The superiority between TAF and ETV remains unclear. Which is the best choice for patients with CHB? Thus, this meta-analysis aimed to evaluate the efficacy and safety of TAF and ETV for patients with CHB.

MEDLINE/PubMed, Cochrane Library, EMBASE, Web of Science and CNKI were searched for eligible studies from inception to January 2024 and a meta-analysis was done.

24 trials with a total of 6753 subjects were screened. TAF significantly improved 12- and 24-week complete virological response (CVR), 12-week biochemical response (BR) and 24-week HBeAg loss, but could not improve 48- and 96-week CVR, 24-, 48- and 96-week BR, 96-week HBeAg loss, adverse events, 48-week HBsAg decline and loss, 12-, 24- and 48-week HBeAg seroconversion, 96-week HCC incidence compared to ETV. Subgroup analysis was conducted according to race, research type and switching. Different results were obtained from different subgroups.

TAF was superior to ETV at 12- and 24-week CVR, 12-week BR and 24-week HBeAg loss. Race and switching might affect the efficacy of TAF and ETV.

Tenofovir alafenamide (TAF) lacks extensive research regarding its impact on hepatocellular carcinoma (HCC). This study evaluated and compared the effects of TAF, tenofovir disoproxil fumarate (TDF), and entecavir (ETV) on HCC incidence using nationwide claim data.

In total, 75,816 patients with treatment-naïve HBV were included in the study and divided into TAF (n = 25,680), TDF (n = 26,954), and ETV (n = 23,182) groups after exclusions. Propensity score matching (1:1:1) resulted in 17,537 patients per group. HCC incidence rates were compared among the groups.

Before matching, the incidence of HCC was significantly lower in the TAF group compared with the TDF and ETV groups (11.47 vs. 15.04 and 14.24 per 1,000 person-years). The incidence rate ratio (IRR) for TDF was 1.31 (1.19-1.44) and for ETV was 1.24 (1.12-1.37). Before matching, the TAF group had a significantly lower HCC compared with TDF and ETV in both patients with and without cirrhosis. After matching, the TAF group had a lower HCC incidence compared with the TDF group (12.38 vs. 15.39, IRR 1.24, p <0.001) but not with ETV group (IRR 1.08, p = 0.219). In patients with cirrhosis, TAF had lower HCC incidence compared with TDF and ETV (30.25 vs. 39.56 and 38.51, respectively). In patients without cirrhosis, the TAF group had a lower HCC incidence compared with the TDF group (IRR 1.19, p = 0.030) but not the ETV group (IRR 0.85, p = 0.066). Cox regression analysis showed that the TAF group had a significantly lower HCC incidence compared with the TDF (hazard ratio 1.335, p <0.001) and ETV groups (hazard ratio 1.162, p = 0.011), after adjusting for age, gender, and cirrhosis status.

The TAF group consistently demonstrated a lower incidence of HCC compared with the TDF and ETV groups, especially in patients with cirrhosis.

This work aimed to fill the knowledge gap regarding the comparative efficacy of tenofovir alafenamide (TAF), tenofovir disoproxil fumarate (TDF), and entecavir (ETV) in reducing the incidence of hepatocellular carcinoma (HCC) in patients with chronic HBV. The results are particularly crucial for healthcare providers and policymakers, because they highlight the significantly lower incidence of HCC associated with TAF, especially in patients with cirrhosis. These results suggest TAF as a preferable antiviral therapy option to mitigate HCC risk, thus influencing clinical decision-making and healthcare guidelines. From a practical perspective, these findings can guide physicians in prescribing more effective treatments, assist researchers in designing further studies to explore the mechanisms behind the effectiveness of TAF, and inform policymakers to craft healthcare policies that optimize patient outcomes while considering potential limitations, such as the observational nature of the study and residual confounding factors.

