Abstract
Whether direct-acting antivirals (DAA) provide comparable survival benefit with interferon (IFN)-based therapy remains unclear. The aim of this study was to compare the outcomes after achieving SVR by IFN-based and DAA therapy after resection of HCV-related hepatocellular carcinoma (HCC). Consecutive 285 patients receiving curative resection for HCV-related HCC were retrospectively enrolled, including 103 (36.1%) and 69 (24.2%) patients with IFN-based and DAA therapy, respectively. Factors associated with recurrence, overall survival (OS) and hepatic decompensation-free survival were evaluated. The SVR rate of DAA was 95.7% in HCC patients. During a median follow-up period of 49.6 months, 102 (35.8%) patients died and 63 (24%) developed hepatic decompensation. By multivariate analysis, SVR by DAA or IFN-based therapy was not associated with early or late HCC recurrence. Achieving SVR (by IFN-based therapy: HR=0.321, P<0.001; by DAA: HR=0.396, P=0.011), BCLC stage B-C (HR=1.914, P=0.024), FIB-4 score >3.25 (HR=1.664, P=0.016) and microvascular invasion (HR=1.603, P=0.048) were independent predictors of OS. Achieving SVR (by IFN-based therapy: HR=0.295, P<0.001; by DAA: HR=0.193, P=0.002), BCLC stage B-C (HR=2.975, P=0.001), GGT >70 U/L (HR=1.931, P=0.015) and cirrhosis (HR=2.035, P=0.007) were independent predictors of decompensation-free survival. The benefit of achieving SVR was consistently observed in cirrhotic and non-cirrhotic patients, and in patients with and without HCC recurrence. In conclusion, achieving SVR by either DAA or IFN-based therapy provide comparable and significant reduction of mortality and hepatic decompensation after surgical resection of HCV-related HCC. DAA therapy should be prescribed for all HCC patients after curative surgical resection.
Keywords: Hepatitis C virus, hepatocellular carcinoma, resection, survival, direct-acting antivirals
Introduction
Chronic hepatitis C (CHC) is a leading cause of hepatocellular carcinoma (HCC), which is the fourth leading cause of cancer-related death globally [1,2]. For patients with HCC diagnosed at early stage, surgical resection is the primary treatment choice for patients with compensated liver function, which may provide better overall outcomes and higher chance of long term cure [3,4]. However, the 5-year recurrence rate after curative resection of HCC remains higher than 60% [5], and the 5-year survival rate was reported to be 52-63% in patients with hepatitis C virus (HCV)-related HCC [6,7]. Furthermore, hepatic decompensation after curative resection of HCV-related HCC, which may occur in 10% of patient at 1 year and 44% at 5 years, still contributes to long-term mortality after successful treatment of early HCC [7].
HCV eradication by interferon-based (IFN-based) therapy has been proven to reduce recurrence and prolong survival in patients with HCV-related HCC after curative treatment [8-11]. Recent advent of IFN-free direct-acting antivirals (DAAs) has introduced high sustained virological response (SVR) rates, even for patients with HCC [12,13]. In patients with HCV-related cirrhosis, eradicating HCV by DAA has been reported to improve survival and reduce the incidence of HCC development [14,15]. In patients with HCV-related HCC, previous studies showed that the risk of HCC recurrence after DAA therapy was similar to that observed in IFN-treated or treatment naïve controls [11]. Although DAA therapy had no significant suppression effect on HCC recurrence, recent studies showed that DAA therapy may improve survival in HCC patients undergoing curative treatment [16-18]. The improvement in survival by DAA might be caused by the reduction in hepatic decompensation after surgery [16]. Whether DAA therapy had comparable benefits to IFN-based therapy in reducing mortality and hepatic decompensation after surgical resection remains unclear. The aim of this study was to compare the outcomes of patients who achieved SVR by IFN-based and DAA therapy after curative surgical resection for HCV-related HCC.
Material and methods
Patients
From November 1, 2007 to April 20, 2019, consecutive 299 patients undergoing surgical resection for HCV-related HCC in Taipei Veterans General Hospital were reviewed retrospectively (Figure 1). The inclusion criteria were as follows: age above 20 years old, HCC undergoing surgical resection, and positive anti-HCV. The exclusion criteria were as follows: patients with non-curative resection, combined hepatocellular-cholangiocarcinoma, or died or lost to follow-up within 3 months of surgery. Prior to surgical resection, HCC was diagnosed according to the diagnostic criteria of the American Association for the Study of Liver Diseases (AASLD) by contrast-enhanced computed tomography (CECT) or magnetic resonance imaging (MRI) [3,19], and was confirmed pathologically after surgery. After surgery, patients were followed every 2-3 months with measurement of serum alpha-fetoprotein (AFP), ultrasonography, CECT or MRI. HCC recurrence was confirmed by CECT or MRI.
Figure 1.
Flow diagram of patient enrollment and grouping.
This study complied with current ethical guidelines and standards of the Declaration of Helsinki, and has been approved by the Institutional Review Board, Taipei Veterans General Hospital (IRB number: 2020-07-011BC).
Outcome assessment
Sustained virological response (SVR) was defined as achieving undetectable HCV viral load at 24 or 12 weeks after the end of IFN-based or DAA treatment, respectively. Early and late recurrence were defined as tumor recurrence developed within or beyond 2 years, respectively, after the surgery [20]. Overall survival (OS) was defined as the time from surgical resection to death. Hepatic decompensation was defined as the occurrence of hyperbilirubinemia (total bilirubin >2 mg/dL), variceal bleeding, ascites, or hepatic encephalopathy [16]. Decompensation-free survival was defined as the time from surgical resection to the date of hepatic decompensation. Twenty-three patients with incomplete information of hepatic decompensation were excluded from analysis of decompensation-free survival.
To address the immortal time bias caused by the varied antiviral-surgery interval in the cohort, we adjusted the overall survival and decompensation-free survival, which was calculated from the date of antiviral therapy to death or hepatic decompensation [21].
Laboratory tests and liver histology
The clinical parameters including age, gender, body mass index (BMI), Barcelona Clinic Liver Cancer (BCLC) stage, Child-Pugh score, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transpeptidase (GGT), creatinine, albumin, total bilirubin levels, platelet counts and AFP levels were recorded. Serum AFP was measured by chemiluminescent microparticle immunoassay (ARCHITECT AFP assay, Abbott Ireland Diagnostics Division, Sligo, Ireland). The biochemistry tests were performed using systemic multi-autoanalyzer (Technicon SMAC, Technicon Instruments Corp., Tarrytown, NY). Anti-HCV was detected by enzyme-linked immunosorbent assay (anti-HCV; Abbott HCV EIA 2.0, Abbott Laboratories, Abbott Park, Illinois, USA HCV). HCV RNA was quantified by either Abbott Real Time HCV assay (with detection limit of 12 IU/mL) or Cobas TaqMan HCV Test v2.0 (Roche Diagnostics GmbH, Mannheim, Germany, with detection limit of 15 IU/mL). HCV genotype was determined by commercially available assay (Cobas HCV GT, Roche Diagnostics GmbH, Mannheim, Germany).
An Albumin-Bilirubin (ALBI) grade and fibrosis-4 index (FIB-4) score were calculated as previously described [22,23]. Histological features, such as tumor size, tumor number, Edmonson histological grade, microvascular invasion, hepatic steatosis, Ishak inflammation scores and Ishak fibrosis grades [24] were obtained.
Statistical analysis
All the statistical analysis was performed using the IBM SPSS Statistics V22 (IBM, Armonk, NY). Descriptive statistic values were shown as median (interquartile range, IQR) or as mean ± standard deviation when appropriate. Continuous variable was compared by Mann-Whitney U test or Kruskal-Wallis test. Categorical variable was compared by Pearson chi-square analysis or the Fisher exact test. We used the Kaplan-Meier method to estimate survival rates, and log-rank test to compare survival curves between different groups. Cox proportional-hazards model was used to analyze the prognostic factors. Factors with P<0.1 by univariate analysis were included in the multivariate analysis by forward stepwise Cox proportional-hazards model. A two-tailed P<0.05 was considered statistically significant.
