Purpose: Age and hepatic fibrosis are the factors that increase the risk of hepatocellular carcinoma over time. We aimed to explore their impact at the initiation of antiviral therapy on hepatocellular carcinoma among chronic hepatitis C (CHC) patients.

Experimental Design: A total of 1,281 biopsy-proven CHC patients receiving IFN-based therapy were followed for a mean period of 5.5 years.

Results: The 5-year cumulative incidence of hepatocellular carcinoma did not differ between non–sustained virological response (SVR) and SVR patients who were <40 years old (7.7% vs. 0.5%, P = 0.1) but was significantly higher in non-SVR patients between 40 and 55 years old (18.0% vs. 1.3%, P < 0.001) and >55 years old (15.1% vs. 7.9%, P = 0.03). Compared with SVR, non-SVR was independently predictive of hepatocellular carcinoma in patients 40 to 55 years old [HR/95% confidence intervals (CI), 10.92/3.78–31.56; P < 0.001] and >55 years old (HR/CI, 1.96/1.06–3.63; P = 0.03) but not in patients <40 years old (HR/CI, 2.76/0.41–18.84; P = 0.3). The 5-year cumulative incidence of hepatocellular carcinoma did not differ between non-SVR and SVR patients whose fibrosis stage was F0–1 (4.6% vs. 1.9%, P = 0.25) but was higher in non-SVR patients with F2–3 (21.4% vs. 4.3%, P < 0.001) or F4 (33.5% vs. 8.4%, P = 0.002). Compared with SVR, non-SVR was independently predictive of hepatocellular carcinoma in patients with F2–3 (HR/CI, 4.36/2.10–9.03; P < 0.001) and F4 (HR/CI, 3.84/1.59–9.30; P = 0.03) but not in those with F0–1 (HR/CI, 1.53/0.49–4.74; P = 0.47).

Conclusions: Delayed hepatitis C virus clearance for patients with CHC >40 years old or with a fibrosis stage >2 increases the risk of hepatocellular carcinoma over time. Clin Cancer Res; 23(7); 1690–7. ©2016 AACR.

Translational Relevance

Age and the degree of hepatic fibrosis are the two major factors that increase the risk of hepatitis C virus (HCV)–related hepatocellular carcinoma over time and, as such, are considered to be time-degenerative factors. In the current longitudinal follow-up study, we identified that an age of more than 40 years and a fibrosis stage >2 are two independent risk factors predictive of hepatocellular carcinoma. Patients who possess either one of these two characteristics should not be deferred for treatment. The benefit of SVR was enhanced in patients between 40 and 55 years old or with an F2–3 fibrosis stage, whose risk of hepatocellular carcinoma was greatly minimized to the level of individuals <40 years old with F0–1 fibrosis stage. However, the preventive effect of viral eradication on hepatocellular carcinoma risk was diminished in patients >55 years old or with F4 fibrosis stage.

Hepatitis C virus (HCV) infects approximately 180 million people and is one of the major causes of hepatocellular carcinoma, one of the leading causes of mortality worldwide (1). IFN-based therapy has been the mainstream of treatment in the past two decades and remains the standard of care in most areas with limited medical resources (2). Successful HCV eradication, namely the achievement of a sustained virological response (SVR), with antiviral therapy greatly reduces the incidence of hepatocellular carcinoma (3, 4). However, the efficacy and safety of this treatment method are suboptimal because of frequent treatment failures and problems of intolerance or ineligibility. The innovative use of IFN-free, direct antiviral agent (DAA) regimens has removed some of these obstacles (5, 6). Although some cost-effectiveness studies have prompted the use of DAAs (7, 8), in reality, treatment hurdles remain due to issues of affordability in resource-constrained areas as well as the unexpected huge budget impact that has resulted in wealthier countries (9). Therefore, the current HCV guidelines by EASL and AASLD-ISDA both recommend that treatment should be prioritized for patients at the greatest risk for disease complications (5, 6).

Several risk factors and predictors may account for the development of HCV-related hepatocellular carcinoma before and after successful antiviral therapy. They include (i) fixed, unchangeable factors, such as sex, host genetics (10), and HCV genotype (11); (ii) fluctuating factors, such as levels of serum r-glutamyl transferase (r-GT; ref. 4) and α-fetoprotein (12); and (iii) factors that degenerate as time progresses, namely the individual's age and the degree of hepatic fibrosis. These two time-degenerative factors are the two major determinants that increase the risk for hepatocellular carcinoma over time if patients are left untreated. The incidence of hepatocellular carcinoma increases progressively with advancing age in all populations (13). Both factors also play an important role in the risk of hepatocellular carcinoma even among patients with SVR (3). Coincidently, these two variables are also the unfavorable factors for the achievement of SVR in patients receiving pegylated IFN (pegIFN) and ribavirin combination therapy (14, 15). The older the patient, the lower the likelihood of achieving a cure using this regimen.

