Aspirin use and risk of hepatocellular carcinoma in patients with chronic hepatitis B with or without cirrhosis.

BACKGROUND AND AIMS: Studies on differential effect of aspirin therapy on HCC risk across the spectrum of liver diseases are lacking. We investigated the association between aspirin use and risks of HCC, liver-associated death, and major bleeding in chronic hepatitis B (CHB) patients with or without cirrhosis. APPROACH AND RESULTS: We identified 329,635 eligible adults with CHB from 2007 through 2017, using the Korean National Health Insurance Service database, including patients who received aspirin for ≥90 consecutive days (n = 20,200) and patients who never received antiplatelet therapy (n = 309,435). Risks of HCC, liver-associated mortality, and major bleeding were estimated in a propensity-score-matched cohort (19,003 pairs), accounting for competing risks. With a median follow-up of 6.7 years, 10-year cumulative incidence of HCC was 9.5% in the aspirin-treated group and 11.3% in the untreated group (adjusted subdistribution hazard ratio [aSHR], 0.85; 95% CI, 0.78-0.92). However, among patients with cirrhosis (2479 pairs), an association of aspirin use with HCC risk was not evident (aSHR, 1.00; 95% CI, 0.85-1.18). Cirrhosis status had a significant effect on the association between aspirin use and HCC risk (pinteraction , n = 0.04). Aspirin use was also associated with lower liver-associated mortality (aSHR, 0.80; 95% CI, 0.71-0.90). Moreover, aspirin use was not associated with major bleeding risk (aSHR, 1.09; 95% CI, 0.99-1.21). CONCLUSIONS: Aspirin use was associated with reduced risks of HCC and liver-associated mortality in adults with CHB. Cirrhosis status had a substantial effect on the association between aspirin use and HCC risk.

Efficacy of Antiviral Prophylaxis up to 6 or 12 Months From Completion of Rituximab in Resolved Hepatitis B Patients: A Multicenter, Randomized Study.

BACKGROUND: Rituximab occasionally induces reactivation of hepatitis B virus (HBV) in patients with resolved HBV, at times with fatal consequences. The optimal duration of prophylactic antiviral therapy in this situation is unclear. We aimed to investigate the difference in HBV reactivation according to the duration of prophylactic tenofovir disoproxil fumarate (TDF) in patients with resolved HBV and receiving rituximab. METHODS: A multicenter, randomized, open-label, prospective study was conducted in hepatitis B surface antigen-negative and anti-HBc-positive non-Hodgkin's lymphoma patients treated with rituximab-based chemotherapy. A total of 90 patients were randomized and received prophylactic TDF from the initiation of rituximab until 6 months (the 6-month group) or 12 months (the 12-month group) after the completion of rituximab. The primary outcome was the difference in HBV reactivation and the secondary outcomes were the difference in hepatitis flare and adverse events between the two groups. RESULTS: In an intention to treat (ITT) analysis, HBV reactivation occurred in 1 of 43 patients (2.3%; 95% confidence interval [CI], 0.41-12%) at a median of 13.3 months in the 6-month group and 2 of 41 patients (4.9%; 95% CI, 1.4-16%) at a median of 13.7 months in the 12-month group. In a per protocol (PP) analysis, HBV reactivation occurred in 1 of 18 patients (5.6%; 95% CI, 0.99-26%) at 13.3 months in the 6-month group and 1 of 13 patients (7.7%; 95% CI, 1.4-33%) at 9.7 months in the 12-month group. The cumulative incidence of HBV reactivation was not significantly different between the two groups in ITT and PP analyses (P = 0.502 and 0.795, respectively). The occurrence of adverse events was not significantly different between the two groups in ITT (9.3% in the 6-month group, 22.0% in the 12-month group, P = 0.193) and PP analyses (5.6% in the 6-month group, 7.7% in the 12-month group, P > 0.999). CONCLUSION: Prophylactic TDF up to 6 months after completion of rituximab-based chemotherapy is sufficient in terms of the efficacy and safety of reducing HBV reactivation in patients with resolved HBV. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02585947.

Impact of HBeAg on Hepatocellular Carcinoma Risk During Oral Antiviral Treatment in Patients With Chronic Hepatitis B.

