Psoas muscle area as a predictor of low muscle mass in Asian patients with compensated advanced chronic liver disease.

PURPOSE: The relationship between the psoas muscle index (PMI) and the appendicular skeletal muscle index (ASMI) in patients with compensated advanced chronic liver disease (cACLD) is not yet understood. Our goal is to determine which level of the lumbar spine best represents the appendicular skeletal muscle. METHODS AND MATERIALS: This retrospective study involved patients with cACLD between January 2020 and December 2021. We documented the patients' body weight, height, gait speed, handgrip strength, appendicular skeletal muscle measured by DXA, and psoas muscle area segmented on computed tomography or magnetic resonance imaging. Low muscle mass, as defined by the Asian working group for sarcopenia, is less than 7.0 kg/m2 in males and less than 5.4 kg/m2 in females. We analyzed the correlation between PMI and ASMI. RESULTS: A total of 134 patients were enrolled in the study, with 74 being male and 60 being female. The mean age was 63.9 ± 7.7 years old. Significant associations (p < 0.001) were found between PMI of all levels and ASMI. In the analysis of Pearson's correlation coefficients, it was noted that the r value increased gradually in both males (r = 0.3197 at L2, 0.4006 at L3, 0.5769 at L4) and females (r = 0.3771 at L2, 0.4557 at L3, 0.5251 at L4). Similarly, the area under the curve (AUC) values predicting low muscle mass were as follows: for males, AUC=0.582 at L2, 0.619 at L3, 0.728 at L4; for females, AUC=0.685 at L2, 0.733 at L3, 0.744 at L4. The cut-off point for PMI in males was 4.12 at L2, 6.25 at L3, and 8.48 at L4, while in females was 2.61 at L2, 4.47 at L3, 6.07 at L4. CONCLUSION: The Psoas muscle index can be used to assess the muscle mass status in patients with cACLD. Among the various levels that can be used, we recommend using the fourth inferior endplate of the lumbar spine, as it shows the highest correlation. Additionally, we suggest using a PMI cut-off point of 8.48 cm2/m2 for males and 6.07 cm2/m2 for females as a predictor of low muscle mass in Asian.

Metformin and statins reduce hepatocellular carcinoma risk in chronic hepatitis C patients with failed antiviral therapy.

Backgrounds and Aim: Chronic hepatitis C (CHC) patients who fail antiviral therapy have a high risk of developing hepatocellular carcinoma (HCC). We investigated the effects of metformin and statins, commonly used to treat diabetes mellitus (DM) and hyperlipidemia (HLP), on HCC risk in CHC patients who failed antiviral therapy. Methods: CHC patients with failed interferon-based therapy were enrolled in a large-scale multicenter cohort study in Taiwan (T-COACH). HCC occurrence 1.5 years after the end of antiviral therapy was identified by linking to the cancer registry databases from 2003 to 2019. After considering death and liver transplantation as competing risks, Gray's cumulative incidence and Cox sub-distribution hazards for HCC development were used. Results: Among the 2,779 CHC patients, 480 (17.3%) developed new-onset HCC and 238 (8.6%) died after antiviral therapy. Metformin non-users with DM had a 51% higher risk of liver cancer than patients without DM, while statin users with HLP had a 50% lower risk of liver cancer than patients without HLP. The 5-year cumulative incidence of HCC was 16.5% in metformin non-users, significantly higher in metformin non-users than in patients without DM (11.3%; adjusted sub-distribution hazard ratio [aSHR]=1.51; P=0.007) and metformin users (3.1%; aSHR=1.59; P=0.022). Conversely, HLP statin users had a significantly lower HCC risk than patients without HLP (3.8% vs. 12.5%; aSHR=0.50; P<0.001). Notably, the unfavorable effect of non-metformin use on increased HCC risk was mainly observed among patients without cirrhosis but not in patients with cirrhosis. In contrast, a favorable effect of statins reduced the risk of HCC in both cirrhotic and non-cirrhotic patients. Conclusion: Metformin for DM and statins for HLP have chemopreventive effects on HCC risk in CHC patients who failed antiviral therapy. These findings emphasize the importance of personalized preventive strategies for managing patients with these clinical profiles.

Hepatitis B relapse after entecavir or tenofovir alafenamide cessation under anti-viral prophylaxis for cancer chemotherapy.