Taken collectively, these observations make it imperative to prioritize candidates that are in urgent need of antiviral therapy and, relying on these time-degenerative factors, identify the optimal treatment time point beyond which therapy will have little impact on long-term disease outcome. The two time-degenerative factors, age and fibrosis, act interactively in contributing to hepatocellular carcinoma. Age per se is also a risk for liver fibrosis (16). It is therefore imperative to judge the independent role of the two factors in hepatocellular carcinoma, respectively. We herein recruited a large cohort of patients who received pegIFN–ribavirin combination therapy. By comparing the incidence of hepatocellular carcinoma in patients with and without SVR after long-term follow-up, we aimed to identify the optimal age and the stage of liver fibrosis at which initiating antiviral treatment can be justified.

Patients with HCV viremia and biopsy-proven chronic hepatitis C (CHC) who were scheduled to receive antiviral therapy were consecutively enrolled at a medical center and three regional hospitals from 1991 to 2012. Patients at risk for human immunodeficiency virus infection, such as men who have sex with men, persons who inject drugs, and patients with history of multiple transfusions, were excluded from the study. Patients receiving either conventional IFN or pegIFN with or without ribavirin were enrolled if their final treatment outcome could be identified. Patients who developed hepatocellular carcinoma before antiviral treatment or patients who were seropositive for hepatitis B surface antigen (ELISA Kits, Abbott) were excluded. Patients with or without an SVR, defined as the seronegativity of HCV RNA throughout a 24-week postantiviral treatment follow-up period, were evaluated for the risk of hepatocellular carcinoma. Hepatocellular carcinoma occurrence was linked directly to the National Cancer Registration of Taiwan in Health and Welfare Data Science Center (Taipei, Taiwan), which collects all primary cancers from all of the hospitals with more than 50 beds in Taiwan as mandated by the Cancer Control Act (17, 18). Serum HCV RNA was detected using qRT-PCR (COBAS AMPLICOR Hepatitis C Virus Test, ver. 2.0; Roche; detection limit: 50 IU/mL) and quantification branched DNA assay (Versant HCV RNA 3.0, Bayer; quantification limit: 615 IU/mL) before 2011. The HCV genotypes were determined using the Okamoto method before 2011 (19). Both the HCV RNA and genotype were detected using real-time PCR assays (RealTime HCV, detection limit: 12 IU/mL; and Abbott RealTime HCV Genotype II, Abbott Molecular) beginning in 2011 (20). The liver histology, which was obtained within one year before starting antiviral therapy, was graded and staged according to the scoring system described by Scheuer (21). The posttreatment follow-up strategy was based on cirrhotic status and treatment outcome, as described previously (4). In general, patients were followed up at least every 3 to 6 months if they had advanced liver disease or did not achieve SVR and at least every 6 to 12 months if they had mild liver disease and achieved SVR. Hepatocellular carcinoma was confirmed and managed in accordance with guidelines set forth by the American Association for the Study of Liver Diseases (22) and Asian Pacific Association for the Study of the Liver (23). All patients provided written informed consent. The Institutional Review Board of the participating hospitals approved the protocols, which conformed to the guidelines of the International Conference on Harmonization for Good Clinical Practice.

Genetic testing

IL28B rs8099917 was selected as the candidate SNP to test its association with hepatocellular carcinoma. The genetic testing was determined using methods that have been described previously (24, 25).

Statistical analyses

Frequency was compared between groups using the χ2 test, with the Yates correction, or Fisher exact test. Group means (presented as the mean ± SD) were compared using ANOVA and Student t test or the nonparametric Mann–Whitney test, when appropriate. Kaplan–Meier analysis and the log-rank test were performed by comparing the differences of the cumulative incidence of hepatocellular carcinoma between patients with and without an SVR. The risk factors independently associated with hepatocellular carcinoma development were evaluated by using Cox regression analysis. The statistical analyses were performed using the SPSS 12.0 statistical package (SPSS). All statistical analyses were based on two-sided hypothesis tests with a significance level of P < 0.05.

Patient profile

A total of 1,281 patients were enrolled in the study (Fig. 1) with a mean follow-up period of 5.5 years (range, 0.5–18.0 years). The basic demographic, virological, and clinical features of the patients are shown in Table 1. The mean age was 50.6 ± 11.4 years. Males accounted for the 54.8% of the population. The patient numbers in the groups of F0–1, F2–3, and F4 fibrosis stages were 592 (46.2%), 548 (42.8%), and 141 (11.0%), respectively. A total of 1,015 (79.2%) patients achieved an SVR, and 266 (20.8%) patients were treatment failures.

