Sorafenib vs. Lenvatinib in advanced hepatocellular carcinoma after Atezolizumab/Bevacizumab Failure: A real-world study.

Background: Atezolizumab plus bevacizumab (ATE+BEV) therapy has become the recommended first-line therapy for patients with unresectable hepatocellular carcinoma (HCC) because of favorable treatment responses. However, there is a lack of data on sequential regimens after ATE+BEV treatment failure. We aimed to investigate the clinical outcomes of patients with advanced HCC who received subsequent systemic therapy for disease progression after ATE+BEV. Methods: This multicenter, retrospective study included patients who started second-line systemic treatment with sorafenib or lenvatinib after HCC progressed on ATE+BEV between August 2019 and December 2022. Treatment response was assessed using the Response Evaluation Criteria in Solid Tumors (version 1.1.). Clinical features of the two groups were balanced through propensity score (PS) matching. Results: This study enrolled 126 patients, 40 (31.7%) in the lenvatinib group, and 86 (68.3%) in the sorafenib group. The median age was 63 years, and males were predominant (88.1%). In PS-matched cohorts (36 patients in each group), the objective response rate was similar between the lenvatinib- and sorafenib-treated groups (5.6% vs. 8.3%; p=0.643), but the disease control rate was superior in the lenvatinib group (66.7% vs. 22.2%; p<0.001). Despite the superior progression-free survival (PFS) in the lenvatinib group (3.5 vs. 1.8 months, p=0.001), the overall survival (OS, 10.3 vs. 7.5 months, p=0.353) did not differ between the two PS-matched treatment groups. Conclusion: In second-line therapy for unresectable HCC after ATE+BEV failure, lenvatinib showed better PFS and comparable OS to sorafenib in a real-world setting. Future studies with larger sample sizes and longer follow-ups are needed to optimize second-line treatment.

Extrahepatic Malignancies Are the Leading Cause of Death in Patients with Chronic Hepatitis B without Cirrhosis: A Large Population-Based Cohort Study.

(1) Background: Accurate statistics on the causes of death in patients with chronic hepatitis B (CHB) are lacking. We investigated mortality rates and causes of death over time. (2) Methods: Data on patients newly diagnosed with CHB from 2007 to 2010 (cohort 1, n = 223,424) and 2012 to 2015 (cohort 2, n = 177,966) were retrieved from the Korean National Health Insurance Service. Mortality data were obtained from Statistics Korea. The causes of death were classified as liver-related (hepatic decompensation or hepatocellular carcinoma [HCC]) or extrahepatic (cardiovascular-related, cerebrovascular-related, or extrahepatic malignancy-related). (3) Results: Over a 10-year follow-up period of 223,424 patients (cohort 1) with CHB, the overall mortality was 1.54 per 100 person-years. The mortality associated with HCC was the highest (0.65 per 100 person-years), followed by mortality related to extrahepatic malignancies (0.26 per 100 person-years), and cardio/cerebrovascular diseases (0.18 per 100 person-years). In the non-cirrhotic CHB (87.4%), 70% (11,198/15,996) of patients died due to non-liver-related causes over ten years. The 10-year overall mortality was 0.86 per 100 person-years. Among these, mortality due to extrahepatic malignancies had the highest rate (0.23 per 100 person-years), followed by mortality related to HCC (0.20 per 100 person-years), and cardio/cerebrovascular diseases (0.16 per 100 person-years). The 5-year mortality associated with extrahepatic malignancies increased from 0.36 per 100 person-years (cohort 1) to 0.40 per 100 person-years (cohort 2). (4) Conclusions: Mortality related to HCC decreased, whereas mortality related to extrahepatic malignancies increased in the antiviral era. Extrahepatic malignancies were the leading cause of death among patients with CHB without cirrhosis.

The care cascade for hepatitis C virus and prognosis of chronic hepatitis C patients treated with antiviral agents in a tertiary hospital.