BACKGROUND: No study has comparing hepatitis B virus (HBV) relapse rates among patients with both cancer and hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) who completed anti-viral prophylaxis for chemotherapy and then stopped taking entecavir or tenofovir alafenamide (TAF). METHODS: A total of 227 HBeAg-negative cancer patients without cirrhosis who previously took entecavir (n = 144) or TAF (n = 83) for antiviral prophylaxis were enrolled. RESULTS: The cumulative incidence of virological and clinical relapse at 2 years was 37% and 10.4%, respectively, in the entecavir group, and 46.7% and 19.5%, respectively, in the TAF group. The multivariate analysis revealed that the use of hematologic malignancy, TAF use, and high-viremia group at baseline were independent risk factors for virological relapse, and use of rituximab, TAF use, higher FIB-4 index and high-viremia group at baseline were independent risk factors for clinical relapse. After propensity score-matching, the patients who discontinued TAF therapy still exhibited higher virological (P = 0.031) and clinical relapse rates (P = 0.012) than did those who discontinued entecavir therapy. The patients were allocated to high- (> 2000 IU/mL), moderate- (between 20 and 2000 IU/mL) and low- (< 20 IU/mL) viremia groups. In the high-viremia group, those who had taken TAF for antiviral prophylaxis had higher rates of virological and clinical relapse than did those who had taken entecavir; in the moderate- and low-viremia groups, no significant difference in virological and clinical relapse rates was detected between the entecavir and TAF groups. Three patients experienced hepatic decompensation upon clinical relapse. All three patients were lymphoma and underwent rituximab therapy. One patient developed acute on chronic liver failure and died even though timely retreatment. CONCLUSIONS: In patients with both cancer and CHB who underwent antiviral prophylaxis, TAF use was associated with a higher chance of HBV relapse than entecavir use after nucleos(t)ide analogue cessation, particularly in the high-viremia group. Patients who are hematologic malignancy and undergo a rituximab-containing cytotoxic therapy should be monitored closely after withdrawal from prophylactic NA treatment.

Regional Differences in Clinical Presentation and Prognosis of Patients With Post-Sustained Virologic Response Hepatocellular Carcinoma.

BACKGROUND & AIMS: Widespread use of direct-acting antivirals for hepatitis C virus infection has been paralleled with increased numbers of patients with hepatocellular carcinoma (HCC) after achieving sustained virologic response (post-SVR HCC) worldwide. Few data compare regional differences in the presentation and prognosis of patients with post-SVR HCC. METHODS: We identified patients with advanced fibrosis (F3/F4) who developed incident post-SVR HCC between March 2015 and October 2021 from 30 sites in Europe, North America, South America, the Middle East, South Asia, East Asia, and Southeast Asia. We compared patient demographics, liver dysfunction, and tumor burden by region. We compared overall survival by region using Kaplan-Meier analysis and identified factors associated with survival using multivariable Cox regression analysis. RESULTS: Among 8796 patients with advanced fibrosis or cirrhosis who achieved SVR, 583 (6.6%) developed incident HCC. There was marked regional variation in the proportion of patients detected by surveillance (range: 59.5%-100%), median maximum tumor diameter (range, 1.8-5.0 cm), and the proportion with multinodular HCC (range, 15.4%-60.8%). The prognosis of patients highly varied by region (hazard ratio range, 1.82-9.92), with the highest survival rates in East Asia, North America, and South America, and the lowest survival rates in the Middle East and South Asia. After adjusting for geographic region, HCC surveillance was associated with early stage detection (Barcelona Clinic Liver Cancer stage 0/A, 71.0% vs 21.3%; P < .0001) and lower mortality rates (adjusted hazard ratio, 0.29; 95% CI, 0.18-0.46). CONCLUSIONS: Clinical characteristics, including early stage detection, and prognosis of post-SVR HCC differed significantly across geographic regions. Surveillance utilization appears to be a high-yield intervention target to improve prognosis among patients with post-SVR HCC globally.

Well-controlled viremia reduces the progression of hepatocellular carcinoma in chronic viral hepatitis patients treated with lenvatinib.