Figure 1.

Patient profile. HCC, hepatocellular carcinoma.

Figure 1.

Patient profile. HCC, hepatocellular carcinoma.

Close modal
Table 1.

Factors with hepatocellular carcinoma occurrence

Cox regression analysis
HCC (n = 80)Non-HCC (n = 1,201)PHR (95% CI)P
Treatment response, n (%)   <0.001   
 SVR 36 (45.0) 979 (81.5)   
 Non-SVR 44 (55.0) 222 (18.5)  3.27 (2.02–5.29) <0.001 
Fibrosis, n (%)   <0.001   
 F01 17 (21.3) 575 (47.9)   
 F23 35 (43.8) 513 (42.7)  2.71 (1.50–4.90) 0.001 
 F4 28 (35.0) 113 (9.4)  5.20 (2.70–10.03) <0.001 
Age (years, mean + SD) 55.4 ± 8.7 50.3 ± 11.5 <0.001 1.04 (1.01–1.06) 0.002 
r-GT, n (%)   0.001   
 <75 U/L, 42 (52.5) 890 (74.1)   
 >75 U/L 35 (43.8) 287 (23.9)  1.62 (1.11–2.38) 0.01 
 Unavailable 3 (3.8) 24 (2.0)  —  
BMI, n (%)   0.019   
 <27 kg/m2, mean + SD 54 (67.5) 945 (78.7)   
 >27 kg/m2, mean + SD 26 (32.5) 256 (21.3)  1.66 (1.02–2.70) 0.04 
Sex, n (%)   0.23   
 Female 31 (38.8) 548 (45.6)   
 Male 49 (61.3) 653 (54.4)  1.65 (1.02–2.66) 0.04 
AST (IU/L, mean + SD) 111.9 ± 57.24 98.62 ± 65.23 0.08 1.00 (1.00–1.01) 0.21 
ALT (IU/L, mean + SD) 138.2 ± 77.23 151.4 ± 106.7 0.15 1.00 (0.99–1.00) 0.07 
IL28B r8099917 genotypea, n (%)   0.001   
 Non-TT 12 (15.0) 101 (8.4)   
 TT 36 (45.0) 781 (65.0)  1.02 (0.71–1.47) 0.91 
HCV genotype, n (%)      
 Non-1 44 (55.0) 564 (47.0) 0.28  
 1 36 (45.0) 625 (52.0)  1.08 (0.69–1.68) 0.75 
F/U duration, year, median, IQR (range) 2.93, 1.33–4.22 (0.07–15.27) 5.60, 3.61–6.86 (0.48–17.95)    
Cox regression analysis
HCC (n = 80)Non-HCC (n = 1,201)PHR (95% CI)P
Treatment response, n (%)   <0.001   
 SVR 36 (45.0) 979 (81.5)   
 Non-SVR 44 (55.0) 222 (18.5)  3.27 (2.02–5.29) <0.001 
Fibrosis, n (%)   <0.001   
 F01 17 (21.3) 575 (47.9)   
 F23 35 (43.8) 513 (42.7)  2.71 (1.50–4.90) 0.001 
 F4 28 (35.0) 113 (9.4)  5.20 (2.70–10.03) <0.001 
Age (years, mean + SD) 55.4 ± 8.7 50.3 ± 11.5 <0.001 1.04 (1.01–1.06) 0.002 
r-GT, n (%)   0.001   
 <75 U/L, 42 (52.5) 890 (74.1)   
 >75 U/L 35 (43.8) 287 (23.9)  1.62 (1.11–2.38) 0.01 
 Unavailable 3 (3.8) 24 (2.0)  —  
BMI, n (%)   0.019   
 <27 kg/m2, mean + SD 54 (67.5) 945 (78.7)   
 >27 kg/m2, mean + SD 26 (32.5) 256 (21.3)  1.66 (1.02–2.70) 0.04 
Sex, n (%)   0.23   
 Female 31 (38.8) 548 (45.6)   
 Male 49 (61.3) 653 (54.4)  1.65 (1.02–2.66) 0.04 
AST (IU/L, mean + SD) 111.9 ± 57.24 98.62 ± 65.23 0.08 1.00 (1.00–1.01) 0.21 
ALT (IU/L, mean + SD) 138.2 ± 77.23 151.4 ± 106.7 0.15 1.00 (0.99–1.00) 0.07 
IL28B r8099917 genotypea, n (%)   0.001   
 Non-TT 12 (15.0) 101 (8.4)   
 TT 36 (45.0) 781 (65.0)  1.02 (0.71–1.47) 0.91 
HCV genotype, n (%)      
 Non-1 44 (55.0) 564 (47.0) 0.28  
 1 36 (45.0) 625 (52.0)  1.08 (0.69–1.68) 0.75 
F/U duration, year, median, IQR (range) 2.93, 1.33–4.22 (0.07–15.27) 5.60, 3.61–6.86 (0.48–17.95)    

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; HCC, hepatocellular carcinoma; IQR, inter-quarter range.

aData available in 930 patients.

