AI-Safe-C Score: Assessing Liver-Related Event Risks in Non-Cirrhotic Patients after Successful Direct-Acting Antiviral Treatment.

BACKGROUND & AIMS: Direct-acting antivirals (DAAs) have considerably improved chronic hepatitis C (HCV) treatment; however, post-sustained virological response (SVR) follow-up typically neglects the risk of liver-related events (LREs). This study introduces and validates artificial intelligence-safe score (AI-Safe-C score) to assess the risk of LREs in non-cirrhotic patients after successful DAA treatment. METHODS: The random survival forest model was trained to predict LREs in 913 non-cirrhotic HCV patients after SVR in Korea and was further tested in a combined cohort from Hong Kong and France (N = 1264). The model's performance was assessed using Harrell's C-index and the area under the time-dependent receiver operating characteristic curve (AUROC). RESULTS: The AI-Safe-C score, which incorporated liver stiffness measurement (LSM), age, sex, and six other biochemical tests-with LSM being ranked as the most important among 9 clinical features-demonstrated a C-index of 0.86 (95% confidence interval [CI]: 0.82-0.90) in predicting LREs in an external validation cohort. It achieved 3- and 5-year LRE AUROCs of 0.88 (95%CI, 0.84-0.92) and 0.79 (95%CI, 0.71-0.87), respectively, and for hepatocellular carcinoma, a C-index of 0.87 (95%CI, 0.81-0.92) with 3- and 5-year AUROCs of 0.88 (95%CI, 0.84-0.93) and 0.82 (95%CI, 0.75-0.90), respectively. Using a cut-off of 0.7, the 5-year LRE rate within a high-risk group was between 3.2% and 6.2%, mirroring the incidence observed in individuals with advanced fibrosis, in stark contrast to the significantly lower incidence of 0.2% to 0.6% in a low-risk group. CONCLUSION: AI-Safe-C score is a useful tool for identifying patients without cirrhosis who are at higher risk of developing LREs. The post-SVR LSM, as integrated within the AI-Safe-C score, plays a critical role in predicting future LREs. IMPACT AND IMPLICATIONS: The AI-Safe-C score introduces a paradigm shift in the management of non-cirrhotic patients post-DAA treatment, a cohort traditionally not included in routine surveillance protocols for LREs. By accurately identifying a subgroup at a comparably high risk of LREs, akin to those with advanced fibrosis, this predictive model facilitates a strategic reallocation of surveillance and clinical resources.

A machine learning model to predict liver-related outcomes after the functional cure of chronic hepatitis B.

BACKGROUND & AIMS: The risk of hepatocellular carcinoma (HCC) and hepatic decompensation persists after hepatitis B surface antigen (HBsAg) seroclearance. This study aimed to develop and validate a machine learning model to predict the risk of liver-related outcomes (LROs) following HBsAg seroclearance. METHODS: A total of 4,787 consecutive patients who achieved HBsAg seroclearance between 2000 and 2022 were enrolled from 6 centers in South Korea and a territory-wide database in Hong Kong, comprising the training (n=944), internal validation (n=1,102), and external validation (n=2,741) cohorts. Three machine learning-based models were developed and compared in each cohort. The primary outcome was the development of any LRO, including HCC, decompensation, and liver-related death. RESULTS: During a median follow-up of 55.2 (interquartile range=30.1-92.3) months, 123 LROs were confirmed (1.1%/person-year) in the Korean cohort. A model with the best predictive performance in the training cohort was selected as the final model (designated as PLAN-B-CURE), which was constructed using a gradient boosting algorithm and 7 variables (age, sex, diabetes, alcohol consumption, cirrhosis, albumin, and platelet count). Compared to previous HCC prediction models, PLAN-B-CURE showed significantly superior accuracy in the training cohort (c-index: 0.82 vs. 0.63-0.70, all P<0.001; area under the receiver operating characteristic curve: 0.86 vs. 0.62-0.72, all P<0.01; area under the precision-recall curve: 0.53 vs. 0.13-0.29, all P<0.01). PLAN-B-CURE showed a reliable calibration function (Hosmer-Lemeshow test P>0.05) and these results were reproduced in the internal and external validation cohorts. CONCLUSION: This novel machine learning model consisting of 7 variables provides reliable risk prediction of LRO after HBsAg seroclearance that can be used for personalized surveillance.