Lenvatinib has been approved as one of the first-line treatments for advanced hepatocellular carcinoma (HCC) due to its high treatment efficacy being non-inferior to sorafenib. Previous studies have shown well-controlled viremia contributes to the prognosis of HCC patients receiving first-line sorafenib; hence, we postulated this association might also exist in HCC patients with lenvatinib treatment. From April 2018 to December 2021, 201 unresectable HCC patients with first-line lenvatinib treatment in our institute were assessed. High-effect nucleoside analogues were administered for hepatitis B virus (HBV) control, while direct-acting antivirals were used for hepatitis C virus (HCV) elimination. Based on our previous study, well-controlled viremia was defined as patients who had undetectable viremia, or who had been receiving antivirals at least 6 months before lenvatinib. This study enrolled 129 patients, including 85 patients with HBV-related HCC (HBV-HCC) and 44 patients with HCV-related HCC (HCV-HCC), respectively. Progression-free survival (PFS) and overall survival (OS) rates between the two groups were not different. Before administration of lenvatinib, 57.1% of the HBV-HCC patients and 88.4% of the HCV-HCC patients had well-controlled viremia, and their PFS (8.8 vs. 3.1 months, p < 0.001) and OS (30.2 vs. 12.8 months, p = 0.041) were better than those who had uncontrolled viremia; moreover, well-controlled viremia reduced tumor progression in multivariate analysis (Hazard ratio: 0.41, 95% confidence interval: 0.25-0.68, p = 0.001) after adjusting for albumin-bilirubin grade and concurrent treatment. HBV or HCV infection was not associated with tumor progression of HCC patients receiving lenvatinib, but viremia, controlled or not, was.

Impact of Genomic Alterations on the Clinical Outcome of Patients With Hepatitis B-related Hepatocellular Carcinoma Receiving Curative Surgery: A Retrospective Cohort Study.

BACKGROUND/AIM: The aim of the current study was to obtain comprehensive genomic information on viral hepatitis B (HBV)-related hepatocellular carcinoma (HCC) and identify potential biomarkers of early recurrence in patients receiving curative surgery. PATIENTS AND METHODS: A total of 104 patients with HBV-related HCC receiving curative surgery at Kaohsiung Chang Gung Memorial Hospital between January 2017 and December 2020 were identified, including 52 patients each with and without recurrence. Next-generation sequencing was performed to investigate genomic alterations caused by surgical resection of specimens. The Kaplan-Meier method was used to estimate disease-free survival and overall survival. RESULTS: The landscape of gene mutations in HCC patients of our cohort showed a median number of single nucleotide variants of 250, a median number of insertions and deletions of 22, and a median number of protein-coding mutations of 185. The 10 most frequently mutated genes were TP53 (43%), TTN (39%), MUC16 (28%), PCLO (25%), OBSCN (22%), ADGRV1 (19%), ALB (18%), SYNE1 (18%), DNAH17 (17%), and RYR1 (17%). The tumour mutation burden was 4.8 mutations per megabase, and high microsatellite instability was reported in only three patients. In addition, the mutational signatures showed that aristolochic acid exposure was highly implicated in our HCC cohort. Five mutant genes, TBC1D4, ITGA4, RPS6KA3, VWA8, and FMN2, were more frequent in the recurrence group than that in the non-recurrence group. CONCLUSION: Our results present an in-depth genomic analysis of HBV-related HCC. The study findings provide an improved understanding of the related molecular mechanisms and identify potential biomarkers associated with early tumour recurrence after curative resection.

Real-world comparison of pembrolizumab and nivolumab in advanced hepatocellular carcinoma.

BACKGROUND: Nivolumab and pembrolizumab have not been directly compared in clinical trials, and the aim of this study is to investigate the efficacy and safety of nivolumab versus pembrolizumab in patients with advanced hepatocellular carcinoma (HCC) in real-world practice. METHODS: We retrospectively reviewed patients with HCC who received intravenous nivolumab or pembrolizumab alone as second-line and later therapy. The objective response was determined according to the Response Evaluation Criteria in Solid Tumors criteria version 1.1. Adverse events (AEs) were graded based on the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. The Kaplan-Meier method was used to analyze progression-free survival (PFS) and overall survival (OS). Prognostic values were estimated using hazard ratios with 95% confidence intervals (CIs). RESULTS: In total, 120 patients were enrolled, including 95 who received nivolumab and 25 who received pembrolizumab. All patients were staged as Barcelona Clinic Liver Cancer stage C, and 29 patients were classified as Child-Pugh classification B (7). The response rate of the pembrolizumab and nivolumab groups were 8.0% and 7.4%, respectively. There was no significant difference in the median PFS between the pembrolizumab and nivolumab groups (2.7 months versus 2.9 months). The median OS in the nivolumab group was longer than that in the pembrolizumab group (10.8 months versus 8.1 months); however, the difference was not statistically significant. The effects of pembrolizumab and nivolumab on the median PFS and OS were consistent across the subgroups based on baseline characteristics. The severity of all AEs was grades 1-2 without treatment interruption or dose adjustment; there was no statistically significant difference in the incidence of treatment-related AEs between these two groups. Additionally, the percentage of patients receiving subsequent therapy was consistent between the two groups. CONCLUSION: The efficacy and safety of pembrolizumab and nivolumab were comparable in the management of patients with pretreated HCC in real-world practice.

