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    Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE

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Independent Risk Factors for Hepatocellular Carcinoma Recurrence after Direct-Acting Antiviral Therapy in Patients with Chronic Hepatitis C

Young-Hwan Ahn1 , Heirim Lee2,3 , Do Young Kim4 , Hye Won Lee4 , Su Jong Yu5 , Young Youn Cho5,6 , Jeong Won Jang7 , Byoung Kuk Jang8 , Chang Wook Kim9 , Hee Yeon Kim9 , Hana Park10 , Hyo Jung Cho1 , Bumhee Park2,3 , Soon Sun Kim1 , and Jae Youn Cheong1

Departments of 1Gastroenterology, 2Biomedical Informatics, and 3Office of Biostatistics, Ajou Research Institute for Innovative Medicine, Ajou University School of Medicine, Suwon, 4Department of Internal Medicine, Yonsei University College of Medicine, 5Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 6Department of Internal Medicine, Chung-Ang University Hospital, 7Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, 8Department of Internal Medicine, Keimyung University School of Medicine, Daegu, 9Division of Hepatology, Department of Internal Medicine, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, and 10Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea

Correspondence to:Jae Youn Cheong
ORCID https://orcid.org/0000-0001-6246-1783
E-mail jaeyoun620@gmail.com
Soon Sun Kim
ORCID https://orcid.org/0000-0002-6862-1896
E-mail cocorico99@gmail.com
Young-Hwan Ahn and Heirim Lee contributed equally to this work as first authors.

Received: May 12, 2020; Revised: June 12, 2020; Accepted: June 15, 2020

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gut and Liver 2021; 15(3): 410-419

Published online May 15, 2021 https://doi.org/10.5009/gnl20151

Copyright © Gut and Liver.

Background/Aims: This study was performed to evaluate the efficacy of direct-acting antivirals (DAAs) in Korean patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) and to investigate the risk factors associated with HCC recurrence.
Methods: A total of 100 patients with HCV-related HCC, who were treated with DAAs between May 2015 and December 2016, were recruited from seven university hospitals in Korea. Claim data of 526 patients with HCC obtained from the Health Insurance Review and Assessment Service in South Korea were used for external validation of the results.
Results: Among the 100 patients, 88% achieved a sustained virological response (SVR) 12 weeks after the end of DAA therapy (SVR12), and 37% experienced HCC recurrence after DAA therapy. Short last HCC treatment durability (<12 months) before DAA commencement was independently associated with HCC recurrence (hazard ratio [HR], 2.89; p=0.011). In the nationwide validation cohort, 20.3% of the patients experienced HCC recurrence. The last HCC treatment with a noncurative method, a short last HCC treatment durability (<12 months), and a longer total duration of HCC treatment (≥18 months) were independently related with HCC recurrence (HR 3.73, p<0.001; HR 3.34, p<0.001; and HR 1.74, p=0.006; respectively).
Conclusions: DAA therapy showed an acceptable SVR12 rate in patients with HCV-related HCC. Short last HCC treatment durability (<12 months) was associated with HCC recurrence after DAA therapy. This finding suggests that the last HCC treatment durability is an important predictor of HCC recurrence after DAA therapy.

Keywords: Carcinoma, hepatocellular, Antiviral agents, Risk factors, Hepatitis C, chronic, Recurrence

Chronic infection with hepatitis C virus (HCV) is a well-known risk factor for liver cirrhosis and hepatocellular carcinoma (HCC), which is one of the most common and fatal malignancies globally.1,2 Direct-acting antivirals (DAAs) exhibit an excellent efficacy against HCV.3-6 While the pegylated interferon plus ribavirin therapy approved in 2001 shows a sustained virological response (SVR) of 42% to 46% in genotype 1 and 76% to 82% in genotypes 2 or 3,7,8 the success rate of DAA therapy is over 86%, even in patients with a decompensated or an advanced liver disease.9,10 Consequently, DAAs have become an indispensable element of hepatitis C treatment. Recently, the World Health Organization has set a goal to treat 80% of the global hepatitis C cases, and reduce annual deaths due to viral hepatitis by 35%, by 2030.11 It is important to elucidate reasonable study outcomes to reduce the uncertainty surrounding DAA therapy, and to allow more patients to be treated, including patients with HCV-associated HCC.

Reportedly, patients with HCC are more resistant to DAA therapy than those without HCC.12-14 SVR rates of 74.4% to 79% and 88% to 91.1% were recorded in American patients with and without HCC, respectively.13,14 However, little is known about the efficacy of DAA therapy in the Asian population. Recent studies have reported unexpectedly high rates of HCC recurrence after a successful DAA treatment.15-17 While a meta-analysis showed no difference in HCC recurrence following DAA or interferon therapy after adjusting for study follow-up time and patient age,18 the issue raises an uncertainty about the appropriate timing of treatment of HCV-infected patients with a history of HCC. Therefore, it is important to identify risk factors associated with HCC recurrence in the DAA-treated patients.

The aim of this study was to evaluate the therapeutic efficacy of DAAs in Asian patients with a history of HCV-induced HCC, and investigate the risk factors for HCC recurrence after DAA therapy.

1. Patient selection

We retrospectively recruited 100 patients with HCV-infected HCC from seven university hospitals in South Korea. Patients who achieved complete response (CR) after HCC treatment and started the DAA therapy between August 2015 and December 2016 were enrolled. Chronic hepatitis C was defined as the presence of the anti-HCV antibody and HCV RNA for more than 6 months. HCC was diagnosed if the tumor had a minimum diameter ≥1 cm, and if typical features of HCC (arterial phase hyperenhancement, washout in the portal venous or delayed phase, threshold growth, and capsule appearance) were observed using multiphase computed tomography and/or magnetic resonance imaging. If these criteria were present but there was a lack of a diagnostic certainty, a liver biopsy was performed to confirm the diagnosis of HCC.19 Patients were excluded if they met any of the following criteria: evidence of autoimmune hepatitis or viral co-infection, such as those with the hepatitis B virus or the human immunodeficiency virus; alcohol consumption >210 g per week for males and >140 g per week for females; no CR after HCC treatment prior to DAA therapy; liver transplantation before DAA therapy; no tumor status assessment after starting DAA therapy; and/or treatment with interferon as part of DAA therapy. The patients were followed-up until HCC recurrence or until January 2018.

For external validation, we used data from patients with an HCV-infected HCC from the Korean Health Insurance Review and Assessment Service (HIRA)20 (Supplementary Fig. 1). HIRA data, which is generated in the process of reimbursing healthcare providers under National Health Insurance, contains specific, yet comprehensive information on the relevant healthcare services, such as procedures, surgeries, examinations, and treatment, including prescriptions and socio-demographic characteristics of patients. In South Korea, National Health Insurance covers approximately 98% of the total population. Moreover, all healthcare providers are required to be covered under the National Health Insurance, which is based on fee-for-services.20 Subjects with HCC (C220 and C229) who were prescribed DAA therapy (638101ATB [daclatasvir], 638001ACH [asunaprevir], 644401ATB [sofosbuvir], 645800ATB [ledipasvir/sofosbuvir], 223604ACH, 223601ACH, and 223601ACH [ribavirin]) between August 2015 and December 2016 were extracted from the HIRA database using the International Classification of Diseases (10th edition).21,22 The exclusion criteria were as follows: autoimmune hepatitis (K75.4) or viral co-infection, including those with the hepatitis B (B18.0, B18.10, B18.18, B18.1, and Z22.5) and the human immunodeficiency virus (Z21.X, Z86.X, B20.X, B21.X, B22.X, B23.X, and B24.X); liver transplantation before DAA therapy; history of DAA therapy before or during HCC treatment. HCC recurrence was defined as reinitiation of HCC treatment after DAA therapy. The patients were followed-up until HCC recurrence or until December 2016. The study protocol was approved by the Institutional Review Board of the Ajou University Hospital (IRB number: AJIRB-MED-MDB-17-031).