Similar recurrence after curative treatment of HBV-related HCC, regardless of HBV replication activity.

BACKGROUND AND AIMS: Antiviral therapy (AVT) is required in patients with newly diagnosed hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), if HBV DNA is detectable. We compared the risk of recurrence according to HBV replication activity at the curative treatment of HBV-related HCC. METHODS: Patients with HBV-related HCC who underwent surgical resection or radiofrequency ablation between 2013 and 2018 were enrolled in this retrospective cohort study. Patients were categorized into two groups according to HBV replication activity at the curative treatment of HBV-related HCC (group 1: patients who met the AVT indication for HBV-related HCC due to detectable HBV DNA but did not meet the AVT indication if without HCC; group 2: patients who met the AVT indication, regardless of HCC). RESULTS: In the entire cohort (n = 911), HCC recurred in 303 (33.3%) patients during a median follow-up of 4.7 years. After multivariate adjustment, group 2 showed a statistically similar risk of HCC recurrence (adjusted hazard ratio [aHR] = 1.18, P = 0.332) compared to that of group 1. In addition, group 2 showed statistically similar risks of early (< 2 years; aHR = 1.31) and late (≥ 2 years; aHR = 0.83) recurrence than that of group 1 (all P>0.05). Propensity score matching and inverse probability of treatment weighting analysis also yielded similar risks of HCC recurrence between the two groups (all P>0.05, log-rank tests). CONCLUSIONS: The risk of HCC recurrence in patients who received curative treatment for newly diagnosed HBV-related HCC was similar regardless of HBV replication activity, if AVT was properly initiated.

Optimal cut-offs of transient elastography and magnetic resonance elastography in diagnosing advanced liver fibrosis in patients with non-alcoholic fatty liver disease: A systematic review and meta-analysis.

Background/aims: Opinions differ regarding transient elastography and magnetic resonance elastography (TE/MRE) cut-offs for diagnosing advanced fibrosis (AF) in patients with non-alcoholic fatty liver disease (NAFLD). We investigated the diagnostic performance and optimal cut-off values of TE and MRE for diagnosing AF. Methods: Literature databases, including Medline, EMBASE, Cochrane Library, and KoreaMed, were used to identify relevant studies published up to June 13, 2023. We selected studies evaluating TE and MRE regarding the degree of liver fibrosis using liver biopsy as the reference. The sensitivity, specificity, and area under receiver operating characteristics curves (AUCs) of the pooled data for TE and MRE for each fibrosis stage and optimal cut-offs for AF were investigated. Results: A total of 19,199 patients from 63 studies using TE showed diagnostic AUC of 0.83(95% confidence interval: 0.80-0.86), 0.83(0.80-0.86), 0.87(0.84-0.90), and 0.94(0.91-0.96) for ≥F1, ≥F2, ≥F3, and F4 stages, respectively. Similarly, 1,484 patients from 14 studies using MRE showed diagnostic AUC of 0.89(0.86-0.92), 0.92(0.89-0.94), 0.89(0.86-0.92), and 0.94(0.91-0.96) for ≥F1, ≥F2, ≥F3, and F4 stages respectively. The diagnostic AUC for AF using TE was highest at 0.90 with a cut-off of 7.1-7.9 kPa, and that of MRE was highest at 0.94 with a cut-off of 3.62-3.8 kPa. Conclusions: TE(7.1-7.9 kPa) and MRE(3.62-3.8 kPa) with the suggested cut-offs showed favorable accuracy for diagnosing AF in patients with NAFLD. This result will serve as a basis for clinical guidelines for non-invasive tests and differential diagnosis of AF.

Assessment of the postoperative prognosis in patients with hepatocellular carcinoma using transient elastography: A systemic review and meta-analysis.