BACKGROUND: Some studies have analyzed the frequency of HCV RNA testing and actual treatment among anti-HCV positive patients in Korea, which has a low prevalence of HCV infection. This study aimed to analyze the diagnosis process, treatment results, and prognosis according to care cascade in patients who are anti-HCV positive. METHODS: Three thousand two hundred fifty-three anti-HCV positive patients presented to a tertiary hospital between January 2005 and December 2020. The number of patients who underwent HCV RNA testing, treatment, and proportion of sustained virologic response (SVR) according to the type of antivirals was investigated. We investigated the cumulative incidence of hepatocellular carcinoma (HCC) and liver cirrhosis. RESULTS: Of a total of 3,253 people, 1,177 (36.2%) underwent HCV RNA testing and 858 (72.9%) were positive for HCV RNA. 494 (57.6%) of HCV RNA positive patients received antiviral treatment, and 443 (89.7%) of initiated hepatitis C treatment experienced SVR. Of the 421 treated patients, 16 (14.2%) developed HCC. The cumulative incidence of HCC at 15 years was significantly different according to the presence of liver cirrhosis (10/83, 29.5% vs. 6/338, 10.8%, p < 0.001). The cumulative incidences of HCC or liver cirrhosis did not show significant differences according to the presence of SVR12 (14/388, 13.2% vs. 2/33, 52.5%, p = 0.084, 21/319, 15.0%, vs. 3/22, 28.7%, p = 0.051). CONCLUSIONS: Owing to the introduction of direct-acting antivirals, high SVR12 was achieved, but the proportion of anti-HCV positive patients who received HCV RNA testing and treatment was not high. HCC surveillance after SVR12 is recommended for chronic hepatitis C patients with cirrhosis.

A phase 2, open-label, randomized, multiple-dose study evaluating Inarigivir in treatment-naïve patients with chronic hepatitis B.

BACKGROUND/AIMS: Novel agents acting against hepatitis B virus (HBV) are needed to improve HBsAg seroclearance or termed as 'functional cure'. Inarigivir (retinoic acid-inducible gene I agonist) has immunomodulatory and direct antiviral actions against HBV. We aimed to determine the safety and efficacy of Inarigivir for the treatment of HBV infection. PATIENTS/METHODS: 80 treatment-naïve patients were randomized in 4 ascending dose cohorts to receive 12 weeks of Inarigivir 25, 50, 100, 200 mg or placebo in a ratio of 4:1. All patients were then given tenofovir for another 12 weeks. RESULTS: Least squares (LS) mean reductions in HBV DNA from baseline increased with higher doses of Inarigivir (0.6116 in 25 mg and 1.5774 in 200 mg groups vs. 0.0352 in placebo group) (95% CI 0.9518-0.2011 and 1.921-1.1634 respectively). LS mean changes in HBV RNA and HBsAg from baseline ranged from -0.3856 to -0.5794 versus -0.1474 and -0.0956 to -0.1818 versus +0.0026 in Inarigivir-treated versus placebo groups respectively. During the tenofovir-treated period, LS mean reductions in HBsAg in the Inarigivir-treated groups ranged from 0.1709 to 0.3529 versus 0.1984 in the placebo group. Inarigivir-treated groups showed mean reductions in ALT from baseline between 23.3 and 33.8 versus 0.7 U/L in the placebo group. Treatment-emergent adverse events related to Inarigivir and placebo occurred in 4.7% and 6.3% patients respectively. CONCLUSIONS: Twelve-week Inarigivir up to 200 mg dose was associated with a reduction of HBV DNA, HBV RNA and antigen levels. A trend for greater HBsAg reduction was observed in Inarigivir pre-treated patients after switching to tenofovir.

Baseline and on-treatment HBcrAg levels as predictors of HBeAg seroconversion in chronic hepatitis B patients treated with antivirals.

HBeAg seroconversion is an important treatment endpoint. We aimed to identify predictors of seroconversion using serum HBsAg and hepatitis B core-related antigen (HBcrAg) in HBeAg-positive patients treated with nucleos(t)ide analogs (NAs). Data and samples from 70 HBeAg-positive patients treated with entecavir or tenofovir between January 2007 and December 2017 were retrospectively analysed. The mean follow-up period was 11 years. The predictive power for HBeAg seroconversion of HBcrAg levels at baseline and 2 years after antiviral therapy was determined using receiver operating curve analysis. Twenty-one patients (30%) achieved HBeAg seroconversion at a mean of 28 (range, 12-84) months after antiviral treatment. The median baseline HBcrAg and HBsAg levels were 6.9(5.7-7.0) vs. 5.8(5.5-6.5) log10 U/mL (p = .006), 4.9(4.5-5.1) vs. 4.5(4.1-5.0) log10 IU/mL (p = .044) in the no seroconversion group and seroconversion group, respectively. In the multivariate analysis, the serum HBcrAg levels at baseline and 2 years after antiviral therapy were predictive factors for HBeAg seroconversion ([HR]; 0.326; [CI], 0.111-0.958; p = .042 and HR, 0.4555; CI, 0.211-0.984; p = .045). HBcrAg levels≤6.5log10 U/mL at baseline and ≤5.3log10 U/mL at 2 years after antiviral therapy had sensitivities of 53.1% and 69.8%, specificities of 95.2% and 70.6%, positive predictive values of 82.6% and 50.0%, and negative predictive values of 82.6% and 84.5%, respectively, with AUROCs of 0.712 (95%CI, 0.596-0.830) and 0.745 (95%CI, 0.599-0.891) for predicting HBeAg seroconversion. In chronic hepatitis B patients treated with NAs, HBcrAg levels≤6.5log10 U/mL at baseline and ≤5.3log10 U/mL at 2 years after antiviral therapy were useful predictive factors of HBeAg seroconversion.