Cumulative incidence of hepatocellular carcinoma and risk factors for hepatocellular carcinoma development

Eighty patients (6.2%) developed hepatocellular carcinoma over 7,308 person-years of follow-up (annual incidence rate, 1.1%), including 36 (3.55%) of the 1,015 SVR patients and 44 (16.54%) of the 226 non-SVR patients, with an annual incidence of 0.6% and 2.6%, respectively. In a univariate analysis, patients who developed hepatocellular carcinoma were older, had a higher body mass index (BMI) and r-GT level, a higher proportion of IL28B rs8099917 non-TT genotype, were in the non-SVR group, and had advanced liver disease. Cox regression analysis of the factors predictive of hepatocellular carcinoma included liver fibrosis [F4 vs. F0–1: HR/95% confidence interval (CI), 5.20/2.70–10.03; P < 0.001; F2–3 vs. F0–1: HR/CI, 2.71/1.50–4.90, P = 0.001), age (HR/CI, 1.04/1.01–1.06; P = 0.002), male gender (HR/CI, 1.65/1.02–2.66; P = 0.04), r-GT levels (HR/CI, 1.62/1.11–2.38; P = 0.01), and BMI (HR/CI, 1.66/1.02–2.70; P = 0.04; Table 1).

Impact of the time-degenerative factor, age, on hepatocellular carcinoma development between patients with and without SVR

We first stratified the patients into three groups by age. Compared with SVR patients, the cumulative incidence of hepatocellular carcinoma in non-SVR patients did not differ in patients who were <40 years old (5-year and 10-year cumulative incidence rate, 7.7% and 7.7% vs. 0.5% and 1.3%, respectively, P = 0.1). However, the cumulative incidence of hepatocellular carcinoma was significantly higher in non-SVR patients compared with SVR patients among those between 40 and 55 years old (5-year and 10-year cumulative incidence rate, 18.0% and 22.9% vs. 1.3% and 1.3%, respectively, P < 0.001) and >55 years old (5-year and 10-year cumulative incidence rate, 15.1% and 24.5% vs. 7.9% and 14.3%, respectively, P = 0.03; Supplementary Fig. S1A–S1C). Compared with SVR, non-SVR was independently predictive of hepatocellular carcinoma in patient groups between 40 and 55 years old (HR/CI, 10.92/3.78–31.56; P < 0.001) and >55 years old (HR/CI, 1.96/1.06–3.63; P = 0.03), but not in the group of patients <40 years old (HR/CI, 2.76/0.41–18.84; P = 0.3, Cox regression analysis; Table 2).

Table 2.

Cox regression analysis of the independent impact of treatment responses on hepatocellular carcinoma in different age groups

