Chronic hepatitis B baseline viral load and on-treatment liver cancer risk: A multinational cohort study of HBeAg-positive patients.

BACKGROUND AND AIMS: A single-nation study reported that pretreatment HBV viral load is associated with on-treatment risk of HCC in patients who are HBeAg-positive without cirrhosis and with chronic hepatitis B initiating antiviral treatment. We aimed to validate the association between baseline HBV viral load and on-treatment HCC risk in a larger, multinational cohort. APPROACH AND RESULTS: Using a multinational cohort from Korea, Hong Kong, and Taiwan involving 7545 adult patients with HBeAg-positive, without cirrhosis and with chronic hepatitis B who started entecavir or tenofovir treatment with baseline HBV viral load ≥5.00 log 10 IU/mL, HCC risk was estimated by baseline viral load. HBV viral load was analyzed as a categorical variable. During continuous antiviral treatment (median, 4.28 y), HCC developed in 200 patients (incidence rate, 0.61 per 100 person-years). Baseline HBV DNA level was independently associated with on-treatment HCC risk in a nonlinear pattern. HCC risk was lowest with the highest baseline viral load (≥8.00 log 10 IU/mL; incidence rate, 0.10 per 100 person-years), but increased sharply as baseline viral load decreased. The adjusted HCC risk was 8.05 times higher (95% CI, 3.34-19.35) with baseline viral load ≥6.00 and <7.00 log 10 IU/mL (incidence rate, 1.38 per 100 person-years) compared with high (≥8.00 log 10 IU/mL) baseline viral load ( p <0.001). CONCLUSIONS: In a multinational cohort of adult patients with HBeAg-positive without cirrhosis and with chronic hepatitis B, baseline HBV viral load was significantly associated with HCC risk despite antiviral treatment. Patients with the highest viral load who initiated treatment had the lowest long-term risk of HCC development.

Clinical outcomes of transarterial chemoembolization in Child-Turcotte Pugh class A patients with a single small (≤3 cm) hepatocellular carcinoma.

BACKGROUND AND AIM: Transarterial chemoembolization (TACE) is one of the standard modalities used to treat unresectable hepatocellular carcinoma (HCC), but the effectiveness of TACE for treating patients with a solitary small (≤3 cm) HCC and well-preserved liver function has not been definitively established. This study aimed to determine the therapeutic impact of TACE in patients with these characteristics. METHODS: This multicenter (four university hospitals) retrospective cohort study analyzed the medical records of 250 patients with a solitary small (≤3 cm) HCC and Child-Turcotte-Pugh (CTP) class A liver function diagnosed over 10 years. Posttreatment outcomes, including overall survival (OS), recurrence-free survival (RFS), and adverse events, were assessed following TACE therapy. RESULTS: One hundred and thirty-eight of the 250 patients (55.2%) treated with TACE achieved complete remission (CR). Overall median OS was 77.7 months, and median OS was significantly longer in the CR group than in the non-CR group (89.1 vs. 58.8 months, P = 0.001). Median RFS was 19.1 months in the CR group. Subgroup analysis identified hypertension, an elevated serum albumin level, and achieving CR as significant positive predictors of OS, whereas diabetes, hepatitis c virus infection, and tumor size (>2 cm) were poor prognostic factors of OS. CONCLUSIONS: The study demonstrates the effectiveness of TACE as a viable alternative for treating solitary small (≤3 cm) HCC in CTP class A patients.

Hepatocellular carcinoma risk in patients with chronic hepatitis B receiving tenofovir- vs. entecavir-based regimens: Individual patient data meta-analysis.