Results
We screened 299 patients with HCV-related HCC undergoing surgery. After excluding the 14 ineligibles, 285 patients were eventually analyzed, including 113 patients without antiviral treatment, 103 patients who received IFN-based treatment and 69 patients who received DAA treatment (Figure 1). The baseline characteristics of the 285 patients were shown in Table 1. The mean age at the time of surgery was 67 years. Majority of the patients were infected with HCV genotype 1 (52.7%) and 2 (42.3%). The median time from surgical resection to antiviral therapy was 3.8 months (IQR: -14.6 to 20.5 months). Nearly half of the IFN-based therapies were conducted before surgery, while majority of the DAA therapies started after surgery. Compared with the IFN-based therapy group, patients in the DAA group were significantly older, female predominant, had significantly higher HCV RNA, AST levels, lower platelet counts, and comprised of a lower proportion of patients with microvascular invasion and higher proportion of patients with poorer hepatic functions in terms of lower albumin levels, higher Child-Pugh score, ALBI grade and FIB-4 score. In 113 untreated patients, 9 of the 24 (37.5%) patients with available HCV viral load data had undetectable HCV RNA. SVR was achieved in 80 (77.7%) and 66 (95%) patients receiving IFN-based therapy and DAA, respectively.
Table 1.
Baseline characteristics of the 285 patients with HCV-related HCC receiving curative surgical resection
| Untreated (n=113, 39.6%) | IFN-based therapy (n=103, 36.1%) | DAA (n=69, 24.2%) | P | |
|---|---|---|---|---|
| Age (years) | 69.3±9.3 | 64.4±8.7 | 67.5±8.7 | <0.001* |
| Sex (male), n (%) | 76 (67.3) | 70 (68.0) | 33 (47.8) | 0.013* |
| BMI (kg/m2) | 24.1±3.9 | 24.9±3.7 | 24.5±3.1 | 0.192 |
| Child-Pugh score 5/6/7, n (%) | 72/41/0 (63.7/36.3/0) | 91/11/1 (88.3/10.7/1.0) | 50/19/0 (72.5/27.5/0) | 0.001* |
| HCV RNA (Log IU/mL)† | 4.74 (1.17-5.90) | 4.87 (3.17-6.02) | 5.80 (5.10-6.51) | <0.001* |
| HCV genotype 1/2/3/6† | 0/4/0/1 (0/80/0/20) | 15/17/0/0 (46.9/53.1/0/0) | 22/9/2/1 (64.7/26.5/5.9/2.9) | 0.010 |
| Antiviral-surgery interval, months | - | 1.4 (-53.0-5.4) | 12.8 (2.5-44.0) | <0.001* |
| Antiviral before surgery, n (%) | - | 55 (53.4) | 12 (17.4) | <0.001* |
| Antiviral after surgery, n (%) | - | 48 (46.6) | 57 (82.6) | |
| 0-12 months after surgery | - | 37 (35.9) | 24 (34.8) | <0.001* |
| 12-24 months after surgery | - | 5 (4.9) | 9 (13.0) | |
| >24 months after surgery | - | 6 (5.8) | 24 (34.8) | |
| Sustained virological response | - | 80 (77.7) | 66 (95.7) | <0.001* |
| Achieved before surgery | - | 41 (39.8) | 10 (14.5) | <0.001* |
| Achieved after surgery | - | 39 (37.9) | 56 (81.2) | |
| 0-12 months after surgery | - | 27 (26.2) | 20 (29.0) | 0.003* |
| 12-24 months after surgery | - | 5 (4.9) | 8 (11.6) | |
| >24 months after surgery | - | 7 (6.8) | 28 (40.6) | |
| BCLC stage 0/A/B/C, n (%) | 7/89/11/6 (6.2/78.8/9.7/5.3) | 11/81/7/4 (10.7/78.6/6.8/3.9) | 5/54/8/2 (7.2/78.3/11.6/2.9) | 0.787 |
| Tumor size (cm) | 3.46±1.93 | 3.77±2.77 | 4.09±3.33 | 0.004 |
| Multiple tumors (>1), n (%) | 20 (17.7) | 18 (17.5) | 17 (24.6) | 0.434 |
| AFP (ng/mL) | 20.7 (6.9-244.5) | 18.3 (5.3-148.6) | 12.4 (5.9-67.7) | 0.251 |
| Albumin (g/dL) | 3.77±0.40 | 4.11±0.43 | 3.89±0.41 | <0.001* |
| Total bilirubin (mg/dL) | 0.71±0.27 | 0.76±0.37 | 0.81±0.36 | 0.411 |
| Albumin-Bilirubin (ALBI) score | -2.510±0.350 | -2.791±0.373 | -2.583±0.386 | <0.001* |
| ALBI grade 1/2, n (%) | 45/68 (39.8/60.2) | 72/31 (69.9/30.1) | 34/35 (49.3/50.7) | <0.001* |
| Platelet count (109/L) | 152±54 | 156±55 | 135±58 | 0.018* |
| ALT (U/L) | 62.5±45.4 | 70.1±64.5 | 67.7±48.0 | 0.511 |
| AST (U/L) | 59.4±38.9 | 54.4±40.9 | 68.1±47.2 | 0.018* |
| GGT (U/L) | 68.3±78.6 | 54.6±52.6 | 56.5±43.8 | 0.190 |
| Creatinine (mg/dL) | 1.04±0.57 | 0.88±0.21 | 1.23±1.78 | 0.048 |
| FIB-4 score <1.45/1.45-3.25/>3.25, n (%) | 5/44/64 (4.4/38.9/56.6) | 12/56/35 (11.7/54.4/34.0) | 1/25/43 (1.4/36.2/62.3) | <0.001* |
| Histological features, n (%)† | ||||
| Edmonson histological grade 1/>1 | 6/106 (5.4/94.6) | 14/88 (13.7/86.3) | 9/60 (13.0/87.0) | 0.089 |
| Microvascular invasion | 73 (66.4) | 66 (64.7) | 30 (43.5) | 0.005* |
| Presence of steatosis | 47 (48.5) | 37 (40.2) | 19 (29.7) | 0.060 |
| Ishak inflammation scores >6 | 26 (23.9) | 17 (16.8) | 5 (7.2) | 0.017 |
| Ishak fibrosis grade 5-6 (cirrhosis), n (%) | 49 (43.4) | 53 (51.5) | 39 (56.5) | 0.200 |
| Median follow-up, months | 42.1 (21.2-68.2) | 65.8 (28.7-90.8) | 49.0 (34.6-81.6) | 0.003 |
| Early recurrence, n (%) | 46 (40.7) | 30 (29.1) | 25 (36.2) | 0.204 |
| Late recurrence, n (%) | 19 (36.5) | 21 (35.6) | 17 (44.7) | 0.632 |
| Death, n (%) | 61 (54.0) | 32 (31.1) | 9 (13.0) | <0.001* |
| Hepatic decompensation, n (%)† | 34 (35.8) | 21 (21.4) | 8 (11.6) | 0.001 |
Quantitative measures are expressed as mean with standard deviation, median (interquartile range) or relative frequency (%). P value represents the comparison of the variables among the untreated, IFN-based therapy and DAA groups.
P<0.05 between IFN-based therapy and DAA groups.
Available baseline HCV RNA data, n=146; available HCV genotype, n=67; available histological features: Edmonson histological grade, n=283; microvascular invasion, n=281; hepatic steatosis, n=253; Ishak inflammation score, n=279; Ishak fibrosis grade, n=285. Eligible for hepatic decompensation analysis, n=262.
Predictors of early and late recurrence
During the median follow-up of 49.6 months, 158 (55.4%) patients developed recurrence of HCC after curative surgical resection, including 101 (35.4%) and 57 (38.3%) patients with early and late recurrence, respectively. In order to study the impact of SVR on early recurrence, patients who achieved SVR after two years of surgery (n=36) were sorted as untreated, while patients who achieved SVR within the first two years after surgery (n=58) were excluded from the analysis of early recurrence. Similarly, 23 patients whose SVR were achieved after two years of surgery were excluded from the analysis of late recurrence.
BCLC stage, SVR by IFN-based therapy, tumor size, tumor number, AFP, GGT and microvascular invasion were factors associated with early recurrence in univariate analysis (Table 2). In multivariate analysis, BCLC stage B-C (hazard ratio (HR=2.862, P<0.001) and tumor size >5 cm (HR=2.694, P<0.001)) were independent predictors of early recurrence.
Table 2.