Age <40 (n = 216)Age 40–55 (n = 561)Age ≥55 (n = 504)
HR (95% CI)PHR (95% CI)PHR (95% CI)P
Treatment response SVR    
 Non-SVR 2.76 (0.41–18.84) 0.30 10.92 (3.78–31.56) <0.0001 1.96 (1.06–3.63) 0.03 
Fibrosis 0–1    
 2–3 6.02 (0.61–59.88) 0.13 3.94 (1.32–11.78) 0.01 2.20 (1.03–4.71) 0.04 
 25.81 (2.15–310.10) 0.01 7.70 (2.39–24.83) 0.0006 4.35 (1.90–9.94) 0.0005 
Sex Female    
 Male 0.82 (0.11–6.00) 0.85 1.24 (0.49–3.18) 0.65 1.84 (1.01–3.36) 0.05 
IL28B rs8099917 Non-TT    
 TT 0.50 (0.09–2.92) 0.44 1.05 (0.56–1.94) 0.89 1.01 (0.63–1.62) 0.98 
HCV genotype Non-1    
 1.22 (0.23–6.52) 0.82 0.42 (0.13–1.31) 0.13 1.48 (0.86–2.55) 0.16 
r-GT <75 U/L    
 ≥75 U/L 1.21 (0.25–5.97) 0.82 1.71 (0.81–3.63) 0.16 1.46 (0.89–2.39) 0.13 
BMI <27 kg/m2    
 ≥27 kg/m2 2.10 (0.17–26.48) 0.57 1.15 (0.47–2.83) 0.76 1.63 (0.87–3.05) 0.12 
ALT Per 1 IU/L increased 0.99 (0.98–1.01) 0.31 1.00 (1.00–1.01) 0.86 1.00 (0.99–1.00) 0.16 
Age <40 (n = 216)Age 40–55 (n = 561)Age ≥55 (n = 504)
HR (95% CI)PHR (95% CI)PHR (95% CI)P
Treatment response SVR    
 Non-SVR 2.76 (0.41–18.84) 0.30 10.92 (3.78–31.56) <0.0001 1.96 (1.06–3.63) 0.03 
Fibrosis 0–1    
 2–3 6.02 (0.61–59.88) 0.13 3.94 (1.32–11.78) 0.01 2.20 (1.03–4.71) 0.04 
 25.81 (2.15–310.10) 0.01 7.70 (2.39–24.83) 0.0006 4.35 (1.90–9.94) 0.0005 
Sex Female    
 Male 0.82 (0.11–6.00) 0.85 1.24 (0.49–3.18) 0.65 1.84 (1.01–3.36) 0.05 
IL28B rs8099917 Non-TT    
 TT 0.50 (0.09–2.92) 0.44 1.05 (0.56–1.94) 0.89 1.01 (0.63–1.62) 0.98 
HCV genotype Non-1    
 1.22 (0.23–6.52) 0.82 0.42 (0.13–1.31) 0.13 1.48 (0.86–2.55) 0.16 
r-GT <75 U/L    
 ≥75 U/L 1.21 (0.25–5.97) 0.82 1.71 (0.81–3.63) 0.16 1.46 (0.89–2.39) 0.13 
BMI <27 kg/m2    
 ≥27 kg/m2 2.10 (0.17–26.48) 0.57 1.15 (0.47–2.83) 0.76 1.63 (0.87–3.05) 0.12 
ALT Per 1 IU/L increased 0.99 (0.98–1.01) 0.31 1.00 (1.00–1.01) 0.86 1.00 (0.99–1.00) 0.16 

Abbreviations: ALT, alanine aminotransferase; HCC, hepatocellular carcinoma.

With SVR patients <40 years old as a reference, we observed that the risk of hepatocellular carcinoma was similar in non-SVR patients who were <40 years old (HR/CI, 4.23/0.85–21.19; P = 0.08) and SVR patients who were between 40 and 55 years old (HR/CI, 0.60/0.14–2.54; P = 0.49). The risk of hepatocellular carcinoma significantly increased in SVR patients >55 years old (HR/CI, 4.18/1.25–13.98; P = 0.02) and was highest in non-SVR patients 40 to 55 years old (HR/CI, 7.80/2.27–26.82; P = 0.001) or non-SVR patients >55 years old (HR/CI, 7.32/2.11–25.34; P = 0.002; Supplementary Table S1; Fig. 2).

Figure 2.

Risk of hepatocellular carcinoma (HCC) in patients with different age groups and treatment responses.

Figure 2.

Risk of hepatocellular carcinoma (HCC) in patients with different age groups and treatment responses.

Close modal

Impact of the time-degenerative factor, fibrosis, on hepatocellular carcinoma development between patients with and without SVR

Patients were stratified into three groups by fibrosis stage. The cumulative incidence of hepatocellular carcinoma did not differ between non-SVR and SVR patients among the F0–1 fibrosis group (5-year and 10-year cumulative incidence rate, 4.6% and 4.5% vs. 1.9% and 3.5%, respectively, P = 0.25). However, non-SVR patients had a significantly higher 5-year cumulative incidence of hepatocellular carcinoma compared with SVR patients among the F2–3 fibrosis group (5-year and 10-year cumulative incidence rate, 21.4% and 27.1% vs. 4.3% and 4.8%, respectively, P < 0.001) or F4 (5-year and 10-year cumulative incidence rate, 33.5% and 58.3% vs. 8.4% and 15.0%, respectively, P = 0.0002; Supplementary Fig. S2A–S2C). Compared with SVR, non-SVR was independently predictive of hepatocellular carcinoma development in the F2–3 group (HR/CI, 4.36/2.10–9.03; P < 0.001) and the F4 group (HR/CI, 3.84/1.59–9.30; P = 0.03), but not in the F0–1 group (HR/CI, 1.53/0.49–4.74; P = 0.47) using Cox regression analysis (Table 3).