BACKGROUND & AIMS: The comparative risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) receiving tenofovir disoproxil fumarate (TDF) vs. entecavir (ETV) remains controversial. In this individual patient data (IPD) meta-analysis, we aimed to compare HCC risk between the two drugs and identify subgroups who may benefit more from one treatment than the other. METHODS: Published meta-analyses, electronic databases and congress proceedings were searched to identify eligible studies through January 2021. We compared HCC risk between the two drugs using a multivariable Cox proportional hazards model with anonymised IPD from treatment-naïve patients with CHB receiving TDF or ETV for ≥1 year. Treatment effect consistency was explored in propensity score matching (PSM), weighting (PSW) and subgroup analyses for age, sex, hepatitis B e-antigen (HBeAg) positivity, cirrhosis and diabetes status. RESULTS: We included 11 studies from Korea, Taiwan and Hong Kong involving 42,939 patients receiving TDF (n = 6,979) or ETV (n = 35,960) monotherapy. Patients receiving TDF had significantly lower HCC risk (adjusted hazard ratio [HR] 0.77; 95% CI 0.61-0.98; p = 0.03). Lower HCC risk with TDF was consistently observed in PSM (HR 0.73; 95% CI 0.59-0.88; p <0.01) and PSW (HR 0.83; 95% CI 0.67-1.03; p = 0.10) analyses and in all subgroups, with statistical significance in the ≥50 years of age (HR 0.76; 95% CI 0.58-1.00; p <0.05), male (HR 0.74; 95% CI 0.58-0.96; p = 0.02), HBeAg-positive (HR 0.69; 95% CI 0.49-0.97; p = 0.03) and non-diabetic (HR 0.79; 95% CI 0.63-1.00; p <0.05) subgroups. CONCLUSION: TDF was associated with significantly lower HCC risk than ETV in patients with CHB, particularly those with HBeAg positivity. Longer follow-up may be needed to better define incidence differences between the treatments in various subgroups. IMPACT AND IMPLICATIONS: Previous aggregate data meta-analyses have reported inconsistent conclusions on the relative effectiveness of tenofovir disoproxil fumarate and entecavir in reducing hepatocellular carcinoma risk in patients with chronic hepatitis B (CHB). This individual patient data meta-analysis on 11 studies involving 42,939 patients from Korea, Taiwan and Hong Kong suggested that tenofovir disoproxil fumarate-treated patients have a significantly lower hepatocellular carcinoma risk than entecavir-treated patients, which was observed in all subgroups of clinical interest and by different analytical methodologies. These findings should be taken into account by healthcare providers when determining the optimal course of treatment for patients with CHB and may be considered in ensuring that treatment guidelines for CHB remain pertinent.

Personalized Antiviral Drug Selection in Patients With Chronic Hepatitis B Using a Machine Learning Model: A Multinational Study.

INTRODUCTION: Tenofovir disoproxil fumarate (TDF) is reportedly superior or at least comparable to entecavir (ETV) for the prevention of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B; however, it has distinct long-term renal and bone toxicities. This study aimed to develop and validate a machine learning model (designated as Prediction of Liver cancer using Artificial intelligence-driven model for Network-antiviral Selection for hepatitis B [PLAN-S]) to predict an individualized risk of HCC during ETV or TDF therapy. METHODS: This multinational study included 13,970 patients with chronic hepatitis B. The derivation (n = 6,790), Korean validation (n = 4,543), and Hong Kong-Taiwan validation cohorts (n = 2,637) were established. Patients were classified as the TDF-superior group when a PLAN-S-predicted HCC risk under ETV treatment is greater than under TDF treatment, and the others were defined as the TDF-nonsuperior group. RESULTS: The PLAN-S model was derived using 8 variables and generated a c-index between 0.67 and 0.78 for each cohort. The TDF-superior group included a higher proportion of male patients and patients with cirrhosis than the TDF-nonsuperior group. In the derivation, Korean validation, and Hong Kong-Taiwan validation cohorts, 65.3%, 63.5%, and 76.4% of patients were classified as the TDF-superior group, respectively. In the TDF-superior group of each cohort, TDF was associated with a significantly lower risk of HCC than ETV (hazard ratio = 0.60-0.73, all P < 0.05). In the TDF-nonsuperior group, however, there was no significant difference between the 2 drugs (hazard ratio = 1.16-1.29, all P > 0.1). DISCUSSION: Considering the individual HCC risk predicted by PLAN-S and the potential TDF-related toxicities, TDF and ETV treatment may be recommended for the TDF-superior and TDF-nonsuperior groups, respectively.

Durability of Sustained Virologic Response and Improvement of Fibrosis Markers after Daclatasvir and Asunaprevir Treatment in Genotype 1b Hepatitis C Virus-Infected Patients: a Real Life and Multicenter Study.