Univariate and multivariate analyses of factors associated with early recurrence within 2 years after surgery
| Univariate | Multivariate | ||||||
|---|---|---|---|---|---|---|---|
|
|
|
||||||
| HR | 95% CI | P | HR | 95% CI | P | ||
| Age (years) | >60 vs ≤60 | 1.141 | 0.711-1.830 | 0.585 | |||
| Sex | Male vs female | 1.052 | 0.705-1.571 | 0.803 | |||
| BMI (kg/m2) | >27 vs ≤27 | 0.769 | 0.471-1.256 | 0.294 | |||
| BCLC stage | B-C vs A | 2.314 | 1.430-3.743 | 0.001 | 2.862 | 1.649-4.969 | <0.001 |
| Child-Pugh score | >5 vs 5 | 1.292 | 0.840-1.989 | 0.244 | |||
| ALBI grade | 2-3 vs 1 | 1.330 | 0.900-1.965 | 0.153 | |||
| HCV RNA (IU/mL) | >8×105 vs ≤8×105 | 1.110 | 0.622-1.892 | 0.700 | |||
| Achieving SVR* | Non-SVR or untreated | 1 | 0.088 | NS | |||
| Interferon-based | 0.438 | 0.210-0.913 | 0.027 | NS | |||
| DAA | 0.935 | 0.341-2.564 | 0.896 | NS | |||
| Tumor size (cm) | >5 vs ≤5 | 2.292 | 1.506-3.490 | <0.001 | 2.694 | 1.671-4.344 | <0.001 |
| Tumor number | >1 vs 1 | 1.867 | 1.207-2.887 | 0.005 | NS | ||
| AFP (ng/mL) | >7 vs ≤7 | 1.782 | 1.092-2.907 | 0.021 | NS | ||
| Bilirubin (mg/dL) | >1.2 vs ≤1.2 | 1.326 | 0.709-2.481 | 0.377 | |||
| Albumin (g/dL) | >3.7 vs ≤3.7 | 0.705 | 0.476-1.044 | 0.081 | |||
| Creatinine (mg/dL) | >1.2 vs ≤1.2 | 1.004 | 0.571-1.766 | 0.988 | |||
| Platelet count (109/L) | >120 vs ≤120 | 0.934 | 0.612-1.426 | 0.753 | |||
| ALT (U/L) | >80 vs ≤80 | 1.218 | 0.804-1.847 | 0.352 | |||
| AST (U/L) | >80 vs ≤80 | 0.957 | 0.592-1.547 | 0.856 | |||
| GGT (U/L) | >70 vs ≤70 | 1.619 | 1.068-2.454 | 0.023 | NS | ||
| FIB-4 score | >3.25 vs ≤3.25 | 1.200 | 0.812-1.774 | 0.361 | |||
| Histological grade | >1 vs 1 | 1.578 | 0.766-3.251 | 0.216 | |||
| Microvascular invasion | Presence vs absence | 1.667 | 1.085-2.559 | 0.020 | NS | ||
| Steatosis | Presence vs absence | 0.732 | 0.475-1.127 | 0.156 | |||
| Ishak inflammation score | >6 vs ≤6 | 1.061 | 0.628-1.790 | 0.825 | |||
| Ishak fibrosis grade | 5-6 vs ≤4 | 0.951 | 0.644-1.405 | 0.801 | |||
HR, hazard ratio; CI, confidence interval; NS, not significant; ALBI, Albumin-Bilirubin.
Fifty-eight patients who achieved SVR within the first two years after surgery were excluded from the analysis of early recurrence. Thirty-six patients who achieved SVR after two years of surgery were classified as untreated in the analysis of early recurrence. Eligible patients for SVR analysis: n=225.
One hundred and twenty-four patients were included in the late recurrence analysis. In univariate analysis, FIB-4 score, platelet counts, serum albumin, GGT, creatinine and AFP levels were factors related to late recurrence (Table 3). By multivariate analysis, platelet counts >120×109/L (HR=0.530, P=0.024) and GGT >70 U/L (HR=1.890, P=0.037) were the independent predictors of late recurrence.
Table 3.
Univariate and multivariate analyses of factors associated with late recurrence after 2 years of surgery
| Univariate | Multivariate | ||||||
|---|---|---|---|---|---|---|---|
|
|
|
||||||
| HR | 95% CI | P | HR | 95% CI | P | ||
| Age (years) | >60 vs ≤60 | 1.353 | 0.738-2.479 | 0.328 | |||
| Sex | Male vs female | 0.659 | 0.369-1.175 | 0.158 | |||
| BMI (kg/m2) | >27 vs ≤27 | 0.868 | 0.458-1.648 | 0.666 | |||
| BCLC stage | B-C vs A | 0.519 | 0.162-1.663 | 0.270 | |||
| Child-Pugh score | >5 vs 5 | 1.493 | 0.809-2.753 | 0.199 | |||
| ALBI grade | 2-3 vs 1 | 1.297 | 0.761-2.212 | 0.339 | |||
| HCV RNA (IU/mL) | >8×105 vs ≤8×105 | 1.436 | 0.665-3.102 | 0.357 | |||
| Achieving SVR* | Non-SVR or untreated | 1 | 0.503 | ||||
| Interferon-based | 0.734 | 0.381-1.413 | 0.354 | ||||
| DAA | 0.522 | 0.120-2.260 | 0.384 | ||||
| Tumor size (cm) | >5 vs ≤5 | 0.848 | 0.362-1.986 | 0.704 | |||
| Tumor number | >1 vs 1 | 1.024 | 0.494-2.121 | 0.950 | |||
| AFP (ng/mL) | >7 vs ≤7 | 1.696 | 0.913-3.152 | 0.094 | NS | ||
| Bilirubin (mg/dL) | >1.2 vs ≤1.2 | 0.708 | 0.252-1.987 | 0.511 | |||
| Albumin (g/dL) | >3.7 vs ≤3.7 | 0.536 | 0.313-0.920 | 0.024 | NS | ||
| Creatinine (mg/dL) | >1.2 vs ≤1.2 | 0.360 | 0.112-1.155 | 0.086 | NS | ||
| Platelet count (109/L) | >120 vs ≤120 | 0.507 | 0.293-0.878 | 0.015 | 0.530 | 0.305-0.921 | 0.024 |
| ALT (U/L) | >80 vs ≤80 | 0.744 | 0.400-1.386 | 0.352 | |||
| AST (U/L) | >80 vs ≤80 | 0.780 | 0.393-1.546 | 0.476 | |||
| GGT (U/L) | >70 vs ≤70 | 1.998 | 1.103-3.619 | 0.022 | 1.890 | 1.040-3.434 | 0.037 |
| FIB-4 score | >3.25 vs ≤3.25 | 1.618 | 0.960-2.727 | 0.071 | NS | ||
| Histological grade | >1 vs 1 | 0.933 | 0.451-1.929 | 0.851 | |||
| Microvascular invasion | Presence vs absence | 1.306 | 0.761-2.241 | 0.332 | |||
| Steatosis | Presence vs absence | 1.214 | 0.679-2.170 | 0.513 | |||
| Ishak inflammation score | >6 vs ≤6 | 1.050 | 0.527-2.089 | 0.890 | |||
| Ishak fibrosis grade | 5-6 vs ≤4 | 1.090 | 0.647-1.838 | 0.745 | |||
HR, hazard ratio; CI, confidence interval; NS, not significant; ALBI, Albumin-Bilirubin.
Twenty-three patients who achieved SVR after two years of surgery were excluded from analysis of late recurrence. Eligible patients for SVR analysis: n=124.
Predictors of overall survival (OS)
One-hundred and two (35.8%) patients died during the follow-up period. In univariate analysis, BCLC stage, Child-Pugh score, ALBI grade, SVR by either IFN-based or DAA therapy, tumor size, albumin, FIB-4 score, microvascular invasion and Ishak inflammation score were associated with OS (Table 4). Multivariate analysis showed BCLC stage B-C (HR=2.005, P=0.015), the achievement of SVR (by IFN-based therapy: HR=0.304, P<0.001; by DAA: HR=0.205, P<0.001, Figure 2A), FIB-4 score >3.25 (HR=1.709, P=0.011) and microvascular invasion (HR=1.631, P=0.040) were independent predictors of OS.
Table 4.
