Magnetic resonance imaging-based risk factors of hepatocellular carcinoma after direct-acting antiviral therapy: A multicenter observational study.

AIM: To determine risk factors associated with hepatocellular carcinoma (HCC) development following direct-acting antiviral (DAA) therapy. METHODS: We enrolled patients with chronic hepatitis C who underwent direct-acting antiviral therapy and achieved sustained virologic response at 12 weeks between 2012 and 2018. Subsequently, patients were followed up. The primary endpoint was the development of HCC or the date of the last follow up when the absence of HCC was confirmed. Uni- and multivariate Cox proportional hazards models were used to identify factors contributing to HCC development, including gadoxetic acid-enhanced magnetic resonance imaging findings. The cumulative incidence rates of HCC development were calculated using the Kaplan-Meier method, and differences between groups were assessed using the log-rank test. RESULTS: The final study cohort comprised 482 patients (median age 70.5 years; 242 men). The median follow-up period was 36.8 months. Among 482 patients, 96 developed HCC (19.9%). The 1-, 3-, and 5-year cumulative rates of HCC development were 4.9%, 18.6%, and 30.5%, respectively. Multivariate analysis revealed that age, male sex, history of HCC, and hepatobiliary phase hypointense nodules without arterial phase hyperenhancement were independent risk factors significantly associated with HCC development (p < 0.001-0.04). The highest risk group included patients with both a history of HCC and the presence of hepatobiliary phase hypointense nodules without arterial phase hyperenhancement (the 1- and 3-year cumulative HCC development rates were 14.2% and 62.2%, respectively). CONCLUSION: History of HCC and presence of hepatobiliary phase hypointense nodules without arterial phase hyperenhancement were strong risk factors for HCC development following direct-acting antiviral therapy.

Improved Liver Function After Sustained Virologic Response Enhanced Prognosis in Hepatitis C with Compensated Advanced Liver Fibrosis.

BACKGROUND AND AIM: Liver function can be improved in patients with chronic hepatitis C virus (HCV) infection who achieved sustained virologic response (SVR) with direct-acting antiviral (DAA) treatment. However, to our knowledge, the impact of liver function improvement after SVR on prognosis has not been investigated. METHODS: A total of 716 patients with chronic HCV infection and compensated advanced liver fibrosis who began receiving DAA treatment between September 2014 and August 2018 in 25 Japanese hospitals and achieved SVR were enrolled. RESULTS: The median age was 73 years, and 336 (47%) and 380 (53%) patients had albumin-bilirubin (ALBI) grade 1 and grade 2, respectively. Improvement to ALBI grade 1 at 1 year after the end of treatment (EOT) was observed in 76% of the patients with baseline ALBI grade 2. Among 380 patients with baseline ALBI grade 2, alanine aminotransferase (ALT) levels ≥ 40 U/L (p < 0.001) and modified ALBI (mALBI) grade 2a (p < 0.001) were significantly associated with improvement to ALBI grade 1 at 1 year after EOT in multivariate analysis. During the median observation period of 51.8 months, 4 and 10 patients with baseline ALBI grade 1 and 2, respectively, died. In patients with baseline ALBI grade 2, only the absence of improvement to ALBI grade 1 at 1 year after EOT was significantly associated with all-cause mortality in univariate analysis. CONCLUSIONS: Baseline ALT levels and mALBI grade were significantly associated with improvement in liver function after SVR. Patients whose liver function improved after SVR could have better prognosis.

Multiomics identifies the link between intratumor steatosis and the exhausted tumor immune microenvironment in hepatocellular carcinoma.

