Graphical Abstract
INTRODUCTION
Hepatitis C virus (HCV) infection is one of the major causes of hepatocellular carcinoma (HCC), with the outcomes of individuals diagnosed with HCC depending on both tumor burden and the degree of liver dysfunction [1]. To date, direct-acting antiviral agents (DAAs) are recommended for HCV infection due to their high rates of eradication and low rates of adverse events. Prior studies have reported the benefits of DAA therapy in reducing incident HCC and mortality among HCV-infected patients [2-4]. Additionally, DAAs are also known to improve survival outcomes, even in HCV-infected patients with a history of curative treatment for early HCC [5,6]. However, the survival benefit of DAA therapy in patients with HCC, particularly in Barcelona Clinic Liver Cancer (BCLC) stages B/C, remains largely uncertain.
In the era of DAA therapy, HCV eradication has become faster and safer, with HCV eradication therapy no longer being a difficult task for HCC patients. A high rate of sustained virological response (SVR) among HCC patients has been reported, though it seems to be lower when compared to patients without HCC. However, the use of DAA in patients with unresectable HCC remains controversial. In our previous hospital-based cohort study which enrolled 97 patients with HCC at BCLC stage B or C, a better survival outcome was disclosed in patients undergoing SVR to DAA therapy [7]. However, considering the limited sample size and potential selection bias, the benefits of DAA therapy in HCC patients need to be further confirmed through a largescale multicenter study.
The Taiwan Association for the Study of the Liver (TASL) HCV Registry (TACR) is a nationwide registry program that establishes and manages the database and biobank of HCV patients receiving DAA therapy in Taiwan. The demographic and virological data of all patients from each participating site have been completely collected and feature well-characterized demographic and virological characteristics, as detailed in previous publications [8-15]. Its nationwide scale is particularly suitable for overcoming the limitations in studies involving HCC patients. The aim of this study was to explore the survival benefit of DAA therapy in patients with HCV-related HCC using a nationwide cohort study.
MATERIALS AND METHODS
Study design
This was an observational, nationwide, cohort study of HCV-infected patients receiving DAA therapy, with or without HCC, through application of TACR data. The study has been approved by the Institutional Review Board of each study site (IRB No. SF19088B), while conforming to the guidelines of the International Conference on Harmonization for Good Clinical Practice. All patients provided written informed consent.
The insurance reimbursement criteria & the consensus for hepatitis C management in Taiwan
According to the reimbursement criteria of Taiwan National Health Insurance, DAA therapy is reimbursed for any patient with a detectable HCV viral load, regardless of underlying conditions, including HCC [16]. Therefore, DAA therapy can be initiated even in patients with active, untreated HCC prior to HCC treatment. However, for patients eligible for curative HCC treatments, the Taiwan consensus on the management of hepatitis C recommends prioritizing HCC treatment before initiating DAA therapy [17]. Conversely, given the accumulating evidence demonstrating high SVR rates in patients with active HCC treated with highly potent, pangenotypic DAA regimens [18,19], it is recommended that DAA therapy be initiated immediately for patients with incurable HCC, irrespective of HCC treatment.
As shown in Supplementary Table 1, the selection of DAAs must conform to their specific indications, including HCV genotypes and/or nonstructural 5A resistance-associated substitutions. In addition, due to the underlying comorbidities commonly observed in HCV carriers, a high prevalence of comedications has been reported [20,21]. To mitigate potential harmful effects caused by drug-drug interactions (DDIs), the Taiwan consensus on the management of hepatitis C recommends a thorough assessment of DDIs before initiating DAA therapy, including interactions with medications used for HCC treatment [17].
Study population and data collection
The TACR is a nationwide registry program, including patients who have received DAA therapy for HCV in Taiwan. By the end of 2020, 48 study sites, including 21 medical centers, 22 regional hospitals and five primary clinics, were participating in the registry [10]. As shown in Figure 1, we screened all patients registered in the TACR during the period from 25 December, 2013 to 31 December, 2020. The inclusion criteria were as follows: (1) aged 20 years or more, (2) detectable HCV RNA, (3) received DAA‐containing regimes for at least one dosage of any DAA, and (4) had virological response available. The exclusion criteria included: (1) hepatitis B virus (HBV) or HIV coinfection, (2) liver transplantation, (3) cancers other than HCC, or (4) terminal-stage HCC prior to DAA treatment initiation.
