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.

Benefits of Hepatitis C Viral Eradication: A Real-World Nationwide Cohort Study in Taiwan.

BACKGROUND: Chronic hepatitis C (CHC) increases the risk of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). This nationwide cohort study assessed the effectiveness of viral eradication of CHC. METHODS: The Taiwanese chronic hepatitis C cohort and Taiwan hepatitis C virus (HCV) registry are nationwide HCV registry cohorts incorporating data from 23 and 53 hospitals in Taiwan, respectively. This study included 27,577 individuals from these cohorts that were given a diagnosis of CHC and with data linked to the Taiwan National Health Insurance Research Database. Patients received either pegylated interferon and ribavirin or direct-acting antiviral agent therapy for > 4 weeks for new-onset LC and liver-related events. RESULTS: Among the 27,577 analyzed patients, 25,461 (92.3%) achieved sustained virologic response (SVR). The mean follow-up duration was 51.2 ± 48.4 months, totaling 118,567 person-years. In the multivariable Cox proportional hazard analysis, the hazard ratio (HR) for incident HCC was 1.39 (95% confidence interval [CI]: 1.00-1.95, p = 0.052) among noncirrhotic patients without SVR compared with those with SVR and 1.82 (95% CI 1.34-2.48) among cirrhotic patients without SVR. The HR for liver-related events, including HCC and decompensated LC, was 1.70 (95% CI 1.30-2.24) among cirrhotic patients without SVR. Patients with SVR had a lower 10-year cumulative incidence of new-onset HCC than those without SVR did (21.7 vs. 38.7% in patients with LC, p < 0.001; 6.0 vs. 18.4% in patients without LC, p < 0.001). CONCLUSION: HCV eradication reduced the incidence of HCC in patients with and without LC and reduced the incidence of liver-related events in patients with LC.

Impact of HCV eradication by directly acting antivirals on glycemic indices in chronic hepatitis C patients -a nationwide Taiwan HCV registry.

BACKGROUND/AIMS: Hepatitis C virus (HCV) eradication using antiviral agents augments the metabolic profile. Changes in glycated hemoglobin (HbA1c) levels in chronic hepatitis C patients who receive glecaprevir/pibrentasvir (GLE/PIB) remain elusive. METHODS: Data from 2417 patients treated with GLE/PIB from the Taiwan HCV Registry were analyzed, and pretreatment HbA1c levels were compared with 3-months after the-end-of treatment levels. A sustained virological response (SVR) was defined as undetectable HCV RNA at 12 weeks after the end of treatment. A significant change in HbA1c level was defined as the 75th percentile of the change in the HbA1c level before and after treatment (decrement >0.2%). RESULTS: Serum HbA1c levels decreased significantly (6.0 vs 5.9%, P < 0.001). Post-treatment HbA1c levels decreased in all subgroups, except in non-SVR patients (5.7 vs 5.7%, P = 0.79). Compared to patients without significant HbA1c improvement (decrement >0.2%), those with HbA1c improvement were older (60.2 vs 58.6 years, P < 0.001), had higher serum creatinine levels (1.9 vs 1.6 mg/dL, P < 0.001), triglycerides (129.8 vs 106.2 mg/dL, P < 0.001), fasting glucose (135.8 vs 104.0 mg/dL, P < 0.001), and pretreatment HbA1c (7.1 vs 5.7%, P < 0.001) and had a higher proportion of male sex (57.9% vs 50.9%, P = 0.003), diabetes (84.3 vs 16.8%, P < 0.001), more advanced stages of chronic kidney disease (CKD) (15.7 vs 11.1 %, P < 0.001), anti-diabetic medication use (47.3 vs 16.4%, P < 0.001) and fatty liver (49.6 vs 38.3 %, P < 0.001). Multivariate analysis revealed that the factors associated with significant HbA1c improvement were age (odds ratio [OR]/95% confidence intervals [CI]: 1.01/1.00-1.02, P = 0.01), HbA1c level (OR/CI: 2.83/2.48-3.24, P < 0.001) and advanced CKD stages (OR/CI: 1.16/1.05-1.28, P = 0.004). If the HbA1c variable was not considered, the factors associated with significant HbA1c improvement included alanine aminotransferase level (OR/CI, 1.002/1.000-1.004, P = 0.01), fasting glucose level (OR/CI: 1.010/1.006-1.013, P < 0.001), and diabetes (OR/CI: 3.35/2.52-4.45, P < 0.001). CONCLUSIONS: The HbA1c levels improved shortly after HCV eradication using GLE/PIB. The improvement in glycemic control can be generalized to all subpopulations, particularly in patients with a higher baseline HbA1c level or diabetes.