2. Definitions

Baseline characteristics, including age, liver function, and the HCV RNA level, were documented at the start of the DAA therapy. HCC treatment duration was defined as the time between the initial HCC treatment and the last HCC treatment before a DAA therapy. Last HCC treatment durability was defined as the time between the final HCC treatment and the start of a DAA therapy. HCC recurrence time was calculated from the start of a DAA treatment. The SVR was determined 12 weeks after the end of a DAA treatment (SVR12). CR acquisition was defined according to modified RECIST criteria, disappearance of any intratumoral arterial enhancement in all target lesions on follow-up image study.23

3. Statistics

Data management and analysis were performed using the R statistical software (version 3.3.4; R Core Team [2014]; R: A language and environment for statistical computing; R Foundation for Statistical Computing, Vienna Austria; http://www.R-project.org/). Differences with p<0.05 were considered statistically significant. All statistical analyses were performed using two-tailed tests: continuous variables were analyzed using the independent samples t-test while categorical data were compared using the Pearson chi-square test or the Fisher exact test. Cumulative probabilities of HCC recurrence were assessed by the Kaplan-Meier analysis. The Cox proportional hazard model was used to identify factors associated with HCC recurrence.

1. Baseline characteristics of the multicenter cohort

The mean age of the subjects was 69.2±8.4 years, and 67% of them were male. The patients were the most commonly infected with the HCV genotype 1b (66%), followed by the genotype 2 (32%), genotype 1a (1%), and genotype 4 (1%). Cirrhosis and diabetes mellitus were diagnosed in 79% and 33% of the patients, respectively. HCC in BCLC (Barcelona Clinic Liver Cancer) stages B or C was detected in 11% of the cohort, whereas modified Union for International Cancer Control stage III or IV disease was found in 12% of the patients; 23% of the subjects had previously received an interferon based therapy (Table 1).

Among the 100 subjects with an HCV-related HCC, 24 underwent radiofrequency ablation (RFA) therapy, 21 were treated with a transarterial chemoembolization (TACE), 19 experienced liver resection, two underwent radiation therapy, one received a transarterial radioembolization, and 33 were treated with multimodal therapy. Regarding the modality of the last HCC treatment, TACE (36%) was the most frequently used, followed by RFA (33%), liver resection (21%), combination therapy (6%), and other therapies (4%). The median follow-up period after a DAA treatment start was 15.8 months (range, 4.4 to 29.9 months).

2. Efficacy of DAA therapy in patients with HCC

The efficacy of DAA therapy in patients with HCC is summarized in Fig. 1. Among the 100 patients in the multicenter cohort, 88 achieved SVR12 with DAA therapy. Even in those who experienced HCC recurrence, the SVR12 acquisition rate was as high as 86.5% (32/37). SVR12 was achieved by 86.1% (68/79) of patients with liver cirrhosis and by 95.2% (20/21) of those without it. The SVR12 rate was 87.9% (58/66) and 87.5% (28/32) with the genotypes 1b and 2, respectively. The only patient with genotype 1a and the only patient with genotype 4 acquired SVR12. Of the 36 patients who started the DAA therapy within 6 months of the last HCC treatment, 33 (91.7%) obtained SVR12. The SVR12 rate did not significantly differ between the groups (Fig. 1).

3. Details of 37 patients with HCC recurrence after DAA therapy

During the median follow-up period of 15.8 months (range, 4.4 to 29.9 months), 37% of the study subjects experienced HCC recurrence; the 1-year and 2-year cumulative recurrence rate was 28.4% and 61.3%, respectively. The median number and size of the recurrent tumors were 1 (range, 1 to 6) and 1.25 cm (range, 0.8 to 5.7 cm), respectively. Regarding the pattern of recurrence, a new intrahepatic recurrence (62.2%) was most commonly detected, followed by a marginal recurrence (16.2%), and a marginal recurrence combined with a new intrahepatic recurrence (5.4%). Extrahepatic recurrence was not observed. The majority of the patients (67.6%) were treated with TACE, 16.2% underwent RFA, while 5.4% received RFA as well as TACE. Radiation therapy, TACE followed by radiation therapy, and TACE followed by sorafenib were used in 2.7% of the cases each. After HCC recurrence, 58.8% of the patients showed CR while 14.7% obtained a partial response. Stable and progressive disease were observed in 5.9% and 20.6% of the cases, respectively.

4. Risk factors for HCC recurrence in the multicenter cohort

According to the univariate analysis, low platelet levels (p=0.040), HCC treatment with a noncurative method such as TACE, transarterial radioembolization, hepatic artery infusion chemotherapy, sorafenib and radiotherapy (p<0.001), last HCC treatment with a noncurative method (p<0.001), HCC treatment duration more than 18 months (p=0.009), and last HCC treatment durability less than 12 months (p=0.006) were related to HCC recurrence. In contrast, age (p=0.127), liver cirrhosis (p=0.159), and SVR12 (p=0.934) were not associated with HCC recurrence (Table 2). Multivariate Cox regression analysis showed that short last HCC treatment durability (<12 months) was only independently associated with HCC recurrence in patients with the HCV-related HCC after the DAA treatment (hazard ratio [HR], 2.89; 95% confidence interval [CI], 1.27 to 6.59; p=0.011) (Table 3, Fig. 2).

In subgroup analysis with patients who were treated with curative modality, mean HCC treatment durability (p=0.046) and last HCC treatment durability less than 12 months (p=0.036) were related to HCC recurrence. In age- and sex-adjusted multivariate Cox regression analysis, the relationship between last HCC treatment durability and HCC recurrence showed no statistical significance (p=0.058) (Supplementary Table 1).

5. External validation using the HIRA cohort

A total of 526 patients with HCV-related HCC and treated with DAAs were identified in the HIRA cohort. Baseline characteristics of the validation cohort have been listed in Table 4. The mean age of the subjects was 66.9±9.6 years, and 63.7% of them were male. Cirrhosis and diabetes were diagnosed in 87.1% and 70.5% of the cases, respectively, and 8% of the subjects had received a previous interferon based therapy. Among the 526 patients, 107 (20.3%) experienced HCC recurrence.

In the univariate analysis, HCC treatment with a noncurative method, the last HCC treatment with a noncurative method, a long duration of the HCC treatment (≥18 months), and short last HCC treatment durability before a DAA therapy (<12 months) were related to HCC recurrence (Table 5). Moreover, the multivariate Cox regression analysis showed that the last HCC treatment with a noncurative method (HR, 3.73; 95% CI, 1.87 to 7.43; p<0.001), HCC treatment duration ≥18 months (HR, 1.74; 95% CI, 1.16 to 2.60; p=0.006), the last HCC treatment durability <12 months (HR, 3.34; 95% CI, 1.95 to 5.71; p<0.001) were independently associated with HCC recurrence (Table 5, Fig. 3).

In the present study, short last HCC treatment durability before a DAA therapy (<12 months) was an independent predictor of HCC recurrence in both the multicenter cohort and the nationwide cohort from the Korean HIRA database. To the best of our knowledge, this is the first study to evaluate the risk factors for predicting HCC recurrence after the DAA therapy in Korean patients with HCV-related HCC.

