, in the untreated group and 6.6%, 18.7% and 25.3%, respectively, in the DAA-treated group (Figure S2).

The Frequency of HCC Treatment

Until tumour progression, 278 HCC treatments were performed in the untreated group (66 resection, 166 ablation, and 46 TACE) and 52 HCC treatments were performed in the DAA-treated group (7 resection, 30 ablation and 15 TACE). The annual incidence of HCC treatment was 82.8% in the untreated group and 23.9% in the DAA-treated group (HR 0.30; p < .001) (Table 2).

Predictors of the Tumour Progression, Liver-related Mortality and Recurrence at new Foci

DAA-induced SVR was associated with a reduction in the risk of tumour progression in univariate analysis (HR 0.27, 95% confidence interval [CI] 0.13–0.57, p < .001) and multivariate analysis (HR 0.28, 95% CI 0.13–0.61, p = .001) after adjusted for age, number of tumours, Child-Pugh score, FIB-4 index, AFP and type of HCC treatment (Table 3). DAA-induced SVR was also associated with a reduction in the risk of liver-related death in univariate analysis (HR 0.11, 95% CI 0.03–0.38, p < .001) and multivariate analysis (HR 0.12, 95% CI 0.04–0.40, p < .001) (Table 4). On the contrary, DAA-induced SVR was not associated with a decrease in the risk of recurrence at new foci by univariate (HR 0.69, 95% CI 0.45–1.06, p = .09) and multivariate analysis (HR 0.68, 95% CI 0.43–1.08, p = .10) (Table S1).

The FIB-4 index was associated with the risk of tumour progression (HR 1.10, p = .004), liver-related mortality (HR 1.14, p = .004) and recurrence at new foci (HR 1.06, p = .02).

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