: Besifovir dipivoxil maleate (BSV) and tenofovir alafenamide fumarate (TAF) have been recently approved in Korea as the initial antiviral agents for chronic hepatitis B (CHB). However, the real-world outcome data for these drugs remain limited. Therefore, we conducted a noninferiority analysis using real-world data to compare the clinical outcomes of the two nucleotide analogs in treatment-naïve patients with CHB.

: We retrospectively investigated a cohort of patients with CHB who received BSV or TAF as first-line antiviral agents. The endpoints were virological response (VR) and liver-related clinical outcomes.

: A total of 537 patients, consisting of 202 and 335 patients administered BSV and TAF, respectively, were followed up for 42 months. No significant difference was observed between the VRs of the patients from the two groups. The rates of biochemical response, virologic breakthrough, and incidence rates of hepatocellular carcinoma did not differ between the groups. However, the hepatitis B e antigen seroclearance rate was higher and the renal function declined less in the BSV group. Multivariable analysis indicated older age, alcohol abuse, cirrhosis and ascites, and lower serum HBV DNA level to be independently associated with increased hepatocellular carcinoma risk. The 1:1 propensity score-matched analysis with 400 patients showed VR rates of 85.0% and 88.7% in the BSV and TAF group patients, respectively, at 2 years. The absolute value of the 95% confidence interval for the difference (-0.04 to 0.12) satisfied the a priori limit of a noninferiority of 0.15.

: BSV is noninferior to TAF in terms of VR, and their clinical outcomes are comparable to CHB.

Chronic hepatitis B virus (HBV) infection, which ultimately leads to liver cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC), remains a significant disease burden worldwide. Despite the use of antiviral therapy (AVT) using oral nucleos(t)ide analogs (NUCs) with high genetic barriers, the risk of HCC development cannot be completely eliminated. Therefore, bi-annual surveillance of HCC using abdominal ultrasonography with or without tumor markers is recommended for at-risk populations. For a more precise assessment of future HCC risk at the individual level, many HCC prediction models have been proposed in the era of potent AVT with promising results. It allows prognostication according to the risk of HCC development, for example, low-vs. intermediate-vs. high-risk groups. Most of these models have the advantage of high negative predictive values for HCC development, allowing exemption from biannual HCC screening. Recently, non-invasive surrogate markers for liver fibrosis, such as vibration-controlled transient elastography, have been introduced as integral components of the equations, providing better predictive performance in general. Furthermore, beyond the conventional statistical methods that primarily depend on multi-variable Cox regression analyses based on the previous literature, newer techniques using artificial intelligence have also been applied in the design of HCC prediction models. Here, we aimed to review the HCC risk prediction models that were developed in the era of potent AVT and validated among independent cohorts to address the clinical unmet needs, as well as comment on future direction to establish the individual HCC risk more precisely.

Though the world-wide hepatitis B virus (HBV) vaccination program has been well completed for almost thirty years in many nations, almost HBV-related hepatocellular carcinoma (HCC) occurs in unvaccinated middle-aged and elderly adults. Apparently, treating 80% of qualified subjects could decrease HBV-related mortality by 65% in a short period. Nevertheless, globally, only 2.2% of CHB patients undergo antiviral therapy. The HBV markers related to HCC occurrence and prevention are as follows: the HCC risk is the highest at a baseline of HBV DNA of 6-7 log copies/mL, and it is the lowest at a baseline of an HBV DNA level of >8 log copies/mL and ≤4 log copies/mL (parabolic, and not linear pattern). The titer of an HBV core-related antigen (HBcrAg) reflecting the amount of HBV covalently closed circular DNA (ccc DNA) in the liver is related to HCC occurrence. The seroclearance of HBs antigen (HBsAg) is more crucial than HBV DNA negativity for the prevention of HCC. In terms of the secondary prevention of hepatitis B-related HCC involving antiviral therapies with nucleos(t)ide analogues (NAs), unsolved issues include the definition of the immune-tolerant phase; the optimal time for starting antiviral therapies with NAs; the limits of increased aminotransferase (ALT) levels as criteria for therapy in CHB patients; the normalization of ALT levels with NAs and the relation to the risk of HCC; and the relation between serum HBV levels and the risk of HCC. Moreover, the first-line therapy with NAs including entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) remains to be clarified. Discussed here, therefore, are the recent findings of HBV markers related to HCC occurrence and prevention, unsolved issues, and the current secondary antiviral therapy for the prevention of HBV-related HCC.