Table 3.

Cox regression analysis of the independent impact of treatment responses on hepatocellular carcinoma in different fibrotic stages

F0–1 (n = 592)F2–3 (n = 548)F4 (n = 141)
HR (95% CI)PHR (95% CI)PHR (95% CI)P
Treatment response SVR    
 Non-SVR 1.53 (0.49–4.74) 0.47 4.36 (2.10–9.03) <0.001 3.84 (1.59–9.30) 0.003 
Age, y <40    
 40–55 1.38 (0.26–7.28) 0.70 1.43 (0.31–6.63) 0.65 1.25 (0.24–6.64) 0.79 
 ≥55 5.24 (1.11–24.68) 0.04 3.04 (0.69–13.30) 0.14 1.15 (0.23–5.82) 0.86 
Sex Female    
 Male 3.16 (0.90–11.14) 0.07 1.70 (0.83–3.50) 0.15 1.04 (0.44–2.46) 0.93 
IL28B rs8099917 Non-TT    
 TT 0.94 (0.38–2.31) 0.89 0.97 (0.56–1.68) 0.92 1.08 (0.59–1.96) 0.80 
HCV genotype Non-1    
 1.09 (0.47–2.54) 0.85 0.86 (0.42–1.75) 0.68 1.14 (0.46–2.78) 0.78 
r-GT <75 U/L    
 ≥75 U/L 2.19 (0.98–4.88) 0.06 1.60 (0.87–2.91) 0.13 1.59 (0.75–3.35) 0.23 
BMI <27 kg/m2    
 ≥27 kg/m2 1.62 (0.53–4.99) 0.40 1.50 (0.71–3.17) 0.28 1.11 (0.48–2.58) 0.80 
ALT Per 1 IU/L increased 1.00 (1.00–1.00) 0.85 1.00 (0.99–1.00) 0.25 1.00 (0.99–1.00) 0.18 
F0–1 (n = 592)F2–3 (n = 548)F4 (n = 141)
HR (95% CI)PHR (95% CI)PHR (95% CI)P
Treatment response SVR    
 Non-SVR 1.53 (0.49–4.74) 0.47 4.36 (2.10–9.03) <0.001 3.84 (1.59–9.30) 0.003 
Age, y <40    
 40–55 1.38 (0.26–7.28) 0.70 1.43 (0.31–6.63) 0.65 1.25 (0.24–6.64) 0.79 
 ≥55 5.24 (1.11–24.68) 0.04 3.04 (0.69–13.30) 0.14 1.15 (0.23–5.82) 0.86 
Sex Female    
 Male 3.16 (0.90–11.14) 0.07 1.70 (0.83–3.50) 0.15 1.04 (0.44–2.46) 0.93 
IL28B rs8099917 Non-TT    
 TT 0.94 (0.38–2.31) 0.89 0.97 (0.56–1.68) 0.92 1.08 (0.59–1.96) 0.80 
HCV genotype Non-1    
 1.09 (0.47–2.54) 0.85 0.86 (0.42–1.75) 0.68 1.14 (0.46–2.78) 0.78 
r-GT <75 U/L    
 ≥75 U/L 2.19 (0.98–4.88) 0.06 1.60 (0.87–2.91) 0.13 1.59 (0.75–3.35) 0.23 
BMI <27 kg/m2    
 ≥27 kg/m2 1.62 (0.53–4.99) 0.40 1.50 (0.71–3.17) 0.28 1.11 (0.48–2.58) 0.80 
ALT Per 1 IU/L increased 1.00 (1.00–1.00) 0.85 1.00 (0.99–1.00) 0.25 1.00 (0.99–1.00) 0.18 

Abbreviations: ALT, alanine aminotransferase; HCC, hepatocellular carcinoma.

With SVR patients with F0–1 as a reference, we found that the risk of hepatocellular carcinoma was similar in non-SVR patients with F0–1 (HR/CI, 1.77/0.64–4.88; P = 0.27) or SVR patients with F2 (HR/CI, 1.78/0.73–4.34; P = 0.20) or F3 fibrosis stages (HR/CI, 1.86/0.72–4.85; P = 0.20). The risk of hepatocellular carcinoma was significantly increased in SVR patients with F4 fibrosis stage (HR/CI, 4.33/1.76–10.64; P = 0.001) and in non-SVR patients with F2 (HR/CI, 6.55/2.57–16.70; P < 0.001) and F3 fibrosis stages (HR/CI, 9.43/3.87–22.99; P < 0.001) and was highest in non-SVR patients with F4 fibrosis stage (HR/CI, 14.86/6.73–32.81; P = 0.001; Supplementary Table S2; Fig. 3)

Figure 3.