Univariate and multivariate analyses of factors associated with overall survival
| Unadjusted overall survival | Adjusted overall survival† | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
|
|
|||||||||||
| Univariate | Multivariate | Univariate | Multivariate | |||||||||
|
|
|
|
|
|||||||||
| HR | 95% CI | P | HR | 95% CI | P | HR | 95% CI | P | HR | 95% CI | P | |
| Age >60 years | 1.265 | 0.789-2.029 | 0.329 | 1.294 | 0.806-2.077 | 0.285 | ||||||
| Male | 0.839 | 0.556-1.267 | 0.405 | 0.938 | 0.621-1.418 | 0.763 | ||||||
| BMI >27 kg/m2 | 0.951 | 0.597-1.514 | 0.832 | 0.921 | 0.578-1.468 | 0.730 | ||||||
| BCLC stage B/C | 1.795 | 1.078-2.988 | 0.025 | 2.005 | 1.142-3.519 | 0.015 | 1.685 | 1.012-2.804 | 0.045 | 1.914 | 1.090-3.361 | 0.024 |
| Child-Pugh score >5 | 2.046 | 1.356-3.088 | 0.001 | NS | 1.981 | 1.312-2.990 | 0.001 | NS | ||||
| ALBI grade >1 | 1.804 | 1.214-2.679 | 0.003 | NS | 1.838 | 1.237-2.732 | 0.003 | NS | ||||
| HCV RNA >8×108 IU/mL | 0.830 | 0.426-1.616 | 0.584 | 0.879 | 0.451-1.714 | 0.705 | ||||||
| SVR status | ||||||||||||
| Non-SVR or untreated | 1 | <0.001 | 1 | <0.001 | 1 | <0.001 | 1 | <0.001 | ||||
| Interferon-based | 0.263 | 0.157-0.442 | <0.001 | 0.304 | 0.179-0.517 | <0.001 | 0.276 | 0.164-0.463 | <0.001 | 0.321 | 0.189-0.545 | <0.001 |
| DAA | 0.195 | 0.098-0.390 | <0.001 | 0.205 | 0.101-0.416 | <0.001 | 0.381 | 0.188-0.770 | 0.007 | 0.396 | 0.193-0.810 | 0.011 |
| Timing of SVR | ||||||||||||
| Non-SVR or untreated | 1 | <0.001 | NS | 1 | <0.001 | NS | ||||||
| SVR before surgery | 0.266 | 0.133-0.532 | <0.001 | NS | 0.264 | 0.132-0.527 | <0.001 | NS | ||||
| SVR after surgery | 0.223 | 0.133-0.374 | <0.001 | NS | 0.329 | 0.197-0.550 | <0.001 | NS | ||||
| SVR before vs after surgery | 1.178 | 0.528-2.629 | 0.689 | 0.829 | 0.371-1.849 | 0.647 | ||||||
| Tumor size >5 cm | 1.880 | 1.215-2.908 | 0.005 | NS | 1.829 | 1.183-2.830 | 0.007 | NS | ||||
| Tumor number >1 | 0.801 | 0.476-1.349 | 0.404 | 0.872 | 0.355-2.142 | 0.376 | ||||||
| AFP >7 ng/mL | 1.502 | 0.921-2.450 | 0.103 | 1.523 | 0.934-2.484 | 0.092 | NS | |||||
| Bilirubin >1.2 mg/dL | 0.699 | 0.306-1.596 | 0.395 | 0.675 | 0.296-1.541 | 0.351 | ||||||
| Albumin >3.7 g/dL | 0.531 | 0.360-0.785 | 0.001 | NS | 0.504 | 0.341-0.746 | 0.001 | NS | ||||
| Creatinine >1.2 mg/dL | 1.430 | 0.837-2.443 | 0.190 | 1.351 | 0.792-2.305 | 0.270 | ||||||
| Platelet count >120×109/L | 0.844 | 0.550-1.295 | 0.437 | 0.788 | 0.512-1.213 | 0.279 | ||||||
| ALT >80 U/L | 1.037 | 0.682-1.577 | 0.864 | 1.018 | 0.670-1.549 | 0.932 | ||||||
| AST >80 U/L | 1.201 | 0.856-2.455 | 0.427 | 1.177 | 0.749-1.850 | 0.479 | ||||||
| GGT >70 U/L | 1.325 | 0.865-2.029 | 0.196 | 1.312 | 0.857-2.009 | 0.212 | ||||||
| FIB-4 score >3.25 | 1.681 | 1.132-2.495 | 0.010 | 1.709 | 1.129-2.587 | 0.011 | 1.783 | 1.199-2.652 | 0.004 | 1.664 | 1.098-2.521 | 0.016 |
| Histological grade >1 | 1.992 | 0.966-4.107 | 0.062 | NS | 1.905 | 0.924-3.929 | 0.081 | NS | ||||
| Microvascular invasion | 2.006 | 1.283-3.136 | 0.002 | 1.631 | 1.022-2.603 | 0.040 | 1.766 | 1.128-2.763 | 0.013 | 1.603 | 1.005-2.557 | 0.048 |
| Steatosis (vs absence) | 0.808 | 0.525-1.244 | 0.333 | 0.749 | 0.486-1.155 | 0.191 | ||||||
| Ishak inflammation score >6 | 1.784 | 1.139-2.795 | 0.011 | NS | 1.780 | 1.136-2.788 | 0.012 | NS | ||||
| Ishak fibrosis grade >4 | 1.342 | 0.909-1.982 | 0.139 | 1.345 | 0.911-1.987 | 0.136 | ||||||
The adjusted overall survival is calculated from the date of antiviral therapy to death.
Figure 2.
Kaplan-Meier curves of overall survival (OS) stratified by sustained virological response (SVR) after interferon (IFN)-based or direct-acting antiviral agent (DAA) in patients with HCV-related HCC receiving surgical resection. A. Unadjusted OS. B. Adjusted OS. C. Adjusted OS in patients with cirrhosis. D. Adjusted OS in patients without cirrhosis. E. Adjusted OS in patients with tumor recurrence. F. Adjusted OS in patients without tumor recurrence.
To address the immortal time bias caused by the varied antiviral-surgery interval in the cohort, we repeated the Cox regression analysis using the adjusted OS, which was calculated from the date of antiviral therapy to death. Multivariate analysis using an adjusted OS showed that BCLC stage B-C (HR=1.914, P=0.024), the achievement of SVR (by IFN-based therapy: HR=0.321, P<0.001; by DAA: HR=0.396, P=0.011, Figure 2B), FIB-4 score >3.25 (HR=1.664, P=0.016) and microvascular invasion (HR=1.603, P=0.048) remained significant predictors of survival (Table 4). The 5-year OS rates before and after adjustment were 48.0%, 81.9%, 83.1% (Figure 2A) and 51.4%, 81.9%, 83.9% (Figure 2B), respectively in patients with non-SVR, SVR by IFN-based therapy and SVR by DAA therapy. Notably, there was no significant difference of OS between patients with SVR by IFN-based or DAA therapy. Furthermore, patients achieving SVR before and after surgery had comparable OS, and both had significantly better OS than patients without antiviral therapy or without achieving SVR.
In subgroup patients with cirrhosis, the 5-year adjusted OS rates were 34.6%, 77.5%, 85.2%, respectively in patients with non-SVR, SVR by IFN-based therapy and SVR by DAA therapy (P<0.001, Figure 2C), whereas in subgroup patients without cirrhosis, the corresponding OS rates were 58.8%, 86.6%, 81.0%, respectively (P=0.007, Figure 2D). Similarly, in subgroup patients who developed tumor recurrence, the 5-year adjusted OS rates were 45.6%, 75.6%, 79.1%, respectively in patients with non-SVR, SVR by IFN-based therapy and SVR by DAA therapy (P<0.001, Figure 2E), whereas in subgroup patients without recurrence, the 3-year OS rates were 70.1%, 93.9%, 88.4%, respectively (P<0.001, Figure 2F).
Predictors of decompensation-free survival
Sixty-three (24.0%) patients developed hepatic decompensation during the follow-up period. In univariate analysis, BCLC stage, Child-Pugh score, ALBI grade, SVR by either IFN-based or DAA therapy, tumor size, albumin, GGT, FIB-4 score, microvascular invasion and Ishak inflammation score (Table 5) were associated with decompensation-free survival. Multivariate analysis showed that BCLC stage B-C (HR=3.042, P=0.001), the achievement of SVR (by IFN-based therapy: HR=0.275, P<0.001; by DAA: HR=0.112, P<0.001, Figure 3A), GGT >70 U/L (HR=2.019, P=0.009) and cirrhosis (HR=2.064, P=0.006) were independent predictors of decompensation-free survival. Further multivariate analysis using an adjusted decompensation-free survival showed that BCLC stage B-C (HR=2.975, P=0.001), the achievement of SVR (by IFN-based therapy: HR=0.295, P<0.001; by DAA: HR=0.193, P=0.002, Figure 3B), GGT >70 U/L (HR=1.931, P=0.015) and cirrhosis (HR=2.035, P=0.007) remained independently associated with decompensation-free survival (Table 5). Similarly, patients achieving SVR before and after surgery had comparable decompensation-free survival, and both had significantly better decompensation-free survival than patients without antiviral therapy or without achieving SVR.