BACKGROUND AND AIMS: Immunotherapy has become the standard-of-care treatment for hepatocellular carcinoma (HCC), but its efficacy remains limited. To identify immunotherapy-susceptible HCC, we profiled the molecular abnormalities and tumor immune microenvironment (TIME) of rapidly increasing nonviral HCC. APPROACHES AND RESULTS: We performed RNA-seq of tumor tissues in 113 patients with nonviral HCC and cancer genome sequencing of 69 genes with recurrent genetic alterations reported in HCC. Unsupervised hierarchical clustering classified nonviral HCCs into three molecular classes (Class I, II, III), which stratified patient prognosis. Class I, with the poorest prognosis, was associated with TP53 mutations, whereas class III, with the best prognosis, was associated with cadherin-associated protein beta 1 (CTNNB1) mutations. Thirty-eight percent of nonviral HCC was defined as an immune class characterized by a high frequency of intratumoral steatosis and a low frequency of CTNNB1 mutations. Steatotic HCC, which accounts for 23% of nonviral HCC cases, presented an immune-enriched but immune-exhausted TIME characterized by T cell exhaustion, M2 macrophage and cancer-associated fibroblast (CAF) infiltration, high PD-L1 expression, and TGF-ß signaling activation. Spatial transcriptome analysis suggested that M2 macrophages and CAFs may be in close proximity to exhausted CD8+ T cells in steatotic HCC. An in vitro study showed that palmitic acid-induced lipid accumulation in HCC cells upregulated PD-L1 expression and promoted immunosuppressive phenotypes of cocultured macrophages and fibroblasts. Patients with steatotic HCC, confirmed by chemical-shift MR imaging, had significantly longer PFS with combined immunotherapy using anti-PD-L1 and anti-VEGF antibodies. CONCLUSIONS: Multiomics stratified nonviral HCCs according to prognosis or TIME. We identified the link between intratumoral steatosis and immune-exhausted immunotherapy-susceptible TIME.

Comparison of atezolizumab plus bevacizumab and lenvatinib in terms of efficacy and safety as primary systemic chemotherapy for hepatocellular carcinoma.

AIM: Atezolizumab plus bevacizumab and lenvatinib have each shown efficacy as primary systemic chemotherapies for hepatocellular carcinoma (HCC) in clinical trials. However, comparative trials of these two treatments have not been conducted. This study aimed to compare the therapeutic outcomes of these two treatments. METHODS: This prospectively registered multicenter study analyzed 272 patients with HCC who received atezolizumab plus bevacizumab (the Atezo + Beva group; n = 90) or lenvatinib (the Len group; n = 182) as primary systemic chemotherapy. After propensity score matching (PSM), 66 patients were assigned to each group. RESULTS: After PSM, the median progression-free survival (PFS) was significantly longer in the Atezo + Beva group than in the Len group (8.8 vs. 5.2 months; p = 0.012). No significant differences were noted between the two groups in terms of median overall survival (not reached vs. 20.6 months; p = 0.577), objective response rates (43.8% vs. 52.4%; p = 0.330), and disease control rates (76.6% vs. 82.5%; p = 0.404). The percentage of patients with modified albumin-bilirubin grades of one or 2a was maintained during treatment in the Atezo + Beva group but decreased over time in the Len group. The rate of discontinuation due to adverse events (AEs) was lower in the Atezo + Beva group than in the Len group (12.1% vs. 28.8%; p = 0.018). CONCLUSIONS: Atezolizumab plus bevacizumab showed prolonged PFS, maintained hepatic reserve, and had lower rates of severe AEs compared with that on using lenvatinib as primary systemic chemotherapy for HCC.

Serum Mac-2 binding protein level predicts the development of liver-related events and colorectal cancer in patients with NAFLD.

We previously demonstrated that Mac-2 binding protein (M2BP) is a useful biomarker for nonalcoholic fatty liver disease (NAFLD), particularly NAFLD fibrosis prediction. In the present study, we investigated the prognostic value of M2BP in patients with NAFLD. A total of 506 patients with biopsy-confirmed NAFLD from 2002 to 2013 were enrolled in this study in Japan. Three hundred fifty-three of these patients with NAFLD were available for follow-up for more than 100 days and showed no liver-related events at the time of entry. Liver-related events were defined as hepatocellular carcinoma (HCC), decompensation, and gastroesophageal varices with variceal treatment. The mean follow-up duration of all the subjects was 2716 ± 1621 days (102-7483 days). Eighteen patients developed new liver-related events (HCC, 8; decompensation, 11; varices, 8). Nine patients developed cardiovascular disease (CVD), and 24 patients developed new cancers in other organs. The median serum M2BP level was 1.603 µg/mL, and we divided our cohort into two groups according to the serum M2BP level: M2BP low group (M2BP Low) and M2BP high group (M2BP Hi). The incidence of HCC was significantly higher in M2BP Hi (n = 8) than in M2BP Low (n = 0). The incidence of liver-related events was significantly higher in M2BP Hi (n = 16) than in M2BP Low (n = 2). The incidences of death, CVD events, and cancer in other organs were not different between the groups. Interestingly, the incidence of colorectal cancer was significantly higher in M2BP Hi (n = 5) than in M2BP Low (n = 0). Conclusion: M2BP is a useful biomarker to predict liver-related events, particularly HCC. Additionally, M2BP is a potential predictive biomarker of colorectal cancer development.

