Five-year on-treatment variables-based PPACS model predicts subsequent hepatocellular carcinoma in entecavir/tenofovir-treated patients.

Considering the lower risk of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients receiving long-term potent antiviral therapy, models predicting HCC after 5 years of therapy are needed. We conducted a multicenter retrospective cohort study to construct and validate a model predicting HCC after 5 years of entecavir (ETV) or tenofovir (TFV) therapy for CHB. The endpoint was HCC after 5 years of ETV/TFV therapy. Information on age, sex, liver cirrhosis (assessed by diagnosis code and confirmed by clinical findings) and type of antiviral agent was obtained at baseline (initiation of ETV/TFV). Laboratory values were collected at baseline and 5 years. Risk factors for HCC were identified in the training set and the final prediction model was validated using the test set. Among 7542 patients, 345 (4.6%) developed HCC after 5 years of ETV/TFV therapy. HCC risk after 5 years of ETV/TFV therapy was increased by 4-fold in patients with liver cirrhosis than in those without cirrhosis at baseline. Furthermore, Platelet counts and Prothrombin time at 5 years, Age at baseline and Sex were associated with risk of HCC and were incorporated into a prediction model, PPACS. PPACS showed a good performance with a time-dependent area under the curve of 0.80 (95% confidence interval, 0.75-0.85) at 8-year of ETV/TFV therapy, a Brier score of 0.031 and an integrated Brier score of 0.006 in the test set. In conclusion, the PPACS model provides a reliable assessment of HCC risk after 5 years of ETV/TFV therapy (https://ppacs.shinyapps.io/shiny_app_up/).

A machine learning model for predicting hepatocellular carcinoma risk in patients with chronic hepatitis B.

BACKGROUND: Machine learning (ML) algorithms can be used to overcome the prognostic performance limitations of conventional hepatocellular carcinoma (HCC) risk models. We established and validated an ML-based HCC predictive model optimized for patients with chronic hepatitis B (CHB) infections receiving antiviral therapy (AVT). METHODS: Treatment-naïve CHB patients who were started entecavir (ETV) or tenofovir disoproxil fumarate (TDF) were enrolled. We used a training cohort (n = 960) to develop a novel ML model that predicted HCC development within 5 years and validated the model using an independent external cohort (n = 1937). ML algorithms consider all potential interactions and do not use predefined hypotheses. RESULTS: The mean age of the patients in the training cohort was 48 years, and most patients (68.9%) were men. During the median 59.3 (interquartile range 45.8-72.3) months of follow-up, 69 (7.2%) patients developed HCC. Our ML-based HCC risk prediction model had an area under the receiver-operating characteristic curve (AUC) of 0.900, which was better than the AUCs of CAMD (0.778) and REAL B (0.772) (both p < .05). The better performance of our model was maintained (AUC = 0.872 vs. 0.788 for CAMD and 0.801 for REAL B) in the validation cohort. Using cut-off probabilities of 0.3 and 0.5, the cumulative incidence of HCC development differed significantly among the three risk groups (p < .001). CONCLUSIONS: Our new ML model performed better than models in terms of predicting the risk of HCC development in CHB patients receiving AVT.

Changes in liver stiffness values assessed using transient elastography in chronic hepatitis B patients treated with tenofovir disoproxil fumarate: a prospective observational study.

BACKGROUND/AIMS: Regression of liver fibrosis during antiviral therapy in chronic hepatitis B (CHB) patients has been demonstrated, but data on the influence of long-term treatment with tenofovir disoproxil fumarate (TDF) on liver stiffness (LS) measured by transient elastography are scarce. We aimed to investigate the changes in LS values during the 144-week TDF therapy in treatment-naïve CHB patients. METHODS: This prospective observational study was conducted from April 2015 to July 2020 at CHA Bundang Medical Center. Laboratory tests and LS measurements were performed at baseline and repeated at weeks 12, 24, 48, 96, and 144. A significant decline in LS was defined as ≥ 30% decrease in LS value at week 96 from baseline. RESULTS: A total of 48 treatment-naïve CHB patients initiating TDF therapy were screened, and 36 patients were included in the final analysis (median age, 46 [interquartile range, 34.5-55.8] years; 19 men [52.8%]). During TDF therapy, the median LS values decreased from 13.8 kPa at baseline to 8.7 kPa, 6.5 kPa, and 6.4 kPa at weeks 48, 96, and 144, respectively (all P < 0.001). At week 96, virological and biochemical responses were achieved in 34 (94.4%) patients and 20 (76.9%) patients, respectively. Moreover, 21 of 36 (58.3%) patients showed a significant decline in LS value. A higher baseline LS value was a single independent predictor for the reduction in LS value at week 96 from baseline (P < 0.001). CONCLUSIONS: During the 144-week TDF therapy, LS values declined significantly in treatment-naïve CHB patients.