BACKGROUND: The long-term data with direct acting antiviral agents were rare. This study investigated the durability of a sustained virologic response (SVR) and the improvement of fibrosis after daclatasvir and asunaprevir (DCV/ASV) treatment in genotype 1b (GT1b) hepatitis C virus (HCV)-infected patients. METHODS: A total of 288 HCV GT1b patients without baseline non-structural 5A (NS5A) resistance-associated substitution (RAS) treated with DCV/ASV were enrolled. Virologic response was measured at 12 weeks and 1 year after treatment completion. In cirrhotic patients, liver function, aspartate transaminase to platelet ratio index (APRI), FIB-4 index, fibrosis index (FI), and liver stiffness measurement (LSM) at baseline and 1 year after treatment completion were evaluated. RESULTS: SVR12 was obtained in 278 patients (96.5%). Six patients who checked NS5A RAS after treatment failure were RAS positive. Only one patient showed no durability of SVR. In cirrhotic patients who achieved SVR12 (n = 59), the changes of albumin (3.8 [2.2-4.7] to 4.3 [2.4-4.9] g/dL; P < 0.001), platelet count (99 [40-329] to 118 [40-399] × 10³/mm³; P < 0.001), APRI (1.8 [0.1-14.8] to 0.6 [0.1-4.8]; P < 0.001), FIB-4 index (5.45 [0.6-32.8] to 3.3 [0.4-12.2]; P < 0.001), FI (5.5 [0.6-32.8] to 3.3 [0.4-12.2]; P < 0.001), and LSM (17.2 [5.3-48.0] to 11.2 [3.7-28.1] kPa; P = 0.001) between baseline and 1 year after treatment completion were observed. CONCLUSION: DCV/ASV treatment for HCV GT1b infected patients without RAS achieved high SVR rates and showed durable SVR. Cirrhotic patients who achieved SVR12 showed the improvement of liver function and fibrosis markers.

Remaining hepatocellular carcinoma risk in chronic hepatitis B patients receiving entecavir/tenofovir in South Korea.

AIM: We aimed to identify the incidence rate of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients treated with entecavir or tenofovir in South Korea, and to identify predictors of HCC development in these patients. METHODS: Between January 2007 and December 2015, 582 CHB patients initially received entecavir (n = 406, 69.8%) or tenofovir (n = 176, 30.2%) for CHB. RESULTS: During a median follow-up of 57.1 months, HCC developed in 38 (6.5%) of the 582 patients, regardless of antiviral agent type. Entecavir- and tenofovir-treated patients had similar HCC development rates (P = 0.471). For the 582 patients, 2-, 4-, and 6-year cumulative HCC development rates were 2.6%, 4.4%, and 8.3%, respectively, and the 2-, 4-, and 6-year cumulative HCC development rates of patients with liver cirrhosis were significantly greater than those of patients without liver cirrhosis (6.2%, 9.8%, and 18.4% vs. 0.3%, 1.1%, and 2.2%, respectively; P < 0.001). Older (≥60 years) patients, regardless of the presence of cirrhosis, and cirrhotic patients aged ≥40 years showed significantly higher risk of HCC development compared to others (both P < 0.05). Multivariate analysis showed that an older age (≥50 years; hazard ratio [HR] 5.02, P = 0.009), and the presence of cirrhosis (HR 4.95, P = 0.002) independently predicted HCC development. CONCLUSIONS: The 6-year cumulative HCC development rate was 6.5% in CHB patients treated with entecavir or tenofovir. Age ≥50 years and liver cirrhosis were found to predict HCC development in these patients.

Therapeutic priorities for solitary large hepatocellular carcinoma in a hepatitis B virus endemic area; an analysis of a nationwide cancer registry database.

BACKGROUND/AIMS: We compared overall survival (OS) of patients with a solitary large (>5 cm) hepatocellular carcinoma (HCC) treated surgically or by transarterial chemoembolization (TACE). METHODS: The archived records of HCC patients registered at the Korean Central Cancer Registry from 2003 through 2005 (registry A, n = 4 520) or from 2008 through 2010 (registry B, n = 4 596) were retrospectively analyzed. In these registries, 578 and 315 patients had a single large HCC, respectively. In registry A, 442 (cohort A) underwent surgery (n = 96) or TACE (n = 346). In registry B, 253 (cohort B) underwent surgery (n = 110) or TACE (n = 143). Cohort C (n = 695) was constructed by combining cohorts A and B, and thus, 206 and 489 patients received surgery and TACE, respectively. RESULTS: In cohort C, cumulative OS rates at 1-, 3-, and 5-years were significantly higher for surgery than TACE (89.3%, 67.4%, and 58.0% vs 67.7%, 38.2%, and 27.2%, respectively, P < 0.001). Similar results were obtained for cohorts A and B, even after propensity-score matching in three cohorts (P values for all <0.05). TACE (HR 2.18, P < 0.001), serum albumin (HR 0.77, P = 0.015), and tumor size (HR 1.06, P < 0.001) were predictors of post-treatment mortality. CONCLUSIONS: Surgery is associated with improved OS for a solitary large HCC of BCLC stage A.