Prediction Model for Intrahepatic Distant Recurrence After Radiofrequency Ablation for Primary Hepatocellular Carcinoma 2 cm or Smaller.

BACKGROUND: Intrahepatic hepatocellular carcinoma (HCC) has a high recurrence rate after radiofrequency ablation (RFA). However, to date, no standalone predictive factors for intrahepatic distant recurrence after curative ablation have been reported. AIMS: The aim of this study was to investigate predictive factors for intrahepatic distant recurrence after curative treatment with RFA for HCCs. METHODS: This multicenter study consisted of 17 institutions that registered 821 patients. The risk factors for intrahepatic distant recurrence after complete ablation by RFA for primary HCC ≤ 2 cm in diameter were identified in a retrospectively collected training set (n = 636) and then validated in a prospectively collected validation set (n = 185). RESULTS: The cumulative intrahepatic distant and local recurrence rates (i.e., entire recurrence rate) in the training set were 23.6% and 53.7% at 1 and 3 years, respectively. The cumulative intrahepatic distant recurrence rates in the training set were 17.0% and 43.8% at 1 and 3 years, respectively. Multivariate analysis of the training set showed that tumor number and serum levels of α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) were independent risk factors for both entire recurrence and intrahepatic distant recurrence. Intrahepatic distant recurrence risk in both the training and validation cohorts was stratified using a scoring system with three factors: tumor number (single or multiple), AFP (< 10 ng/ml or ≥ 10 ng/ml), and DCP (< 50 mAU/ml or ≥ 50 mAU/ml). CONCLUSION: The scoring system composed of tumor number, AFP, and DCP is useful for classifying the risk of intrahepatic distant recurrence after curative ablation for HCC.

Interleukin-6 Is a Circulating Prognostic Biomarker for Hepatocellular Carcinoma Patients Treated with Combined Immunotherapy.

Atezolizumab/bevacizumab (Atezo/Bev) combination therapy has become a front-line therapy for advanced hepatocellular carcinoma (HCC), but approximately 20% of patients are nonresponders. We investigated circulating biomarkers to predict therapeutic outcomes. We performed simultaneous measurement of 34 proteins using a multiplex bead-based immunoassay in baseline plasma from 34 patients who underwent Atezo/Bev therapy as first- or second-line treatment. Logistic regression analysis showed that plasma IL-6 and interferon alpha (IFNα) levels were significant predictors of non-responders (odds ratio of 13.33 and FDR p = 0.021 for IL-6 and IFNα). The progression-free survival (PFS) and overall survival (OS) of patients with high IL-6 levels were significantly shorter than those of patients with low IL-6 levels. Next, we measured baseline plasma IL-6 levels in 64 HCC patients who underwent Atezo/Bev therapy by ELISA. The IL-6-high group showed higher female ratio, AST levels, tumor markers, Child-Pugh score, and vascular invasion ratio. The PFS and OS of the IL-6-high group were significantly shorter than those of the IL-6-low group. Multivariate Cox proportional hazards analysis showed that IL-6 level and age were independent risk factors for disease progression (hazard ratio of 2.785 and p = 0.015 for IL-6, and hazard ratio 0.306 and p = 0.03 for age). In conclusion, circulating IL-6 levels are a novel prognostic biomarker for advanced HCC patients who undergo combined immunotherapy.

Serum growth differentiation factor 15 predicts hepatocellular carcinoma occurrence after hepatitis C virus elimination.