Background and Aims: This meta-analysis examined whether preoperative vibration-controlled transient elastography (VCTE) can predict postoperative complications and recurrence in patients undergoing hepatic resection for hepatocellular carcinoma (HCC). Methods: A systematic literature search was conducted using Ovid-Medline, EMBASE, Cochrane, and KoreaMed databases. Out of 431 individual studies, thirteen published between 2008 and 2022 were included. Five studies focused on HCC recurrence, while eight examined postoperative complications. Results: The meta-analysis of five studies on HCC recurrence showed that the high-risk group with a high VCTE score had a significantly increased recurrence rate after hepatic resection (hazard ratio [HR], 2.14). The cutoff value of VCTE in the high-risk group of HCC recurrence was 7.4-13.4kPa, the sensitivity was 0.60 (95% CI 0.47-0.72), and the specificity was 0.60 (95% CI 0.46-0.72). The area under the receiver operating characteristic curve (AUC) of the liver stiffness measured by VCTE to predict the HCC recurrence was 0.63 (95% CI 0.59-0.67). The meta-analysis on the postoperative complications revealed a significantly increased risk of postoperative complications in the high-risk group (12-25.6kPa) with a high VCTE value (risk ratio [RR], 8.32). The AUC of the liver stiffness measured by VCTE to predict the postoperative complications was 0.87(95% CI 0.84-0.90), the sensitivity was 0.76 (95% CI 0.55-0.89) and the specificity was 0.85 (95% CI 0.73-0.92). Conclusions: This meta-analysis suggests that preoperative VCTE in patients undergoing hepatic resection for HCC is useful in identifying individuals at a high risk of postoperative complications and HCC recurrence.

Diagnostic Accuracy of Transient Elastography for Staging Liver Fibrosis in Autoimmune Liver Diseases: A Systematic Review and Meta-Analysis.

Background/Aims: The assessment of liver fibrosis is crucial for managing autoimmune liver diseases such as primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), and primary sclerosing cholangitis (PSC). However, data on the efficacy of noninvasive tests (NITs) for these diseases are limited. This meta-analysis evaluated the diagnostic accuracy of vibration-controlled transient elastography (VCTE) for staging fibrosis in patients with autoimmune liver disease. Methods: Searches were conducted in PubMed, Embase, CINAHL, Web of Science, and Cochrane Library databases to assess the diagnostic accuracy of VCTE against histology as the reference standard in adult patients with autoimmune liver disease. The summary area under the curve (sAUC) and diagnostic odds ratio were calculated for significant fibrosis (SF), advanced fibrosis (AF), and cirrhosis, defined as METAVIR stages F≥2, F≥3, and F=4, respectively, according to liver biopsy. Results: Fourteen articles were included, comprising 559 PBC patients from six studies, 388 AIH patients from five studies, and 151 PSC patients from three studies. VCTE demonstrated good performance for fibrosis staging in PBC, AIH, and PSC. In PBC, sAUCs of VCTE were 0.87 (95% confidence interval, 0.80-0.94), 0.89 (0.85-0.94), and 0.99 (0.96-1.00) for staging SF, AF, and cirrhosis, respectively. In AIH, the sAUCs were 0.88 (0.84-0.92), 0.88 (0.83-0.93), and 0.92 (0.88-0.96), respectively, while in PSC, they were 0.88 (0.82-0.95), 0.95 (0.90-1.00), and 0.92 (0.84-0.99), respectively. The cutoff values for AF were 7.5-17.9 kPa in PBC, 8.18-12.1 kPa in AIH, and 9.6 kPa in PSC. Conclusions: VCTE shows high diagnostic accuracy for staging liver fibrosis in patients with autoimmune liver diseases such as PBC, AIH, and PSC. This non-invasive and reliable method serves as a valuable tool for the evaluation and monitoring of fibrosis in these lifelong diseases.

Agile 3+ and Agile 4 scores predict chronic kidney disease development in metabolic dysfunction-associated steatotic liver disease.