MAFLD Predicts the Risk of Cardiovascular Disease Better than NAFLD in Asymptomatic Subjects with Health Check-Ups.

BACKGROUND AND AIM: Metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed to compensate for the conventional concept of nonalcoholic fatty liver disease (NAFLD). We investigated the superiority of MAFLD versus NAFLD in predicting the risk of atherosclerotic cardiovascular disease (ASCVD). METHODS: A total of 2,144 subjects without a history of ASCVD, who underwent a comprehensive medical health check-up, were selected for the study. The associations between fatty liver status and coronary risk surrogates, such as coronary artery calcium score (CACS), coronary artery disease, quantitative stenosis grade, and 10-year ASCVD risk, were analyzed. RESULTS: MAFLD and NAFLD were identified in 995 (46.4%) and 891 (41.6%) subjects, respectively. Subjects with MAFLD or NAFLD were more likely to be male and had a significantly higher prevalence of central obesity, obesity, hypertension, diabetes, and dyslipidemia (all, p < 0.05) than their counterparts. In terms of coronary risk surrogates, the MAFLD or NAFLD population had a significantly higher proportion of subjects with CACS > 100, coronary artery disease, higher grade of coronary artery stenosis, and higher 10-year ASCVD risk (all, p < 0.05) than their counterparts. Multivariable logistic regression models showed an independent association between MAFLD/NAFLD and coronary risk surrogates (all, p < 0.05). However, NAFLD only, defined as 'NAFLD, but not MAFLD,' was not associated with an increased coronary risk, compared to MAFLD. CONCLUSIONS: Although both MAFLD and NAFLD discriminated different ASCVD risks, MAFLD predicted the risk of ASCVD better than NAFLD in asymptomatic subjects who underwent medical health check-ups.

Long-term survival after CCRT and HAIC followed by ALPPS for hepatocellular carcinoma with portal vein invasion: a case report.

There are various methods for treating advanced hepatocellular carcinoma with portal vein invasion, such as systemic chemotherapy, transarterial chemoembolization, transarterial radioembolization, and concurrent chemoradiotherapy. These methods have similar clinical efficacy but are designed with a palliative aim. Herein, we report a case that experienced complete remission through "associating liver partition and portal vein ligation for staged hepatectomy (ALPPS)" after concurrent chemoradiotherapy and hepatic artery infusion chemotherapy. In this patient, concurrent chemoradiotherapy and hepatic artery infusion chemotherapy induced substantial tumor shrinkage, and hypertrophy of the nontumor liver was sufficiently induced by portal vein ligation (stage 1 surgery) followed by curative resection (stage 2 surgery). Using this approach, long-term survival with no evidence of recurrence was achieved at 16 months. Therefore, the optimal use of ALPPS requires sufficient consideration in cases of significant hepatocellular carcinoma shrinkage for curative purposes.

Anti-HBc IgG Levels: A Predictor of HBsAg Seroclearance in Chronic Hepatitis B Patients with Nucleos(t)ide Analogue-Induced HBeAg Seroclearance.