Table 5.
Univariate and multivariate analyses of factors associated with decompensation-free survival
| Unadjusted overall survival | Adjusted overall survival† | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
|
|
|||||||||||
| Univariate | Multivariate | Univariate | Multivariate | |||||||||
|
|
|
|
|
|||||||||
| HR | 95% CI | P | HR | 95% CI | P | HR | 95% CI | P | HR | 95% CI | P | |
| Age >60 years | 0.896 | 0.518-1.549 | 0.694 | 0.919 | 0.531-1.589 | 0.762 | ||||||
| Male | 0.629 | 0.364-1.087 | 0.097 | NS | 0.681 | 0.394-1.177 | 0.169 | |||||
| BMI >27 kg/m2 | 1.239 | 0.701-2.191 | 0.461 | 1.190 | 0.673-2.103 | 0.550 | ||||||
| BCLC stage B/C | 2.254 | 1.223-4.154 | 0.009 | 3.042 | 1.600-5.784 | 0.001 | 2.219 | 1.204-4.089 | 0.011 | 2.975 | 1.567-5.648 | 0.001 |
| Child-Pugh score >5 | 2.361 | 1.414-3.943 | 0.001 | NS | 2.339 | 1.399-3.912 | 0.001 | NS | ||||
| ALBI grade >1 | 2.221 | 1.331-3.706 | 0.002 | NS | 2.254 | 1.351-3.760 | 0.002 | NS | ||||
| HCV RNA >8×108 IU/mL | 0.900 | 0.431-1.881 | 0.779 | 0.973 | 0.464-2.037 | 0.941 | ||||||
| SVR status | ||||||||||||
| Non-SVR or untreated | 1 | <0.001 | 1 | <0.001 | 1 | <0.001 | 1 | <0.001 | ||||
| Interferon-based | 0.323 | 0.176-0.593 | <0.001 | 0.275 | 0.148-0.511 | <0.001 | 0.345 | 0.189-0.631 | 0.001 | 0.295 | 0.159-0.546 | <0.001 |
| DAA | 0.140 | 0.050-0.389 | <0.001 | 0.112 | 0.040-0.313 | <0.001 | 0.234 | 0.083-0.658 | 0.006 | 0.193 | 0.068-0.542 | 0.002 |
| Timing of SVR | ||||||||||||
| Non-SVR or untreated | 1 | <0.001 | NS | 1 | <0.001 | NS | ||||||
| SVR before surgery | 0.219 | 0.086-0.553 | 0.001 | NS | 0.218 | 0.086-0.552 | 0.001 | NS | ||||
| SVR after surgery | 0.310 | 0.174-0.555 | <0.001 | NS | 0.441 | 0.248-0.785 | 0.005 | NS | ||||
| SVR before vs after surgery | 0.710 | 0.259-1.941 | 0.504 | 0.485 | 0.177-1.330 | 0.160 | ||||||
| Tumor size >5 cm | 1.791 | 1.013-3.166 | 0.045 | NS | 1.785 | 1.010-3.156 | 0.046 | NS | ||||
| Tumor number >1 | 0.859 | 0.448-1.648 | 0.648 | 0.884 | 0.461-1.696 | 0.712 | ||||||
| AFP >7 ng/mL | 1.106 | 0.619-1.979 | 0.733 | 1.121 | 0.627-2.006 | 0.700 | ||||||
| Bilirubin >1.2 mg/dL | 1.378 | 0.626-3.030 | 0.426 | 1.358 | 0.618-2.984 | 0.446 | ||||||
| Albumin >3.7 g/dL | 0.473 | 0.288-0.777 | 0.003 | NS | 0.453 | 0.276-0.745 | 0.002 | NS | ||||
| Creatinine >1.2 mg/dL | 0.767 | 0.330-1.781 | 0.537 | 0.725 | 0.312-1.682 | 0.454 | ||||||
| Platelet count >120×109/L | 0.843 | 0.491-1.448 | 0.536 | 0.805 | 0.467-1.387 | 0.434 | ||||||
| ALT >80 U/L | 1.556 | 0.938-2.581 | 0.087 | NS | 1.582 | 0.954-2.622 | 0.075 | NS | ||||
| AST >80 U/L | 1.427 | 0.818-2.490 | 0.211 | 1.443 | 0.827-2.517 | 0.197 | ||||||
| GGT >70 U/L | 1.705 | 1.015-2.863 | 0.044 | 2.019 | 1.188-3.431 | 0.009 | 1.668 | 0.993-2.800 | 0.053 | 1.931 | 1.139-3.273 | 0.015 |
| FIB-4 score >3.25 | 1.483 | 0.900-2.442 | 0.122 | 1.584 | 0.958-2.617 | 0.073 | NS | |||||
| Histological grade >1 | 1.311 | 0.595-2.891 | 0.502 | 1.193 | 0.542-2.625 | 0.661 | ||||||
| Microvascular invasion | 1.641 | 0.965-2.790 | 0.068 | NS | 1.533 | 0901-2.609 | 0.115 | |||||
| Steatosis (vs absence) | 0.772 | 0.447-1.336 | 0.356 | 0.715 | 0.412-1.241 | 0.233 | ||||||
| Ishak inflammation score >6 | 1.829 | 1.035-3.233 | 0.038 | NS | 1.771 | 1.001-3.132 | 0.049 | NS | ||||
| Ishak fibrosis grade >4 | 1.533 | 0.930-2.526 | 0.094 | 2.064 | 1.234-3.450 | 0.006 | 1.541 | 0.935-2.541 | 0.090 | 2.035 | 1.218-3.401 | 0.007 |
The adjusted decompensation-free survival is calculated from the date of antiviral therapy to hepatic decompensation.
Figure 3.
Kaplan-Meier curves of decompensation-free survival stratified by sustained virological response (SVR) after interferon (IFN)-based or direct-acting antiviral agent (DAA). A. Unadjusted decompensation-free survival. B. Adjusted decompensation-free survival. C. Adjusted decompensation-free survival in patients with cirrhosis. D. Adjusted decompensation-free survival in patients without cirrhosis. E. Adjusted decompensation-free survival in patients with tumor recurrence. F. Adjusted decompensation-free survival in patients without tumor recurrence.
The 5-year decompensation-free survival rates with and without adjustment were 59.7%, 86.5%, 92.0% (Figure 3A) and 61.1%, 86.3%, 90.9% (Figure 3B), respectively in patients with non-SVR, SVR by IFN-based therapy and SVR by DAA therapy. There was no significant difference of decompensation-free survival between patients with SVR by IFN-based or DAA therapy.
In subgroup patients with cirrhosis, the 5-year adjusted decompensation-free survival rates were 44.0%, 86.5%, 92.4%, respectively in patients with non-SVR, SVR by IFN-based therapy and SVR by DAA therapy (P<0.001, Figure 3C), whereas in subgroup patients without cirrhosis, the corresponding decompensation-free survival rates were 70.7%, 86.7%, 91.8%, respectively (P=0.049, Figure 3D). Similarly, in subgroup patients who developed tumor recurrence, the 5-year adjusted decompensation-free survival rates were 53.4%, 78.6%, 88.7%, respectively in patients with non-SVR, SVR by IFN-based therapy and SVR by DAA therapy (P=0.005, Figure 3E), whereas in subgroup patients without recurrence, the 3-year decompensation-free survival rates were 77.8%, 96.6, 95.5, respectively (P=0.029, Figure 3F).
Discussion
Previous studies have reported that IFN-based therapy may reduce the incidence of recurrence and improve overall survival in HCC patients undergoing resection [8-11], whereas DAA therapy had neutral effect on HCC recurrence [11], but improved overall survival could still be observed after DAA therapy for patients undergoing resection [16-18]. Currently there was no data comparing the effect of DAA and IFN-based therapy in reducing mortality and hepatic decompensation after surgical resection. In this study, we demonstrated that tumor factors were associated with early recurrence and surrogate markers of hepatic fibrosis were related to late recurrence after surgical resection for HCV-related HCC. Although HCV eradication had neutral effect on HCC recurrence, patients achieving SVR by DAA and IFN-based therapy had significantly improved OS and reduced hepatic decompensation. Furthermore, this is the first study to show the comparable benefits in reducing mortality and hepatic decompensation between patients who achieved SVR by DAA and IFN-based therapy.