Changes in general and central fatness are associated with hepatocellular carcinoma: A Korean nationwide longitudinal study.

We investigated the impact of short-term changes in general and central fatness on the risk of hepatocellular carcinoma (HCC) in a large, population-based cohort. We screened 7 221 479 subjects who underwent health examinations provided by the National Health Insurance Service of South Korea in 2009 and 2011. In total, 6 789 472 subjects were included in the final analysis. General fatness was defined as a body mass index (BMI) ≥25 kg/m2 , and central fatness was defined as a waist circumference (WC) ≥90 cm in men and ≥85 cm in women. Subjects were classified according to the change in body fatness between 2009 and 2011, as follows: (a) persistent no fatness as no fatness in both 2009 and 2011, (b) reversed fatness as fatness in 2009, but no fatness in 2011, (c) incident fatness as no fatness in 2009, but fatness in 2011 or (d) persistent fatness as fatness in both 2009 and 2011. During a median 6.4-year follow-up, we documented 9952 HCC cases. Compared to subjects with a persistent no general fatness, the risk of HCC significantly increased in those with incident (adjusted hazard ratio [aHR] = 1.10, 95% confidence interval [CI] = 1.01-1.20) and persistent (aHR = 1.28, 95% CI = 1.23-1.34) general fatness. Compared to subjects with persistent no central fatness, those with incident and persistent central fatness showed a significantly increased risk of HCC (aHR = 1.19, 95% CI = 1.11-1.27 and aHR = 1.33, 95% CI = 1.26-1.40, respectively). Taken together, these findings indicate the importance of strategies for preventing and reversing body fatness to reduce the incidence of HCC.

Long-term renal safety between patients with chronic hepatitis B receiving tenofovir vs. entecavir therapy: A multicenter study.

Renal safety is a critical issue in chronic hepatitis B (CHB) patients receiving long-term entecavir (ETV) or tenofovir disofuroxil fumarate (TDF) therapy. We investigated their effects on estimated glomerular filtration rate (eGFR). Treatment-naive CHB patients receiving ETV or TDF for ≥1 year were recruited. The eGFR was assessed using the Chronic Kidney Disease Epidemiology Collaboration equation. We calculated average annual percent change (AAPC) in eGFR using Joinpoint regression. At the beginning of the observation, the ETV group had more unfavorable conditions than the TDF group: lower eGFR and higher FIB-4 and APRI than the TDF group (all p < .001). After 6 years of antiviral therapy, the mean eGFR in the ETV group (n = 1793) was maintained (96.0 at first year to 95.6 ml/min/1.73 m2 at sixth year; AAPC -0.09%; p = .322), whereas that in the TDF group (n = 1240) significantly decreased annually (101.9 at first year to 96.9 ml/min/1.73 m2 at sixth year; AAPC -0.88%; p < .001). Notably, in the TDF group, even patients without diabetes (AAPC -0.80%; p = 0.001) or hypertension (AAPC -0.87%; p = .001) experienced significant decrease in eGFR. Expectably, accompanying diabetes (AAPC -1.59%; p = .011) or hypertension (AAPC -1.00%; p = .002) tended to accelerate eGFR decrease. TDF treatment (odds ratio 1.66, p < .001), along with eGFR<60 ml/min/1.73 m2 , serum albumin<3.5 mg/dl, and hypertension, were independently associated with ongoing renal dysfunction, defined as a negative slope of the mean eGFR change. In conclusion, compared with ETV, long-term TDF treatment induced slow, but progressive renal dysfunction. Although the annual eGFR change by TDF was small, careful monitoring is necessary, especially in patients requiring life-long therapy.

Gamma-glutamyl transpeptidase dynamics as a biomarker for advanced fibrosis in non-alcoholic fatty liver disease.