BACKGROUND/AIMS: We investigated the efficiency of the indirect ratio of anti-HBc IgG at predicting HBsAg seroclearance in patients with nucleos(t)ide analogue (NA)-induced HBeAg seroclearance. METHODS: We performed a retrospective study that included 366 chronic hepatitis B patients (March 2007 to December 2016) at a single tertiary hospital. These patients were HBsAg seropositive, and experienced NA-induced HBeAg seroclearance. The indirect ratio of light absorbance of anti-HBc IgG levels were measured with chemiluminescent microparticle immunoassay using the Architect Anti-HBc assay (Abbott Laboratories, IL, USA) as a qualitative method prior to antiviral therapy. We calculated the cumulative incidences of HBsAg seroclearance based on the anti-HBc IgG levels. RESULTS: After a 10-year follow-up, 48 patients experienced HBsAg seroclearance (13.1%). Thirty-three of 179 patients who had an indirect ratio of light absorbance of anti-HBc IgG < 11 RLU (relative light unit) showed HBsAg seroclearance (18.4%); 15 of 187 patients who had an indirect ratio of light absorbance of anti-HBc IgG ≥ 11 RLU showed HBsAg seroclerance (8.0%) (p = 0.003). In multivariate analysis, age, and ALT at the time of HBeAg seroclearance were predictors of HBsAg seroclearance. Especially, the relative risk of HBsAg seroclearance in patients with baseline anti-HBc IgG levels < 11 RLU was 2.213 (95% CI, 1.220-4.014), compared to that in patients with higher levels of anti-HBc IgG at baseline (p = 0.009). CONCLUSION: Using an indirect method for anti-HBc IgG levels, baseline anti-HBc IgG levels (< 11RLU), age (≥ 50 years), and ALT (≥ 40 IU/L) might be associated with HBsAg seroclearance in patients with NA-induced HBeAg seroclearance.

Risk assessment of hepatocellular carcinoma and liver-related events using ultrasonography and transient elastography in patients with chronic hepatitis B.

Cirrhosis has prognostic value. We investigated whether the combined use of ultrasonography (US) and transient elastography (TE) to diagnose cirrhosis is beneficial for the risk assessment of hepatocellular carcinoma (HCC) and liver-related events in patients with chronic hepatitis B (CHB). A total of 9300 patients with CHB who underwent US and TE in two institutions between 2006 and 2018 were enrolled. TE value ≥13 kPa was set to indicate cirrhosis. Patients were divided into four groups: US(+)TE(+) (cirrhosis by US and TE), US(+)TE(-) (cirrhosis by US, but not by TE), US(-)TE(+) (cirrhosis by TE, but not by US) and US(-)TE(-) (non-cirrhosis by US and TE).The patients were predominantly male (n = 5474, 58.9%) with a mean age of 47.5 years. The proportions of patients with cirrhosis diagnosed by US and TE were 17.2% (n = 1595) and 13.2% (n = 1225), respectively. The proportion of patients with discordant results in diagnosing cirrhosis by US and TE was 18.7% (n = 1740). During follow-up (median: 60.0 months), HCC and liver-related events developed in 481 (5.2%) and 759 (8.2%) patients, respectively. The cumulative incidence rates of HCC and liver-related events were highest in the US(+)TE(+) group, intermediate-high in the US(-)TE(+) group, intermediate-low in the US(+)TE(-) group and lowest in the US(-)TE(-) group (overall p < .001). Cirrhosis assessed using US and TE was a major predictor of HCC and liver-related event development in patients with CHB. Cirrhosis assessed using TE seemed better in predicting HCC or liver-related events than using US, when cirrhosis diagnosis was discordant by US and TE.

Continuing besifovir dipivoxil maleate versus switching from tenofovir disoproxil fumarate for treatment of chronic hepatitis B: Results of 192-week phase 3 trial.

BACKGROUND/AIMS: Besifovir dipivoxil maleate (BSV), an acyclic nucleotide phosphonate, shows potent antiviral activity against hepatitis B virus. Our previous 48-week trial revealed that BSV has comparable antiviral efficacy to tenofovir disoproxil fumarate (TDF) and better safety profiles in terms of improved renal and bone safety. This extension study evaluated the prolonged efficacy and safety of BSV in treatment-naive chronic hepatitis B patients. METHODS: Patients continued to participate in an open-label BSV study after an initial 48-week double-blind comparison of BSV and TDF treatment. The antiviral efficacy and drug safety was evaluated up to 192 weeks in two groups: patients continuing BSV treatment (BSV-BSV) and patients switching from TDF to BSV after 48 weeks (TDF-BSV). RESULTS: Among 197 patients receiving randomized treatments, 170 (86%) entered the open-label phase and 152 (77%) entered the 192-week extension study. Virological response rates over 192 weeks were 92.50% and 93.06% in the BSV-BSV and TDF-BSV groups, respectively (P=0.90). Hepatitis B envelop antigen seroconversion and alanine aminotransferase normalization rates were similar between the groups (P=0.75 and P=0.36, respectively). There were no drug-resistant mutations to BSV. Bone mineral density and renal function were well preserved in the BSV-BSV group, whereas these initially worsened then recovered after switching therapy in the TDF-BSV group. CONCLUSION: BSV maintained potent antiviral efficacy after 192 weeks and showed no evidence of drug resistance. BSV was safe, well tolerated, and effective in patients who switched from TDF to BSV. Trial Registration Number: NCT01937806 (date: 10 Sep 2013).