The IFN-based therapy had poorer tolerability and was limited to younger patients with better liver function reserve. As a result, we observed that HCC patients who received IFN-based therapy were significantly younger and had better liver function profile. In contrast, patients treated with DAA were older and had significantly higher HCV viral load and poorer liver function reserve. Nevertheless, a high SVR rate of 95.7% was observed in patient who mainly received DAA after surgical resection, which was concordant with previous observation of comparable high SVR rate in patients with inactive HCC and patients without HCC [25]. Since DAA therapy was only available in recent few years, we observed that about one third of patients received DAA therapy more than 2 years after surgery. Since DAA therapy is now widely available, early initiation of DAA after curative treatment of HCC is suggested as SVR after DAA therapy may result in improved liver function and facilitate additional HCC-directed therapy.
By multivariate analysis, BCLC stage and tumor size were shown as independent predictors of early recurrence, while platelet count and GGT levels were predictors of late recurrence, which were consistent with previous studies that tumor factors were the main determinants of early recurrence and hepatic fibrosis and inflammation were main predictors of late recurrence [20,26]. The elevation of GGT accounts in part for the adaption and over-compensation of oxidative stress in the liver, and was shown to be associated with fibrosis progression in patients with chronic hepatitis C [27,28]. Serum GGT level has also been shown to predict the occurrence of HCC in patients with HCV infection [29,30]. Our results indicate that GGT could be a novel predictive biomarker for late recurrence of HCV-related HCC. High HCV viral load has been shown to be associated with higher risk of HCC development [31]. In this study, we did not observe a significant association between baseline HCV viral load and the outcomes of HCC after resection. Since HCV clearance by either IFN-based or DAA therapy would eradicate the long-term effect of HCV viremia, baseline HCV viral load might no longer be a significant factor of HCC recurrence or survival after SVR, which was similar to our previous observations that baseline HBV viral load was not associated with recurrence in patients with HBV-related HCC under antiviral therapy [32,33]. The impact of SVR by DAA on HCC recurrence was a controversial issue [34]. Although some studies showed that SVR by antiviral therapy was associated with lower recurrence rate of HCV-related HCC [8,35], our data did not show a significant correlation between SVR and HCC recurrence. The benefit of SVR on HCC recurrence needs to be confirmed by further long-term follow-up studies.
We identified BCLC stage, FIB-4 score, microvascular invasion and achieving SVR as independent predictors of OS. Tumor stage and liver fibrosis score are well known factors associated with OS in HCC patients [36]. Previous studies showed that SVR by IFN or DAA therapy may improve the survival of patients with HCC after surgical resection [11,16-18]. Consistent with previous reports, we showed that patients with SVR had significantly better OS, and the survival benefit was comparable between patients treated with DAA and IFN-based therapy. Among our patients with SVR, both DAA and IFN-based therapy appears to exert a 70% risk reduction in all-cause mortality than those without SVR, despite the fact that the hepatic reserve at baseline was notably less favorable in patients receiving DAA therapy than IFN-based therapy. Besides, patients achieving SVR before and after surgery had comparable survival outcomes after surgery. The survival benefit of achieving SVR was consistently observed in cirrhotic and non-cirrhotic patients, and in patients with and without HCC recurrence. Comparable to previous publication regarding patients with surgically-treated HCV-related HCC, the 5-year survival in our patients without SVR was around 50% [6], whereas patients achieving SVR may have a 5-year OS rate of higher than 80%. Of note, the 5-year mortality rate was still higher than 40% in untreated patients without tumor recurrence, suggesting that hepatic decompensation still contribute to mortality in significant proportion of untreated patients even with HCC cure (Figure 2F).
Hepatic decompensation was considered to be an important survival factor after surgical resection of HCC. Currently, only few studies addressed the impact of SVR on hepatic decompensation after surgical resection [16]. In this study, we showed that BCLC stage, GGT levels, cirrhosis status and achieving SVR were independent predictors of hepatic decompensation after resection. Tumor stage was associated with tumor recurrence after surgery, which might lead to hepatic decompensation due to tumor progression. Cirrhosis is also a well-known predictor of hepatic decompensation over the long-term, even in patients achieving SVR [37]. We observed that baseline GGT level, which was a surrogate marker of fibrosis progression in CHC, not only correlated with late recurrence, but also predict hepatic decompensation after surgical resection for HCV-related HCC. Importantly, achieving SVR by either DAA or IFN-based therapy could reduce the risk hepatic decompensation more than 70% after surgery, and the benefit was also comparable between patients treated with DAA and IFN-based therapy. The benefit of maintaining liver function reserve after SVR was consistently observed in cirrhotic and non-cirrhotic patients, and in patients with and without HCC recurrence. Our data suggest that SVR by either DAA or IFN-based therapy provide comparable and significant benefit in reducing hepatic decompensation after surgical resection of HCV-related HCC. The well-preserved liver function leads to long-term survival in patients without tumor recurrence, and provides a better chance of receiving rescue therapy for patients with recurrence.
Despite the comparable benefits of the DAA or IFN-based therapy in terms of reducing mortality and hepatic decompensation, DAA therapy had significantly higher SVR rate, shorter treatment duration and fewer side effects, and was more tolerable in patients with cirrhosis and hepatic decompensation. With accumulating evidences showing the benefit of DAA therapy for HCC patients undergoing resection, DAA therapy should be encouraged for all HCC patients with HCV viremia after surgery.
This study has some limitations. First, this is a retrospective study in a single medical center in Taiwan. Second, since DAA therapy was introduced only in recent 5 years, whereas IFN-based therapy has been used for more than 10 years, the follow-up time of DAA therapy group was shorter than the IFN-based therapy group. However, the median follow-up time of DAA therapy group was still longer than 4 years in this study. Besides, as DAA was only available in recent years, most patients received DAA later after surgical resection, which might result in immortal time bias. Nevertheless, we used adjusted OS and decompensation-free survival to minimize immortal time bias, and the survival analysis of OS and decompensation-free survival before and after adjustment consistently showed significant reduction of mortality and decompensation by achieving SVR. Third, the case number in the DAA group is relatively small. Further long-term follow-up studies with larger case number are needed to prove the long-term benefit of DAA therapy. Fourth, HCV viral load data were not available in majority of the untreated patients, and certain proportion of these patients may have undetectable HCV RNA. Since patient with spontaneous HCV clearance may have better outcomes than viremic cases without treatment [31], the disparity of OS and decompensation-free survival between patients with and without SVR would be higher after excluding untreated patients with undetectable HCV RNA.
In conclusion, achieving SVR by either DAA or IFN-based therapy provides comparable and significant reduction of mortality and hepatic decompensation after surgical resection of HCV-related HCC. The well-maintained liver function reserve may provide long-term survival for patients without recurrence, and may offer the opportunity of receiving rescue therapy for patients with recurrence. The SVR rate of DAA for patients with HCV-related HCC after surgical resection remains higher than 95%. DAA therapy should be initiated early for all HCC patients after curative surgical resection.
Acknowledgements
The authors thank the Clinical Research Core Laboratory, Taipei Veterans General Hospital for providing their facilities to conduct this study. The study was supported by grants from Taipei Veterans General Hospital, Taipei, Taiwan (V110C-094, V110C-144), and Ministry of Science and Technology, Taiwan (MOST 108-2628-B-075-006, MOST 109-2628-B-075-022).
Disclosure of conflict of interest
None.