BACKGROUND AND AIM: It is unclear whether changes in lipid profile and liver biochemistry are associated with advanced fibrosis. METHODS: Patients diagnosed with non-alcoholic fatty liver disease (NAFLD) between 2009 and 2017 were included. The changes in blood tests were calculated as follows: [(value at 6 months - value at baseline)/value at baseline] × 100. The endpoint was advanced fibrosis determined by the NAFLD fibrosis score, calculated every year from diagnosis until 2019. Cox proportional hazards models were used to identify factors predicting advanced fibrosis. RESULTS: After a median follow-up of 31.7 (19.4-50.8) months, advanced fibrosis occurred in 64 (6.3%) of 1021 patients. Gamma-glutamyl transpeptidase (GGT) levels (72.9 vs 51.1 IU/L; P = 0.23) and ΔGGT (+6.0% vs -6.9%; P = 0.06) were higher in the advanced fibrosis group. ΔGGT (hazard ratio [HR] 1.03; P < 0.001) was significantly associated with advanced fibrosis after adjusting for age and platelet count. The positive ΔGGT group showed a higher incidence of advanced fibrosis and the 1-standard deviation increment in ΔGGT showed a significant association with advanced fibrosis both in statin users (HR, 1.35) and in non-users (HR, 1.31; Ps < 0.05). The restricted cubic spline model identified a positive correlation between ΔGGT and the NAFLD fibrosis scores (P < 0.001). ΔGGT showed sensitivity of 64.2%, specificity of 52.6%, and negative predictive value of 98.3% in predicting advanced fibrosis. CONCLUSIONS: ΔGGT calculated at 6 months following NAFLD diagnosis is associated with advanced fibrosis.

Long-term effects of entecavir and tenofovir treatment on the fibrotic burden in patients with chronic hepatitis B.

BACKGROUND AND AIM: Antiviral therapy (AVT) induces fibrosis regression in patients with chronic hepatitis B. We investigated long-term effects of entecavir (ETV) versus tenofovir (TDF) on fibrotic burden. METHODS: Treatment-naïve chronic hepatitis B patients who had begun ETV or TDF were recruited from four tertiary hospitals. The aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis index based on four factors (FIB-4) were used to determine fibrotic burden. RESULTS: In the entire population (n = 3277), although patients treated with ETV had higher baseline APRI (1.71 vs 1.07, P < 0.001) and FIB-4 (3.60 vs 2.80, P < 0.001) than those treated with TDF, significant fibrosis regression was identified during 6 years of AVT in both ETV (APRI, mean 1.71 â†’ 0.48, P < 0.001; FIB-4, mean 3.60 â†’ 2.21, P < 0.001) and TDF groups (APRI, mean 1.07 â†’ 0.43, P < 0.001; FIB-4, mean 2.80 â†’ 2.19, P < 0.001). In patients without cirrhosis (n = 2366), baseline APRI was significantly higher in ETV group than in TDF group (1.72 vs 0.97, P < 0.001); however, they became similar after 6 months. Similarly, baseline FIB-4 was significantly higher in ETV group than in TDF group (3.25 vs 2.35, P < 0.001), but became similar from 4 to 6 years. In patients with cirrhosis (n = 911), baseline APRI (1.70 vs 1.34, P < 0.001) and FIB-4 (4.62 vs 3.91, P = 0.005) were higher in ETV group than in TDF, however, both parameters became statistically similar from 6 months to 6 years. CONCLUSION: Significant regression of APRI and FIB-4 was observed during long-term ETV and TDF treatment. Despite higher baseline fibrotic burden in ETV group, fibrotic burden between the groups eventually converged through significant fibrosis regression after 1 to 4 years of AVT.

High body mass index hinders fibrosis improvement in patients receiving long-term tenofovir therapy in hepatitis B virus-related cirrhosis.