Higher rate of HBsAg loss after discontinuation of tenofovir than entecavir in patients with chronic hepatitis B.

BACKGROUND/AIMS: To compare the rates of hepatitis B surface antigen (HBsAg) loss after discontinuation of entecavir versus tenofovir disoproxil fumarate (TDF) in patients with chronic hepatitis B (CHB) without cirrhosis. METHODS: A total of 891 patients who received entecavir (n = 556) or TDF (n = 335) followed up post-treatment for at least 12 months were retrospectively assessed. A total of 677 patients who had continued entecavir or TDF therapy for at least 4 years were enrolled as the continued group. RESULTS: Patients who discontinued TDF had higher rates of virological and clinical relapse and retreatment than patients who discontinued entecavir in both the HBeAg-positive and HBeAg-negative subgroups. In the entire discontinued cohort, the cumulative rates of HBsAg loss at 7 years were 22.6% and 35.4% in the entecavir and TDF groups respectively. Patients who discontinued TDF had significantly higher rates of HBsAg loss than patients who discontinued entecavir therapy in all (p = 0.019) and propensity score-matched (p = 0.015) patients, especially among the subgroups who achieved a sustained response (p < 0.001). Cox regression analysis revealed that TDF, longer treatment duration and lower HBsAg levels at end of treatment were independently associated with HBsAg loss in the entire discontinued group. The incidence of HBsAg loss was significantly higher in the discontinued group than in the continued group after propensity score matching (p < 0.001), including HBeAg-positive and HBeAg-negative patients. CONCLUSIONS: Patients who discontinued TDF had significantly higher rates of HBsAg loss than patients who discontinued entecavir, especially among the subgroups without HBV relapse after cessation of therapy.

Nomogram to Predict the Long-Term Overall Survival of Early-Stage Hepatocellular Carcinoma after Radiofrequency Ablation.

Our objective was to develop a predictive nomogram that could estimate the long-term survival of patients with very early/early-stage hepatocellular carcinoma (HCC) undergoing radiofrequency ablation (RFA). For this retrospective study, we enrolled 950 patients who initially received curative RFA for HCC at Barcelona Clinic Liver Cancer (BCLC) stages 0 and A between 2002 and 2016. Factors predicting poor survival after RFA were investigated through a Cox proportional hazard model. The nomogram was constructed using the investigated variables influencing overall survival (OS). After a median follow-up time of 6.25 years, 400 patients had died, and 17 patients had received liver transplantation. The 1-,3-,5-,7-, and 10-year OS rates were 94.5%, 73.5%, 57.9%, 45.7%, and 35.8%, respectively. Multivariate analysis showed that age greater than 65 years, albumin-bilirubin (ALBI) grades 2 and 3, AST-to-platelet ratio index (APRI) greater than 1, tumor size larger than 3 cm, diabetes mellitus, end-stage renal disease, and tumor number greater than 1 were significantly associated with poor OS. The nomogram was constructed using these seven variables. The validation results showed a good concordance index of 0.683. When comparing discriminative ability to tumor, node, and metastasis (TNM), BCLC, and Cancer of the Liver Italian Program (CLIP) staging systems, our nomogram had the highest C-index for predicting mortality. This nomogram provides useful information on prognosis post-RFA as a primary treatment and aids physicians in decision-making.

The Efficacy and Safety of Ramucirumab in Heavily Pretreated Advanced Hepatocellular Carcinoma.

BACKGROUND/AIM: Ramucirumab has been approved for the management of hepatocellular carcinoma (HCC) after progression on sorafenib; however, the data on ramucirumab in heavily pretreated HCC are limited. This study aimed to investigate the real-world efficacy and safety of ramucirumab in patients with heavily pretreated advanced HCC. PATIENTS AND METHODS: Patients with advanced HCC who received intravenous ramucirumab as second-line and later therapy were retrospectively reviewed. Kaplan-Meier method was used to analyze progression-free survival (PFS) and overall survival (OS). Additionally, prognostic factors were estimated using hazard ratios with 95% confidence intervals. RESULTS: In total, 31 patients with advanced HCC who received ramucirumab were enrolled, including 11 patients with second-line treatment and 20 with third-line and later-line treatment. The objective response rate was 3.2% with a disease control rate (DCR) of 45.2%, and the DCR of ramucirumab between the second-line group and the third-line and later-line groups did not differ. The median PFS and OS were 2.1 months and 6.7 months, respectively, in the whole population. In the multivariate analyses, alpha-fetoprotein <1,000 ng/ml was an independent prognostic factor for better PFS and OS. All adverse events were classified as grade 1-2 without grade 3-4 toxicities or drug-related mortality. Additionally, 51.6% of patients received subsequent therapy after progression on ramucirumab. CONCLUSION: The results of our study show the efficacy and safety of ramucirumab in patients with heavily pretreated HCC in real-world practice.