References
- 1.Global Burden of Disease Liver Cancer Collaboration. Akinyemiju T, Abera S, Ahmed M, Alam N, Alemayohu MA, Allen C, Al-Raddadi R, Alvis-Guzman N, Amoako Y, Artaman A, Ayele TA, Barac A, Bensenor I, Berhane A, Bhutta Z, Castillo-Rivas J, Chitheer A, Choi JY, Cowie B, Dandona L, Dandona R, Dey S, Dicker D, Phuc H, Ekwueme DU, Zaki MS, Fischer F, Fürst T, Hancock J, Hay SI, Hotez P, Jee SH, Kasaeian A, Khader Y, Khang YH, Kumar A, Kutz M, Larson H, Lopez A, Lunevicius R, Malekzadeh R, McAlinden C, Meier T, Mendoza W, Mokdad A, Moradi-Lakeh M, Nagel G, Nguyen Q, Nguyen G, Ogbo F, Patton G, Pereira DM, Pourmalek F, Qorbani M, Radfar A, Roshandel G, Salomon JA, Sanabria J, Sartorius B, Satpathy M, Sawhney M, Sepanlou S, Shackelford K, Shore H, Sun J, Mengistu DT, Topór-Mądry R, Tran B, Ukwaja KN, Vlassov V, Vollset SE, Vos T, Wakayo T, Weiderpass E, Werdecker A, Yonemoto N, Younis M, Yu C, Zaidi Z, Zhu L, Murray CJL, Naghavi M, Fitzmaurice C. The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the global burden of disease study 2015. JAMA Oncol. 2017;3:1683–1691. doi: 10.1001/jamaoncol.2017.3055. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Spearman CW, Dusheiko GM, Hellard M, Sonderup M. Hepatitis C. Lancet. 2019;394:1451–1466. doi: 10.1016/S0140-6736(19)32320-7. [DOI] [PubMed] [Google Scholar]
- 3.Heimbach JK, Kulik LM, Finn RS, Sirlin CB, Abecassis MM, Roberts LR, Zhu AX, Murad MH, Marrero JA. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018;67:358–380. doi: 10.1002/hep.29086. [DOI] [PubMed] [Google Scholar]
- 4.Cucchetti A, Zhong J, Berhane S, Toyoda H, Shi K, Tada T, Chong CCN, Xiang BD, Li LQ, Lai PBS, Ercolani G, Mazzaferro V, Kudo M, Cescon M, Pinna AD, Kumada T, Johnson PJ. The chances of hepatic resection curing hepatocellular carcinoma. J Hepatol. 2020;72:711–717. doi: 10.1016/j.jhep.2019.11.016. [DOI] [PubMed] [Google Scholar]
- 5.Lee IC, Huang YH, Chau GY, Huo TI, Su CW, Wu JC, Lin HC. Serum interferon gamma level predicts recurrence in hepatocellular carcinoma patients after curative treatments. Int J Cancer. 2013;133:2895–2902. doi: 10.1002/ijc.28311. [DOI] [PubMed] [Google Scholar]
- 6.Koda M, Tanaka S, Takemura S, Shinkawa H, Kinoshita M, Hamano G, Ito T, Kawada N, Shibata T, Kubo S. Long-term prognostic factors after hepatic resection for hepatitis C virus-related hepatocellular carcinoma, with a special reference to viral status. Liver Cancer. 2018;7:261–276. doi: 10.1159/000486902. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Cabibbo G, Petta S, Barbara M, Attardo S, Bucci L, Farinati F, Giannini EG, Negrini G, Ciccarese F, Rapaccini GL, Di Marco M, Caturelli E, Zoli M, Borzio F, Sacco R, Virdone R, Marra F, Mega A, Morisco F, Benvegnu L, Gasbarrini A, Svegliati-Baroni G, Foschi FG, Olivani A, Masotto A, Nardone G, Colecchia A, Persico M, Craxi A, Trevisani F, Camma C Italian Liver Cancer (ITA.LI.CA) group. Hepatic decompensation is the major driver of death in HCV-infected cirrhotic patients with successfully treated early hepatocellular carcinoma. J Hepatol. 2017;67:65–71. doi: 10.1016/j.jhep.2017.01.033. [DOI] [PubMed] [Google Scholar]
- 8.Mazzaferro V, Romito R, Schiavo M, Mariani L, Camerini T, Bhoori S, Capussotti L, Calise F, Pellicci R, Belli G, Tagger A, Colombo M, Bonino F, Majno P, Llovet JM HCC Italian Task Force. Prevention of hepatocellular carcinoma recurrence with alpha-interferon after liver resection in HCV cirrhosis. Hepatology. 2006;44:1543–1554. doi: 10.1002/hep.21415. [DOI] [PubMed] [Google Scholar]
- 9.Shiratori Y, Shiina S, Teratani T, Imamura M, Obi S, Sato S, Kolke Y, Yoshida H, Omata M. Interferon therapy after tumor ablation improves prognosis in patients with hepatocellular carcinoma associated with hepatitis C virus. Ann Intern Med. 2003;138:299–306. doi: 10.7326/0003-4819-138-4-200302180-00008. [DOI] [PubMed] [Google Scholar]
- 10.Hsu CS, Chao YC, Lin HH, Chen DS, Kao JH. Systematic review: impact of interferon-based therapy on HCV-related hepatocellular carcinoma. Sci Rep. 2015;5:9954. doi: 10.1038/srep09954. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Manthravadi S, Paleti S, Pandya P. Impact of sustained viral response postcurative therapy of hepatitis C-related hepatocellular carcinoma: a systematic review and meta-analysis. Int J Cancer. 2017;140:1042–1049. doi: 10.1002/ijc.30521. [DOI] [PubMed] [Google Scholar]
- 12.Falade-Nwulia O, Suarez-Cuervo C, Nelson DR, Fried MW, Segal JB, Sulkowski MS. Oral direct-acting agent therapy for hepatitis C virus infection: a systematic review. Ann Intern Med. 2017;166:637–648. doi: 10.7326/M16-2575. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Beste LA, Green PK, Berry K, Kogut MJ, Allison SK, Ioannou GN. Effectiveness of hepatitis C antiviral treatment in a USA cohort of veteran patients with hepatocellular carcinoma. J Hepatol. 2017;67:32–39. doi: 10.1016/j.jhep.2017.02.027. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Calvaruso V, Cabibbo G, Cacciola I, Petta S, Madonia S, Bellia A, Tine F, Distefano M, Licata A, Giannitrapani L, Prestileo T, Mazzola G, Di Rosolini MA, Larocca L, Bertino G, Digiacomo A, Benanti F, Guarneri L, Averna A, Iacobello C, Magro A, Scalisi I, Cartabellotta F, Savalli F, Barbara M, Davi A, Russello M, Scifo G, Squadrito G, Camma C, Raimondo G, Craxi A, Di Marco V Rete Sicilia Selezione Terapia HCV (RESIST-HCV) Incidence of hepatocellular carcinoma in patients with HCV-associated cirrhosis treated with direct-acting antiviral agents. Gastroenterology. 2018;155:411–421. e414. doi: 10.1053/j.gastro.2018.04.008. [DOI] [PubMed] [Google Scholar]
- 15.Backus LI, Belperio PS, Shahoumian TA, Mole LA. Direct-acting antiviral sustained virologic response: impact on mortality in patients without advanced liver disease. Hepatology. 2018;68:827–838. doi: 10.1002/hep.29811. [DOI] [PubMed] [Google Scholar]
- 16.Cabibbo G, Celsa C, Calvaruso V, Petta S, Cacciola I, Cannavo MR, Madonia S, Rossi M, Magro B, Rini F, Distefano M, Larocca L, Prestileo T, Malizia G, Bertino G, Benanti F, Licata A, Scalisi I, Mazzola G, Di Rosolini MA, Alaimo G, Averna A, Cartabellotta F, Alessi N, Guastella S, Russello M, Scifo G, Squadrito G, Raimondo G, Trevisani F, Craxi A, Di Marco V, Camma C Rete Sicilia Selezione Terapia HCV (RESIST-HCV) and Italian Liver Cancer (ITA.LI.CA) Group. Direct-acting antivirals after successful treatment of early hepatocellular carcinoma improve survival in HCV-cirrhotic patients. J Hepatol. 2019;71:265–273. doi: 10.1016/j.jhep.2019.03.027. [DOI] [PubMed] [Google Scholar]