Long-term suppression of hepatitis B virus with tenofovir (TDF) induces fibrosis regression, and repeated liver stiffness (LS) measurement can indicate the improvement of fibrosis. We aimed to investigate predictors for LS improvement assessed by changes in patients receiving long-term TDF therapy in chronic hepatitis B (CHB) with liver cirrhosis. CHB patients with histologically proven liver cirrhosis who received TDF as the first-line therapy from 2012 to 2015 were recruited. LS and controlled attenuation parameter (CAP) measurements were repeated at baseline and 3 years after therapy. Liver stiffness improvement was defined as a drop of LS value ≥30% from the baseline. A total of 131 patients were enrolled (mean age 51.4% and male 64.9%). After 3 years of TDF therapy, the mean LS value significantly improved (from 14.7 to 8.6 kPa, P < .001), and 96 (73.3%) patients have achieved LS improvement. Predictors associated with improvement of LS were low body mass index (BMI), HBeAg positivity, and low CAP value at baseline. In multivariate analysis, low BMI was a single factor independently associated with LS improvement (odds ratio 0.680, 95% CI 0.560-0.825, P < .001). Patients with BMI < 23.5, had a 1.96 times more chance of achieving LS improvement compared to those with BMI ≥ 23.5 (90.1% vs. 46.0%, P = .001). High BMI was a single significant factor hindering the fibrosis improvement in patients receiving long-term TDF therapy in CHB with liver cirrhosis. Life style modification and BMI reduction should be encouraged to enhance fibrosis improvement.

Improvement of Liver Fibrosis after Long-Term Antiviral Therapy Assessed by Fibroscan in Chronic Hepatitis B Patients With Advanced Fibrosis.

OBJECTIVES: Performing repeated liver biopsies to assess the improvement of liver fibrosis is impractical. The purpose of this prospective cohort study was to assess the improvement of liver fibrosis during antiviral treatment by serial liver stiffness (LS) measurement using Fibroscan in chronic hepatitis B (CHB) patients with advanced fibrosis. METHODS: Nucleos(t)ide analog-naive CHB patients with advanced fibrosis in histological findings (stage ≥F3), high viral load (hepatitis B virus DNA ≥2,000 IU/ml), and normal liver enzyme levels (<2 × upper normal limit) before starting antiviral treatment were included in this study. LS measurement was performed at baseline and annually for 5 years during antiviral treatment. Five-year fibrosis improvement was defined as LS value <7.2 kPa (

Noninvasive Prediction of Erosive Esophagitis Using a Controlled Attenuation Parameter (CAP)-Based Risk Estimation Model.

BACKGROUND: Erosive esophagitis and fatty liver share obesity and visceral fat as common critical pathogenesis. However, the relationship between the amount of hepatic fat and the severity of erosive esophagitis was not well investigated, and there is no risk estimation model for erosive esophagitis. AIM: To evaluate the relationship between the amount of hepatic fat and the severity of erosive esophagitis and then develop a risk estimation model for erosive esophagitis. METHODS: We enrolled 1045 consecutive participants (training cohort, n = 705; validation cohort, n = 340) who underwent esophagogastroduodenoscopy and CAP. The relationship between severity of fatty liver and erosive esophagitis was investigated, and independent predictors for erosive esophagitis that have been investigated through logistic regression analyses were used as components for establishing a risk estimation model. RESULTS: The prevalence of erosive gastritis was 10.7 %, and the severity of erosive esophagitis was positively correlated with the degree of hepatic fatty accumulation (P < 0.05). A CAP-based risk estimation model for erosive esophagitis using CAP, Body mass index, and significant alcohol Drinking as constituent variables was established and was dubbed the CBD score (AUROC = 0.819, range 0-11). The high-risk group (CBD score ≥3) showed significantly higher risk of having erosive esophagitis than the low-risk group (CBD score <3) (24.1 vs. 2.7 %, respectively; P < 0.001). The diagnostic accuracy of CBD score was maintained in the validation cohort (AUROC = 0.848). CONCLUSION: The severity of erosive esophagitis was positively correlated with the degree of hepatic fatty accumulation, and the CBD score might be a simple CAP-based risk model for predicting erosive esophagitis.

Normal controlled attenuation parameter values: a prospective study of healthy subjects undergoing health checkups and liver donors in Korea.

BACKGROUND/AIMS: The controlled attenuation parameter (CAP) is a noninvasive method of assessing hepatic steatosis. We defined the normal range of CAP values in healthy subjects and evaluated the associated factors. METHODS: CAP values were measured in a cohort of healthy subjects who were screened as living liver transplantation donors and those who underwent health checkups. Subjects with current or a history of chronic liver disease, abnormalities on liver-related laboratory tests, or fatty liver on ultrasonography or biopsy were excluded. RESULTS: The mean age of the 264 recruited subjects (131 males and 133 females; 76 potential liver donors and 188 subjects who had undergone health checkups) was 49.2 years. The mean CAP value was 224.8 ± 38.7 dB/m (range 100.0-308.0 dB/m), and the range of normal CAP values (5th-95th percentiles) was 156.0-287.8 dB/m. The mean CAP value was significantly higher in the health checkup than in the potential liver donor group (227.5 ± 42.0 vs. 218.2 ± 28.3 dB/m, P = 0.040). CAP values did not differ significantly according to gender or age in either group (all P > 0.05). In a multivariate linear regression analysis, body mass index (ß = 0.271, P = 0.024) and triglyceride levels (ß = 0.348, P = 0.008) were found to be independently associated with CAP values. CONCLUSION: We determined the normal range of CAP values and found that body mass index and triglyceride levels were associated with the CAP values of healthy subjects.