BACKGROUND AND AIMS: Despite the development of transient elastography (TE)-based Agile scores for diagnosing fibrotic burden in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), their applicability in predicting kidney outcomes remains unclear. We aimed to investigate the association between liver fibrotic burden, as assessed by Agile scores, and the risk of incident chronic kidney disease (CKD) in patients with MASLD. METHODS: A total of 3240 participants with MASLD but without pre-existing CKD who underwent TE between July 2006 and October 2018 were selected. The primary outcome was incident CKD, defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or proteinuria (≥1+ on dipstick) on two consecutive measurements. The secondary outcome was a 25% decline in eGFR measured on two consecutive visits. RESULTS: During a median follow-up of 3.6 years, 187 participants (5.8%) developed incident CKD. When stratified into three groups according to Agile 3+ scores, multivariable Cox models revealed that risk of incident CKD was 2.77-fold (95% confidence interval [CI], 1.89-4.07; p < 0.001) higher in the high-risk group (Agile 3+ >0.68), compared to the low-risk group (Agile 3+ <0.45). During a median follow-up of 3.4 years, the high-risk group had a 2.41-fold higher risk (95% CI, 1.86-3.12; p < 0.001) of experiencing the secondary outcome, compared to the low-risk group. Similar findings were observed for Agile 4 scores. Prediction testing revealed that Agile scores were better predictors of kidney outcomes, compared to liver stiffness measured by TE. CONCLUSIONS: In patients with MASLD, but without CKD, advanced liver fibrosis measured by Agile scores was significantly associated with a higher risk of incident CKD.

Long-term liver-related outcomes and liver stiffness progression of statin usage in steatotic liver disease.

BACKGROUND: Statins have multiple benefits in patients with metabolic-associated steatotic liver disease (MASLD). AIM: To explore the effects of statins on the long-term risk of all-cause mortality, liver-related clinical events (LREs) and liver stiffness progression in patients with MASLD. METHODS: This cohort study collected data on patients with MASLD undergoing at least two vibration-controlled transient elastography examinations at 16 tertiary referral centres. Cox regression analysis was performed to examine the association between statin usage and long-term risk of all-cause mortality and LREs stratified by compensated advanced chronic liver disease (cACLD): baseline liver stiffness measurement (LSM) of ≥10 kPa. Liver stiffness progression was defined as an LSM increase of ≥20% for cACLD and from <10 kPa to ≥10 or LSM for non-cACLD. Liver stiffness regression was defined as LSM reduction from ≥10 kPa to <10 or LSM decrease of ≥20% for cACLD. RESULTS: We followed up 7988 patients with baseline LSM 5.9 kPa (IQR 4.6-8.2) for a median of 4.6 years. At baseline, 40.5% of patients used statins, and cACLD was present in 17%. Statin usage was significantly associated with a lower risk of all-cause mortality (adjusted HR=0.233; 95% CI 0.127 to 0.426) and LREs (adjusted HR=0.380; 95% CI 0.268 to 0.539). Statin usage was also associated with lower liver stiffness progression rates in cACLD (HR=0.542; 95% CI 0.389 to 0.755) and non-cACLD (adjusted HR=0.450; 95% CI 0.342 to 0.592), but not with liver stiffness regression (adjusted HR=0.914; 95% CI 0.778 to 1.074). CONCLUSIONS: Statin usage was associated with a relatively lower long-term risk of all-cause mortality, LREs and liver stiffness progression in patients with MASLD.

Non-invasive prediction of post-sustained virological response HCC in HCV: A systematic review and meta-analysis.