BACKGROUND: After hepatitis C virus (HCV) elimination, patients should be followed up due to risk of hepatocellular carcinoma (HCC). Growth differentiation factor 15 (GDF15) is a cytokine induced by mitochondrial dysfunction or oxidative stress. Aim To evaluate the prognostic value of GDF15 for HCC occurrence after HCV elimination. METHODS: We measured GDF15 levels in stored serum from patients with chronic HCV infection without a history of HCC who had achieved sustained virological response with direct-acting antiviral agents (DAAs). The patients were randomly divided into derivation (n = 964) and validation (n = 642) cohorts. RESULTS: In the derivation cohort, serum GDF15 levels were higher in those with HCC occurrence after DAA treatment than in those without. Multivariate Cox proportional hazards analysis revealed baseline GDF15 (>1350 pg/mL, HR 2.54), AFP (>5 ng/mL, HR 2.00), and the FIB-4 index (>3.25, HR 2.69) to be independent risk factors for HCC. Scoring based on GDF15, AFP and the FIB-4 index stratified HCC occurrence risk. In the validation cohort, the cumulative HCC occurrence rate at 3 years was 0.64%, 3.27% and 15.3% in low-score (N = 171), medium-score (N = 300) and high-score (N = 166) groups, respectively. In the total cohort, scoring divided patients with a FIB-4 index ≤3.25, whose HCC occurrence rate was 2.0% at 3 years, into medium-score and low-score groups with HCC occurrence rates at 3 years of 3.76% and 0.24%, respectively. CONCLUSIONS: Serum GDF15 predicts de novo HCC occurrence. Scoring using GDF15, AFP, and the FIB-4 index can predict de novo HCC occurrence risk after HCV elimination.

Hyperprogressive disease in patients with unresectable hepatocellular carcinoma receiving atezolizumab plus bevacizumab therapy.

BACKGROUND: Atezolizumab plus bevacizumab was approved for hepatocellular carcinoma (HCC) patients in 2020, but treatment outcomes of atezolizumab plus bevacizumab in real-world settings remain unclear. Hyperprogressive disease (HPD), an acceleration of tumor growth occurring in some types of malignancies treated with immune checkpoint inhibitors, was assessed in HCC patients receiving atezolizumab plus bevacizumab. METHODS: Tumor growth kinetics (TGK) and tumor growth rate (TGR) were calculated at pre- and post-treatment in 88 Japanese patients with HCC receiving atezolizumab plus bevacizumab. Hyperprogressive disease was defined as progressive disease (PD) with ≥ two-fold increase in TGK and TGR. The association of baseline characteristics with HPD was analyzed. RESULTS: The best objective responses were partial response, stable disease, and PD in 12 (13.6%), 51 (58.0%), and 25 (28.4%) patients, respectively. The median progression-free survival was 5.0 months. Eleven (12.5%) and 9 (10.2%) patients had a TGK ratio and a TGR ratio of ≥2, respectively. Hyperprogressive disease was observed in nine patients (10.2%) and they showed significantly shorter overall survival than patients without HPD (median, 4.3 months vs. not reached; p < 0.001). Patients with HPD had larger and more intrahepatic tumors, higher levels of α-fetoprotein and lactate dehydrogenase, and higher neutrophil-to-lymphocyte ratio (NLR) at baseline than patients without HPD. NLR of ≥3 at baseline was identified as the only independent factor associated with HPD in multivariate analysis. CONCLUSIONS: Hyperprogressive disease was observed in 10.2% of HCC patients receiving atezolizumab plus bevacizumab, and an elevated NLR at baseline had an increased risk of HPD.

The FIB-4 Index Predicts the Development of Liver-Related Events, Extrahepatic Cancers, and Coronary Vascular Disease in Patients with NAFLD.