Controlled attenuation parameter (CAP) for detection of hepatic steatosis in patients with chronic liver diseases: a prospective study of a native Korean population.

BACKGROUND: Controlled attenuation parameter (CAP) is a non-invasive method of measuring hepatic steatosis using a process based on transient elastography. We investigated the diagnostic accuracy of CAP in detecting hepatic steatosis in patients with chronic liver disease (CLD). METHODS: A total of 135 patients with CLD who underwent liver biopsy and CAP were consecutively enrolled in this prospective study. The performance of CAP for detection of hepatic steatosis compared with liver biopsy was calculated using area under receiver operating characteristics curves (AUROC). Steatosis was categorized into S0 (<5%), S1 (5-33%), S2 (34-66%) and S3 (>66% of hepatocytes). RESULTS: Male gender predominated (n = 87, 64%) and the median age was 51 years. The aetiologies of CLD included non-alcoholic fatty liver disease (n = 56, 41.5%) and chronic viral hepatitis because of hepatitis B (n = 47, 34.8%) and C (n = 12, 8.9%). Steatosis repartition was: S0 31.1% (n = 42), S1 43.7% (n = 59), S2 18.5% (n = 25) and S3 6.7% (n = 9) respectively. In the multivariate analysis, steatosis grade and body mass index were independently associated with CAP (all P < 0.001), whereas fibrosis stage and activity grade were not. The AUROCs of CAP were 0.885 for ≥S1 (sensitivity 73.1%, specificity 95.2%), 0.894 for ≥S2 (sensitivity 82.4%, specificity 86.1%) and 0.800 for S3 (sensitivity 77.8%, specificity 84.1%). The optimal cut-off CAP values that maximized the Youden index were 250 dB/m (≥S1), 299 dB/m (≥S2), and 327 dB/m (=S3) respectively. CONCLUSIONS: Our data showed that CAP had high diagnostic accuracy for detecting hepatic steatosis in patients with CLD and suggested that CAP is also applicable for Asian patients.

Community-acquired vs. nosocomial spontaneous bacterial peritonitis in patients with liver cirrhosis.

BACKGROUND/AIMS: Spontaneous bacterial peritonitis (SBP) is a common complication in patients with end-stage liver disease, but reports comparing community-acquired SBP (CA-SBP) with nosocomial SBP (N-SBP) are rare. This study compared the clinical characteristics, microbiological characteristics, and treatment outcomes of patients with CA-SBP and N-SBP. METHODOLOGY: Records for 248 patients (173 men, 75 women) with cirrhosis who experienced SBP were retrospectively reviewed. RESULTS: The study population included 202 (81.5%) patients with CA-SBP and 46 (18.5%) patients with N-SBP. Patients with CA-SBP or N-SBP showed no significant differences in baseline or microbiological characteristics, except for a high frequency of previous SBP history in the N-SBP population (P=0.020). During hospitalization, antibiotic switching and in-hospital mortality were significantly higher for patients with N-SBP than CA-SBP (35.6% vs. 8.9%; P=0.001 and 30.4% vs. 12.9%; P=0.028). There were 202 (81.5%) deaths during the follow-up period, with longer overall survival time in patients with CA-SBP (7.9 vs. 3.9 months; P=0.041). However, time to recurrence was not significantly different between the two groups (4.7 vs. 3.6 months; P=0.910). CONCLUSIONS: N-SBP was significantly associated with increased antibiotic switching, higher in-hospital mortality and shorter overall survival. Third-generation cephalosporin may be inappropriate as first-line empirical antibiotics for patients with N-SBP.

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.

Sorafenib vs. Lenvatinib in advanced hepatocellular carcinoma after atezolizumab/bevacizumab failure: A real-world study.