At present, there are a variety of antiviral drugs for HBV in clinical practice, but there is no standard scheme for transcatheter arterial chemoembolization(TACE) combined with antiviral drugs. The aim of this study was to investigate whether TACE must be combined with antiviral therapy in patients of HBV-related hepatocellular carcinoma(HCC). Meanwhile, the efficacy and safety of TACE combined with entecavir and TACE combined with tenofovir in the treatment of HBV-related HCC were compared.

This study included 536 patients with HBV-related HCC who underwent TACE in Union Hospital from March 2017 to March 2020, and they met the criteria. They were divided into three groups: control group (N = 212): TACE alone; Entecavir group (N = 220): TACE combined with entecavir; and Tenofovir group (N = 228): TACE combined with tenofovir. We conducted a retrospective study to analyze the efficacy and safety of the three groups of patients.

Objective response rate(ORR): 29.2% in control group, 54.1% in entecavir group, and 63.2% in tenofovir group (P < 0.05). Disease control rate(DCR): 63.7% in control group, 80.9% in entecavir group, and 88.1% in tenofovir group (P < 0.05). Median overall survival(mOS): control group, 12.2 months; entecavir group, 17.3 months; tenofovir group, 22.5 months (p < 0.05). Median progression-free survival (mPFS): control group, 9.3 months; entecavir group, 15.5 months; tenofovir group, 16.6 months (p < 0.05). At 6 months, there was an increase in creatinine(Cr) and a decrease in glomeruar filtration rate(GFR) in tenofovir group, which were statistically different from control and entecavir groups (p < 0.05).

TACE combined with entecavir and TACE combined with tenofovir had higher ORR and DCR, longer OS and PFS than TACE alone. The OS of TACE combined with tenofovir was higher than that of TACE combined with entecavir. TACE combined with tenofovir is a safe strategy, but we cannot completely ignore the impact of tenofovir on renal function.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.

High incidence of hepatocellular carcinoma (HCC) exists in patients with liver cirrhosis (LC), but the predictive accuracy of noninvasive scoring systems (NSSs) is yet to be elucidated. The present study aimed to evaluate the predictive ability of fibrosis-4 (FIB-4), aminotransferase-to-platelet ratio index (APRI), and gamma-glutamyl transpeptidase to platelet ratio (GPR) in patients with LC, and to establish a new model with more accuracy.

Data from 94 patients with compensated LC and 134 patients with decompensated cirrhosis (DC) were collected. The prediction accuracy of NSSs, including APRI, GPR, and FIB-4, was compared.

During a median follow-up of 37.5 months, 9 patients in the compensated LC group and 38 in the DC group developed HCC. For 228 patients, the area under the receiver operating characteristic curve (AUROC) of APRI, GPR, and FIB-4 was 0.596, 0.625, and 0.654, respectively. Multivariable logistic analysis showed that age, gamma-glutamyl transpeptidase (GGT), and platelet (PLT) were independent risk factors for HCC development, and a new model encompassing age, GGT, and PLT was superior to NSSs (all P<0.05). With an optimal cutoff value of 0.216, Model (Age_GGT_PLT) achieved 68.09% sensitivity and 69.61% specificity.

NSSs, including APRI, GPR, and FIB-4, has a non-optimal accuracy in predicting HCC development in patients with HBV-related LC. Thus, the new model consisting of age, GGT, and PLT may be more accurate than NSSs.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.