The prognosis of nonalcoholic fatty liver disease (NAFLD) patients depends on liver-related events (LREs), extrahepatic cancers, and major adverse cardiovascular events (MACEs). The fibrosis-4 (FIB-4) index is one of the most reliable and useful predictors of the degree of liver fibrosis. Recent studies have reported that the FIB-4 index is also useful for predicting LREs and MACEs in NAFLD patients. In the present study, we investigated the prognostic value of the FIB-4 index in NAFLD patients. A total of 506 biopsy-confirmed NAFLD patients from six hepatology centers in Japan from 2002 to 2013 were enrolled in this study. Of these NAFLD patients, 353 were available for more than 100 days of follow-up and did not exhibit events (LREs, extrahepatic cancers, MACEs) at the time of entry. The mean follow-up duration of all the subjects was 2716 ± 1621 days (102-7483 days). New LREs (hepatocellular carcinoma (HCC) (n = 8), decompensation (n = 11), bleeding varices (n = 8)) developed in 18 patients. Twenty-four and twelve patients developed extrahepatic cancers and MACEs, respectively. The median FIB-4 index was 1.255; we divided our cohort into two groups according to this (FIB4 Low, FIB4 Hi). The incidence of HCC tended to be higher in FIB4 Hi (n = 7) than in FIB4 Low (n = 1). The incidence of LREs was significantly higher in FIB4 Hi (n = 17) than in FIB4 Low (n = 1). The incidence of extrahepatic cancers was significantly higher in FIB4 Hi (n = 20) than in FIB4 Low (n = 4); the incidence of MACEs was also significantly higher in FIB4 Hi (n = 10) than in FIB4 Low (n = 2). The FIB-4 index is a useful biomarker for predicting not only LREs but also extrahepatic cancers and MACEs.

Prediction model for hepatocellular carcinoma occurrence in patients with hepatitis C in the era of direct-acting anti-virals.

BACKGROUND: Several factors associated with hepatocellular carcinoma (HCC) occurrence after sustained virological response (SVR) in patients with hepatitis C have been reported. However, few validation studies have been performed in the era of direct-acting anti-virals (DAAs). AIMS: To develop a prediction model for HCC occurrence after DAA-mediated SVR and validate its usefulness. METHODS: We analysed 2209 patients with SVR and without a history of HCC who initiated DAA treatment at 24 Japanese hospitals. These patients were divided into a training set (1473 patients) and a validation set (736 patients). RESULTS: In the training set, multivariate Cox proportional hazards analysis showed that the baseline BMI (≥25.0 kg/m2 , P = 0.024), baseline fibrosis-4 (FIB-4) index (≥3.25, P = 0.001), albumin level at SVR (<4.0 g/dL, P = 0.010) and alpha-foetoprotein level at SVR (≥5.0 ng/mL, P = 0.006) were significantly associated with HCC occurrence. We constructed a prediction model for HCC occurrence with these four factors (2 points were added for the FIB-4 index, and 1 point was added for each of the other three factors). Receiver operating characteristics curve analysis identified a score of 2 as the optimal cut-off value for the prediction model (divided into 0-1 and 2-5). In the validation set, the sensitivity and negative predictive value for HCC occurrence were 87.5% and 99.7%, respectively, at 2 years and 71.4% and 98.0%, respectively, at 3 years. CONCLUSION: A prediction model combining these four factors contributes to an efficient surveillance strategy for HCC occurrence after DAA-mediated SVR.

Management of Hepatocellular Carcinoma in Japan: JSH Consensus Statements and Recommendations 2021 Update.

The Clinical Practice Manual for Hepatocellular Carcinoma was published based on evidence confirmed by the Evidence-based Clinical Practice Guidelines for Hepatocellular Carcinoma along with consensus opinion among a Japan Society of Hepatology (JSH) expert panel on hepatocellular carcinoma (HCC). Since the JSH Clinical Practice Guidelines are based on original articles with extremely high levels of evidence, expert opinions on HCC management in clinical practice or consensus on newly developed treatments are not included. However, the practice manual incorporates the literature based on clinical data, expert opinion, and real-world clinical practice currently conducted in Japan to facilitate its use by clinicians. Alongside each revision of the JSH Guidelines, we issued an update to the manual, with the first edition of the manual published in 2007, the second edition in 2010, the third edition in 2015, and the fourth edition in 2020, which includes the 2017 edition of the JSH Guideline. This article is an excerpt from the fourth edition of the HCC Clinical Practice Manual focusing on pathology, diagnosis, and treatment of HCC. It is designed as a practical manual different from the latest version of the JSH Clinical Practice Guidelines. This practice manual was written by an expert panel from the JSH, with emphasis on the consensus statements and recommendations for the management of HCC proposed by the JSH expert panel. In this article, we included newly developed clinical practices that are relatively common among Japanese experts in this field, although all of their statements are not associated with a high level of evidence, but these practices are likely to be incorporated into guidelines in the future. To write this article, coauthors from different institutions drafted the content and then critically reviewed each other's work. The revised content was then critically reviewed by the Board of Directors and the Planning and Public Relations Committee of JSH before publication to confirm the consensus statements and recommendations. The consensus statements and recommendations presented in this report represent measures actually being conducted at the highest-level HCC treatment centers in Japan. We hope this article provides insight into the actual situation of HCC practice in Japan, thereby affecting the global practice pattern in the management of HCC.