Utility of needle-knife fistulotomy as an initial method of biliary cannulation to prevent post-ERCP pancreatitis in a highly selected at-risk group: a single-arm prospective feasibility study.

BACKGROUND/AIMS: The aim of this study was to assess the feasibility of needle-knife fistulotomy (NKF) as an initial procedure for biliary access in patients with stones in the common bile duct (CBD) who were at increased risk for post-ERCP pancreatitis (PEP). METHOD: Fifty-five patients who underwent ERCP with NKF for CBD stones at our institution between July 2013, and May 2015, were prospectively enrolled in this study. They had one or more of the following risk factors for PEP: young age (<60 years), female sex, or normal CBD diameter (≤9 mm). The procedure was performed by an expert biliary endoscopist (S.J.). The success rate of biliary cannulation and CBD stone removal, and the incidence rate of adverse events were assessed. RESULTS: Seventeen patients had 1 risk factor for PEP, 27 had 2, and 11 had 3. The median procedure times for NKF and CBD stone removal after NKF were 2.1 minutes (range, 0.2-8.7 min) and 6.5 minutes (range, 1.1-28.3 min), respectively. Success rates of CBD cannulation and stone removal using NKF were 96.3% (53/55) and 92.7% (51/55), respectively. None of the patients experienced PEP. Retroperitoneal duodenal perforation occurred in 1 patient (1.8%), but it was successfully treated by conservative management. CONCLUSION: NKF might be feasible as an initial procedure for biliary access in patients with CBD stones who are at high risk for PEP if the procedure is performed by an expert biliary endoscopist. (Clinical trial registration number: KCT0001698.).

Clinical effect of add-on Primovist-enhanced magnetic resonance imaging on preoperative tumor staging in hepatocellular carcinoma patients.

BACKGROUND/AIMS: We analyzed the incidence of change of Barcelona Clinic Liver Cancer (BCLC) stage after add-on Primovist-enhanced magnetic resonance imaging (MRI) in hepatocellular carcinoma (HCC) patients with Barcelona Clinic Liver Cancer stage 0 or A as determined by liver dynamic computed tomography (LDCT). METHODS: A total of 166 patients enrolled prospectively between August 2012 and December 2014 were retrospectively analyzed. The rates of stage change after Primovist-enhanced MRI and the treatment finally adopted in patients with stage change were evaluated. RESULTS: Of the 166 patients, 24 (18.6%) had truly new HCCs. Forty-six (27.7%) and 120 (72.3%) patients had BCLC stages 0 and A, respectively, before Primovist-enhanced MRI, but after Primovist-enhanced MRI, 28 (16.9%), 134 (80.7%), and 4 (2.4%) patients had BCLC stages 0, A, and B, respectively. Tumor stage changed in 22 (13.3%) patients, from 0 to A (18, 39.1%) or A to B (4, 3.3%). CONCLUSIONS: Add-on Primovist-enhanced magnetic resonance imaging can change BCLC stage with 13.3% in patients with BCLC 0 or A staged HCC, as determined by LDCT. J. Surg. Oncol. 2016;114:106-111. © 2016 Wiley Periodicals, Inc.

Prediction of postoperative liver failure using gadoxetic acid-enhanced magnetic resonance imaging in patients with hepatocellular carcinoma.

BACKGROUND: We intended to determine the usefulness of gadoxetic acid-enhanced magnetic resonance (MR) imaging on preoperative prediction of the risk of postoperative liver failure (PLF) using measurement of relative liver enhancement (RLE) in patients who underwent surgical resection of hepatocellular carcinoma (HCC). METHODS: A total of 121 HCC patients who had underwent gadoxetic acid-enhanced MRI before surgery between January 2012 and April 2015 at our hospital was retrospectively analyzed. RLE was calculated as the ratio of signal intensity measurements of the liver parenchyma in each liver segment before and 20 min after intravenous administration of gadoxetic acid. PLF was defined based on the "50-50 criteria" (prothrombin time <50% and serum bilirubin >5 mg/dL on 5 days after surgery). RESULTS: Of the 121 patients, 74 (61.2%) patients had liver cirrhosis, clinically. Median tumor size 2.8 cm (range, 1-14 cm), 106 (87.6%) patients had a single HCC, and 101 (83.5%) patients had HCC within Milan criteria. Based on the "50-50 criteria", PLF was observed in 7 (5.8%) patients. Mean RLE was significantly lower in patients with PLF than those without it (55.9% vs 85.5%, P < 0.01). In a multivariate analysis, decreased RLE was a significant independent risk factor for PLF in HCC patients (odds ratio 0.97, P = 0.03). Optimal cut-off RLE value was 82.36. CONCLUSIONS: RLE was significantly lower in patients with PLF than those without it. Measurement of RLE using gadoxetic acid-enhanced MR imaging before surgery can be useful for prediction of PLF in HCC patients who receive surgical treatment.