Background: Despite advances in antiviral therapy for hepatitis C virus (HCV) infection, hepatocellular carcinoma (HCC) still develops even after sustained viral response (SVR) in patients with advanced liver fibrosis or cirrhosis. This meta-analysis investigated the predictive performance of transient elastography (TE) and fibrosis 4-index (FIB-4) for the development of HCC after SVR. Methods: We searched PubMed, MEDLINE, EMBASE, and the Cochrane Library for studies examining the predictive performance of these tests in adult patients with HCV. Two authors independently screened the studies' methodological quality and extracted data. Pooled estimates of sensitivity, specificity, and area under the curve (AUC) were calculated for HCC development using random-effects bivariate logit normal and linear-mixed effect models. Results: We included 27 studies (169,911 patients). Meta-analysis of HCC after SVR was possible in nine TE and 15 FIB-4 studies. Regarding the prediction of HCC development after SVR, the pooled AUCs of pre-treatment TE >9.2-13 kPa and FIB-4 >3.25 were 0.79 and 0.73, respectively. TE >8.4-11 kPa and FIB-4 >3.25 measured after SVR, maintained good predictive performance, albeit slightly reduced (pooled AUCs: 0.77 and 0.70, respectively). The identified optimal cut-off value for HCC development after SVR was 12.6 kPa for pre-treatment TE. That of TE measured after the SVR was 11.2 kPa. Conclusion: TE and FIB-4 showed acceptable predictive performance for HCC development in patients with HCV who achieved SVR, underscoring their utility in clinical practice for guiding surveillance strategies. Future studies are needed to validate these findings prospectively and validate their clinical impact.

Lack of association between early on-treatment HBeAg seroclearance and development of hepatocellular carcinoma or decompensated cirrhosis.

Background & Aims: The association between hepatitis B envelope antigen (HBeAg) seroclearance during long-term nucleos(t)ide analogue (NA) treatment and the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) remains unclear. Here, we aimed to investigate the association of HBeAg seroclearance during potent NA treatment with the development of HCC and decompensated cirrhosis. Methods: Using a multicenter historical cohort including 2,392 non-cirrhotic adult patients with HBeAg-positive CHB who initiated NA treatment with tenofovir or entecavir, the risk of HCC and decompensated cirrhosis was compared between patients who achieved HBeAg seroclearance within 36 months of NA treatment (the HBeAg-loss group) and those who did not (the HBeAg-maintained group), using inverse probability of treatment weighting. Results: Over a median of 6.6 years of NA treatment, 1,077 patients achieved HBeAg seroclearance (HBeAg loss rate = 6.0 per 100 person-years), 64 patients developed HCC (HCC incidence rate = 0.39 per 100 person-years), and 46 patients developed decompensated cirrhosis (decompensation incidence rate = 0.28 per 100 person-years). The HBeAg-loss and HBeAg-maintained groups had a similar risk of developing HCC (hazard ratio 0.89; 95% CI 0.47-1.68; p = 0.72) and decompensated cirrhosis (hazard ratio 0.98; 95% CI 0.48-1.81; p = 0.91). Compared with delayed HBeAg seroclearance beyond 10 years of NA treatment, the risk of HCC was comparable in those who achieved earlier HBeAg seroclearance at any time point within 10 years, regardless of baseline age and fibrotic burden. Conclusions: Early HBeAg seroclearance during NA treatment was not associated with a reduced risk of development of HCC or decompensated cirrhosis in non-cirrhotic HBeAg-positive patients with CHB. Impact and implications: The association between hepatitis B envelope antigen (HBeAg) seroclearance during long-term nucleos(t)ide analogue treatment and the risk of hepatocellular carcinoma in patients with chronic hepatitis B remains unclear. Our findings indicate that early on-treatment HBeAg seroclearance within 3 years was not associated with the development of hepatocellular carcinoma or decompensated cirrhosis. Achieving HBeAg seroclearance may not be an appropriate surrogate endpoint for preventing the development of liver-related outcomes in non-cirrhotic patients with HBeAg-positive chronic hepatitis B treated with nucleos(t)ide analogues.

Prevalence of clinically significant liver fibrosis in the general population: A systematic review and meta-analysis.