Lower Serum Sodium Levels Are Associated with the Therapeutic Effect of Sorafenib on Hepatocellular Carcinoma.

BACKGROUND AND AIM: Although the serum sodium level has been reported to be a prognostic and predictive marker for the therapeutic effects of lung cancer and renal cell carcinoma treated with molecular targeted therapy, the serum sodium level has not been investigated in hepatocellular carcinoma (HCC) patients treated with sorafenib. The aim of our analysis was to assess the prognostic role of serum sodium levels in these patients. METHODS: We retrospectively analyzed 341 HCC patients treated with sorafenib between 2009 and 2012 in our hospital and other related institutions. RESULTS: A total of 178 patients were enrolled in this study. The median age was 72 years (44-88), and 148 patients (83%) were male. The median overall survival (OS) was 12.9 months, and the median time to progression (TTP) was 3.1 months. Hyponatremia (hazard ratio (HR) 1.78, 95% confidence interval (CI) 1.26-2.52), a lower sodium level (HR 1.57, 95% CI 1.07-2.80), and a high level of α-fetoprotein (AFP) (≥ 200 ng/mL) (HR 1.78, 95% CI 1.26-2.52) were independent prognostic factors for TTP. We also categorized the patients into three groups according to serum sodium and AFP levels: Group A (n = 39) (serum sodium > 140 mEq/L, AFP < 200 ng/mL), Group C (n = 58) (serum sodium ≤ 140 mEq/L, AFP ≥ 200 ng/mL), and Group B (n = 81) (other patients). Significantly longer TTP and OS were observed in the following order: Groups A, C, and B. CONCLUSION: Serum sodium levels are associated with the effectiveness of sorafenib. The serum sodium level can predict the therapeutic effect of sorafenib in advanced HCC patients.

Primary adenosquamous carcinoma of the liver detected during cancer surveillance in a patient with primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is associated with significant risk for hepatobiliary cancers. Primary hepatic adenosquamous carcinoma (ASC), a rare subtype of cholangiocarcinoma, is composed of both adenocarcinoma and squamous cell carcinoma components. We herein report the case of a patient with PSC who was diagnosed with ASC of the liver during cancer surveillance. A 74-year-old male patient was diagnosed with PSC based on blood chemistry and magnetic resonance cholangiopancreatography findings, and regular surveillance for hepatobiliary cancers was initiated. Four years later, the level of carbohydrate antigen 19-9 rapidly increased, and abdominal imaging studies revealed a cystic mass, 40 mm in diameter, containing a solid component in the right liver lobe. Right lobectomy was performed with a pre-operative diagnosis of cholangiocarcinoma; however, the definitive diagnosis was ASC based on the presence of adenocarcinoma and squamous cell carcinoma components in the resected tumor. The patient did not receive post-operative chemotherapy, but was alive for more than 4 years without recurrence at last follow-up. The present case illustrates that regular surveillance and curative resection might achieve long-term survival in hepatic ASC, which has a poor prognosis.

Initial treatment response to transarterial chemoembolization as a predictive factor for Child-Pugh class deterioration prior to refractoriness in hepatocellular carcinoma.