Conventional meta-analyses with aggregated study-level data have yielded conflicting results for the comparative effectiveness of tenofovir disoproxil fumarate vs entecavir in reducing hepatocellular carcinoma (HCC) risk among patients with chronic hepatitis B virus. Within-study heterogeneity, between-study heterogeneity, and the inability of conventional meta-analyses to capture time-to-event data were associated with these results.

To perform a reconstructed individual patient data meta-analysis of high-quality propensity score-matched studies to provide robust estimates for comparative HCC risk between groups receiving tenofovir or entecavir.

Medline and Embase databases were searched from inception to October 6, 2021.

The initial search yielded 3435 articles. Fourteen studies that used propensity score matching to balance baseline characteristics were included in the final analysis.

The Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was followed. Individual patient data were reconstructed from Kaplan-Meier curves. Risk of HCC was evaluated using random-effects hazard ratios (HRs) via a shared-frailty model and a Cox proportional hazards model stratified by study group. Restricted mean survival time (RMST) analysis was conducted to account for varying estimated treatment effect across time.

The comparative risk of HCC with tenofovir vs entecavir treatment.

From analysis of 14 studes with 24 269 patients (10 534 receiving tenofovir and 13 735 receiving entecavir; mean age, 49.86 [95% CI, 48.35-51.36] years; 65.05% [95% CI, 58.60%-71.00%] men), tenofovir was associated with decreased HCC incidence compared with entecavir (stratified Cox HR, 0.85 [95% CI, 0.76-0.94] at 5 years; P = .002). However, there was no significant difference in subanalysis of clinical cohort studies (stratified Cox HR, 0.92 [95% CI, 0.80-1.06] at 5 years; P = .24). Among administrative database studies, proportionality was violated, and HRs could not be obtained via Cox proporational hazards-based models. The mean time to HCC development in RMST analysis was 2.8 (95% CI, 1.8-3.7) weeks longer (P < .001) for tenofovir vs entecavir at 5 years. The RMST analyses for other subgroups revealed either insignificant or minimal differences (<3 weeks) in the mean time to HCC at 5 years.

In this meta-analysis, there was no clinically meaningful difference in the risk of HCC between patients who received entecavir and patients who received tenofovir. There was no difference between tenofovir and entecavir among clinical cohort studies, whereas the mean time to HCC development was less than 3 weeks longer for patients who received tenofovir vs those who received entecavir at year 5 among administrative database studies. The choice between tenofovir or entecavir should be decided based on patient convenience and tolerability.

Previous smaller meta-analyses comparing the incidence of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients treated with tenofovir disoproxil fumarate (TDF) versus entecavir (ETV) provided controversial results. This updated meta-analysis aimed to reliably identify any difference in the HCC incidence between TDF-treated or ETV-treated CHB patients in general or in specific subgroups.

PubMed, EMBASE, Web of Science, and Cochrane Library were systematically searched for relevant studies with hazard ratios (HRs) for HCC between TDF-treated and ETV-treated CHB patients. Retrieved dates ranged from January 2009 to October 2021. HRs with or without adjustment were pooled with random-effects model.

Twenty-four comparative studies involving 37 771 CHB patients treated with TDF and 72 094 treated with ETV were included. TDF was associated with lower risk of HCC compared with ETV, with pooled unadjusted HR of 0.76 (95% confidence interval [CI]: 0.67-0.86) (24 studies) and adjusted HR of 0.81 (95% CI: 0.72-0.91) (21 studies). In propensity score matching cohorts, the TDF superiority was confirmed for unadjusted HR 0.83 (95% CI: 0.71-0.97) (14 studies) and was close to significance for adjusted HR (0.78, 95% CI: 0.58-1.04) (8 studies). Subgroup analyses showed that TDF was associated with lower HCC risk than ETV treatment in CHB patients who were from Asia (adjusted HR: 0.76, 95% CI: 0.66-0.87; 15 studies) or nucleos(t)ide naïve (adjusted HR:0.74, 95% CI: 0.65-0.84; 18 studies).