As outlined in our previously published studies [8-15], we retrieved comprehensive information from the TACR for analysis, including patient demographic characteristics (e.g., age, gender, body mass index [BMI], smoking and alcoholism), underlying comorbidities (e.g., liver cirrhosis, HCC, diabetes mellitus [DM], hypertension [HTN], cerebral vascular accident [CVA], coronary artery disease [CAD] and chronic kidney disease [CKD]), laboratory data (e.g., alanine aminotransferase [ALT], bilirubin, albumin, and HCV virological characteristics (HCV genotype, HCV RNA level, and virological responses to antivirals). Liver cirrhosis was defined by liver histology, transient elastography or the presence of clinical radiological evidence of cirrhosis. The presentation of liver cirrhosis and Child-Turcotte-Pugh (CTP) scores were recorded. Hepatic decompensation was defined as CTP scores ≥7. HCC was diagnosed by histological or typical image findings based on the guidelines of the American Association for the Study of Liver Diseases [22].
The DAA regimens used in this study were recorded, and pangenotypic regimens included glecaprevir/pibrentasvir, sofosbuvir/velpatasvir, and sofosbuvir/velpatasvir/voxilaprevir. Adherence to the DAA treatment of the enrolled subjects was also recorded and analyzed.
Study outcomes and linked databases
The primary endpoint of this study was overall survival (OS) of the study subjects. We linked the data taken from TACR with the National Health Insurance Research Database, where the dates of patient death could be retrieved [8]. Patients were followed up from the date of accessing SVR, i.e., the 12th week after completing DAA therapy, until the occurrence of death or the end of this study period (31 December, 2020), in which OS was defined.
Statistical analysis
Data was expressed as mean±standard deviation for continuous variables, and case number (percentage of the total number) for categorical variables. As appropriate, the Student’s t-test was used to compare the data of continuous variables, while chi-square or Fisher’s exact tests were used to compare those of categorical variables. The multivariable logistic regression model was applied to determine the independent factors related to SVR, in which the adjusted odds ratio (aOR) with a 95% confidence interval (CI) was presented. The multivariable Cox regression model was applied to determine the independent factors related to OS, in which the adjusted hazard ratio (aHR) with a 95% CI was presented. The Kaplan–Meier method was used to estimate the cumulative incidences of patient mortality, while the log-rank test was used to compare the incidence differences seen in different study groups. A P-value below 0.05 was defined as being statistically significant. All statistical analyses were performed using the SAS Enterprise Guide.
RESULTS
Patient characteristics
Figure 1 demonstrates the patient selection process, in which 31,894 patients were enrolled in the TACR cohort during the period from December 2013 to December 2020. After excluding patients as the exclusion criteria, 23,774 individuals were eventually enrolled for final analysis, with 2,205 cases (9.3%) and 21,569 (90.7%) having underlying HCC or not, respectively. As shown in Table 1, when compared to patients in the non-HCC group, patients in the HCC group were significantly older (70.5 vs. 61.6 years) and male-predominant (49.8% vs. 45.2%), with higher percentages in underlying comorbidities such as DM, HTN, CAD and CKD. However, BMI was not significantly different between the two study groups. Not surprisingly, the liver related parameters were more severe in the HCC group, including ALT, bilirubin and CTP scores, with the patient proportion of liver cirrhosis being significantly higher (63.7% vs. 25.7%). The mean HCV RNA was 5.9±1.0 log IU/mL, while HCV genotype 1 was significantly higher. The adherence to DAA treatment was better in those without HCC (99.6%). The proportion of BCLC stage 0, A, B and C was 22.2%, 52.3%, 16.5% and 9.0%, respectively.
Analysis of SVR in the whole population
The SVR rate of DAA therapy in the whole patient population was 98.6%, with it being seen as significantly lower in the HCC group when compared to that of the non-HCC group (96.6% vs. 98.8%; P<0.001). However, the SVR rate remained higher than 95% among patients with HCC.