Effects of Statin Use on the Development and Progression of Nonalcoholic Fatty Liver Disease: A Nationwide Nested Case-Control Study.

INTRODUCTION: The use of statins in nonalcoholic fatty liver disease (NAFLD) may reduce cardiovascular morbidity, although their effect on NAFLD itself is not well known. We aimed to investigate the role of statins on the development of de novo NAFLD and progression of significant liver fibrosis. METHODS: This study included 11,593,409 subjects from the National Health Information Database of the Republic of Korea entered in 2010 and followed up until 2016. NAFLD was diagnosed by calculating fatty liver index (FLI), and significant liver fibrosis was evaluated using the BARD score. Controls were randomly selected at a ratio of 1:5 from individuals who were at risk of becoming the case subjects at the time of selection. RESULTS: Among 5,339,901 subjects that had a FLI < 30 and included in the non-NAFLD cohort, 164,856 subjects eventually had NAFLD developed. The use of statin was associated with a reduced risk of NAFLD development (adjusted odds ratio [AOR] 0.66; 95% confidence interval [CI] 0.65-0.67) and was independent of associated diabetes mellitus (DM) (with DM: AOR 0.44; 95% CI 0.41-0.46, without DM: AOR 0.71; 95% CI 0.69-0.72). From 712,262 subjects with a FLI > 60 and selected in the NAFLD cohort, 111,257 subjects showed a BARD score ≥ 2 and were defined as liver fibrosis cases. The use of statins reduced the risk of significant liver fibrosis (AOR 0.43; 95% CI 0.42-0.44), independent of DM (with DM: AOR 0.31; 95% CI 0.31-0.32, without DM: AOR 0.52; 95% CI 0.51-0.52). DISCUSSION: In this large population-based study, statin use decreased the risk of NAFLD occurrence and the risk of liver fibrosis once NAFLD developed.

Dynamics of liver stiffness-based risk prediction model during antiviral therapy in patients with chronic hepatitis B.

OBJECTIVE: The liver stiffness-based risk prediction models predict hepatocellular carcinoma (HCC) development. We investigated the influence of antiviral therapy (AVT) on liver stiffness-based risk prediction model in patients with chronic hepatitis B (CHB). METHODS: Patients with CHB who initiated AVT were retrospectively recruited from 13 referral Korean institutes. The modified risk estimation for hepatocellular carcinoma in chronic hepatitis B (mREACH-B) model was selected for the analysis. RESULTS: Between 2007 and 2015, 1034 patients with CHB were recruited. The mean age of the study population (639 men and 395 women) was 46.8 years. During AVT, the mREACH-B score significantly decreased from the baseline to 3 years of AVT (mean 9.21 → 7.46, P < 0.05) and was maintained until 5 years of AVT (mean 7.23, P > 0.05). The proportion of high-risk patients (mREACH-B score ≥11) was significantly reduced from the baseline to 2 years of AVT (36.4% → 16.4%, P < 0.001) and was maintained until 5 years of AVT (12.2%, P > 0.05). The mREACH-B scores at baseline and 1 year of AVT independently predicted HCC development (hazard ratio = 1.209-1.224) (all P < 0.05). The cumulative incidence rate of HCC was significantly different at 5 years of AVT among risk groups (high vs. high-intermediate vs. low-intermediate vs. low) from baseline (4.5% vs. 3.2% vs. 1.5% vs. 0.8%) and 1 year (11.8% vs. 4.6% vs. 1.8% vs. 0.6%) (all P < 0.05, log-rank tests). CONCLUSIONS: The mREACH-B score was dynamically changed during AVT. Thus, repeated assessment of the mREACH-B score is required to predict the changing risk of HCC development in patients with CHB undergoing AVT.

Phase I Radiation Dose-Escalation Study to Investigate the Dose-Limiting Toxicity of Concurrent Intra-Arterial Chemotherapy for Unresectable Hepatocellular Carcinoma.