BACKGROUND & AIMS: Antiviral treatment from hepatitis B envelope antigen (HBeAg)-positive status may attenuate the integration of hepatitis B virus DNA into the host genome causing hepatocellular carcinoma (HCC). We investigated the impact of HBeAg status at the onset of antiviral treatment on the risk of HCC. METHODS: The incidence of HCC was evaluated in Korean patients with chronic hepatitis B who started entecavir or tenofovir in either HBeAg-positive or HBeAg-negative phase. The results in the Korean cohort were validated in a Caucasian PAGE-B cohort. RESULTS: A total of 9143 Korean patients (mean age, 49.2 years) were included: 49.1% were HBeAg-positive and 49.2% had cirrhosis. During follow-up (median, 5.1 years), 916 patients (10.0%) developed HCC. Baseline HBeAg positivity was not associated with the risk of HCC in the entire cohort or cirrhotic subcohort. However, in the non-cirrhotic subcohort, HBeAg positivity was independently associated with a lower risk of HCC in multivariable (adjusted hazard ratio [aHR], 0.41; 95% confidence interval [CI], 0.26-0.66), propensity score-matching (aHR, 0.46; 95% CI, 0.28-0.76), and inverse probability weighting analyses (aHR, 0.44; 95% CI, 0.28-0.70). In the Caucasian cohort (n = 719; mean age, 51.8 years; HBeAg-positive, 20.3%; cirrhosis, 34.8%), HBeAg-positivity was not associated with the risk of HCC either in the entire cohort or cirrhotic subcohort. In the non-cirrhotic subcohort, none of the HBeAg-positive group developed HCC, although the difference failed to reach statistical significance (aHR, 0.21; 95% CI, 0.00-1.67). CONCLUSIONS: This multinational cohort study implies that HBeAg positivity at the onset of antiviral treatment seems to be an independent factor associated with a lower risk of HCC in patients with chronic hepatitis B without cirrhosis, but not in those with cirrhosis.

Effectiveness of Lenvatinib Versus Sorafenib for Unresectable Hepatocellular Carcinoma in Patients with Hepatic Decompensation.

BACKGROUND/AIM: Lenvatinib and sorafenib are currently available to treat patients with advanced hepatocellular carcinoma (HCC). However, since the clinical trials evaluating the efficacy of lenvatinib and sorafenib included only patients with Child-Pugh class A, little is known about the effectiveness of the treatments in patients with hepatic decompensation. We compared the effectiveness of lenvatinib and sorafenib in decompensated patients with unresectable HCC. METHODS: Consecutive patients who were classified as Child-Pugh class B or C and received lenvatinib or sorafenib as first-line systemic therapy for unresectable HCC between November 2018 and April 2020 at a tertiary referral center were included in this retrospective study. The primary outcome was overall survival (OS), and the secondary outcomes were progression-free survival (PFS), time-to-progression, best overall tumor response, and safety profiles. RESULTS: Among 94 patients, 34 received lenvatinib and 60 received sorafenib. The median OS was 4.1 months (95% confidence interval [CI], 2.9-5.2): 4.2 months (95% CI, 2.9-5.3) for lenvatinib and 4.1 months (95% CI, 2.7-6.4) for sorafenib. The treatment regimen was not associated with significant improvement in OS after adjusting for covariables (adjusted hazard ratio [aHR], 0.92; 95% CI, 0.54-1.54; P = 0.74). The treatment regimen was not an independent predictor of PFS (lenvatinib vs. sorafenib; aHR, 0.77; 95% CI, 0.48-1.24; P = 0.28). HRs were maintained even after balancing with the inverse probability treatment weighting method. Objective response rates were 11.8% and 6.7% in patients receiving lenvatinib and sorafenib, respectively (P = 0.45). Ten patients in both groups (five in the lenvatinib group and five in the sorafenib group) underwent dose modification due to adverse events, and significant difference was not observed between the treatment groups (P = 0.49). CONCLUSION: The effectiveness of lenvatinib and sorafenib was comparable for the treatment of unresectable HCC in decompensated patients.

Metabolic Dysfunction-Associated Steatotic Liver Disease and Metabolic Dysfunction-Associated Steatotic Liver Disease with Increased Alcohol Intake Increase the Risk of Developing Hepatocellular Carcinoma and Incident or Decompensated Cirrhosis: A Korean Nationwide Study.