Current evidence from a sizable population suggests that TDF is associated with significantly lower HCC risk compared with ETV treatment in patients who are from Asia and/or nucleos(t)ide naïve.

Oral nucleos(t)ide analogues (NUCs) are recommended as first-line therapy for chronic hepatitis B due to higher HBV-DNA suppression rates and safety profile. Long-term treatment with NUCs is often necessary to achieve durable viral suppression.

This review provides an overview of the long-term safety data that have become available since entecavir (ETV) and tenofovir disoproxil fumarate (TDF) were first approved, and recent data on tenofovir alafenamide (TAF) in patients with CHB.

NUCs generally show remarkable safety in patients taking them for long periods. Nevertheless, renal and bone toxicity may occur in a minority of patients on TDF therapy. These effects have been overcome by the recent release of TAF. Moreover, the currently available data do not allow firm conclusions on superiority of TDF on ETV about HCC risk reduction. Observational studies involving more homogeneous cohorts are therefore needed; furthermore long-term studies assessing impact of TAF on this important topic are warranted.

Esophageal varices (EVs) can be accurately predicted using PH and varices risk scores. We aimed to validate their prognostic performances. Methods: We enrolled patients with B-viral cirrhosis as the training cohort (n = 503). Areas under receiver operating characteristic curves (AUROCs) for HEV were calculated for PH (=-5.953 + 0.188 × liver stiffness (LS) + 1.583 × sex (1:male/0:female) + 26.705 × spleen diameter/platelet count ratio) and varices (=-4.364 + 0.538 × spleen diameter -0.049 × platelet count -0.044 × LS + 0.001 × LS × platelet count) risk scores, and compared to LSPS (=LS × spleen diameter/platelet count). An independent cohort was recruited for further validation (n = 222). In the training cohort, the varices risk score showed the highest AUROC (0.926), followed by the PH risk score (0.924) and LSPS (0.924), but without any statistically significant differences. For varices risk scores ≤-1.70 and ≥1.48, a 95.0% negative predictive value (NPV) and 91.2% positive predictive value (PPV) were observed, respectively. At PH risk scores ≤2.25 and ≥7.71, 95.0% NPV and 90.0% PPV were observed, respectively. At LSPS ≤1.73 and ≥13.9, 95.3% NPV and 95.0% PPV were observed, respectively. The EV bleeding (EVB) risk during follow-up increased stepwise and significantly when stratified by PH, varices risk scores, and LSPS (all p < 0.001). In the validation cohort, NPVs were generally similar when stratified by PH (88.2%), varices risk scores (93.2%), and LSPS (88.9%); however, corresponding PPVs were suboptimal. PH and variceal risk scores are reliable for predicting HEV and future EVB. Patients with PH and varices risk scores ≤2.25 and ≤-1.70, respectively, may avoid endoscopy safely. For convenience, LSPS might be a good alternative, with comparable prognostic performance to these two models.

Chronic hepatitis B virus (HBV) infection is a worldwide health problem leading to severe liver dysfunction, including liver cirrhosis and hepatocellular carcinoma. Although current antiviral therapies for chronic HBV infection have been improved and can lead to a strong suppression of viral replication, it is difficult to completely eliminate the virus with these therapies once chronic HBV infection is established in the host. Furthermore, chronic HBV infection alters intracellular metabolism and signalling pathways, resulting in the activation of carcinogenesis in the liver. HBV produces four viral proteins: hepatitis B surface-, hepatitis B core-, hepatitis B x protein, and polymerase; each plays an important role in HBV replication and the intracellular signalling pathways associated with hepatocarcinogenesis. In vitro and in vivo experimental models for analyzing HBV infection and replication have been established, and gene expression analyses using microarrays or next-generation sequencing have also been developed. Thus, it is possible to clarify the molecular mechanisms for intracellular alterations, such as endoplasmic reticulum stress, oxidative stress, and epigenetic modifications. In this review, the impact of HBV viral proteins and intracellular alterations in HBV-associated hepatocarcinogenesis are discussed.