AIM: Repeated transarterial chemoembolization (TACE) for intermediate-stage hepatocellular carcinoma (HCC) eventually leads to either deteriorated hepatic reserve or TACE refractoriness. Switching to molecular targeted agents after TACE requires preservation of hepatic reserve. This study aimed to investigate the predictive factors associated with early deterioration of hepatic reserve by repeated TACE prior to refractoriness. METHODS: Ninety-three patients with intermediate-stage HCC who underwent TACE as the first-line treatment and had a Child-Pugh class A hepatic reserve were retrospectively analyzed. The time to Child-Pugh class deterioration (TTCPD), defined as the duration from initial TACE to the diagnosis of Child-Pugh class B or C prior to TACE refractoriness, was assessed. Patients who progressed to TACE refractoriness prior to Child-Pugh class deterioration were censored at TACE refractoriness. RESULTS: The radiological response to initial TACE was assessed as responders and non-responders in 59 (63.4%) and 34 (36.6%) patients, respectively. The median TTCPD was 40.6 months in all patients. The hepatic reserve in 31 (33.3%) patients deteriorated to Child-Pugh class B or C prior to TACE refractoriness. In the multivariate analysis, non-response to initial TACE, albumin-bilirubin grade 2, and non-selective TACE were identified as independent predictors associated with a shortened TTCPD. The TTCPD was significantly shorter in the non-responders than in the responders to initial TACE (median, 19.6 vs. 55.9 months; P < 0.001). CONCLUSIONS: Failure to respond to initial TACE was a predictive factor for early deterioration of hepatic reserve prior to TACE refractoriness in intermediate-stage HCC patients with repeated TACE.

Clinical outcomes of direct-acting antiviral treatments for patients with hepatitis C after hepatocellular carcinoma are equivalent to interferon treatment.

AIM: It remains unclear how direct-acting antiviral (DAA) treatments influence hepatocellular carcinoma (HCC) recurrence and survival in comparison with interferon (IFN). METHODS: In total, 338 patients with chronic hepatitis C virus (HCV) infection and previous HCC treatments who initiated IFN (N = 88, IFN group) or DAA treatment (N = 250, DAA group) from January 2005 to November 2017 at 23 hospitals and achieved sustained virologic response (SVR) were analyzed. Cumulative HCC recurrence and survival rates were compared between the two groups using propensity score (PS) matching. RESULTS: After PS matching, 63 patients were selected for each group. The cumulative HCC recurrence rates at 1 and 3 years were 20.6% and 34.6% in the IFN group and 19.2% and 43.0% in the DAA group, respectively; the difference in cumulative HCC recurrence rates between the two groups was not significant (P = 0.332). No significant differences in HCC recurrence patterns were observed between the two groups. Overall survival rates at 1 and 3 years were 100% and 96.6% in the IFN group and 100% and 96.4% in the DAA group, respectively; the difference in overall survival rates between the two groups was not significant (P = 0.132). No significant differences in HCC recurrence and overall survival rates were observed between the two groups in subgroup analyses of patients receiving curative treatment (liver resection or radiofrequency ablation) for the most recent HCC before HCV treatment. CONCLUSIONS: The recurrence rates and patterns of HCC and overall survival rates do not differ between SVR patients receiving IFN and DAA treatments.

Pre-existing minor variants with NS5A L31M/V-Y93H double substitution are closely linked to virologic failure with asunaprevir plus daclatasvir treatment for genotype 1b hepatitis C virus infection.

BACKGROUND: L31 and Y93 in the NS5A region of the hepatitis C virus (HCV) are the most important substitution positions associated with resistance to direct-acting antiviral (DAA) treatment. METHODS: We analyzed the frequency of NS5A L31M/V and Y93/H in NS5A inhibitor-naive HCV genotype 1 patients who received asunaprevir plus daclatasvir combination treatment using a conventional sequencing method and a deep sequencing method that can distinguish a single substitution at either position and a double substitution at both positions with a 0.1% detection threshold. RESULTS: The frequency of substitutions at both sites using the conventional method was very low, with 1 in 14 non-responders and 0 in 42 randomly selected responder patients. On the other hand, for the deep sequencing method, cases with double substitutions in the tandem sequence were detected in 8/14 non-responders and 1/42 responders (p<0.0001). For the conventional method, substitutions were detected at any position in 6/14 non-responders and 2/42 responders (p = 0.0019), with a clear difference between the two groups. The difference was also clear with the deep sequencing method, with 11/14 non-responders and 8/42 responders. Interestingly, for the deep sequencing method, the single substitution of L31 was found in 6/14 non-responders and 7/42 responders, whereas single substitutions of Y93 or double substitutions were found in 7/14 vs. 1/42 and 8/14 vs. 1/42 patients, respectively. CONCLUSIONS: NS5A L31 and Y93 substitutions were detected in tandem by the deep sequencing methods in several genotype 1 patients, who may be more resistant to DAA treatment containing an NS5A inhibitor.