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.

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.

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.

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.

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.

Seven centimeters as an optimal cutoff value for prognosis stratification in large monofocal hepatocellular carcinoma.

PURPOSE: Barcelona Clinic Liver Cancer (BCLC) guidelines designate monofocal hepatocellular carcinoma (HCC) > 2 cm as BCLC A, and large monofocal HCC is defined at > 5 cm. We aimed to evaluate the optimal cutoff value for large monofocal HCC based on prognosis stratification. METHODS: From 2011 to 2018, 3055 patients with newly diagnosed HCC, who were managed in our institution, including 868 patients with monofocal HCC > 2 cm and 330 patients with BCLC B, were enrolled in this retrospective study. RESULTS: Monofocal HCC > 5 cm patients had worse overall survival (OS) than monofocal HCC 2-5 cm patients (5-year OS: 54% vs. 57%; p = 0.047), confirmed by multivariate analysis (hazard ratio (HR): 1.492, 95% confidence interval (CI): 1.055-2.110; p = 0.024). Monofocal HCC > 5 cm patients had better OS than BCLC B HCC patients (5-year OS: 54% vs. 25%; p < 0.001), confirmed by multivariate analysis (HR: 0.670, 95% CI: 0.481-0.934; p = 0.018). Using 7 cm as the monofocal HCC cutoff value resulted in worse OS than monofocal HCC 2-7 cm (5-year OS: 50% vs. 57%; p = 0.02), confirmed by multivariate analysis (HR: 1.625, 95% CI: 1.039-2.540; p = 0.033). Monofocal HCC > 7 cm patients had better OS than BCLC B patients (p = 0.006). However, no significant difference was identified in the multivariate analysis (HR: 0.726; 95% CI: 0.473-1.115; p = 0.144). CONCLUSIONS: The prognosis of monofocal HCC > 7 cm was similar to that of BCLC B, indicating that 7 cm represents an optimal cutoff value for prognosis stratification in large monofocal HCC.

Effects of direct anti-viral agents on the gut microbiota in patients with chronic hepatitis C.

BACKGROUND/PURPOSE: Gut microbiology is associated with liver disease due to gut-liver circulation via the gut microbial-liver axis. There is a paucity of data regarding the effects of treatment to cure hepatitis C virus (HCV) infection on the gut microbiota. The aim of this study was to evaluate the fecal microbiota before and after treatment with direct antiviral agents (DAA) in patients with HCV infection. METHODS: This prospective study was conducted at Kaohsiung Chung-Gung Memorial Hospital, Taiwan, between December 2019 and November 2020. We recruited patients with chronic hepatitis C (CHC) receiving DAA treatment. Fecal samples were collected twice: at baseline (before DAA treatment; CHC group) and 24 weeks after the end of treatment (EOT; SVR24 group), and once from healthy controls at baseline (control group). The taxonomic composition of the gut microbiota was determined using 16 S ribosomal RNA gene sequencing of stool samples. RESULTS: A total of 60 patients with CHC and 60 healthy controls matched by age and gender were enrolled. All patients achieved a sustained virologic response (SVR). Alpha diversity was not significantly difference between any groups. Analysis of similarities (ANOSIM) revealed minor differences in the microbial community structure between the control group and CHC group (R = 0.0146, P = 0.098) and less significant differences between the CHC group and SVR24 group (R = -0.0139; P = 0.94). Three phyla and eight genera were differentially abundant between the control group and CHC group. CONCLUSION: Individuals with CHC do not exhibit significant gut microbiota alterations and eradication of HCV by DAA is not associated with significant modification of the gut microbiota.

Earlier and Higher Rate of Hepatitis B Virus Relapse After Discontinuing Tenofovir Versus Entecavir in Hepatitis B e Antigen-Positive Patients.