Short last HCC treatment durability (<12 months) was the only common independent risk factor for HCC recurrence in the both multicenter cohort and nationwide HIRA cohort. The last HCC treatment with a noncurative method and a long total duration of the HCC treatment (≥18 months) prior to the DAA therapy were independent risk factors in the HIRA cohort, but not in the multicenter cohort. This discrepancy may be explained by differences in the two study populations. HIRA data, as national claims data, does not include information on the HCC stage or radiological findings, making it difficult to confirm CR in patients. Therefore, the validation cohort was more heterogeneous than the test cohort, which may have contributed to different risk factors for HCC recurrence in the two study groups.

Meanwhile, even if short last HCC treatment durability is an independent risk factor for HCC recurrence, it is difficult to interpret the finding that the delayed DAA therapy reduces the risk of HCC recurrence. Two recent meta-analyses and a large cohort study found that DAA therapy was not associated with an increased risk of HCC recurrence.18,24,25 One of the meta-analyses pointed out that factors associated with HCC recurrence included a history of prior HCC recurrence and a short interval between HCC CR and initiation of the DAA treatment. The authors concluded that HCC recurrence rate was acceptable after the DAA therapy, particularly if the latter was delayed at least 6 months after HCC CR.24 However, a recent large cohort study that defined HCC recurrence time based on the timing of HCC CR showed that commencement of DAA therapy within 6 months of CR was not a risk factor for overall or an early HCC recurrence.25 As mentioned above, there has been a debate on the optimal timing of starting DAA treatment after acquiring CR. Several studies calculated the time to HCC recurrence from the start of the DAA therapy, leading to an immortal time bias.24 The present study also cannot be free from this bias. Therefore, we could not clearly suggest an appropriate time point about initiation of DAA therapy for patients with HCC who achieved CR. It is more appropriate to describe “short last HCC treatment durability” rather than “short interval between last HCC treatment and DAA therapy” as a risk factor for HCC recurrence.

Other well-known risk factors for HCC development, including liver cirrhosis, diabetes mellitus, male gender, and old age, were not associated with an increased HCC recurrence.26-29 Our findings were found to be in line with a study with 59 patients who underwent a DAA therapy after HCC treatment who showed no significant differences in these factors between patients with and without HCC recurrence.15 While liver cirrhosis, diabetes mellitus, male gender, and old age are well-established risk factors for HCC development in patients with chronic hepatitis C, their role in HCC recurrence is unclear. This may be due to the differences in follow-up period between patients with a new and a recurrent HCC.

A few studies have suggested that patients with HCC are resistant to the DAA therapy.12-14 In 2017, Beste et al.13 reported that, of the 17,487 recipients of an HCV treatment, the overall SVR12 rate was 91.1% in the non-HCC group and 74.4% in the HCC group. In another study, the SVR12 rate was 79% and 88% in patients with and without HCC, respectively.14 There are several proposed theories explaining the observation of relatively low SVR12 rates in patients with HCC. HCC may act as a reservoir for HCV replication.12,30 Moreover, the HCC cells, which are mainly supplied by branches of the hepatic artery,31 and exhibit downregulated levels of the membrane transporters essential for the DAA uptake, such as OATP1B1,12,32 may have limited penetration of DAAs. Herein, the overall SVR12 rate after DAA therapy was 88%, which increased to 91.7% in patients who underwent the DAA therapy within 6 months of the last HCC treatment. Considering the kind of DAA therapy in the current study (Table 1), an overall SVR12 rate of 88% is satisfactory. Further studies with more potent DAAs will be needed to confirm the efficacy of DAA therapy in patients with HCC.

The current study has several limitations. First, it did not include a control group, which made it difficult to ascertain whether DAA therapy itself could increase the risk of HCC recurrence. Second, this study included 46 patients who had received noncurative modality as last treatment. To secure as many patients as possible, patients with noncurative modality were also included. Considering this limitation, a subgroup analysis was conducted on 54 patients treated with curative method. Subgroup analysis showed that last HCC treatment durability less than 12 months was not significantly associated with HCC recurrence but tended to increase risk (p=0.058). Further, we did not define the HCC recurrence time based on the timing of CR. The purpose of the current study was to define risk factors for HCC recurrence after the DAA therapy; thus, we started the follow-up after commencement of the DAA therapy. Additionally, patients treated with heterogenous methods were recruited, and it was not possible to confirm CR in the HIRA cohort. As very few patients with an HCV-related HCC have been treated with DAAs in South Korea, we sought to recruit as many participants as possible. We included patients who obtained a CR in the multicenter cohort, and confirmed the risk factors in the HIRA cohort, although the two cohorts partly overlapped.

In conclusion, the efficacy of DAA therapy was found to be acceptable in patients with an HCV-related HCC. However, short last HCC treatment durability before the DAA therapy (<12 months) was associated with HCC recurrence. This finding suggests that the last HCC treatment response durability is an important predictor of HCC recurrence.

This study was supported in part by the Scientific Research Fund of the Korean Liver Cancer Study Group (2017) and by a grant of the Korean Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI19C0872 and HI18C0531).

Study concept and design: S.S.K., J.Y.C. Data acquisition: H.L., D.Y.K., H.W.L., S.J.Y., Y.Y.C., J.W.J., B.K.J., C.W.K., H.Y.K., H.P. Data analysis and interpretation: Y.H.A., H.L., H.J.C., B.P. Drafting of the manuscript: Y.H.A., S.S.K. Critical revision of the manuscript for important intellectual content: S.S.K., J.Y.C. Statistical analysis: H.L., S.S.K. Obtained funding: S.S.K., J.Y.C. All authors approved the final draft of the manuscript submitted to the journal.

Fig. 1.Rates of the SVR 12 weeks after the end of DAA therapy (SVR12) in patients with hepatitis C virus-related HCC.
SVR, sustained virological response; DAA, direct-acting antiviral agent; HCC, hepatocellular carcinoma; CR, complete response.
Fig. 2.Cumulative probabilities of a recurrence of hepatocellular carcinoma (HCC) according to the last HCC treatment durability (A) and the total duration of the HCC treatment (B) in the multicenter cohort.
Fig. 3.Cumulative probabilities of a recurrence of hepatocellular carcinoma (HCC) according to the last HCC treatment durability (A) and the total duration of the HCC treatment (B) in the nationwide Health Insurance Review and Assessment Service cohort.

Baseline Characteristics of 100 Multicenter Cohort Subjects

Characteristics Value (n=100)
Age, yr 69.2±8.4
Male sex 67 (67)
Diabetes mellitus 33 (33)
Liver cirrhosis 79 (79)
Child-Pugh
A 95 (95)
B 4 (4)
C 1 (1)
BCLC stage
0 34 (34)
A 55 (55)
B 7 (7)
C 4 (4)
mUICC stage
I 48 (48)
II 40 (40)
III 10 (10)
IV 2 (2)
Hemoglobin, g/dL 13.0±1.5
Platelet, ×103/μL 112.1±57.5
Creatinine, mg/dL 0.80±0.19
Albumin, g/dL 3.67±0.47
Total bilirubin, mg/dL 1.08±0.55
AST, IU/L 63.7±33.0
ALT, IU/L 46.5±30.6
INR 1.08±0.18
AFP, ng/mL 37.7±75.1
HCV genotype
1a 1 (1)
1b 66 (66)
2 32 (32)
4 1 (1)
Previous interferon-based treatment 23 (23)
HCV RNA, log10 IU/mL 5.42±0.92
DAA combination
Daclatasvir+asunaprevir 59 (59)
Sofosbuvir+ribavirin 33 (33)
Ledipasvir/sofosbuvir 8 (8)

Data are presented as the mean±SD or number (%).