Background/Aims: Although important, clinically significant liver fibrosis is often overlooked in the general population. We aimed to examine the prevalence of clinically significant liver fibrosis using noninvasive tests (NITs) in the general population. Methods: We collected data from four databases (MEDLINE, Embase, Cochrane Library, and KoreaMed) from inception to June 13, 2023. Original articles reporting the prevalence of clinically significant liver fibrosis in the general population were included. The Stata metaprop function was used to obtain the pooled prevalence of liver fibrosis with NITs in the general population. Results: We screened 6,429 articles and included 45 eligible studies that reported the prevalence of clinically significant liver fibrosis in the general population. The prevalence of advanced liver fibrosis, using the high probability cutoff of the fibrosis-4 (FIB-4) index, was 2.3% (95% confidence interval [CI], 1.2-3.7%). The prevalence of significant liver fibrosis, advanced liver fibrosis, and liver cirrhosis, assessed using vibration-controlled transient elastography (VCTE) among the general population, was 7.3% (95% CI, 5.9-8.8%), 3.5% (95% CI, 2.7-4.5), and 1.2% (95% CI, 0.8-1.8%), respectively. Region-based subgroup analysis revealed that the highest prevalence of advanced fibrosis using the high probability cutoff of the FIB-4 index was observed in the American region. Furthermore, the American region exhibits the highest prevalence of significant liver fibrosis, advanced liver fibrosis, and liver cirrhosis, using VCTE. Conclusions: Previously undiagnosed clinically significant liver fibrosis is found in the general population through NITs. Future research is necessary to stratify the risk in the general population.

Risk Assessment of Hepatitis B virus-related Hepatocellular Carcinoma Development Using Transient Elastography: Systematic Review and Meta-analysis.

Background and Aims: Liver stiffness measurement (LSM) using transient elastography (TE) can assess fibrotic burden in chronic liver diseases. The systematic review and meta-analysis was conducted to determine whether LSM using TE can predict the risk of development of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. Methods: A systematic literature search of the Ovid-Medline, EMBASE, Cochrane, and KoreaMed databases (from January 2010 to June 2023) was conducted. Of the 1,345 individual studies identified, 10 studies that used TE were finally registered. Hazard ratios (HRs) and the 95% confidence interval (CIs) were considered summary estimates of treatment effect sizes of ≥ 11 kilopascal (kPa) standard for HCC development. Meta-analysis was performed using the restricted Maximum Likelihood random effects model. Results: Among the ten studies, data for risk ratios for HCC development could be obtained from nine studies. When analyzed for the nine studies, the HR for HCC development was high at 3.33 (95% CI, 2.45-4.54) in CHB patients with a baseline LSM of ≥ 11 kPa compared to patients who did not. In ten studies included, LSM of ≥ 11 kPa showed the sensitivity and specificity for predicting HCC development were 61% (95% CI, 50-71%) and 78% (95% CI, 66-86%), respectively, and the diagnostic accuracy was 0.74 (95% CI, 0.70-0.77). Conclusions: The risk of HCC development was elevated in CHB patients with TE-determined LSM of ≥11 kPa. This finding suggests that TE-determined LSM values may aid the risk prediction of HCC development in CHB patients.

Transient elastography for significant fibrosis in treatment-naïve CHB patients: A systematic review and meta-analysis.

Background and Aims: Accurate diagnosis of significant liver fibrosis in patients with chronic hepatitis B (CHB) is crucial when determining whether to initiate antiviral treatment (AVT). We conduct a meta-analysis to assess the diagnostic performance of transient elastography (TE) for significant liver fibrosis in AVT-naïve CHB patients with serum alanine transaminase (ALT) levels within 5-fold the upper limit of normal (ULN). Methods: The Ovid-Medline, EMBASE, Cochrane, and KoreaMed databases were searched to identify studies that compared the performance of TE and liver biopsy (reference standard) when diagnosing significant liver fibrosis (≥ F2) in AVT-naïve CHB patients with ALT within 5-fold the ULN. A hierarchical summary receiver operating characteristic curve (HSROC) and bivariate model were performed to evaluate the diagnostic performance of TE in the meta-analysis. Results: Eight studies (2,003 patients) were included. The summary sensitivity and specificity for diagnosis of significant liver fibrosis were 0.78 [95% confidence interval (CI), 0.66-0.86] and 0.72 (95% CI, 0.60-0.82), respectively. The HSROC for the diagnosis of significant liver fibrosis was 0.81 (95% CI, 0.72-0.86). The optimal cut-off value of TE for diagnosis of significant liver fibrosis was 7.7 kPa with a sensitivity of 0.64 (95% CI, 0.50-0.76) and specificity of 0.83 (95% CI, 0.72-0.90). Conclusions: Our study demonstrated that TE has an acceptable diagnostic performance for significant liver fibrosis in AVT-naïve CHB patients with ALT within 5-fold the ULN.