Risk of hepatocellular carcinoma (HCC) in patients with different fibrotic stages and treatment responses.

Figure 3.

Risk of hepatocellular carcinoma (HCC) in patients with different fibrotic stages and treatment responses.

Close modal

Undoubtedly, all patients who are chronically infected with HCV should be treated, except for individuals with anticipated short life expectancies (5, 6). However, in reality, the huge budget impact of DAAs has now restricted universal access to treatment for most patients with CHC. Beyond the issue of cost-effectiveness (8, 26), the growing need for more professionals to diagnose, evaluate, and provide care for patients with HCV is another major concern (27). Therefore, whether patients with HCV infection should be prioritized for treatment has become a serious issue (5, 6, 28). Value-based patient prioritization may provide a solution and may actually be a must-be action in response to the abrupt demand for manpower and surging costs (27). Patient age and the degree of hepatic fibrosis are the two major time-degenerative predictors of HCV-related hepatocellular carcinoma if patients are left untreated. In the current study, we identified that an age of more than 40 years and a fibrosis stage >2 are two independent risk factors predictive of hepatocellular carcinoma. Patients who possess either one of these two characteristics should not be deferred for treatment. The benefit of SVR was enhanced in patients between 40 and 55 years old or with an F2–3 fibrosis stage, whose risk of hepatocellular carcinoma was greatly minimized to the level of individuals <40 years old with F0–1 fibrosis stage. However, the preventive effect of viral eradication on hepatocellular carcinoma risk was diminished in patients >55 years old or with F4 fibrosis stage.

With reference to liver-related complications, patients with compensated advanced chronic liver disease, which reflects a disease spectrum ranging from severe fibrosis and cirrhosis (F3 and F4 by METAVIR score), are at risk for developing clinically significant portal hypertension (29). Therefore, both the AASLD and EASL recommend that patients with advanced fibrosis (F3/4) should be prioritized to receive antiviral therapy (5, 6). In the current study, we also observed that patients with CHC with a fibrosis score ≥2 had a significantly increased risk of hepatocellular carcinoma if they exhibited persistent viremia. Our results suggest that we should reprioritize patients with moderate fibrosis, F2, as urgent candidates for treatment with the aim of preventing hepatocellular carcinoma, similar to the prioritization scheme set forth for patients with advanced liver disease. The World Health Organization has recently defined patients with a METAVIR score ≥2 as having “significant fibrosis” (30). The current study is in line with this definition not only with regard to pathologic grading but also in terms of long-term clinical outcomes. Treating patients with a fibrosis score >2 is not only justified, but mandatory (6). Although hepatocellular carcinoma can still develop in the background of mild liver fibrosis even with HCV eradication (4), patients with liver cirrhosis have the greatest risk of developing hepatocellular carcinoma with an annual rate of approximately 3% to 8% (31). Successful viral eradication has greatly reduced the incidence of hepatocellular carcinoma in patients with advanced liver disease by 75% (32). However, as confirmed in this study, the risk of hepatocellular carcinoma remains 4- to 5-fold higher in SVR patients (4) with cirrhosis. Closer surveillance after viral eradication is mandatory in this high-risk population. The incidence of hepatocellular carcinoma increases progressively with advancing age regardless of the etiology (33).

Age is one of the most critical determinants for hepatocellular carcinoma development in association with HCV infection (4, 11). It is unclear up to what age the threat of hepatocellular carcinoma exists and whether SVR reduces this age-related risk. Furthermore, age itself is a risk factor of HCV-related liver fibrosis (16, 34), which confounds any association between hepatocellular carcinoma and age. The progression of fibrosis has been shown to be rapid in individuals close to 40 years and older (35). The independent risk of age in hepatocellular carcinoma must be carefully addressed by adjusting for fibrosis. We demonstrated that the risk of hepatocellular carcinoma did not differ between patients with or without SVR if they were <40 years old. Thus, deferring treatment for younger patients with CHC might be an alternative choice in resource-restricted areas. However, patients who are >40 years old should be urgently treated particularly if they have a fibrosis score ≥2. For patients between 40 to 55 years old, the risk of hepatocellular carcinoma could be greatly reduced by successful antiviral therapy resulting in a risk comparable with that of patients <40 years old. Notably, the preventive effect of SVR for hepatocellular carcinoma was diminished in patients >55 years old. A 4-fold increased risk of hepatocellular carcinoma was observed in the SVR patients >55 years old compared with those <40 years old. Similar to cirrhotic patients, elderly subjects should be closely monitored for hepatocellular carcinoma even if they benefit from viral eradication. Our results provide evidence for prioritizing patients to receive HCV treatment based on an evaluation of the time-degenerative factors, age and hepatic fibrosis, and offers a scheme of implementation. However, patients with a high risk of severe extrahepatic complications, a risk of HCV transmission and coinfection with hepatitis B or HIV should also be prioritized to receive urgent treatment regardless of their age and stage of fibrosis.