BCLC, Barcelona Clinic Liver Cancer; mUICC, modified Union for International Cancer Control; AST, aspartate aminotransferase; ALT, alanine aminotransferase; INR, international normalized ratio; AFP, alpha-fetoprotein; HCV, hepatitis C virus; DAA, direct-acting antiviral agent.


Univariate Analysis for Risk Factors for HCC Recurrence in the Multicenter Cohort

Variable Subjects without
HCC recurrence (n=63)
Subjects with
HCC recurrence (n=37)
p-value
Age, yr 68.7±8.9 69.9±7.4 0.127
Male sex 42 (66.7) 25 (67.6) 0.926
Diabetes mellitus 22 (34.9) 11 (29.7) 0.594
Liver cirrhosis 47 (74.6) 32 (86.5) 0.159
Child-Pugh 0.377
A 60 (95.2) 35 (94.6)
B 3 (4.8) 1 (2.7)
C 0 1 (2.7)
Hemoglobin, g/dL 13.0±1.6 12.9±1.3 0.238
Platelet, ×103/μL 121.9±64.5 95.4±38.1 0.040
Total bilirubin, mg/dL 1.06±0.57 1.11±0.53 0.399
Albumin, g/dL 3.7±0.5 3.6±0.4 0.208
AST, IU/L 62.4±30.7 66.0±37.0 0.831
ALT, IU/L 46.9±30.0 45.9±32.7 0.570
Creatinine, mg/dL 0.81±0.20 0.77±0.15 0.145
INR 1.07±0.19 1.10±0.18 0.823
AFP, ng/mL 30.4±65.0 50.1±90.0 0.405
HCV RNA, log10 IU/mL 5.42±0.99 5.42±0.79 0.091
Genotype 0.348
1a 1 (1.6) 0
1b 44 (69.8) 22 (59.5)
2 18 (28.6) 14 (37.8)
4 0 1 (2.7)
SVR 12 56 (88.9) 32 (86.5) 0.934
BCLC stage 0.248
0 23 (36.5) 11 (29.7)
A 35 (55.6) 20 (54.1)
B 2 (3.2) 5 (13.5)
C 3 (4.8) 1 (2.7)
mUICC stage 0.064
I 34 (54.0) 14 (37.8)
II 24 (38.1) 16 (43.2)
III 3 (4.8) 7 (18.9)
IV 2 (3.2) 0
HCC treatment using noncurative modality* 27 (42.9) 29 (78.4) <0.001
Last HCC treatment using noncurative modality* 20 (31.7) 26 (70.3) <0.001
HCC treatment duration (≥18 mo) 12 (19.0) 16 (43.2) 0.009
Last HCC treatment durability (<12 mo) 32 (50.8) 29 (78.4) 0.006
Last HCC treatment durability, day 528.7±661.9 271.5±319.6 0.009
DAA combination 0.417
Daclatasvir+asunaprevir 39 (61.9) 20 (54.1)
Sofosbuvir+ribavirin 18 (28.6) 15 (40.5)
Ledipasvir/sofosbuvir 6 (9.5) 2 (5.4)

Data are presented as the mean±SD or number (%).

HCC, hepatocellular carcinoma; AST, aspartate aminotransferase; ALT, alanine aminotransferase; INR, international normalized ratio; AFP, alpha-fetoprotein; HCV, hepatitis C virus; SVR, sustained virologic response; BCLC, Barcelona Clinic Liver Cancer; mUICC, modified Union for International Cancer Control; DAA, direct-acting antiviral agent.

*Noncurative modality included transarterial chemoembolization, transarterial radioembolization, hepatic artery infusion chemotherapy, sorafenib and radiotherapy; †Statistically significant, p<0.05.


Multivariate Analysis for Risk Factors for HCC Recurrence in the Multicenter Cohort

Multivariate analysis HR 95% CI p-value
Platelet (<10×103/μL) 1.74 0.86–3.52 0.119
HCC treatment with noncurative modality* 1.78 0.49–6.38 0.374
Last HCC treatment with noncurative modality* 2.18 0.69–6.82 0.179
HCC treatment duration (≥18 mo) 1.97 0.99–3.88 0.050
Last HCC treatment durability (<12 mo) 2.89 1.27–6.59 0.011

HCC, hepatocellular carcinoma; HR, hazard ratio; CI, confidence interval.

*Noncurative modality included transarterial chemoembolization, transarterial radioembolization, hepatic artery infusion chemotherapy, sorafenib and radiotherapy; †Statistically significant, p<0.05.


Baseline Characteristics of 526 Subjects in the HIRA Cohort

Characteristics Value (n=526)
Age, yr 66.9±9.6
Male sex 335 (63.7)
Diabetes mellitus 371 (70.5)
Liver cirrhosis 458 (87.1)
Previous interferon-based treatment 42 (8.0)
DAA combination
Daclatasvir+asunaprevir 327 (62.2)
Sofosbuvir+ribavirin 127 (24.1)
Ledipasvir/sofosbuvir 61 (11.6)
Sofosbuvir+daclatasvir 11 (2.1)
HCC treatment modality before DAA therapy
Resection 3 (0.6)
RFA 135 (25.7)
TACE 226 (43.0)
Multi-modality 146 (27.8)
Other therapies 16 (2.9)
Last HCC treatment modality before DAA therapy
Resection 4 (0.8)
RFA 185 (35.2)
TACE 296 (56.3)
Combination treatment 17 (3.2)
Other therapies 24 (4.6)

Data are presented as the mean±SD or number (%).

HIRA, Health Insurance Review and Assessment; DAA, direct-acting antiviral agent; HCC, hepatocellular carcinoma; RFA, radiofrequency ablation; TACE, transarterial chemoembolization.


Risk Factor Analysis for HCC Recurrence in the HIRA Cohort

Risk factor Subjects without
HCC recurrence
(n=419)
Subjects with
HCC recurrence
(n=107)
Univariate
p-value
Multivariate analysis

HR 95% CI p-value
Age, yr 66.8±9.8 67.4±8.9 0.867
Male sex 267 (63.7) 68 (63.6) 0.903
Diabetes mellitus 200 (71.6) 71 (66.4) 0.160
Liver cirrhosis 360 (85.9) 98 (91.6) 0.103
HCC treatment using noncurative modality* 290 (69.2) 96 (89.7) <0.001 0.75 0.42–1.33 0.330
Last HCC treatment using noncurative modality* 244 (58.2) 93 (86.9) <0.001 3.73 1.87–7.43 <0.001
HCC treatment duration (≥18 mo) 100 (23.9) 44 (41.1) <0.001 1.74 1.16–2.60 0.006
Last HCC treatment durability (<12 mo) 236 (56.3) 91 (85.0) <0.001 3.34 1.95–5.71 <0.001

Data are presented as the mean±SD or number (%).

HCC, hepatocellular carcinoma; HIRA, Health Insurance Review and Assessment; HR, hazard ratio; CI, confidence interval.

*Noncurative modality included transarterial chemoembolization, transarterial radioembolization, hepatic artery infusion chemotherapy, sorafenib and radiotherapy; †Statistically significant, p<0.05.