BACKGROUND/AIMS: 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.

Effect of direct-acting antivirals on disease burden of hepatitis C virus infection in South Korea in 2007-2021: a nationwide, multicentre, retrospective cohort study.

Background: It is unclear whether direct-acting antivirals (DAAs) treatment improves the disease burden in hepatitis C virus (HCV) infection. This study aimed to investigate the effect of DAA treatment on the reduction of disease burden in patients with HCV infection using individual participant data. Methods: This nationwide multicentre retrospective cohort study recruited patients with HCV infection from 29 tertiary institutions in South Korea. The data collection was done from medical records in each institution. The study included the untreated patients and the DAAs-treated patients and excluded those with a history of interferon-based treatments. Disease burden was the primary outcome, as represented by disability-adjusted life years (DALYs). Improvement in fibrosis after DAA treatment was assessed using APRI, FIB-4 index, and liver stiffness (LS) as assessed by transient elastography. Clinical outcomes were hepatocellular carcinoma (HCC), decompensation, and mortality. Findings: Between January 1, 2007, and February 17, 2022, data from 11,725 patients with HCV infection, 8464 (72%) of whom were treated with DAAs, were analysed. DAA treatment significantly improved APRI- (median 0.64 [interquartile range (IQR), 0.35-1.31]-0.33 [0.23-0.52], p < 0.0001), FIB-4- (median 2.42 [IQR, 1.48-4.40]-1.93 [1.31-2.97], p < 0.0001), and liver LS-based fibrosis (median 7.4 [IQR, 5.3-12.3]-6.2 [4.6-10.2] kPa, p < 0.0001). During the median follow-up period of 27.5 months (IQR, 10.6-52.4), 469 patients died (4.0%), 586 (5.0%) developed HCC, and 580 (4.9%) developed decompensation. The APRI-based DALY estimate was significantly lower in the DAA group than in the untreated group (median 4.55 vs. 5.14 years, p < 0.0001), as was the FIB-4-based DALY estimate (median 5.43 [IQR, 3.00-6.44] vs. 5.79 [3.85-8.07] years, p < 0.0001). The differences between the untreated and DAA groups were greatest in patients aged 40-60 years. In multivariable analyses, the DAA group had a significantly reduced risk of HCC, decompensation, and mortality compared with the untreated group (hazard ratios: 0.41 [95% confidence interval (CI), 0.34-0.48], 0.31 [95% CI, 0.30-0.38], and 0.22 [95% CI, 0.17-0.27], respectively; p < 0.0001). Interpretation: Our findings suggest that DAA treatment is associated with the improvement of liver-related outcomes and a reduction of liver fibrosis-based disease burden in patients with HCV infection. However, further studies using liver biopsy are needed to clarify the effect of DAA treatment on the reduction in the exact fibrosis-based disease burden beyond noninvasive tests. Funding: The Korea Disease Control and Prevention Agency.

Asian Pacific Association for the Study of the Liver clinical practice guidelines on liver transplantation.

Liver transplantation is a highly complex and challenging field of clinical practice. Although it was originally developed in western countries, it has been further advanced in Asian countries through the use of living donor liver transplantation. This method of transplantation is the only available option in many countries in the Asia-Pacific region due to the lack of deceased organ donation. As a result of this clinical situation, there is a growing need for guidelines that are specific to the Asia-Pacific region. These guidelines provide comprehensive recommendations for evidence-based management throughout the entire process of liver transplantation, covering both deceased and living donor liver transplantation. In addition, the development of these guidelines has been a collaborative effort between medical professionals from various countries in the region. This has allowed for the inclusion of diverse perspectives and experiences, leading to a more comprehensive and effective set of guidelines.

Partial virological response to adefovir add-on lamivudine rescue therapy in patients with lamivudine-resistant chronic hepatitis B.