Usefulness of controlled attenuation parameter in monitoring clinically relevant decline of hepatic steatosis for non-alcoholic fatty liver disease.

BACKGROUND AND AIMS: Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) is the reference standard of hepatic steatosis assessment. This study evaluates usefulness of controlled attenuation parameter (CAP) in monitoring the clinically relevant outcome by MRI-PDFF for non-alcoholic fatty liver disease (NAFLD) patients. METHODS: NAFLD patients were enrolled prospectively. Instruction was given in lifestyle modifications with exercise and control of metabolic factors. MRI-PDFF and CAP were performed at enrollment and follow-up, with the diagnostic validity of CAP in monitoring clinically relevant outcome defined as a decline of ≥30% relative to baseline value by MRI-PDFF. RESULTS: A total of 75 patients (male/female: 49/26, mean age: 53.2) were enrolled. Baseline MRI-PDFF, CAP and liver stiffness was 14.4%, 300.2 dB/m and 6.5 kPa. In a median interval of 369 days, thirteen (17.3%) patients achieved clinically relevant outcome with decline of 46.7 dB/m by CAP, compared with increase of 5.1 in the other patients. In multivariate analysis, clinically relevant outcome was associated with changes (Δ) of CAP and glucose. Assessed by area under receiver operating curve, the performances of ΔCAP in predicting clinically relevant outcome were 0.815 and 0.808, and with the specificity of >90%, the ΔCAP cutoff was -46 dB/m and -15% relative to baseline value; sensitivity was 53.8% and 46.2% with negative predictive value of 90.3% and 88.9% respectively. CONCLUSIONS: For NAFLD patients, CAP exhibited good performance in monitoring clinically relevant decline of hepatic steatosis in MRI-PDFF. With the cutoffs of -46 dB/m or -15%, ΔCAP is useful in excluding clinical relevant outcome achievement.

Post-treatment HBsAg decline predicts high rate of HBsAg loss after stopping entecavir or tenofovir in HBeAg-negative patients without retreatment.

BACKGROUND/AIMS: Little is known about the role of post-treatment HBsAg decline in HBsAg loss following nucleos(t)ide analogues cessation. METHODS: HBeAg-negative patients without cirrhosis who previously received entecavir or tenofovir disoproxil fumarate (TDF) were enrolled (n=530). All patients were followed-up post-treatment for >24 months. RESULTS: Of the 530 patients, 126 achieved sustained response (Group I), 85 experienced virological relapse without clinical relapse and retreatment (Group II), 67 suffered clinical relapse without retreatment (Group III) and 252 received retreatment (Group IV). The cumulative incidence of HBsAg loss at 8 years was 57.3% in Group I, 24.1% in Group II, 35.9% in Group III and 7.3% in Group IV. Cox regression analysis showed that nucleos(t)ide analogue experience, lower HBsAg levels at end-of-treatment (EOT) and higher HBsAg decline at 6 months after EOT were independently associated with HBsAg loss in Group I and Groups II+III. The rates of HBsAg loss at 6 years in patients with HBsAg decline >0.2 log IU/mL in Group I and HBsAg decline >0.15 log IU/mL in Group II+III at 6 months after EOT were 87.7% and 47.1%, respectively. CONCLUSION: The HBsAg loss rate was high and post-treatment HBsAg decline could predict high HBsAg loss rate among HBeAg-negative patients who discontinued entecavir or TDF and did not need retreatment.

Prediction model of hepatocellular carcinoma in patients with hepatitis B virus-related compensated cirrhosis receiving antiviral therapy.