Concurrent intra-arterial chemotherapy and radiotherapy (iA-CCRT) can increase the response rate in hepatocellular carcinoma (HCC), but may cause a higher toxicity. We conducted this Phase I study to investigate the dose-limiting toxicity of iA-CCRT for HCC. In total, 52.5 Gy in 25 fractions was prescribed as planning target volume (PTV) 1 at dose level 1. The dose escalation was 0.2 Gy per fraction and up to 2.5 Gy, with 62.5 Gy at level 3. Concurrent intra-arterial 5-fluorouracil was administered during the first and fifth weeks of radiotherapy (RT). Toxicities were graded using the Common Toxicity Criteria for Adverse Events, version 4.0. Results: Seventeen patients with HCC were analyzed: four at dose level 1, 6 at level 2, and 7 at level 3. The mean irradiated dose administered to the uninvolved liver at each dose level was 21.3, 21.6, and 18.2 Gy, respectively. There was no grade ≥3 gastrointestinal toxicity; two patients experienced grade 3 hyperbilirubinemia. All patients had Child-Pugh class A disease, but 3 patients developed class B disease after iA-CCRT. During a median follow-up of 13 months, the median progression-free survival (PFS) and overall survival (OS) were 10 and 22 months, respectively. Patients treated at dose level 3 showed improved PFS and OS. Conclusions: Radiation dose escalation of iA-CCRT did not cause any significant toxicities in patients with advanced HCC. Further large-scale studies with long-term follow-up are needed to determine the efficacy and feasibility of higher doses of iA-CCRT.

Besifovir Dipivoxil Maleate 144-Week Treatment of Chronic Hepatitis B: An Open-Label Extensional Study of a Phase 3 Trial.

INTRODUCTION: Chronic hepatitis B (CHB) remains a major worldwide public health concern. Besifovir dipivoxil maleate (BSV) is a new promising treatment for CHB. However, long-term efficacy and safety have not yet been evaluated. Therefore, the goal of the study is to determine the antiviral efficacy and safety of BSV treatment over a 144-week duration (BSV-BSV) in comparison with those of a sequential treatment with tenofovir disoproxil fumarate (TDF) followed by a 96-week duration BSV administration (TDF-BSV). METHODS: After 48 weeks of a double-blind comparison between BSV and TDF treatments, patients continued the open-label BSV study. We evaluated antiviral efficacy and drug safety up to 144 weeks for BSV-BSV and TDF-BSV groups. The primary endpoint was a virological response (hepatitis B virus DNA < 69 IU/mL). RESULTS: Among the 197 patients enrolled, 170 and 158 patients entered the second-year and third-year open-label phase extensional study, respectively, whereas 153 patients completed the 144-week follow-up. The virological response rate over the 144-week period was 87.7% and 92.1% in BSV-BSV and TDF-BSV groups, respectively (P = 0.36). The rates of ALT normalization and HBeAg seroconversion were similar between the groups. No drug-resistant mutations to BSV were noted. Bone mineral density and renal function were well preserved in the BSV-BSV group and were significantly improved after switching therapy in TDF-BSV patients. DISCUSSION: This extensional study of a phase 3 trial (NCT01937806) suggests that BSV treatment is efficacious and safe for long-term use in treatment-naïve and TDF-experienced patients with CHB.

Extremely low risk of hepatocellular carcinoma development in patients with chronic hepatitis B in immune-tolerant phase.

BACKGROUND: Anti-viral therapy is not indicated for patients with chronic hepatitis B (CHB) in the immune-tolerant phase. AIMS: To investigate the cumulative incidence of phase change and hepatocellular carcinoma (HCC) and independent predictors for phase change in patients with CHB in immune-tolerant phase. METHODS: In total, 946 patients in immune-tolerant phase, defined as hepatitis B e antigen positivity, HBV-DNA >20 000 IU/mL and alanine aminotransferase (ALT) ≤40 IU/L, between 1989 and 2017 were enrolled from eight institutes. RESULTS: The mean age of study population (429 men and 517 women) was 36.7 years. The mean ALT and HBV-DNA levels were 24.6 IU/L and 8.50 log10 IU/mL, respectively. Of the study population, 476 (50.3%) patients remained in immune-tolerant phase throughout the study period (median: 63.6 months). The cumulative incidence rates of phase change and HCC at 10 years were 70.7% and 1.7%, respectively. Multivariate analyses revealed that HBV-DNA level >107  IU/mL was associated independently with a reduced risk of phase change (hazard ratio [HR] = 0.734, P = 0.008), whereas a high ALT level, above the cut-off recommended in the Korean Association for the Study of the Liver guidelines (34 IU/L for men and 30 IU/L for women), was associated independently with a greater risk of phase change (HR = 1.885, P < 0.001). CONCLUSIONS: The criterion of HBV-DNA level > 107  IU/mL may be useful to define immune-tolerant phase. In addition, an extremely low risk of HCC development was observed in patients with CHB in immune-tolerant phase.

Cumulative incidence of hepatocellular carcinoma and hepatitis B surface antigen Seroclearance after Nucleos(t) ide analogue-induced hepatitis B e antigen Seroclearance.