Diagnostic accuracy of the Fibrosis-4 index for advanced liver fibrosis in metabolic dysfunction-associated steatotic liver disease with type 2 diabetes: A systematic review and meta-analysis.

Background/Aims: The Fibrosis-4 index (FIB-4) is a non-invasive test widely used to rule out advanced liver fibrosis (AF) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, its diagnostic accuracy in MASLD patients with type 2 diabetes mellitus (T2DM) are controversial due to the high prevalence of AF in this population. Methods: Research focusing on the diagnostic accuracy of FIB-4 for liver fibrosis as validated by liver histology in MASLD patients with T2DM was included, and 12 studies (n=5,624) were finally included in the meta-analysis. Sensitivity, specificity, hierarchical summary receiver operating characteristic (HSROC), positive predictive values (PPVs), and negative predictive values (NPVs) at low cutoffs (1.3-1.67) and high cutoffs (2.67-3.25) for ruling in and out AF, were calculated. Results: At low cutoffs, the meta-analysis revealed a sensitivity of 0.74, specificity of 0.62, and HSROC of 0.75. At high cutoffs, the analysis showed a sensitivity of 0.33, specificity of 0.92, and HSROC of 0.85, suggesting FIB-4 as useful for identifying or excluding AF. In subgroup analyses, high mean age and F3 prevalence were associated with lower sensitivity. The calculated NPV and PPV were 0.82 and 0.49 at low cutoffs, whereas the NPV was 0.28 and the PPV was 0.70 at high cutoffs. There were insufficient estimated NPVs <0.90 at a hypothesized prevalence of AF >30% at an FIB-4 cutoff range of 1.3-1.67. Conclusions: Collectively, FIB-4 has moderate diagnostic accuracy for identifying or excluding AF in MASLD patients with T2DM, but more evidence must be accumulated due to the limited number of currently reported studies and their heterogeneity.

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.

Comparison between Nivolumab and Regorafenib as Second-line Systemic Therapies after Sorafenib Failure in Patients with Hepatocellular Carcinoma.

PURPOSE: Nivolumab and regorafenib are second-line therapies for patients with advanced hepatocellular carcinoma (HCC). We aimed to compare the effectiveness of nivolumab and regorafenib. MATERIALS AND METHODS: We retrospectively reviewed patients with HCC treated with nivolumab or regorafenib after sorafenib failure. Progression-free survival (PFS) and overall survival (OS) were analyzed. An inverse probability of treatment weighting using the propensity score (PS) was performed to reduce treatment selection bias. RESULTS: Among the 189 patients recruited, 137 and 52 patients received regorafenib and nivolumab after sorafenib failure, respectively. Nivolumab users showed higher Child-Pugh B patients (42.3% vs. 24.1%) and shorter median sorafenib maintenance (2.2 months vs. 3.5 months) compared to regorafenib users. Nivolumab users showed shorter median OS (4.2 months vs. 7.4 months, p=0.045) than regorafenib users and similar median PFS (1.8 months vs. 2.7 months, p=0.070). However, the median overall and PFS did not differ between the two treatment groups after the 1:1 PS matching (log-rank p=0.810 and 0.810, respectively) and after the stabilized inverse probability of treatment weighting (log-rank p=0.445 and 0.878, respectively). In addition, covariate-adjusted Cox regression analyses showed that overall and PFS did not significantly differ between nivolumab and regorafenib users after 1:1 PS matching and stabilized inverse probability of treatment weighting (all p>0.05). CONCLUSION: Clinical outcomes of patients treated with nivolumab and regorafenib after sorafenib treatment failure did not differ significantly.