BACKGROUND/AIMS: In patients with lamivudine (LAM)-resistant chronic hepatitis B (CHB) receiving adefovir (ADV) add-on LAM therapy, insufficient viral suppression or the appearance of additional ADV resistance has remained unresolved. This study determined the partial virological response (PVR) criteria to predict a virological response (VR) at week 96 in these patients. METHODS: 96 patients with LAM-resistant CHB (ADV add-on LAM therapy >2 years) were analyzed. For predicting VR at week 96, the area under the receiver operating characteristic curve values at different time points were compared to establish the optimal time point, and the maximal Youden index was calculated to determine the optimal cut-off hepatitis B virus (HBV) DNA level. RESULTS: 50 (52.1%) patients achieved VR at 2 years after ADV add-on LAM therapy. The optimal PVR criteria were determined to be HBV DNA 500 IU/ml at week 48. 44 (45.8%) patients who met optimal PVR criteria showed a significantly higher risk for detectable HBV DNA levels at week 96 than those with a favorable VR (HBV DNA <500 IU/ml) at week 48. CONCLUSIONS: This study suggested optimal PVR criteria in patients with LAM-resistant CHB receiving ADV add-on LAM therapy. Modification of the antiviral agent regimen should be considered if the serum HBV DNA level exceeds 500 IU/ml at week 48.

The Incidence and Care Cascade of the Hepatitis C Virus in Korea.

Background/Aims: The 2030 hepatitis C virus (HCV) elimination targets of the World Health Organization are an 80% reduction in incidence and 65% reduction in mortality compared to the 2015 rates. However, information on the nationwide incidence and treatment rates of HCV infection are limited. We aimed to investigate the nationwide incidence and status of the care cascade for HCV infection in Korea. Methods: This study used data from the Korea Disease Control and Prevention Agency linked with the data of the Korea National Health Insurance Service. Linkage to care was defined as visiting hospitals twice or more due to HCV infection within 1.5 years of the index date. The treatment rate was the number who had been prescribed antiviral medication within 1.5 years from the index date out of patients newly diagnosed with HCV. Results: The new HCV infection rate was 17.2 per 100,000 person-years (n=8,810) in 2019. The number of new HCV infections was the highest in patients aged 50 to 59 years (n=2,480), and the new HCV infection rate significantly increased with age (p<0.001). Among newly infected patients with HCV, the linkage to care rate was 78.2% (78.2% men, 78.2% women) and the treatment rate was 58.1% (56.8% men, 59.3% women) within 1.5 years. Conclusions: The new HCV infection rate was 17.2 per 100,000 person-years in Korea. It is necessary to continuously monitor the incidence and care cascade of HCV to establish proper strategies to reach the goal of HCV elimination by 2030.

Predictive biomarkers of survival in patients with advanced hepatocellular carcinoma receiving atezolizumab plus bevacizumab treatment.

BACKGROUND: Since atezolizumab plus bevacizumab (ATE+BEV) regimen for patients with unresectable hepatocellular carcinoma (HCC) was released quite recently, real-world data are lacking. We evaluated efficacy, safety, and predictive biomarkers for survival in patients receiving ATE+BEV. METHODS: Between 2020 and 2021, HCC patients receiving ATE+BEV at academic teaching hospitals were recruited. Treatment response was assessed using the Response Evaluation Criteria in Solid Tumors (version 1.1.). RESULTS: Among 121 patients enrolled, the median age was 63 years, with male predominance (82.6%). Complete response, partial response, stable disease, and progressive disease were identified in 2.5%, 26.4%, 54.5%, and 16.6%, respectively. Patients with alpha-fetoprotein and des-gamma-carboxy prothrombin (DCP) response, defined as ≥30% and ≥50% decreases, respectively, at the first response evaluation relative to baseline, and those with neutrophil-to-lymphocyte ratio (NLR) <2.5, had significantly higher objective response rates (42.6% vs. 21.5%, 50.0% vs. 26.2%, and 39.0% vs. 19.4%, respectively; all p < 0.05). During follow-up, the median overall survival (OS) was not reached, and the median progression-free survival (PFS) was 5.7 months. Multivariable analyses showed that macrovascular invasion (adjusted hazard ratio [aHR] 2.541; p = 0.017), DCP ≥186 mAU/ml (aHR 5.102; p < 0.001), NLR ≥2.5 (aHR 3.584; p = 0.001), and an NLR decrease ≥10% at the first response (aHR 0.305; p = 0.002) were independent predictors of OS, and DCP ≥186 mAU (aHR 2.311; p = 0.002) and NLR ≥2.5 (aHR 1.938; p = 0.012) were independent predictors of PFS. Grade ≥3 treatment-related adverse events (AEs) occurred in 33 (27.3%) patients. CONCLUSION: ATE+BEV showed favorable efficacy and safety. Baseline high DCP and NLR may be useful prognostic predictors for OS and PFS.