BACKGROUND: Hepatitis B e antigen (HBeAg) seroclearance has been considered as the treatment endpoint in HBeAg-positive patients with chronic hepatitis B (CHB). Although HBeAg seroclearance has been accomplished, some aspects are yet unclear. We investigated the cumulative incidence of hepatocellular carcinoma (HCC) and evaluated hepatitis B surface antigen (HBsAg) seroclearance in patients undergoing nucleos(t) ide analogue (NA)-induced HBeAg seroclearance. METHODS: In this retrospective cohort study, 203 patients with CHB were HBsAg and HBeAg seropositive before NA (entecavir or tenofovir) treatment. All patient who experienced NA -induced HBeAg seroclearance were recruited. Patients with documented HBeAg seroclearance were followed-up every 6 months. Baseline characteristics and laboratory results were recorded. RESULTS: The mean age at HBeAg seroclearance was 40 years (range, 20-84), and the mean follow-up duration was 5 years (range, 2-11). The cumulative incidence of HCC was 1.5 to 11.5% at 1 to 8 years after HBeAg seroclearance. Cirrhosis was the only significant factor for HCC development (hazard ratio [HR], 24.651; confidence interval [CI], 3.018 to 201.365; P = 0.003). The cumulative incidence of HBsAg seroclearance was 3.5 to 18.7% after 1 to 8 years from HBeAg seroclearance. CONCLUSIONS: A significant proportion of patients developed HCC after NA-induced HBeAg seroclearance. The presence of liver cirrhosis at the time of HBeAg seroclearance serves as an independent factor for HCC development. Some patients with NA-induced HBeAg seroclearance achieved HBsAg seroclearance.

Value of controlled attenuation parameter in fibrosis prediction in nonalcoholic steatohepatitis.

BACKGROUND: Liver stiffness measurement (LSM) tends to overestimate fibrosis stage in nonalcoholic fatty liver disease (NAFLD). Controlled attenuation parameter (CAP), provided by LSM device, has been introduced for noninvasive quantification of hepatic steatosis. AIM: To determine the role of CAP values in predicting liver fibrosis stage by LSM in nonalcoholic steatohepatitis (NASH). METHODS: One hundred eighty-four patients with biopsy proven NASH had LSM and CAP evaluated at baseline. Among them, 130 patients had 1-year follow up LSM and analyzed for the changes of LSM after pioglitazone or ursodeoxycholic acid (UDCA) treatment. RESULTS: In Kleiner fibrosis stage F0-1, LSM values increased at higher CAP tertile (P = 0.001), and in F2, at middle and higher tertiles (P = 0.027). No difference across CAP tertiles was noticed in F3-4 (P = 0.752). Receiver operating characteristic curve for LSM cutoff in diagnosis of F ≥ 2 identified 8.05 kPa for lower CAP tertile, 9.35 kPa for middle, and 10.55 kPa for high tertile. When changes in proportion of significant fibrosis (F ≥ 2) were assessed among pioglitazone and UDCA treated patients considering CAP values, pioglitazone treated patients demonstrated decrease in proportion of high LSM. CONCLUSION: In patient with NAFLD, interpretation of LSM in association with CAP scores may provide helpful information sparing unnecessary liver biopsy.

Development and validation of a prognostic model for patients with hepatocellular carcinoma undergoing radiofrequency ablation.

BACKGROUND: There are large variations in prognosis among hepatocellular carcinoma (HCC) patients undergoing radiofrequency ablation (RFA). However, current staging or scoring systems hardly discriminate the outcome of HCC patients treated with RFA. METHODS: A total of 757 treatment-naïve HCC patients undergoing RFA (derivation cohort) were analyzed to establish a nomogram for disease-free survival (DFS) based on Cox proportional hazard regression model. Accuracy of the nomogram was assessed and compared with conventional staging or scoring systems. Furthermore, external validation was performed in an independent cohort including 208 patients (validation cohort). RESULTS: Tumor size, tumor number, alpha-fetoprotein, prothrombin induced by vitamin K absence-II, lymphocyte count, albumin, and presence of ascites were adopted to construct the prognostic nomogram from the derivation cohort. Calibration curves to predict probability of DFS at 3 and 5 years after RFA showed good agreements between the nomogram and actual observations. The concordance index of the present nomogram was 0.759 (95% confidence interval 0.728-0.790), which was superior to those of conventional staging or scoring systems (range 0.505-0.683, all P < .001). These results were also reproduced in the validation cohort. CONCLUSION: Our simple-to-use nomogram optimized for treatment-naïve HCC patients undergoing RFA provided better prognostic performance than conventional staging or scoring systems.