- 17.Singal AG, Rich NE, Mehta N, Branch AD, Pillai A, Hoteit M, Volk M, Odewole M, Scaglione S, Guy J, Said A, Feld JJ, John BV, Frenette C, Mantry P, Rangnekar AS, Oloruntoba O, Leise M, Jou JH, Bhamidimarri KR, Kulik L, Ioannou GN, Huang A, Tran T, Samant H, Dhanasekaran R, Duarte-Rojo A, Salgia R, Eswaran S, Jalal P, Flores A, Satapathy SK, Kagan S, Gopal P, Wong R, Parikh ND, Murphy CC. Direct-acting antiviral therapy for hepatitis C virus infection is associated with increased survival in patients with a history of hepatocellular carcinoma. Gastroenterology. 2019;157:1253–1263. e1252. doi: 10.1053/j.gastro.2019.07.040. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Dang H, Yeo YH, Yasuda S, Huang CF, Iio E, Landis C, Jun DW, Enomoto M, Ogawa E, Tsai PC, Le A, Liu M, Maeda M, Nguyen B, Ramrakhiani N, Henry L, Cheung R, Tamori A, Kumada T, Tanaka Y, Yu ML, Toyoda H, Nguyen MH. Cure with interferon-free direct-acting antiviral is associated with increased survival in patients with hepatitis C virus-related hepatocellular carcinoma from both east and west. Hepatology. 2020;71:1910–1922. doi: 10.1002/hep.30988. [DOI] [PubMed] [Google Scholar]
- 19.Marrero JA, Kulik LM, Sirlin CB, Zhu AX, Finn RS, Abecassis MM, Roberts LR, Heimbach JK. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018;68:723–750. doi: 10.1002/hep.29913. [DOI] [PubMed] [Google Scholar]
- 20.Portolani N, Coniglio A, Ghidoni S, Giovanelli M, Benetti A, Tiberio GA, Giulini SM. Early and late recurrence after liver resection for hepatocellular carcinoma: prognostic and therapeutic implications. Ann Surg. 2006;243:229–235. doi: 10.1097/01.sla.0000197706.21803.a1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Chi CT, Chen CY, Su CW, Chen PY, Chu CJ, Lan KH, Lee IC, Hou MC, Huang YH. Direct-acting antivirals for patients with chronic hepatitis C and hepatocellular carcinoma in Taiwan. J Microbiol Immunol Infect. 2021;54:385–395. doi: 10.1016/j.jmii.2019.09.006. [DOI] [PubMed] [Google Scholar]
- 22.Johnson PJ, Berhane S, Kagebayashi C, Satomura S, Teng M, Reeves HL, O’Beirne J, Fox R, Skowronska A, Palmer D, Yeo W, Mo F, Lai P, Inarrairaegui M, Chan SL, Sangro B, Miksad R, Tada T, Kumada T, Toyoda H. Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade. J. Clin. Oncol. 2015;33:550–558. doi: 10.1200/JCO.2014.57.9151. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, S Sulkowski M, Torriani FJ, Dieterich DT, Thomas DL, Messinger D, Nelson M APRICOT Clinical Investigators. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43:1317–1325. doi: 10.1002/hep.21178. [DOI] [PubMed] [Google Scholar]
- 24.Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, Denk H, Desmet V, Korb G, MacSween RN. Histological grading and staging of chronic hepatitis. J Hepatol. 1995;22:696–699. doi: 10.1016/0168-8278(95)80226-6. [DOI] [PubMed] [Google Scholar]
- 25.Ji F, Yeo YH, Wei MT, Ogawa E, Enomoto M, Lee DH, Iio E, Lubel J, Wang W, Wei B, Ide T, Preda CM, Conti F, Minami T, Bielen R, Sezaki H, Barone M, Kolly P, Chu PS, Virlogeux V, Eurich D, Henry L, Bass MB, Kanai T, Dang S, Li Z, Dufour JF, Zoulim F, Andreone P, Cheung RC, Tanaka Y, Furusyo N, Toyoda H, Tamori A, Nguyen MH. Sustained virologic response to direct-acting antiviral therapy in patients with chronic hepatitis C and hepatocellular carcinoma: a systematic review and meta-analysis. J Hepatol. 2019;71:473–485. doi: 10.1016/j.jhep.2019.04.017. [DOI] [PubMed] [Google Scholar]
- 26.Wu JC, Huang YH, Chau GY, Su CW, Lai CR, Lee PC, Huo TI, Sheen IJ, Lee SD, Lui WY. Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma. J Hepatol. 2009;51:890–897. doi: 10.1016/j.jhep.2009.07.009. [DOI] [PubMed] [Google Scholar]
- 27.Silva IS, Ferraz ML, Perez RM, Lanzoni VP, Figueiredo VM, Silva AE. Role of gamma-glutamyl transferase activity in patients with chronic hepatitis C virus infection. J Gastroenterol Hepatol. 2004;19:314–318. doi: 10.1111/j.1440-1746.2003.03256.x. [DOI] [PubMed] [Google Scholar]
- 28.Everhart JE, Wright EC. Association of gamma-glutamyl transferase (GGT) activity with treatment and clinical outcomes in chronic hepatitis C (HCV) Hepatology. 2013;57:1725–1733. doi: 10.1002/hep.26203. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Audureau E, Carrat F, Layese R, Cagnot C, Asselah T, Guyader D, Larrey D, De Ledinghen V, Ouzan D, Zoulim F, Roulot D, Tran A, Bronowicki JP, Zarski JP, Riachi G, Cales P, Peron JM, Alric L, Bourliere M, Mathurin P, Blanc JF, Abergel A, Chazouilleres O, Mallat A, Grange JD, Attali P, d’Alteroche L, Wartelle C, Dao T, Thabut D, Pilette C, Silvain C, Christidis C, Nguyen-Khac E, Bernard-Chabert B, Zucman D, Di Martino V, Sutton A, Pol S, Nahon P ANRS CO12 CirVir group. Personalized surveillance for hepatocellular carcinoma in cirrhosis - using machine learning adapted to HCV status. J Hepatol. 2020;73:1434–1445. doi: 10.1016/j.jhep.2020.05.052. [DOI] [PubMed] [Google Scholar]
- 30.Huang CF, Yeh ML, Tsai PC, Hsieh MH, Yang HL, Hsieh MY, Yang JF, Lin ZY, Chen SC, Wang LY, Dai CY, Huang JF, Chuang WL, Yu ML. Baseline gamma-glutamyl transferase levels strongly correlate with hepatocellular carcinoma development in non-cirrhotic patients with successful hepatitis C virus eradication. J Hepatol. 2014;61:67–74. doi: 10.1016/j.jhep.2014.02.022. [DOI] [PubMed] [Google Scholar]
- 31.Lee MH, Yang HI, Lu SN, Jen CL, Yeh SH, Liu CJ, Chen PJ, You SL, Wang LY, Chen WJ, Chen CJ. Hepatitis C virus seromarkers and subsequent risk of hepatocellular carcinoma: long-term predictors from a community-based cohort study. J. Clin. Oncol. 2010;28:4587–4593. doi: 10.1200/JCO.2010.29.1500. [DOI] [PubMed] [Google Scholar]
- 32.Lee IC, Chau GY, Yeh YC, Chao Y, Huo TI, Su CW, Lin HC, Hou MC, Huang YH. Risk of recurrence in chronic hepatitis B patients developing hepatocellular carcinoma with antiviral secondary prevention failure. PLoS One. 2017;12:e0188552. doi: 10.1371/journal.pone.0188552. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Lee IC, Lei HJ, Chau GY, Yeh YC, Wu CJ, Su CW, Hou TI, Chao Y, Lin HC, Hou MC, Huang YH. Predictors of long-term recurrence and survival after resection of HBV-related hepatocellular carcinoma: the role of HBsAg. Am J Cancer Res. 2021 [PMC free article] [PubMed] [Google Scholar]
- 34.Saraiya N, Yopp AC, Rich NE, Odewole M, Parikh ND, Singal AG. Systematic review with meta-analysis: recurrence of hepatocellular carcinoma following direct-acting antiviral therapy. Aliment Pharmacol Ther. 2018;48:127–137. doi: 10.1111/apt.14823. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Ochi H, Hiraoka A, Hirooka M, Koizumi Y, Amano M, Azemoto N, Watanabe T, Yoshida O, Tokumoto Y, Mashiba T, Yokota T, Abe M, Michitaka K, Hiasa Y, Joko K. Direct-acting antivirals improve survival and recurrence rates after treatment of hepatocellular carcinoma within the Milan criteria. J Gastroenterol. 2020;56:90–100. doi: 10.1007/s00535-020-01747-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Marasco G, Colecchia A, Colli A, Ravaioli F, Casazza G, Bacchi Reggiani ML, Cucchetti A, Cescon M, Festi D. Role of liver and spleen stiffness in predicting the recurrence of hepatocellular carcinoma after resection. J Hepatol. 2019;70:440–448. doi: 10.1016/j.jhep.2018.10.022. [DOI] [PubMed] [Google Scholar]
- 37.Verna EC, Morelli G, Terrault NA, Lok AS, Lim JK, Di Bisceglie AM, Zeuzem S, Landis CS, Kwo P, Hassan M, Manns MP, Vainorius M, Akushevich L, Nelson DR, Fried MW, Reddy KR. DAA therapy and long-term hepatic function in advanced/decompensated cirrhosis: real-world experience from HCV-TARGET cohort. J Hepatol. 2020;73:540–548. doi: 10.1016/j.jhep.2020.03.031. [DOI] [PubMed] [Google Scholar]