BACKGROUND: This study investigated the incidence and predictors of hepatitis B virus (HBV) relapse in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B who discontinued entecavir (ETV) or tenofovir disoproxil fumarate (TDF). METHODS: A total of 205 and 111 HBeAg-positive patients without cirrhosis who had stopped ETV or TDF treatment, respectively, for at least 6 months were recruited. RESULTS: In the entire cohort, patients with HBeAg seroconversion during treatment, and propensity score-matched patients, those who discontinued TDF had significantly higher rates of virological and clinical relapse than patients who discontinued ETV therapy. Multivariate analysis identified that TDF was independently associated with virological and clinical relapse in the entire cohort and subgroup analysis. Patients with HBeAg loss without anti-HBe antibody formation during treatment had significantly higher rates of off-therapy HBV relapse and HBeAg seroreversion than patients with HBeAg seroconversion during treatment. The hepatitis B core-related antigen (HBcrAg) level at end of treatment (EOT) was independently associated with HBV relapse and HBeAg seroreversion in all patients and patients with HBeAg seroconversion during treatment. CONCLUSIONS: TDF therapy, HBeAg loss without seroconversion during treatment, and higher HBcrAg levels at EOT are significant predictors of HBV relapse in HBeAg-positive patients who discontinued ETV or TDF.

Impact of Sofosbuvir-Based Direct-Acting Antivirals on Renal Function in Chronic Hepatitis C Patients With Impaired Renal Function: A Large Cohort Study From the Nationwide HCV Registry Program (TACR).

BACKGROUND & AIMS: Sofosbuvir is approved for chronic hepatitis C (CHC) patients with severe chronic kidney disease (CKD). The impact of sofosbuvir-based therapy on renal function augmentation on a real-world nationwide basis is elusive. METHODS: The 12,995 CHC patients treated with sofosbuvir-based (n = 6802) or non-sofosbuvir-based (n = 6193) regimens were retrieved from the Taiwan nationwide real-world HCV Registry Program. Serial estimated glomerular filtration rate (eGFR) levels were measured at baseline, end of treatment (EOT), and end of follow-up (EOF) (3 months after EOT). RESULTS: The eGFR decreased from baseline (91.4 mL/min/1.73 m2) to EOT (88.4 mL/min/1.73 m2; P < .001) and substantially recovered at EOF (88.8 mL/min/1.73 m2) but did not return to pretreatment levels (P < .001). Notably, a significant decrease in eGFR was observed only in patients with baseline eGFR ≥90 mL/min/1.73 m2 (from 112.9 to 106.4 mL/min/1.73 m2; P < .001). In contrast, eGFR increased progressively in patients whose baseline eGFR was <90 mL/min/1.73 m2 (from 70.0 to 71.5 mL/min/1.73 m2; P < .001), and this increase was generalized across different stages of CKD. The trend of eGFR amelioration was consistent irrespective of sofosbuvir usage. Multivariate adjusted analysis demonstrated that baseline eGFR >90 mL/min/1.73 m2 was the only factor independently associated with significant slope coefficient differences of eGFR (-1.98 mL/min/1.73 m2; 95% confidence interval, -2.24 to -1.72; P < .001). The use of sofosbuvir was not an independent factor associated with eGFR change. CONCLUSIONS: Both sofosbuvir and non-sofosbuvir-based regimens restored renal function in CHC patients with CKD, especially in those with significant renal function impairment.

Low-dose nivolumab in advanced hepatocellular carcinoma.

BACKGROUND: The approved dose of nivolumab is 3 mg/kg or a flat dose of 240 mg for indications. There is no dose-response relationship for nivolumab; therefore, a low-dose regimen may be an option to reduce financial toxicity. This study was designed to investigate the efficacy and safety of low-dose nivolumab in the management of hepatocellular carcinoma (HCC). METHODS: We retrospectively reviewed patients with HCC who received 20 or 100 mg of nivolumab intravenously every 2 weeks. The objective response rate was determined in accordance with the Response Evaluation Criteria in Solid Tumors criteria version 1.1. The Cox regression model and Kaplan-Meier method were used to analyze hazard factors, progression-free survival (PFS), and overall survival (OS). Adverse events (AEs) were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. RESULTS: In total, 78 patients were enrolled, including 49 with hepatitis B virus (HBV) and 23 with hepatitis C virus (HCV). All patients were staged as Barcelona Clinic Liver Cancer stage C, and 20 patients were classified as having Child-Pugh classification B (7). Nivolumab 20 mg was an independent prognostic factor for better PFS, and albumin-bilirubin grade 1 was the independent prognostic factor for superior OS in the multivariate analyses. Patients with better HBV (HBV DNA < 500 IU/ml) and HCV (HCV RNA undetectable) controls had superior OS. All AEs were grade 1-2 in severity, and all patients tolerated nivolumab without treatment interruption or dose adjustment. Additionally, 31 patients underwent subsequent therapy after nivolumab treatment. CONCLUSION: Low-dose nivolumab may be effective with manageable toxicity and can be an alternative option to reduce financial toxicity in patients with advanced HCC who cannot afford the high cost of immune checkpoint inhibitors in real-world practice.