As shown in Table 2, in the analysis for SVR-related factors, female gender (aOR 1.42; 95% CI 1.14–1.77; P=0.002), HCV genotype 1 (aOR 2.20; 95% CI 1.74–2.77; P<0.001), pangenotypic DAA regimen (aOR 2.14; 95% CI 1.63–2.81; P<0.001), DAA adherence >80% (aOR 31.51; 95% CI 20.23–49.09; P<0.001), liver cirrhosis (CTP score 5-6: aOR 0.76; 95% CI 0.60–0.97; P=0.028 & CTP score ≥7: aOR 0.47; 95% CI 0.26–0.85; P=0.012) and coexisting HCC (aOR 0.41; 95% CI 0.31–0.54; P<0.001) were all independent factors related to SVR.
Analysis of OS in the whole patient population
As shown in Table 3, in analysis of the prognostic factors related to OS, age >65 years (aHR 1.79; 95% CI 1.55–2.07; P<0.001), DM (aHR 1.51; 95% CI 1.37–1.81; P<0.001), CVA (aHR 1.45; 95% CI 1.10–1.91; P=0.009), CKD (aHR 2.22; 95% CI 1.93–2.54; P<0.001), liver cirrhosis (CTP score 5-6: aHR 1.59; 95% CI 1.37–1.83; P<0.001 & CTP score ≥7: aHR 5.49; 95% CI 4.35–6.92; P<0.001) and coexisting HCC (aHR 3.99, 95% CI 3.48-4.58; P<0.001) were all independent factors related to a decreased OS rate. In contrast, female gender (aHR 0.61; 95% CI 0.53–0.69; P<0.001) and SVR to DAA therapy (aHR 0.46; 95% CI 0.35–0.60; P<0.001) were independent factors related to an increased OS rate.
As shown in Figure 2, the 3-year cumulative incidence of OS was significantly higher in patients with SVR, when compared to that seen in patients without SVR (94.0%, 95% CI 93.5–94.4 vs. 78.5%, 95% CI 71.8–83.8; P<0.001). After adjusting for the factors of age, gender, DM, HTN, CVA, CAD, CKD, HCC and liver cirrhosis, SVR was associated with improved OS (aHR 0.46; 95% CI 0.35–0.60; P<0.001), when compared to non-SVR.
Analysis of OS among patients with baseline HCC
As shown in Table 4, DM (aHR 1.32; 95% CI 1.06–1.64; P=0.012), CKD (aHR 1.56; 95% CI 1.21–1.90; P<0.001), liver cirrhosis (CTP score 5-6: aHR 1.27; 95% CI 1.00–1.62; P=0.048 & CTP score ≥7: aHR 3.21; 95% CI 2.25–4.60; P<0.001), and HCC in BCLC stage B or C (aHR 1.78; 95% CI 1.44–2.21; P<0.001) were all independent factors related to a decreased OS. In contrast, female gender (aHR 0.74; 95% CI 0.61–0.93; P=0.005) and SVR (aHR 0.41; 95% CI 0.28–0.59; P<0.001) were independent factors related to an increased OS.
As shown in Figure 3, the 3-year cumulative incidence of OS was significantly higher in patients with SVR, when compared to that seen in patients without SVR (79.2%, 95% CI 77.2–81.2 vs. 48.3%, 95% CI 34.3–61.0; P<0.001). After adjusting for gender, DM, CKD, liver cirrhosis and BCLC stage, SVR was associated with improved OS (aHR 0.41; 95% CI 0.28–0.59; P<0.001), when compared to non-SVR.
We further analyzed the impact of SVR on different HCC stages. As shown in Figure 4, the 3-year cumulative incidence of OS was the highest among BCLC stage 0/A patients with SVR, but was lowest among BCLC stage B/C patients without SVR (P<0.001). After adjusting for gender, DM, CKD, and liver cirrhosis, SVR was respectively associated with improved OS in BCLC stage 0/A patients (aHR 0.47; 95% CI 0.29–0.77; P=0.002) and BCLC stage B/C patients (aHR 0.34; 95% CI 0.19–0.59; P<0.001), when compared to non-SVR.
DISCUSSION
This study is so far the first nationwide and largest cohort study investigating the survival benefits of DAA therapy in HCC patients. We report that although HCC may be a factor related to a reduced SVR rate in DAA therapy, the SVR rate among HCC patients remains very high. A lower SVR rate should not be a reason to withhold DAA therapy for HCC patients. Importantly, HCV eradication, i.e., SVR, through DAA therapy, is associated with improved OS in patients no matter whether they have HCC or not. Moreover, not only in early-stage HCC, i.e., BCLC stage 0/A, but also in BCLC stage B/C HCC, SVR is associated with improved OS, with DAA therapy being helpful for patients diagnosed with any-stage HCC who do not have a short-life expectancy.