Accuracy of transient elastography in assessing liver fibrosis in chronic viral hepatitis: A multicentre, retrospective study.

BACKGROUND/AIMS: Transient elastography (TE) has become an alternative to liver biopsy (LB). This study investigated the diagnostic performance of liver stiffness (LS) measurement using TE in Korean patients with chronic hepatitis B and C (CHB and CHC). METHODS: From April 2006 to June 2014, 916 patients (567 CHB and 349 CHC) who underwent LB and TE at 15 centres were analyzed. The Batts and Ludwig scoring system was used for histologic assessment. Aspartate aminotransferase (AST)-to-platelet ratio indexes (APRI) were calculated. Area under the receiver operating characteristic curve (AUROC) was used. RESULTS: The median age, LS value, and APRI score were 45 years, 8.8 kPa, and 0.61, respectively, in CHB patients vs. 51 years, 6.8 kPa and 0.55, respectively, in CHC patients. TE was significantly superior to APRI in CHB patients (AUROC 0.774 vs. 0.72 for ≥F2, 0.849 vs. 0.812 for ≥F3, and 0.902 vs. 0.707 for F4, respectively; all P < 0.05). Furthermore, TE was significantly superior for predicting ≥ F3 stage (AUROC 0.865 vs. 0.840, P = 0.009) whereas it was similar for predicting ≥ F2 and F4 stage (AUROC 0.822 vs. 0.796; 0.910 vs. 0.884; all P > 0.05) in CHC patients. In CHB patients, optimal cut-off LS values were 7.8 kPa for ≥F2, 8.2 kPa for ≥ F3, and 11.6 kPa for F4, vs. 6.8 kPa, 8.6 kPa, and 14.5 kPa, respectively, in CHC patients. CONCLUSIONS: TE can accurately assess the degree of liver fibrosis in Korean patients with CVH. TE was superior to APRI for predicting each fibrosis stage.

Tumor Necrosis Factor-Alpha Gene Polymorphism Associated With Development of Hepatitis B Virus-associated Hepatocellular Carcinoma.

GOAL AND BACKGROUND: Host genetic diversity may play roles in development of HCC. This study was conducted to validate the effects of tumor necrosis factor-alpha (TNF-α) gene polymorphism on development of hepatocellular carcinoma (HCC) in patients chronically infected with hepatitis B virus (HBV). STUDY: The study cohort comprised 224 patients with HBV-associated HCC and 206 with HBV-associated liver cirrhosis (LC). Using chromosomal DNA, TNF-α promoter gene polymorphisms were determined at 3 common single-nucleotide polymorphism (SNP) sites (TNF-α-1031 T>C, TNF-α-857 C>T, and TNF-α-308 G>A) using a single base extension method. The genotype distributions were compared between the 2 groups. All the HBV-associated LC patients were followed up regularly every 6 to 12 months for surveillance of HCC development. RESULTS: In the cross-sectional analysis, the frequency of TNF-α-857 T allele was much higher in patients with HCC compared with those with LC (42% vs. 31%, P<0.01). Of 206 HBV-associated LC patients, 12 (5.8%) developed HCC during the median follow-up period of 36 months. The cumulative occurrence rates of HCC were significantly higher in patients with TNF-α-857 T allele than those withTNF-α-857 C/C genotype (1-, 3-, and 5-y rates: 2.9%, 12.8%, and 20.7% vs. 0%, 3.1%, and 5.3%, respectively; P=0.013). However, the other genetic polymorphisms of TNF-α promoter gene did not affect the development of HCC. In multivariate analysis, TNF-α-857 T allele was a significant predictor of HCC development (hazard ratio 6.29, P=0.01). CONCLUSION: Our data suggest that TNF-α-857 T allele is closely associated with development of HCC in HBV-associated LC patients.

Conscious Sedation Using Midazolam and Sequential Flumazenil in Cirrhotic Patients for Prophylactic Endoscopic Variceal Ligation.