Follow-Up Liver Stiffness Measurements after Liver Resection Influence Oncologic Outcomes of Hepatitis-B-Associated Hepatocellular Carcinoma with Liver Cirrhosis.

The severity of liver fibrosis can be noninvasively evaluated by measuring liver stiffness (LS) using transient elastography. This study aimed to evaluate the prognostic value of achieving low liver stiffness measurement (LSM) in patients with cirrhosis confirmed from the resected liver due to hepatocellular carcinoma (HCC). A total of 184 patients that received curative surgery for HCC related to the hepatitis B virus at Barcelona Clinic Liver Cancer stage 0⁻A, and had a METAVIR fibrosis score of 4 were investigated. LSM significantly decreased after antiviral therapy during follow-up (p = 0.001), and achieving LSM ≤8 kilopascal (kPa) suggested a reduced risk of late recurrence (>12 months) (hazard ratio (HR), 0.519; 95% confidence interval (CI), 0.307⁻0.877; p = 0.014). Older age at surgery (≥45 years) and multiple HCC nodules predicted an increased risk of late recurrence (HR, 3.270; 95% CI, 1.296⁻8.251; p = 0.012; and HR, 3.146; 95% CI, 1.396⁻7.089; p = 0.006). Decreased LSM also suggested decreased mortality (HR, 0.251; 95% CI, 0.086⁻0.756; p = 0.045) along with baseline low aspartate aminotransferase-to-platelet ratio index (APRI) score (<1.5) (HR, 0.251; 95% CI, 0.086⁻0.759; p = 0.041). Having early HCC recurrence (HR, 9.416; 95% CI, 3.566⁻24.861; p < 0.001) and microvascular tumor invasion (HR, 3.191; 95% CI, 1.188⁻8.568; p = 0.021) predicted increased mortality. Among HCC patients with liver cirrhosis under antiviral therapy, achieving low LSM (≤8 kPa) predicted reduced late HCC recurrence.

Aromatase Inhibitors and Newly Developed Nonalcoholic Fatty Liver Disease in Postmenopausal Patients with Early Breast Cancer: A Propensity Score-Matched Cohort Study.

BACKGROUND: Unlike tamoxifen, the relationship between aromatase inhibitor use in postmenopausal patients with breast cancer and nonalcoholic fatty liver disease (NAFLD) has not been delineated. MATERIALS AND METHODS: A retrospective analysis of 253 patients with early breast cancer without baseline NAFLD and treated with nonsteroidal aromatase inhibitors was performed. Among them, 220 patients were matched for sex, age, and menstruation status with healthy patients, and the prevalence of NAFLD was compared. NAFLD was determined by hepatic steatosis index in the absence of other known liver diseases. The presence of significant liver fibrosis in patients with NAFLD was determined noninvasively by AST-platelet ratio index, FIB-4 score, and NAFLD fibrosis score (NFS). RESULTS: Postmenopausal patients with breast cancer undergoing treatment with aromatase inhibitors had higher prevalence of NAFLD independent of body mass index (BMI) and underlying diabetes mellitus (DM). Although the aromatase inhibitor group showed higher fibrotic burden by NFS, independent of BMI and DM, the proportion of advanced fibrosis did not show statistically significant differences between AI-treated patients and the healthy patients. Those with abnormal baseline fasting glucose levels are suggested to have increased risk of NAFLD development after aromatase inhibitor treatment. In addition, patients with NAFLD developed after aromatase inhibitor use had significantly lower disease-free survival than those without NAFLD, although there was no significant difference in overall survival. CONCLUSION: Results of this study suggest that inhibition of estrogen synthesis in postmenopausal women undergoing treatment with aromatase inhibitors could increase the risk of NAFLD, which might have some influence on the prognosis of patients with breast cancer. IMPLICATIONS FOR PRACTICE: Unlike tamoxifen, the role of aromatase inhibitor treatment use in postmenopausal patients with breast cancer in development of fatty liver is not well known. In this propensity-matched cohort study, postmenopausal patients with breast cancer treated with aromatase inhibitors had increased risk of nonalcoholic fatty liver disease compared with healthy women after menopause, independent of obesity and diabetes mellitus. The results show possible adverse influence of the newly developed fatty liver on breast cancer disease-free survival and suggest a necessity for further validation. Fatty liver may need to be considered as an adverse event for aromatase inhibitor treatment.