In previous small-scale studies, although the SVR rates of DAA therapy in HCC patients were varied, ranging from 79% to 98%, HCC was commonly found to be a factor related to a lower SVR rate [23,24]. However, due to the rapid progress being seen in DAA development in recent years, the SVR rate in patients with genotype 1 to genotype 6 has become very high, nearly 100% in the per-protocol analysis of previous clinical trials using pangenotypic DAAs [25,26]. The high SVR rate among HCC patients in this study may be due to a large proportion of patients receiving HCV pangenotypic genotype-oriented DAA therapies, which have been reimbursed by the National Health Insurance program of Taiwan [27]. Although the SVR rate in HCC patients is expected to be lower when compared to non-HCC patients, the small difference in the rate may be omitted. This is because the SVR-related survival benefits in HCC patients should be certainly cost-effective.
Liver function is one of the most important prognostic factors in patients with HCC during each tumor stage [28], however most HCC patients suffer from underlying advanced liver fibrosis, significant portal HTN, and even liver decompensation [29]. Moreover, the HCC treatments, including curative treatments, locoregional treatments, and systemic therapies, may further impair liver function. However, impaired liver function may not only result in liver decompensation and death, but it may also delay HCC treatments [29]. Because achieving SVR through DAA therapy can improve liver function, it is reasonable to believe that pa-tient survival can be prolonged after curative or even palliative HCC treatments. However, the process of liver function improvement is not dramatically changed, and DAA therapy may not be beneficial in time for HCC patients with a short life expectancy, such as those in the terminal stage of HCC [30]. As demonstrated in this study, the survival benefit of SVR became more and more significant during the follow-up period.
In the past, although SVR achieved through interferon therapy could reduce the HCC recurrence rate and improve patient survival rates in those with early-stage HCC receiving curative treatments [31], patients with unresectable HCC or severe liver cirrhosis were often excluded from interferon therapy due to its high side effect possibility, long treatment period, and low SVR rate [32]. However, in the current era of DAA therapy, HCV eradication has become faster, safer and easier, even in those patients experiencing advanced liver diseases or severe underlying disorders [33-35]. Therefore, DAA therapy can be safely used in HCC patients. Although determining the optimal timing for HCV treatment intervention following HCC development is a clinical issue, particularly for patients with untreated or active HCC, the high SVR rates observed among HCC patients across various stages in this study may provide indirect evidence addressing this issue. The timing of DAA therapy and HCC treatment is no longer as conflicting as it was in the era of interferon-based therapy. In patients with early-stage HCC following curative treatments, DAA therapy can reduce the HCC recurrence rate and further improve OS. For example, in a prospective multiple-center study performed in Italy, DAA therapy significantly reduced as high as a 61% risk of death, a 30% risk of HCC recurrence and a 68% risk of hepatic decompensation, after a mean follow-up period of 21.4 months [5]. Moreover, in previous single center-based studies, DAA therapy was considered to be helpful in improving OS in patients diagnosed with BCLC stage B/C HCC [7,24]. This nationwide study further provides strong evidence that DAA therapy should become an essential component nowadays in the management of HCV-infected HCC patients across various HCC stages.
Several limitations should be addressed in this study. First, although selection bias should have been minimized in this nationwide study, all study subjects used in this study were Taiwanese. More large-scale validation studies from other countries or populations should be welcome. Second, some patients receiving DAA therapy had been excluded in the final analysis, such as those with HBV or HIV coinfection; therefore, further investigations for these special populations should be encouraged in the future. Third, a DAA-untreated control group was lacking. Conducting a study to establish a DAA-untreated control group should not be considered an ethical procedure. Fortunately, we were able to include patients who did not achieve SVR as the control group in this large-scale study. Fourth, due to the limited resources available for this study, including the constrained study timeframe, further analyses focusing on specific subpopulations, such as HCC patients receiving immunotherapy, could not be performed. Nevertheless, the positive findings of our study provide a strong foundation for future investigations.
In conclusion, this nationwide cohort study provides strong evidence that DAA therapy can achieve high SVR rates, even in HCC patients. Achieving SVR can significantly improve the survival of HCC patients, across various HCC stages. DAA therapy is highly recommended for all HCC patients who do not have a short life expectancy.
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