Predictors of Virological Suppression After Clinical Relapse in Patients Who Discontinued Entecavir or Tenofovir.

BACKGROUND: The predictors of persistent virological suppression after clinical relapse remain unclear. AIMS: To investigate the predictors of retreatment or persistent virological suppression after clinical relapse in chronic hepatitis B (CHB) patients who discontinued entecavir or tenofovir disoproxil fumarate (TDF). METHODS: A total of 243 hepatitis B e antigen-negative CHB patients without cirrhosis who experienced clinical relapse after entecavir or TDF cessation were enrolled. RESULTS: Of the 243 CHB patients, 192 received retreatment and 51 did not receive retreatment after clinical relapse. Of the 51 patients without retreatment, 23 achieved persistent virological suppression (persistent HBV DNA < 2000 IU/mL at least 2 years) and 10 experienced hepatitis B surface antigen (HBsAg) loss. The Cox regression analysis showed that short consolidation duration, short duration of the first clinical relapse from the end of treatment (EOT), and high bilirubin and HBV DNA levels at the first clinical relapse were independent predictors of retreatment. Long duration of the first clinical relapse from the EOT and low HBsAg levels at the first clinical relapse were independent factors of patients with persistent virological suppression. The rates of persistent virological suppression at the first clinical relapse among patients with HBsAg < 100 and ≥ 100 IU/mL were 44.4% (12/27) and 5.1% (11/216) (P < 0.001), respectively. Baseline HBsAg levels and no retreatment requirement were independent factors associated with HBsAg loss. CONCLUSIONS: The HBsAg of 100 IU/mL at the first clinical relapse could predict persistent virological suppression after clinical relapse in patients who discontinued entecavir or TDF therapy.

The characteristics of patients with macrovascular invasion in hepatocellular carcinoma: when East meets West.

PURPOSE: To evaluate the prevalence and extension of macrovascular invasion (MaVI) in a large cohort of hepatocellular carcinoma (HCC) patients and analyze the association between MaVI and overall survival (OS). METHODS: From 2011 to 2018, 2540 patients with newly diagnosed HCC who were managed in our institution were enrolled in this retrospective study. Tumor invasion of the intrahepatic branches of the portal or hepatic veins was defined as peripheral MaVI. Tumor invasion of the main portal vein or inferior vena cava was defined as central MaVI. RESULTS: MaVI prevalence was 16.2% (n = 411). Among patients with Barcelona Clinic Liver Cancer (BCLC) stage C and Child-Pugh class A, 165 patients presented with peripheral MaVI and 89 patients with central MaVI. The median OS was 13.2 months (95% confidence interval [CI]: 11.4-15.4) in the peripheral MaVI group and 6.6 months (95% CI: 3.6-9.5) in the central MaVI group (p < 0.001). In patients with BCLC stage C and Child-Pugh class B or BCLC stage D, 68 patients presented with peripheral MaVI and 89 patients with central MaVI. The median OS was 3.6 months (95% CI: 3.1-4.2) in the peripheral MaVI group and 2.8 months (95% CI: 2.1-3.4) in the central MaVI group (p = 0.674). CONCLUSION: The extension of MaVI significantly affected patient survival only in those with BCLC stage C and Child-Pugh class A. In patients with BCLC stage C and Child-Pugh class B or BCLC stage D, survival was poor irrespective of MaVI status.

Incorporating albumin-bilirubin grade and up-to-seven criteria to predict outcomes of patients with intermediate stage hepatocellular carcinoma after transarterial (chemo)embolization.