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Article

Original Article

Gut and Liver 2021; 15(3): 410-419

Published online May 15, 2021 https://doi.org/10.5009/gnl20151

Copyright © Gut and Liver.

Independent Risk Factors for Hepatocellular Carcinoma Recurrence after Direct-Acting Antiviral Therapy in Patients with Chronic Hepatitis C

Young-Hwan Ahn1 , Heirim Lee2,3 , Do Young Kim4 , Hye Won Lee4 , Su Jong Yu5 , Young Youn Cho5,6 , Jeong Won Jang7 , Byoung Kuk Jang8 , Chang Wook Kim9 , Hee Yeon Kim9 , Hana Park10 , Hyo Jung Cho1 , Bumhee Park2,3 , Soon Sun Kim1 , and Jae Youn Cheong1

Departments of 1Gastroenterology, 2Biomedical Informatics, and 3Office of Biostatistics, Ajou Research Institute for Innovative Medicine, Ajou University School of Medicine, Suwon, 4Department of Internal Medicine, Yonsei University College of Medicine, 5Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 6Department of Internal Medicine, Chung-Ang University Hospital, 7Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, 8Department of Internal Medicine, Keimyung University School of Medicine, Daegu, 9Division of Hepatology, Department of Internal Medicine, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, and 10Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea

Correspondence to:Jae Youn Cheong
ORCID https://orcid.org/0000-0001-6246-1783
E-mail jaeyoun620@gmail.com
Soon Sun Kim
ORCID https://orcid.org/0000-0002-6862-1896
E-mail cocorico99@gmail.com
Young-Hwan Ahn and Heirim Lee contributed equally to this work as first authors.

Received: May 12, 2020; Revised: June 12, 2020; Accepted: June 15, 2020

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background/Aims: This study was performed to evaluate the efficacy of direct-acting antivirals (DAAs) in Korean patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) and to investigate the risk factors associated with HCC recurrence.
Methods: A total of 100 patients with HCV-related HCC, who were treated with DAAs between May 2015 and December 2016, were recruited from seven university hospitals in Korea. Claim data of 526 patients with HCC obtained from the Health Insurance Review and Assessment Service in South Korea were used for external validation of the results.
Results: Among the 100 patients, 88% achieved a sustained virological response (SVR) 12 weeks after the end of DAA therapy (SVR12), and 37% experienced HCC recurrence after DAA therapy. Short last HCC treatment durability (<12 months) before DAA commencement was independently associated with HCC recurrence (hazard ratio [HR], 2.89; p=0.011). In the nationwide validation cohort, 20.3% of the patients experienced HCC recurrence. The last HCC treatment with a noncurative method, a short last HCC treatment durability (<12 months), and a longer total duration of HCC treatment (≥18 months) were independently related with HCC recurrence (HR 3.73, p<0.001; HR 3.34, p<0.001; and HR 1.74, p=0.006; respectively).
Conclusions: DAA therapy showed an acceptable SVR12 rate in patients with HCV-related HCC. Short last HCC treatment durability (<12 months) was associated with HCC recurrence after DAA therapy. This finding suggests that the last HCC treatment durability is an important predictor of HCC recurrence after DAA therapy.

Keywords: Carcinoma, hepatocellular, Antiviral agents, Risk factors, Hepatitis C, chronic, Recurrence

INTRODUCTION

Chronic infection with hepatitis C virus (HCV) is a well-known risk factor for liver cirrhosis and hepatocellular carcinoma (HCC), which is one of the most common and fatal malignancies globally.1,2 Direct-acting antivirals (DAAs) exhibit an excellent efficacy against HCV.3-6 While the pegylated interferon plus ribavirin therapy approved in 2001 shows a sustained virological response (SVR) of 42% to 46% in genotype 1 and 76% to 82% in genotypes 2 or 3,7,8 the success rate of DAA therapy is over 86%, even in patients with a decompensated or an advanced liver disease.9,10 Consequently, DAAs have become an indispensable element of hepatitis C treatment. Recently, the World Health Organization has set a goal to treat 80% of the global hepatitis C cases, and reduce annual deaths due to viral hepatitis by 35%, by 2030.11 It is important to elucidate reasonable study outcomes to reduce the uncertainty surrounding DAA therapy, and to allow more patients to be treated, including patients with HCV-associated HCC.

Reportedly, patients with HCC are more resistant to DAA therapy than those without HCC.12-14 SVR rates of 74.4% to 79% and 88% to 91.1% were recorded in American patients with and without HCC, respectively.13,14 However, little is known about the efficacy of DAA therapy in the Asian population. Recent studies have reported unexpectedly high rates of HCC recurrence after a successful DAA treatment.15-17 While a meta-analysis showed no difference in HCC recurrence following DAA or interferon therapy after adjusting for study follow-up time and patient age,18 the issue raises an uncertainty about the appropriate timing of treatment of HCV-infected patients with a history of HCC. Therefore, it is important to identify risk factors associated with HCC recurrence in the DAA-treated patients.

The aim of this study was to evaluate the therapeutic efficacy of DAAs in Asian patients with a history of HCV-induced HCC, and investigate the risk factors for HCC recurrence after DAA therapy.

MATERIALS AND METHODS

1. Patient selection

We retrospectively recruited 100 patients with HCV-infected HCC from seven university hospitals in South Korea. Patients who achieved complete response (CR) after HCC treatment and started the DAA therapy between August 2015 and December 2016 were enrolled. Chronic hepatitis C was defined as the presence of the anti-HCV antibody and HCV RNA for more than 6 months. HCC was diagnosed if the tumor had a minimum diameter ≥1 cm, and if typical features of HCC (arterial phase hyperenhancement, washout in the portal venous or delayed phase, threshold growth, and capsule appearance) were observed using multiphase computed tomography and/or magnetic resonance imaging. If these criteria were present but there was a lack of a diagnostic certainty, a liver biopsy was performed to confirm the diagnosis of HCC.19 Patients were excluded if they met any of the following criteria: evidence of autoimmune hepatitis or viral co-infection, such as those with the hepatitis B virus or the human immunodeficiency virus; alcohol consumption >210 g per week for males and >140 g per week for females; no CR after HCC treatment prior to DAA therapy; liver transplantation before DAA therapy; no tumor status assessment after starting DAA therapy; and/or treatment with interferon as part of DAA therapy. The patients were followed-up until HCC recurrence or until January 2018.

For external validation, we used data from patients with an HCV-infected HCC from the Korean Health Insurance Review and Assessment Service (HIRA)20 (Supplementary Fig. 1). HIRA data, which is generated in the process of reimbursing healthcare providers under National Health Insurance, contains specific, yet comprehensive information on the relevant healthcare services, such as procedures, surgeries, examinations, and treatment, including prescriptions and socio-demographic characteristics of patients. In South Korea, National Health Insurance covers approximately 98% of the total population. Moreover, all healthcare providers are required to be covered under the National Health Insurance, which is based on fee-for-services.20 Subjects with HCC (C220 and C229) who were prescribed DAA therapy (638101ATB [daclatasvir], 638001ACH [asunaprevir], 644401ATB [sofosbuvir], 645800ATB [ledipasvir/sofosbuvir], 223604ACH, 223601ACH, and 223601ACH [ribavirin]) between August 2015 and December 2016 were extracted from the HIRA database using the International Classification of Diseases (10th edition).21,22 The exclusion criteria were as follows: autoimmune hepatitis (K75.4) or viral co-infection, including those with the hepatitis B (B18.0, B18.10, B18.18, B18.1, and Z22.5) and the human immunodeficiency virus (Z21.X, Z86.X, B20.X, B21.X, B22.X, B23.X, and B24.X); liver transplantation before DAA therapy; history of DAA therapy before or during HCC treatment. HCC recurrence was defined as reinitiation of HCC treatment after DAA therapy. The patients were followed-up until HCC recurrence or until December 2016. The study protocol was approved by the Institutional Review Board of the Ajou University Hospital (IRB number: AJIRB-MED-MDB-17-031).