The feasibility and performance of predicting hepatocellular carcinoma (HCC) using a combined albumin-bilirubin (ALBI) and fibrosis-4 (FIB-4)-based model remain unclear in patients with compensated cirrhosis and chronic hepatitis B (CHB) receiving long-term nucleos(t)ide analog (NA) therapy. We enrolled 1158 NA-naïve patients with compensated cirrhosis and CHB treated with entecavir or tenofovir disoproxil fumarate. The patients' baseline characteristics, hepatic reserve, and fibrosis indices were analyzed. The combination of ALBI and FIB-4 was used to develop a prediction model of HCC. In this cohort, the cumulative incidence rates of HCC at 3, 5, and 10 years were 8.1%, 13.2%, and 24.1%, respectively. The combination of ALBI and FIB-4, Diabetes mellitus, and Alpha-fetoprotein (AFDA) were independent risk factors for HCC. The combined ALBI and FIB-4-based prediction model (i.e., AFDA) stratified the cumulative risk of HCC into three groups (with risk scores of 0, 1-3, 4-6) among all patients (P < 0.001). AFDA exhibited the highest area under the receiver operating characteristic (0.6812) for predicting HCC, which was higher than those of aMAP (0.6591), mPAGE-B (0.6465), CAMD (0.6379), and THRI (0.6356) and significantly higher than those of PAGE-B (0.6246), AASL-HCC (0.6242), and HCC-RESCUE (0.6242). Patients with a total score of 0 (n = 187, 16.1% of total patients) had the lowest cumulative HCC incidence of 3.4% at 5 years. The combined ALBI and FIB-4-based prediction model can stratify the risk of HCC in patients with compensated cirrhosis and CHB receiving NA therapy.

Short Half-Life of Des-γ-Carboxy Prothrombin Is a Superior Factor for Early Prediction of Outcomes of Hepatocellular Carcinoma Treated with Radiofrequency Ablation.

BACKGROUND: The role of des-γ-carboxy prothrombin (DCP) in patients undergoing radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) needs to be clarified. MATERIALS AND METHODS: 174 HCC patients that underwent RFA were enrolled. We calculated the HLs of DCP from the available values before and on first day after ablation and assessed the correlation between HLs of DCP and RFA efficacy. RESULTS: Of 174 patients, 63 with pre-ablation DCP concentrations of ≥80 mAU/mL were analyzed. The ROC analysis showed the optimal cut-off value of HLs of DCP for predicting RFA response was 47.5 h. Therefore, we defined short HLs of DCP < 48 h as a predictor of favorable treatment response. Of 43 patients with a complete radiological response, 34 (79.1%) had short HLs of DCP. In 36 patients with short HLs of DCP, 34 (94.4%) had a complete radiologic response. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were 79.1%, 90.0%, 82.5%, 94.4%, and 66.7%. During the 12-month follow-up, patients who had short HLs of DCP had a better disease-free survival rate than patients with long HLs of DCP (p < 0.001). CONCLUSIONS: Short HLs of DCP < 48 h calculated on the first day post-RFA are a useful predictor for treatment response and recurrence-free survival after RFA.

Efficacy and Safety of Lenvatinib After Progression on First-line Atezolizumab Plus Bevacizumab Treatment in Advanced Hepatocellular Carcinoma Patients.

BACKGROUND/AIM: This study aimed to assess the clinical impact of lenvatinib after disease progression on atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma (HCC). PATIENTS AND METHODS: A total of 14 patients who received lenvatinib after failure of atezolizumab plus bevacizumab and all patients were classified as having a Barcelona Clinic Liver Cancer stage C. Six patients had macrovascular invasion, and a liver occupation rate of >50% was reported in seven patients. The Kaplan-Meier method was performed to analyze the cumulative survival, while log-rank test was used to detect the differences. The dose of lenvatinib was determined based on body weight. RESULTS: The participants' responses to lenvatinib treatment were as follows: 21.4% achieved partial response (PR), while 35.7% had a stable disease, with a disease control rate of 57.1%. The median progression-free survival (PFS) and overall survival (OS) were 4.2 months and 8.3 months, respectively; the median PFS and OS were 6.7 months and 10.5 months in the PR group. No significant difference was observed in the median PFS and OS between patients with and without macrovascular invasion or liver occupation rate of >50%. Most of the adverse events (AEs) were categorized as grade 1-2; all patients tolerated the AEs, and no drug-related mortality was reported. Additionally, half of the population underwent subsequent therapy after progression on lenvatinib treatment. CONCLUSION: Lenvatinib is effective and can be safely used as second-line systemic therapy after progression on atezolizumab plus bevacizumab in patients with advanced HCC in real-world clinical practice.

HBV relapse rates in patients who discontinue tenofovir disoproxil fumarate with or without switching to tenofovir alafenamide.