BACKGROUND/PURPOSE: This study is to use albumin-bilirubin (ALBI) grade and up-to-7 (UT7) criteria to assess outcomes of patients with intermediate stage hepatocellular carcinoma (HCC) after transarterial (chemo)embolization (TA(C)E). METHODS: Between January 2012 and January 2019, newly diagnosed intermediate HCC patients underwent TA(C)E were enrolled and analyzed. The demographics, clinical characteristics and survival were obtained from medical chart reviews. RESULTS: A total of 359 patients were enrolled and 30.4% of them were within UT7 criteria (UT7 (-)). There were 36.5%, 59.3%, and 4.2% of the patients with ALBI grade I, II, and III, respectively. Beyond UT7 (UT7 (+)) and ALBI grade II/III were associated with overall mortality in multivariate analysis. Based on ALBI grade I/II/III and UT7 -/+, patients were classified into six groups as ALBI grade I plus UT7 (-), II plus UT7 (-), III plus UT7 (-), I plus UT7 (+), II plus UT7 (+), and III plus UT7(+). Distributions of median survival were 47.5, 32.9, 15, 34.3, 16.7 and 14.3 months, respectively. Patients with statistically insignificant survivals were further combined. Patients with ALBI grade I plus UT7 (-) were reclassified as ALBI-U class I, whereas ALBI grade II plus UT7 (-) and I plus UT7 (+) were ALBI-U class II, and the others were ALBI-U class III. There were 8.4%, 48.7%, and 42.9% of patients in ALBI-U class I, II, and III, respectively. The 5-year survival rate was 48.8%, 22.5%, and 13.7% in ALBI-U class I, II, and III, respectively (p < 0.01). CONCLUSION: ALBI-U classification was useful in predicting outcomes of patient with intermediate stage HCC after TA(C)E.

Reappraisal of the roles of alpha-fetoprotein in hepatocellular carcinoma surveillance using large-scale nationwide database and hospital-based information.

BACKGROUND/PURPOSE: Controversies over the use of alpha-fetoprotein (AFP) for detection of hepatocellular carcinoma (HCC) existed from guidelines. Using large-scale database and hospital-based information, we aimed to reappraise the role of AFP in HCC surveillance, including proportion of AFP elevation by stage of HCC, additional benefit of AFP in combination of ultrasonography (US) in the detection of early HCC, and survival in early HCC with high AFP levels. METHODS: This retrospective study enrolled 43,437 patients from database of the Taiwan Cancer Registry (TCR) and 4250 patients from Kaohsiung Chang Gung Memorial Hospital (KCGMH) between January 2011 and December 2017. RESULTS: The HCC cases in KCGMH accounted for 9.8% of the total cases in the TCR. Among both nationwide database and hospital-based information, the proportion of early HCC patients with an AFP level of ≥20 ng/mL was approximately 40%. In KCGMH, the proportion of patients with an AFP level of ≥20 ng/mL and a virus-related (hepatitis B and C) etiology was around 41.7%; furthermore, among patients with early HCC, those with an AFP level of ≥20 ng/mL had 4.7 years of median survival and 48.3% of the 5-year overall survival rate. By hospital electronic medical records review of early HCC cohort in KCGMH, approximately 10.9% of patients with AFP levels ≥20 ng/mL had US-undetectable early HCC. CONCLUSION: This study suggested that AFP in combination with US would add an additional benefit as being a prompted role for detection of early HCC in patients with US-undetectable HCC.

Ledipasvir/sofosbuvir for HCV genotype 1, 2, 4-6 infection: Real-world evidence from a nationwide registry in Taiwan.

BACKGROUND/PURPOSE: The Taiwan Association for the Study of the Liver (TASL) HCV Registry (TACR) is a nationwide registry of chronic hepatitis C patients in Taiwan. This study evaluated antiviral effectiveness of ledipasvir (LDV)/sofosbuvir (SOF) in patients in the TACR. METHODS: Patients enrolled in TACR from 2017-2020 treated with LDV/SOF were eligible. The primary outcome was the proportion of patients with sustained virologic response 12 weeks after end of treatment (SVR12). RESULTS: 5644 LDV/SOF ± ribavirin-treated patients were included (mean age: 61.4 years; 54.4% female). Dominant viral genotypes were GT1 (50.8%) and GT2 (39.3%). 1529 (27.1%) patients had liver cirrhosis, including 201 (3.6%) with liver decompensation; 686 (12.2%) had chronic kidney disease. SVR12 was achieved in 98.6% of the overall population and in 98.2% and 98.7% of patients with and without cirrhosis, respectively. SVR12 rates in patients with compensated cirrhosis treated with LDV/SOF without RBV were >98%, regardless of prior treatment experience. SVR12 was 98.6%, 98.4%, 100%, 100%, and 98.7% among those with GT1, GT2, GT4, GT5, and GT6 infections, respectively. Although patient numbers were relatively small, SVR12 rates of 100% were reported in patients infected with HCV GT2, GT5, and GT6 with decompensated cirrhosis and 98% in patients with severely compromised renal function. LDV/SOF adherence ≤60% (P < 0.001) was the most important factor associated with treatment failure. Incidence of adverse events was 15.8%, with fatigue being the most common. CONCLUSION: LDV/SOF is effective and well tolerated in routine clinical practice in Taiwan. Cure rates were high across patient populations.