2. Definitions

Baseline characteristics, including age, liver function, and the HCV RNA level, were documented at the start of the DAA therapy. HCC treatment duration was defined as the time between the initial HCC treatment and the last HCC treatment before a DAA therapy. Last HCC treatment durability was defined as the time between the final HCC treatment and the start of a DAA therapy. HCC recurrence time was calculated from the start of a DAA treatment. The SVR was determined 12 weeks after the end of a DAA treatment (SVR12). CR acquisition was defined according to modified RECIST criteria, disappearance of any intratumoral arterial enhancement in all target lesions on follow-up image study.23

3. Statistics

Data management and analysis were performed using the R statistical software (version 3.3.4; R Core Team [2014]; R: A language and environment for statistical computing; R Foundation for Statistical Computing, Vienna Austria; http://www.R-project.org/). Differences with p<0.05 were considered statistically significant. All statistical analyses were performed using two-tailed tests: continuous variables were analyzed using the independent samples t-test while categorical data were compared using the Pearson chi-square test or the Fisher exact test. Cumulative probabilities of HCC recurrence were assessed by the Kaplan-Meier analysis. The Cox proportional hazard model was used to identify factors associated with HCC recurrence.

RESULTS

1. Baseline characteristics of the multicenter cohort

The mean age of the subjects was 69.2±8.4 years, and 67% of them were male. The patients were the most commonly infected with the HCV genotype 1b (66%), followed by the genotype 2 (32%), genotype 1a (1%), and genotype 4 (1%). Cirrhosis and diabetes mellitus were diagnosed in 79% and 33% of the patients, respectively. HCC in BCLC (Barcelona Clinic Liver Cancer) stages B or C was detected in 11% of the cohort, whereas modified Union for International Cancer Control stage III or IV disease was found in 12% of the patients; 23% of the subjects had previously received an interferon based therapy (Table 1).

Among the 100 subjects with an HCV-related HCC, 24 underwent radiofrequency ablation (RFA) therapy, 21 were treated with a transarterial chemoembolization (TACE), 19 experienced liver resection, two underwent radiation therapy, one received a transarterial radioembolization, and 33 were treated with multimodal therapy. Regarding the modality of the last HCC treatment, TACE (36%) was the most frequently used, followed by RFA (33%), liver resection (21%), combination therapy (6%), and other therapies (4%). The median follow-up period after a DAA treatment start was 15.8 months (range, 4.4 to 29.9 months).

2. Efficacy of DAA therapy in patients with HCC

The efficacy of DAA therapy in patients with HCC is summarized in Fig. 1. Among the 100 patients in the multicenter cohort, 88 achieved SVR12 with DAA therapy. Even in those who experienced HCC recurrence, the SVR12 acquisition rate was as high as 86.5% (32/37). SVR12 was achieved by 86.1% (68/79) of patients with liver cirrhosis and by 95.2% (20/21) of those without it. The SVR12 rate was 87.9% (58/66) and 87.5% (28/32) with the genotypes 1b and 2, respectively. The only patient with genotype 1a and the only patient with genotype 4 acquired SVR12. Of the 36 patients who started the DAA therapy within 6 months of the last HCC treatment, 33 (91.7%) obtained SVR12. The SVR12 rate did not significantly differ between the groups (Fig. 1).

3. Details of 37 patients with HCC recurrence after DAA therapy

During the median follow-up period of 15.8 months (range, 4.4 to 29.9 months), 37% of the study subjects experienced HCC recurrence; the 1-year and 2-year cumulative recurrence rate was 28.4% and 61.3%, respectively. The median number and size of the recurrent tumors were 1 (range, 1 to 6) and 1.25 cm (range, 0.8 to 5.7 cm), respectively. Regarding the pattern of recurrence, a new intrahepatic recurrence (62.2%) was most commonly detected, followed by a marginal recurrence (16.2%), and a marginal recurrence combined with a new intrahepatic recurrence (5.4%). Extrahepatic recurrence was not observed. The majority of the patients (67.6%) were treated with TACE, 16.2% underwent RFA, while 5.4% received RFA as well as TACE. Radiation therapy, TACE followed by radiation therapy, and TACE followed by sorafenib were used in 2.7% of the cases each. After HCC recurrence, 58.8% of the patients showed CR while 14.7% obtained a partial response. Stable and progressive disease were observed in 5.9% and 20.6% of the cases, respectively.

4. Risk factors for HCC recurrence in the multicenter cohort

According to the univariate analysis, low platelet levels (p=0.040), HCC treatment with a noncurative method such as TACE, transarterial radioembolization, hepatic artery infusion chemotherapy, sorafenib and radiotherapy (p<0.001), last HCC treatment with a noncurative method (p<0.001), HCC treatment duration more than 18 months (p=0.009), and last HCC treatment durability less than 12 months (p=0.006) were related to HCC recurrence. In contrast, age (p=0.127), liver cirrhosis (p=0.159), and SVR12 (p=0.934) were not associated with HCC recurrence (Table 2). Multivariate Cox regression analysis showed that short last HCC treatment durability (<12 months) was only independently associated with HCC recurrence in patients with the HCV-related HCC after the DAA treatment (hazard ratio [HR], 2.89; 95% confidence interval [CI], 1.27 to 6.59; p=0.011) (Table 3, Fig. 2).

In subgroup analysis with patients who were treated with curative modality, mean HCC treatment durability (p=0.046) and last HCC treatment durability less than 12 months (p=0.036) were related to HCC recurrence. In age- and sex-adjusted multivariate Cox regression analysis, the relationship between last HCC treatment durability and HCC recurrence showed no statistical significance (p=0.058) (Supplementary Table 1).

5. External validation using the HIRA cohort

A total of 526 patients with HCV-related HCC and treated with DAAs were identified in the HIRA cohort. Baseline characteristics of the validation cohort have been listed in Table 4. The mean age of the subjects was 66.9±9.6 years, and 63.7% of them were male. Cirrhosis and diabetes were diagnosed in 87.1% and 70.5% of the cases, respectively, and 8% of the subjects had received a previous interferon based therapy. Among the 526 patients, 107 (20.3%) experienced HCC recurrence.

In the univariate analysis, HCC treatment with a noncurative method, the last HCC treatment with a noncurative method, a long duration of the HCC treatment (≥18 months), and short last HCC treatment durability before a DAA therapy (<12 months) were related to HCC recurrence (Table 5). Moreover, the multivariate Cox regression analysis showed that the last HCC treatment with a noncurative method (HR, 3.73; 95% CI, 1.87 to 7.43; p<0.001), HCC treatment duration ≥18 months (HR, 1.74; 95% CI, 1.16 to 2.60; p=0.006), the last HCC treatment durability <12 months (HR, 3.34; 95% CI, 1.95 to 5.71; p<0.001) were independently associated with HCC recurrence (Table 5, Fig. 3).

DISCUSSION

In the present study, short last HCC treatment durability before a DAA therapy (<12 months) was an independent predictor of HCC recurrence in both the multicenter cohort and the nationwide cohort from the Korean HIRA database. To the best of our knowledge, this is the first study to evaluate the risk factors for predicting HCC recurrence after the DAA therapy in Korean patients with HCV-related HCC.