BACKGROUND/AIMS: The incidence and relapse pattern in patients stopping tenofovir alafenamide (TAF), a prodrug of tenofovir which is more concentrated in hepatocytes, is unknown. METHODS: HBeAg-negative CHB patients stopping tenofovir disoproxil fumarate (TDF) (off-TDF) or who had switched to TAF more than 3 months before discontinuation (off-TAF) were recruited. The propensity score-matching method (PSM) was used, creating a ratio of 1:3 between the off-TAF versus the off-TDF groups to adjust for associated factors. RESULTS: After PSM, 180 off-TDF and 60 off-TAF patients were analyzed. The cumulative rates of virological and clinical relapse at 52 weeks were 75.1% and 58.5% respectively in the off-TDF group and 91.1% and 61.6% in the off-TAF group. Patients in the off-TAF group had significantly higher rates of virological relapse than those in the off-TDF group (p = 0.021), but not clinical relapse (p = 0.785). Multivariate cox regression analysis showed that off-TAF group was an independent factor for virological relapse, but not clinical relapse. Severity of clinical relapse and hepatic decompensation rate were comparable between off-TDF and off-TAF groups CONCLUSIONS: The off-TAF group had a higher virological relapse rate than the off-TDF group. The difference in clinical relapse pattern and severity was not clinically important between the two groups.

Combined baseline HBcrAg and end-of-treatment HBsAg predict HBV relapse after entecavir or tenofovir cessation.

BACKGROUND: For patients with chronic hepatitis B (CHB), the optimal stopping criteria for entecavir or tenofovir disoproxil fumarate treatment remain unclear. METHODS: This study recruited CHB patients with levels of hepatitis B surface antigen (HBsAg) <100 IU/mL at the end of treatment (EOT) from Kaohsiung (n = 190) and Linkou (n = 188) Chang Gung Memorial Hospitals for use as development and validation groups, respectively. RESULTS: In the development group, 108 patients with HBsAg ≤40 IU/mL were used for analysis of predictors of HBV relapse and HBsAg loss. Multivariate analysis showed that age, nucleos(t)ide analogue (NA)-experienced status, baseline hepatitis B core-related antigen (HBcrAg) and HBsAg at EOT were associated independently with virological and clinical relapse. An HBsAg level of 20 IU/mL at EOT was the best cut-off value for minimizing HBV relapse. Patients with EOT HBsAg ≤20 IU/mL had lower virological and clinical relapse rates and higher HBsAg loss rates than those with EOT HBsAg 21-40 IU/mL and HBsAg 41-100 IU/mL in the development and validation groups. The virological and clinical relapse rates were very low (5-year rates: 6.5% and 0%, respectively) and HBsAg loss rate was very high (5-year rate: 81.7%) in patients with a combination of baseline HBcrAg ≤4 log U/mL and EOT HBsAg ≤20 IU/mL in the development group. CONCLUSIONS: A combination of baseline HBcrAg ≤4 log U/mL and EOT HBsAg level ≤20 IU/mL might reduce the risk of HBV relapse and increase HBsAg loss rate, and might be helpful for off-NA follow-up strategy.

Metformin reduces hepatocellular carcinoma incidence after successful antiviral therapy in patients with diabetes and chronic hepatitis C in Taiwan.

BACKGROUND & AIMS: Diabetes mellitus (DM) is known to increase the risk of hepatocellular carcinoma (HCC) among individuals with chronic hepatitis C (CHC). We aimed to evaluate whether metformin reduces HCC risk among individuals with DM and CHC after successful antiviral therapy. METHODS: Individuals with CHC who achieved a sustained virological response (SVR) after interferon-based therapy were enrolled in a large-scale, multicenter cohort in Taiwan (T-COACH). Cases of HCC at least 1 year after SVR were identified through linkage to the catastrophic illness and cancer registry databases. RESULTS: Of 7,249 individuals with CHC enrolled in the study, 781 (10.8%) had diabetes and 647 (82.8%) were metformin users. During a median follow-up of 4.4 years, 227 patients developed new-onset HCC. The 5-year cumulative HCC incidence was 10.9% in non-metformin users and 2.6% in metformin users, compared to 3.0% in individuals without DM (adjusted hazard ratio [aHR] 2.83; 95% CI 1.57-5.08 and aHR 1.46; 95% CI 0.98-2.19, respectively). Cirrhosis was the most important factor significantly associated with higher HCC risk in Cox regression analysis, followed by DM non-metformin use, older age, male sex, and obesity; whereas hyperlipidemia with statin use was associated with a lower HCC risk. Using the two most crucial risk factors, cirrhosis and DM non-metformin use, we constructed a simple risk model that could predict HCC risk among individuals with CHC after SVR. Metformin use was shown to reduce the risk of all liver-related complications. CONCLUSIONS: Metformin use greatly reduced HCC risk after successful antiviral therapy in individuals with diabetes and CHC. A simple risk stratification model comprising cirrhosis and DM non-metformin use could predict long-term outcomes in individuals with CHC after SVR. IMPACT AND IMPLICATIONS: The current study provides evidence that metformin could reduce hepatocellular carcinoma (HCC) incidence after successful antiviral therapy among those with diabetes and chronic hepatitis C in a large-scale nationwide cohort study. Although successful antiviral therapy greatly reduces HCC risk in individuals with chronic hepatitis C, those with cirrhosis, diabetes, obesity, and the elderly remain at high risk of HCC development. We demonstrated that a simple risk model composed of two crucial unfavorable factors, cirrhosis and diabetes without metformin use, predicts the risk of HCC and major liver-related complications after successful antiviral therapy in individuals with chronic hepatitis C. Metformin use is highly recommended for individuals with diabetes and chronic hepatitis C after viral eradication to reduce the risk of HCC.