Unlike Western population, an SVR rate of 80% could be attained in Taiwanese patients with pegIFN/ribavirin. The limitation of the current study is that the results were generated from IFN-based treatments rather than the DAA IFN-free regimens and the relative case limitation in patients aged <40 years old. However, the long-term effect of DAA IFN-free regimens on the development of hepatocellular carcinoma is currently unknown due to the limited duration of follow-up after the broad application of the new regimens. Furthermore, IFn has antiviral, antineoplastic, and immunomodulatory effects, all of which represent mechanisms that might contribute to the prevention of hepatocellular carcinoma in patients with CHC. In spite of very high antiviral potency, DAAs lack antineoplastic and immunomodulatory effect. Further study regarding hepatocellular carcinoma prevention in the era of DAAs is warranted and awaits exploration.

The role of occult HBV infection (OBI) in hepatocellular carcinoma is elusive (36, 37). It has been shown that its impact was less important in HCV patients (38). Even though patients with HBV dual infection were not allocated in the cohort, we could not completely exclude the potential impact of OBI on HCV-related hepatocellular carcinoma development in the endemic area. Further studies are warranted to address this issue.

Public health policymakers should devote their efforts toward reducing the burden of disease. However, the relationship between health care providers and insurers in terms of the cost of antiviral therapy is complex and takes into account multiple factors, such as patient income, life expectancy, HCV prevalence, and the peak age of infection as well as the availability and type of medical facilities in different regions (39, 40). The current study offers a solution that addresses the constraints surrounding the availability of clinical services and the treatment costs before the era in which DAAs will be affordable and broadly available.

In conclusion, we provide solid evidence for the benefits of using time-degenerative risk factors that increase the risk of hepatocellular carcinoma for prioritizing patients to receive anti-HCV therapy. For patients who are <40 years old or with F0–1 fibrosis stage, treatment can be deferred in resource-restricted areas because the incidence of hepatocellular carcinoma does not differ between patients with or without viral eradication. However, patients >40 years old or with a fibrosis score >2 are a watershed for immediate treatment. Patients between 40 and 55 years old or with an F2–3 fibrosis stage would benefit from viral eradication the most because the risk of hepatocellular carcinoma in this age group is as low for individuals <40 years old or with F0–1 fibrosis stage. Finally, patients >55 years old and with F4 fibrosis stage should be closely monitored for hepatocellular carcinoma even after achieving an SVR.

M. Yu reports receiving commercial research grants from Bristol-Myers Squibb, Gilead, and Roche, has received speakers bureau honoraria from and is a consultant/advisory board member for Abbvie, Bristol-Myers Squibb, Gilead, MSD, and Roche. W. Chuang reports receiving speakers bureau honoraria from Bristol-Myers Squibb, Gilead, MSD, and Roche and is a consultant/advisory board member for Abbvie, Gilead, PharmaEssentia, and Roche. No potential conflicts of interest were disclosed by the other authors.

Conception and design: M.-L. Yu, C.-Y. Dai, W.-L. Chuang

Development of methodology: M.-L. Yu, P.-C. Tsai, W.-L. Chuang

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): M.-L. Yu, M.-L. Yeh, C.-I. Huang, M.-H. Hsieh, M.-Y. Hsieh, Z.-Y. Lin, S.-C. Chen, J.-F. Huang, W.-L. Chuang

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): M.-L. Yu, C.-F. Huang, P.-C. Tsai, J.-F. Huang, W.-L. Chuang

Writing, review, and/or revision of the manuscript: M.-L. Yu, C.-F. Huang, C.-Y. Dai, W.-L. Chuang

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): M.-L. Yu, M.-L. Yeh, S.-C. Chen

Study supervision: M.-L. Yu, C.-Y. Dai, W.-L. Chuang

This study was supported by grants from the Kaohsiung Medical University Hospital (KMUH-103-3R04, KMUH102-2T01 and KMUH103-10V04) and Kaohsiung Medical University (NSYSUKMU105-P025, KMU-TP103E06, KMU-TP103E07, KMU-TP103E08, KMU-TP104E07, KMU-TP103E08, KMU-TP103E09, and KMU-DK105006). The linkage cancer registry database was supported by Health and Welfare Data Science Center, Taiwan.

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