Short last HCC treatment durability (<12 months) was the only common independent risk factor for HCC recurrence in the both multicenter cohort and nationwide HIRA cohort. The last HCC treatment with a noncurative method and a long total duration of the HCC treatment (≥18 months) prior to the DAA therapy were independent risk factors in the HIRA cohort, but not in the multicenter cohort. This discrepancy may be explained by differences in the two study populations. HIRA data, as national claims data, does not include information on the HCC stage or radiological findings, making it difficult to confirm CR in patients. Therefore, the validation cohort was more heterogeneous than the test cohort, which may have contributed to different risk factors for HCC recurrence in the two study groups.

Meanwhile, even if short last HCC treatment durability is an independent risk factor for HCC recurrence, it is difficult to interpret the finding that the delayed DAA therapy reduces the risk of HCC recurrence. Two recent meta-analyses and a large cohort study found that DAA therapy was not associated with an increased risk of HCC recurrence.18,24,25 One of the meta-analyses pointed out that factors associated with HCC recurrence included a history of prior HCC recurrence and a short interval between HCC CR and initiation of the DAA treatment. The authors concluded that HCC recurrence rate was acceptable after the DAA therapy, particularly if the latter was delayed at least 6 months after HCC CR.24 However, a recent large cohort study that defined HCC recurrence time based on the timing of HCC CR showed that commencement of DAA therapy within 6 months of CR was not a risk factor for overall or an early HCC recurrence.25 As mentioned above, there has been a debate on the optimal timing of starting DAA treatment after acquiring CR. Several studies calculated the time to HCC recurrence from the start of the DAA therapy, leading to an immortal time bias.24 The present study also cannot be free from this bias. Therefore, we could not clearly suggest an appropriate time point about initiation of DAA therapy for patients with HCC who achieved CR. It is more appropriate to describe “short last HCC treatment durability” rather than “short interval between last HCC treatment and DAA therapy” as a risk factor for HCC recurrence.

Other well-known risk factors for HCC development, including liver cirrhosis, diabetes mellitus, male gender, and old age, were not associated with an increased HCC recurrence.26-29 Our findings were found to be in line with a study with 59 patients who underwent a DAA therapy after HCC treatment who showed no significant differences in these factors between patients with and without HCC recurrence.15 While liver cirrhosis, diabetes mellitus, male gender, and old age are well-established risk factors for HCC development in patients with chronic hepatitis C, their role in HCC recurrence is unclear. This may be due to the differences in follow-up period between patients with a new and a recurrent HCC.

A few studies have suggested that patients with HCC are resistant to the DAA therapy.12-14 In 2017, Beste et al.13 reported that, of the 17,487 recipients of an HCV treatment, the overall SVR12 rate was 91.1% in the non-HCC group and 74.4% in the HCC group. In another study, the SVR12 rate was 79% and 88% in patients with and without HCC, respectively.14 There are several proposed theories explaining the observation of relatively low SVR12 rates in patients with HCC. HCC may act as a reservoir for HCV replication.12,30 Moreover, the HCC cells, which are mainly supplied by branches of the hepatic artery,31 and exhibit downregulated levels of the membrane transporters essential for the DAA uptake, such as OATP1B1,12,32 may have limited penetration of DAAs. Herein, the overall SVR12 rate after DAA therapy was 88%, which increased to 91.7% in patients who underwent the DAA therapy within 6 months of the last HCC treatment. Considering the kind of DAA therapy in the current study (Table 1), an overall SVR12 rate of 88% is satisfactory. Further studies with more potent DAAs will be needed to confirm the efficacy of DAA therapy in patients with HCC.

The current study has several limitations. First, it did not include a control group, which made it difficult to ascertain whether DAA therapy itself could increase the risk of HCC recurrence. Second, this study included 46 patients who had received noncurative modality as last treatment. To secure as many patients as possible, patients with noncurative modality were also included. Considering this limitation, a subgroup analysis was conducted on 54 patients treated with curative method. Subgroup analysis showed that last HCC treatment durability less than 12 months was not significantly associated with HCC recurrence but tended to increase risk (p=0.058). Further, we did not define the HCC recurrence time based on the timing of CR. The purpose of the current study was to define risk factors for HCC recurrence after the DAA therapy; thus, we started the follow-up after commencement of the DAA therapy. Additionally, patients treated with heterogenous methods were recruited, and it was not possible to confirm CR in the HIRA cohort. As very few patients with an HCV-related HCC have been treated with DAAs in South Korea, we sought to recruit as many participants as possible. We included patients who obtained a CR in the multicenter cohort, and confirmed the risk factors in the HIRA cohort, although the two cohorts partly overlapped.

In conclusion, the efficacy of DAA therapy was found to be acceptable in patients with an HCV-related HCC. However, short last HCC treatment durability before the DAA therapy (<12 months) was associated with HCC recurrence. This finding suggests that the last HCC treatment response durability is an important predictor of HCC recurrence.

Supplemental Materials

ACKNOWLEDGEMENTS

This study was supported in part by the Scientific Research Fund of the Korean Liver Cancer Study Group (2017) and by a grant of the Korean Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI19C0872 and HI18C0531).

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

AUTHOR CONTRIBUTIONS

Study concept and design: S.S.K., J.Y.C. Data acquisition: H.L., D.Y.K., H.W.L., S.J.Y., Y.Y.C., J.W.J., B.K.J., C.W.K., H.Y.K., H.P. Data analysis and interpretation: Y.H.A., H.L., H.J.C., B.P. Drafting of the manuscript: Y.H.A., S.S.K. Critical revision of the manuscript for important intellectual content: S.S.K., J.Y.C. Statistical analysis: H.L., S.S.K. Obtained funding: S.S.K., J.Y.C. All authors approved the final draft of the manuscript submitted to the journal.

Fig 1.

Figure 1.Rates of the SVR 12 weeks after the end of DAA therapy (SVR12) in patients with hepatitis C virus-related HCC.
SVR, sustained virological response; DAA, direct-acting antiviral agent; HCC, hepatocellular carcinoma; CR, complete response.
Gut and Liver 2021; 15: 410-419https://doi.org/10.5009/gnl20151

Fig 2.

Figure 2.Cumulative probabilities of a recurrence of hepatocellular carcinoma (HCC) according to the last HCC treatment durability (A) and the total duration of the HCC treatment (B) in the multicenter cohort.
Gut and Liver 2021; 15: 410-419https://doi.org/10.5009/gnl20151

Fig 3.

Figure 3.Cumulative probabilities of a recurrence of hepatocellular carcinoma (HCC) according to the last HCC treatment durability (A) and the total duration of the HCC treatment (B) in the nationwide Health Insurance Review and Assessment Service cohort.
Gut and Liver 2021; 15: 410-419https://doi.org/10.5009/gnl20151

Table 1 Baseline Characteristics of 100 Multicenter Cohort Subjects

CharacteristicsValue (n=100)
Age, yr69.2±8.4
Male sex67 (67)
Diabetes mellitus33 (33)
Liver cirrhosis79 (79)
Child-Pugh
A95 (95)
B4 (4)
C1 (1)
BCLC stage
034 (34)
A55 (55)
B7 (7)
C4 (4)
mUICC stage
I48 (48)
II40 (40)
III10 (10)
IV2 (2)
Hemoglobin, g/dL13.0±1.5
Platelet, ×103/μL112.1±57.5
Creatinine, mg/dL0.80±0.19
Albumin, g/dL3.67±0.47
Total bilirubin, mg/dL1.08±0.55
AST, IU/L63.7±33.0
ALT, IU/L46.5±30.6
INR1.08±0.18
AFP, ng/mL37.7±75.1
HCV genotype
1a1 (1)
1b66 (66)
232 (32)
41 (1)
Previous interferon-based treatment23 (23)
HCV RNA, log10 IU/mL5.42±0.92
DAA combination
Daclatasvir+asunaprevir59 (59)
Sofosbuvir+ribavirin33 (33)
Ledipasvir/sofosbuvir8 (8)

Data are presented as the mean±SD or number (%).