Retreatment Efficacy and Renal Safety of Tenofovir Alafenamide, Entecavir, and Tenofovir Disoproxil Fumarate After Entecavir or Tenofovir Cessation.

BACKGROUND: We aimed to compare the one-year retreatment efficacy and renal safety of entecavir, tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) after HBV relapse in patients who discontinued entecavir or TDF. METHODS: This retrospective study included 289 chronic hepatitis B (CHB) patients without cirrhosis who received entecavir (n = 93), TDF (n = 103), or TAF (n = 86) retreatment for at least 12 months after entecavir or TDF cessation. RESULTS: The rate of virological response (HBV DNA < 20 IU/mL) at 12 months of retreatment was 79/93 (84.9%) in the entecavir group, 92/103 (89.3%) in the TDF group, and 72/86 (83.7%) in the TAF group. The rate of ALT normalization (ALT ≤ 40 U/L) after 12 months of retreatment was 76/93 (81.7%) in the entecavir group, 77/103 (74.7%) in the TDF group , and 73/86 (84.9%) in the TAF group. There was no significant difference in the rates of virological response (p = 0.495) and ALT normalization (p = 0.198) among the three groups. Multivariate analysis showed that lower HBV DNA and HBsAg levels at baseline were independently associated with virological response at 12 months of retreatment. The TDF group (37.8 ± 34.8 U/L) had higher ALT levels at 12 months of retreatment than the TAF (27. ± 17.9 U/L, p = 0.015) and entecavir (28.3 ± 19.3 U/L, p = 0.022) groups. In patients with eGFR 60-90 mL/min/1.73 m2, eGFR change between baseline and 12 months of retreatment increased in the entecavir and TAF groups and decreased in the TDF group. CONCLUSIONS: TAF could be one of the retreatment options for retreatment of HBV relapse after entecavir or TDF cessation.

HBcrAg Predicts Hepatocellular Carcinoma Development in Chronic B Hepatitis Related Liver Cirrhosis Patients Undergoing Long-Term Effective Anti-Viral.

Hepatitis B core-related antigen (HBcrAg) is a predictor of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. Studies on anti-viral therapy have shown that the use of NUC therapy in HBV patients could reduce the incidence of HCC. However, the incidence of HCC continues to increase after long-term anti-viral therapy. The relationship between HBcrAg and HCC development in CHB-related liver cirrhosis (LC) patients undergoing long-term anti-viral therapy is still unclear. This study enrolled 1108 treatment-naïve CHB patients diagnosed with HBV-related LC receiving NUC therapy from April 1999 to February 2015. The baseline biomarkers, disease history, and following results were collected by the hospital. Among the 1108 patients, 219 developed HCC within a median follow-up period of 6.85 years. A multivariable Cox regression model was used, with adjustment for age, gender, FIB-4, DM, and HBsAg-HQ. The adjusted hazard ratios for the HBcrAg tertile levels were 1.70 (95%CI: 1.21, 2.39) and 2.14 (95%CI: 1.50, 3.05) for levels 3.4-4.9 and >4.9 logU/mL, respectively, compared with levels ≤3.4. The effect of the HBcrAg level on HCC incidence was found to be significantly modified by HBsAg-HQ, where lower HBsAg-HQ (≤ 3) values were associated with a significantly higher risk, but HBsAg-HQ levels >3 were not. Our results highlight that, after adjustment for potential confounding factors, patients with CHB-related LC and higher HBcrAg levels are at significant risk for HCC development, even while undergoing long-term effective anti-viral therapy. The HBcrAg level is therefore an independent risk factor for HCC development, especially for patients with HBsAg-HQ levels <3.