Antiviral agents for chronic hepatitis B (CHB) reduced the risk of hepatocellular carcinoma (HCC) development. The outcomes of entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) were compared in patients with CHB.

Between 2017 and 2019, treatment-naïve patients with CHB treated with ETV, TDF, and TAF were recruited from three Korean tertiary institutes. The cumulative incidences of HCC and orthotopic liver transplantation (OLT) or mortality were calculated and compared using Kaplan-Meier analysis before and after trimatch.

Among recruited 2082 patients, 43 patients developed HCC, whereas 66 developed OLT or mortality. Before trimatch, the cumulative incidence of HCC was statistically similar among patients treated with three antiviral agents (p = 0.340). However, the cumulative probability of OLT or mortality development in patients treated with ETV or TDF was significantly higher than that of patients with TAF before trimatch (all p < 0.05). On multivariate analysis, male sex [hazard ratio (HR) 2.990] and older age (HR 1.044) were independently associated with an increased risk of HCC development, whereas higher platelet count (HR 0.993) was independently associated with a decreased risk (all p < 0.05). The type of antiviral agents did not significantly influence the risk of HCC and OLT or mortality development (all p > 0.05). After trimatch, no significant difference in the cumulative probability for HCC and OLT or mortality according to antiviral agents was found (all p > 0.05).

The outcomes of ETV, TDF, and TAF on the risk of HCC and OLT or mortality were statistically similar in treatment-naïve patients with CHB.

Hepatocellular carcinoma (HCC) risk prediction is important to developing individualized surveillance approaches. We designed a novel HCC prediction model using liver stiffness on transient elastography for patients receiving antiviral therapy against hepatitis B virus (HBV) infection. We recruited 2037 patients receiving entecavir or tenofovir as first-line antivirals and used the Cox regression analysis to determine key variables for model construction. Within 58.1 months (median), HCC developed in 182 (8.9%) patients. Patients with HCC showed a higher prevalence of cirrhosis (90.7% vs. 45.9%) and higher liver stiffness values (median 13.9 vs. 7.2 kPa) than those without. A novel nomogram (score 0-304) was established using age, platelet count, cirrhosis development, and liver stiffness values, which were independently associated with increased HCC risk, along with hepatitis B e antigen positivity and serum albumin and total bilirubin levels. Cumulative HCC probabilities were 0.7%, 5.0%, and 22.7% in the low- (score ≤87), intermediate- (88-222), and high-risk (≥223) groups, respectively. The c-index value was 0.799 (internal validity: 0.805), higher than that of the PAGE-B (0.726), modified PAGE-B (0.756), and modified REACH-B (0.761) models (all p < 0.05). Our nomogram showed acceptable performance in predicting HCC in Asian HBV-infected patients receiving potent antiviral therapy.

Hepatitis B virus (HBV) is the one of most common causes of the hepatocellular carcinoma (HCC), especially in eastern world. The aim of this review is to try to understand the relationship between HBV and HCC and to reveal the role of prevention and treatment of HBV infection in reducing the incidence of HCC. Strategies to prevent HCC due to HBV can be classified into three categories. These are primary, secondary, and tertiary preventions. Hepatitis B vaccine is now in the most vital position in preventing HBV-associated HCC. In patients with chronic hepatitis B infection, suppressing viral load with potent antivirals such as tenofovir disoproxil fumarate (TDF) and entecavir (ETV) prevents the development of HCC and improves prognosis by reducing recurrence after HCC treatments. There is currently no clear consensus on which of these drugs should be preferred. Although data on tenofovir alafenamide (TAF) are scarce, available data with TDF suggest that TAF therapy will also be a strong actor for HCC.