The role of hepatitis B virus core-related antigen in predicting hepatitis B virus relapse after cessation of entecavir in hepatitis B e antigen-negative patients.

This study investigated the ability of hepatitis B core-related antigen (HBcrAg) to predict hepatitis B virus (HBV) relapse in HBeAg-negative patients after cessation of entecavir therapy. A total of 301 HBeAg-negative patients without cirrhosis who had stopped entecavir therapy for at least 12 months were recruited. All patients fulfilled the stopping criteria proposed by the APASL 2012 guidelines. The five-year cumulative rates of virological relapse, clinical relapse and HBsAg loss were 71.6%, 57.3% and 18.7%, respectively. Serum HBsAg at end of treatment (EOT) was an independent predictor of virological relapse, clinical relapse and HBsAg loss; an EOT HBsAg of 150 IU/ml was the optimal cut-off value. The 5-year virological relapse rates for patients with <150 and ≥150 IU/ml HBsAg at EOT were 43.3% and 82.2% (p < 0.001), clinical relapse rates were 32.3% and 66.3% (p < 0.001), and HBsAg loss rates were 46.1% and 5.2% (p < 0.001), respectively. A baseline HBcrAg of 4 IU/ml was the optimal cut-off value for predicting HBV relapse. Among patients with an EOT HBsAg <150 IU/ml, the five-year virological relapse rates for patients with baseline HBcrAg levels ≤4 and >4 log U/ml were 27.9% and 59.1% (p = 0.006) and the clinical relapse rates were 18% and 48.1% (p = 0.014), respectively. EOT HBcrAg was not a significant predictor of virological or clinical relapse after cessation of entecavir. In conclusion, the combination of an EOT HBsAg of 150 IU/ml and baseline HBcrAg of 4 log U/ml can effectively predict the risk of HBV relapse after stopping entecavir therapy.

Factors associated with treatment failure of direct-acting antivirals for chronic hepatitis C: A real-world nationwide hepatitis C virus registry programme in Taiwan.

BACKGROUND/AIMS: Direct-acting antivirals (DAAs) are highly effective in treating chronic hepatitis C virus (HCV)-infected patients. The real-world treatment outcome in Taiwanese patients on a nationwide basis is elusive. METHODS: The Taiwan HCV Registry (TACR) programme is a nationwide registry platform including 48 study sites, which is organized and supervised by the Taiwan Association for the Study of the Liver. The primary endpoint was sustained virological response (SVR12, undetectable HCV RNA 12 weeks after end-of-treatment). RESULTS: A total of 13 951 registered patients with SVR12 data available were analysed (mean age, 63.0 years; female, 55.9%; HCV genotype-1 [GT1], 57.9%; cirrhosis, 38.4%; preexisting hepatocellular carcinoma [HCC], 10.6%; and hepatitis B virus coinfection, 7.7%). The overall SVR12 rate was 98.3%, with 98.7%, 98.0%, 98.4% and 97.4% in treatment-naïve noncirrhotic, treatment-naïve cirrhotic, treatment-experienced noncirrhotic and treatment-experienced cirrhotic patients, respectively. The SVR12 rate was > 95% across all subgroups except treatment-experienced cirrhotic patients who received sofosbuvir/ribavirin (88.7%), treatment-naïve noncirrhotic patients (94.8%) and treatment-experienced cirrhotic (94.8%) patients who received daclatasvir/asunaprevir. The most important factor associated with treatment failure was DAA adherence < 60% ( adjusted odds ratio [aOR]/95% confidence interval [CI]: 117.1/52.4-261.3, P < .001), followed by GT3/GT2 (aOR/CI: 5.78/2.25-14.9, P = .0003 and aOR/CI: 1.55/1.05-2.29, P = .03, compared with GT1), active hepatocellular carcinoma (aOR/CI: 4.29/2.57-7.16, P < .001), the use of sofosbuvir/ribavirin (aOR/CI: 2.51/1.67-3.77, P < .001) and daclatasvir/asunaprevir (aOR/CI: 3.29/1.94-5.58, P < .001), decompensated liver cirrhosis (aOR/CI: 2.50/1.20-5.22, P = .02) and high HCV viral loads (aOR/CI: 2.16/1.57-2.97, P < .001). CONCLUSIONS: DAAs are highly effective in treating Taiwanese HCV patients in the real-world setting. Maintaining DAA adherence and selecting highly efficacious regimens are keys to ensure treatment success.