BACKGROUND/AIMS: This study investigated the safety of endoscopic variceal ligation (EVL) under conscious sedation with midazolam and sequential flumazenil after procedure in these patients. METHODS: A total of 279 patients who underwent secondary prophylactic EVL at our institution between April 2012 and June 2014, were enrolled. Conscious sedation was achieved using intravenous midazolam, and flumazenil was routinely used as an antidote immediately after EVL. Patients with sleep (n = 165) and non-sleep (n = 55) endoscopy were matched using propensity score analysis (3:1). Frequencies of overt hepatic encephalopathy (HEP) and patient' satisfactions with EVL were compared between the 2 groups. RESULTS: Of the 279 patients, 155 (55.6%) were of Child-Turcotte-Pugh (CTP) class, B or C, and 224 (80.3%) patients underwent sleep endoscopy. After propensity score analysis, overt HEP was observed in 1 (0.4%) of the 165 patients in the sedated group, but not found in any in the non-sedated group. Patient' satisfaction with EVL was better in the sedated group (p < 0.001). Twenty-nine (65.9%) of the 44 patients with CTP class C underwent sleep endoscopy, and only one (3.4%) experienced overt HEP. CONCLUSIONS: Prophylactic EVL under conscious sedation using midazolam and flumazenil is probably safe in cirrhotic patients without experience of HEP, even in those of CTP class C.

Transarterial chemoembolization versus surgery/radiofrequency ablation for recurrent hepatocellular carcinoma with or without microvascular invasion.

BACKGROUND/AIMS: Microvascular invasion (MVI) is a well-known prognostic factor of postoperative recurrence and of overall survival (OS) in patients with hepatocellular carcinoma (HCC). We compared the treatment outcomes of transarterial chemoembolization (TACE) and surgery/radiofrequency ablation (RFA) according to the presence of MVI in patients with early or late recurrent HCC that presented as Barcelona Clinical Liver Cancer (BCLC) stage 0 or A after curative resection for HCC. METHODS: A consecutive 68 patients with recurrent HCC of BCLC stage 0 or A at our institution between 1998 and 2012 were retrospectively enrolled. We compared the outcomes of patients treated by TACE or surgery/RFA. Tumor recurrence after curative resection was classified as early (≤ 12 months) or late (> 12 months) recurrence. RESULTS: Median tumor size was 1.5 cm (range, 1-10 cm), and 67 (98.5%) had HCCs within the Milan criteria. Median post-retreatment follow-up duration was 27 months (range, 1-109 months). Of the 68 patients, 19 (27.9%) underwent surgery/RFA, 47 (69.1%) TACE, and 2 (2.9%) were lost to follow-up. After retreatment, TACE showed significantly higher OS and recurrence-free survival rates than surgery/RFA in MVI-positive patients (P = 0.03 and P = 0.05, respectively), but not in MVI-negative patients (P = 0.95 and P = 0.98, respectively). In particular, in early recurred MVI-positive patients, TACE had a significantly higher OS rate than surgery/RFA (P = 0.01). CONCLUSIONS: TACE may be the more effective treatment option for recurrent HCC of BCLC stage 0 or A than surgery/RFA in MVI-positive patients, especially in those that recur early after curative resection.

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.

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.

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.

Machine learning-based clinical decision support system for treatment recommendation and overall survival prediction of hepatocellular carcinoma: a multi-center study.

The treatment decisions for patients with hepatocellular carcinoma are determined by a wide range of factors, and there is a significant difference between the recommendations of widely used staging systems and the actual initial treatment choices. Herein, we propose a machine learning-based clinical decision support system suitable for use in multi-center settings. We collected data from nine institutions in South Korea for training and validation datasets. The internal and external datasets included 935 and 1750 patients, respectively. We developed a model with 20 clinical variables consisting of two stages: the first stage which recommends initial treatment using an ensemble voting machine, and the second stage, which predicts post-treatment survival using a random survival forest algorithm. We derived the first and second treatment options from the results with the highest and the second-highest probabilities given by the ensemble model and predicted their post-treatment survival. When only the first treatment option was accepted, the mean accuracy of treatment recommendation in the internal and external datasets was 67.27% and 55.34%, respectively. The accuracy increased to 87.27% and 86.06%, respectively, when the second option was included as the correct answer. Harrell's C index, integrated time-dependent AUC curve, and integrated Brier score of survival prediction in the internal and external datasets were 0.8381 and 0.7767, 91.89 and 86.48, 0.12, and 0.14, respectively. The proposed system can assist physicians by providing data-driven predictions for reference from other larger institutions or other physicians within the same institution when making treatment decisions.