BCLC, Barcelona Clinic Liver Cancer; mUICC, modified Union for International Cancer Control; AST, aspartate aminotransferase; ALT, alanine aminotransferase; INR, international normalized ratio; AFP, alpha-fetoprotein; HCV, hepatitis C virus; DAA, direct-acting antiviral agent.


Table 2 Univariate Analysis for Risk Factors for HCC Recurrence in the Multicenter Cohort

VariableSubjects without
HCC recurrence (n=63)
Subjects with
HCC recurrence (n=37)
p-value
Age, yr68.7±8.969.9±7.40.127
Male sex42 (66.7)25 (67.6)0.926
Diabetes mellitus22 (34.9)11 (29.7)0.594
Liver cirrhosis47 (74.6)32 (86.5)0.159
Child-Pugh0.377
A60 (95.2)35 (94.6)
B3 (4.8)1 (2.7)
C01 (2.7)
Hemoglobin, g/dL13.0±1.612.9±1.30.238
Platelet, ×103/μL121.9±64.595.4±38.10.040
Total bilirubin, mg/dL1.06±0.571.11±0.530.399
Albumin, g/dL3.7±0.53.6±0.40.208
AST, IU/L62.4±30.766.0±37.00.831
ALT, IU/L46.9±30.045.9±32.70.570
Creatinine, mg/dL0.81±0.200.77±0.150.145
INR1.07±0.191.10±0.180.823
AFP, ng/mL30.4±65.050.1±90.00.405
HCV RNA, log10 IU/mL5.42±0.995.42±0.790.091
Genotype0.348
1a1 (1.6)0
1b44 (69.8)22 (59.5)
218 (28.6)14 (37.8)
401 (2.7)
SVR 1256 (88.9)32 (86.5)0.934
BCLC stage0.248
023 (36.5)11 (29.7)
A35 (55.6)20 (54.1)
B2 (3.2)5 (13.5)
C3 (4.8)1 (2.7)
mUICC stage0.064
I34 (54.0)14 (37.8)
II24 (38.1)16 (43.2)
III3 (4.8)7 (18.9)
IV2 (3.2)0
HCC treatment using noncurative modality*27 (42.9)29 (78.4)<0.001
Last HCC treatment using noncurative modality*20 (31.7)26 (70.3)<0.001
HCC treatment duration (≥18 mo)12 (19.0)16 (43.2)0.009
Last HCC treatment durability (<12 mo)32 (50.8)29 (78.4)0.006
Last HCC treatment durability, day528.7±661.9271.5±319.60.009
DAA combination0.417
Daclatasvir+asunaprevir39 (61.9)20 (54.1)
Sofosbuvir+ribavirin18 (28.6)15 (40.5)
Ledipasvir/sofosbuvir6 (9.5)2 (5.4)

Data are presented as the mean±SD or number (%).

HCC, hepatocellular carcinoma; AST, aspartate aminotransferase; ALT, alanine aminotransferase; INR, international normalized ratio; AFP, alpha-fetoprotein; HCV, hepatitis C virus; SVR, sustained virologic response; BCLC, Barcelona Clinic Liver Cancer; mUICC, modified Union for International Cancer Control; DAA, direct-acting antiviral agent.

*Noncurative modality included transarterial chemoembolization, transarterial radioembolization, hepatic artery infusion chemotherapy, sorafenib and radiotherapy; †Statistically significant, p<0.05.


Table 3 Multivariate Analysis for Risk Factors for HCC Recurrence in the Multicenter Cohort

Multivariate analysisHR95% CIp-value
Platelet (<10×103/μL)1.740.86–3.520.119
HCC treatment with noncurative modality*1.780.49–6.380.374
Last HCC treatment with noncurative modality*2.180.69–6.820.179
HCC treatment duration (≥18 mo)1.970.99–3.880.050
Last HCC treatment durability (<12 mo)2.891.27–6.590.011

HCC, hepatocellular carcinoma; HR, hazard ratio; CI, confidence interval.

*Noncurative modality included transarterial chemoembolization, transarterial radioembolization, hepatic artery infusion chemotherapy, sorafenib and radiotherapy; †Statistically significant, p<0.05.


Table 4 Baseline Characteristics of 526 Subjects in the HIRA Cohort

CharacteristicsValue (n=526)
Age, yr66.9±9.6
Male sex335 (63.7)
Diabetes mellitus371 (70.5)
Liver cirrhosis458 (87.1)
Previous interferon-based treatment42 (8.0)
DAA combination
Daclatasvir+asunaprevir327 (62.2)
Sofosbuvir+ribavirin127 (24.1)
Ledipasvir/sofosbuvir61 (11.6)
Sofosbuvir+daclatasvir11 (2.1)
HCC treatment modality before DAA therapy
Resection3 (0.6)
RFA135 (25.7)
TACE226 (43.0)
Multi-modality146 (27.8)
Other therapies16 (2.9)
Last HCC treatment modality before DAA therapy
Resection4 (0.8)
RFA185 (35.2)
TACE296 (56.3)
Combination treatment17 (3.2)
Other therapies24 (4.6)

Data are presented as the mean±SD or number (%).

HIRA, Health Insurance Review and Assessment; DAA, direct-acting antiviral agent; HCC, hepatocellular carcinoma; RFA, radiofrequency ablation; TACE, transarterial chemoembolization.


Table 5 Risk Factor Analysis for HCC Recurrence in the HIRA Cohort

Risk factorSubjects without
HCC recurrence
(n=419)
Subjects with
HCC recurrence
(n=107)
Univariate
p-value
Multivariate analysis

HR95% CIp-value
Age, yr66.8±9.867.4±8.90.867
Male sex267 (63.7)68 (63.6)0.903
Diabetes mellitus200 (71.6)71 (66.4)0.160
Liver cirrhosis360 (85.9)98 (91.6)0.103
HCC treatment using noncurative modality*290 (69.2)96 (89.7)<0.0010.750.42–1.330.330
Last HCC treatment using noncurative modality*244 (58.2)93 (86.9)<0.0013.731.87–7.43<0.001
HCC treatment duration (≥18 mo)100 (23.9)44 (41.1)<0.0011.741.16–2.600.006
Last HCC treatment durability (<12 mo)236 (56.3)91 (85.0)<0.0013.341.95–5.71<0.001

Data are presented as the mean±SD or number (%).

HCC, hepatocellular carcinoma; HIRA, Health Insurance Review and Assessment; HR, hazard ratio; CI, confidence interval.

*Noncurative modality included transarterial chemoembolization, transarterial radioembolization, hepatic artery infusion chemotherapy, sorafenib and radiotherapy; †Statistically significant, p<0.05.


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Gut and Liver

Vol.15 No.6
November, 2021

pISSN 1976-2283
eISSN 2005-1212

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