Introduction: This study aimed to investigate the liver-related outcomes of newly suggested metabolic dysfunction-associated steatotic liver disease (MASLD) and MASLD with increased alcohol intake (MetALD), as well as alcohol-associated liver disease (ALD). Methods: From a National Health Insurance Service Health Screening Cohort, we included 369,094 participants who underwent health checkups between 2009 and 2010 in South Korea. Steatotic liver disease (SLD) was defined as a fatty liver index ≥60. The risk of primary liver cancer (PLCa), hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), incident cirrhosis, and decompensated cirrhosis was compared with no SLD. The subdistribution hazard ratio (SHR) was calculated using the Fine-Gray model regarding competing risks. Results: A total of 3,232 participants (0.9%) developed PLCa during the median follow-up of 3,227,176 person-years: 0.5% with no SLD, 1.1% with MASLD, 1.3% with MetALD, and 1.9% with ALD. Competing risk analysis revealed that compared with no SLD, MASLD (SHR: 1.65; 95% CI: 1.44-1.88), MetALD (SHR: 1.87; 95% CI: 1.52-2.29), and ALD (SHR: 1.86; 95% CI: 1.39-2.49) were associated with an increased risk of PLCa. MASLD (SHR: 1.96; 95% CI: 1.67-2.31), MetALD (SHR: 2.23; 95% CI: 1.75-2.84), and ALD (SHR: 2.34; 95% CI: 1.67-3.29) were associated with a higher risk of HCC. No significant difference was observed in the risk of iCCA. The risk of incident cirrhosis and decompensated cirrhosis increased in the order of no SLD, MASLD, MetALD, and ALD. Conclusion: MASLD, MetALD, and ALD have an increased risk of PLCa, HCC, incident cirrhosis, and decompensated cirrhosis but not iCCA. These findings may serve as a robust ground for the prognostic value of the newly suggested MASLD and MetALD.

Outcomes of Various Classes of Oral Antidiabetic Drugs on Nonalcoholic Fatty Liver Disease.

Importance: Several oral antidiabetic drug (OAD) classes can potentially improve patient outcomes in nonalcoholic fatty liver disease (NAFLD) to varying degrees, but clinical data on which class is favored are lacking. Objective: To investigate which OAD is associated with the best patient outcomes in NAFLD and type 2 diabetes (T2D). Design, Setting, and Participants: This retrospective nonrandomized interventional cohort study used the National Health Information Database, which provided population-level data for Korea. This study involved patients with T2D and concomitant NAFLD. Exposures: Receiving either sodium-glucose cotransporter 2 (SGLT2) inhibitors, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, or sulfonylureas, each combined with metformin for 80% or more of 90 consecutive days. Main Outcomes and Measures: The main outcomes were NAFLD regression assessed by the fatty liver index and composite liver-related outcome (defined as liver-related hospitalization, liver-related mortality, liver transplant, and hepatocellular carcinoma) using the Fine-Gray model regarding competing risks. Results: In total, 80 178 patients (mean [SD] age, 58.5 [11.9] years; 43 007 [53.6%] male) were followed up for 219 941 person-years, with 4102 patients experiencing NAFLD regression. When compared with sulfonylureas, SGLT2 inhibitors (adjusted subdistribution hazard ratio [ASHR], 1.99 [95% CI, 1.75-2.27]), thiazolidinediones (ASHR, 1.70 [95% CI, 1.41-2.05]), and DPP-4 inhibitors (ASHR, 1.45 [95% CI, 1.31-1.59]) were associated with NAFLD regression. SGLT2 inhibitors were associated with a higher likelihood of NAFLD regression when compared with thiazolidinediones (ASHR, 1.40 [95% CI, 1.12-1.75]) and DPP-4 inhibitors (ASHR, 1.45 [95% CI, 1.30-1.62]). Only SGLT2 inhibitors (ASHR, 0.37 [95% CI, 0.17-0.82]), not thiazolidinediones or DPP-4 inhibitors, were significantly associated with lower incidence rates of adverse liver-related outcomes when compared with sulfonylureas. Conclusions and Relevance: The results of this cohort study suggest that physicians may lean towards prescribing SGLT2 inhibitors as the preferred OAD for individuals with NAFLD and T2D, considering their potential benefits in NAFLD regression and lower incidences of adverse liver-related outcomes. This observational study should prompt future research to determine whether prescribing practices might merit reexamination.

Evolutionary changes in metabolic dysfunction-associated steatotic liver disease and risk of hepatocellular carcinoma: A nationwide cohort study.

BACKGROUND/AIMS: To determine the association between evolutionary changes in metabolic dysfunction-associated steatotic liver disease (MASLD) status and the risk of hepatocellular carcinoma (HCC) in a nationwide population-based cohort. METHODS: Information on study participants was derived from the Korea National Health Insurance Service database. The study population consisted of 5,080,410 participants who underwent two consecutive biennial health screenings between 2009 and 2012. All participants were followed up until HCC, death, or 31 December 2020. The association of evolutionary changes in MASLD status, as assessed by the fatty liver index and cardiometabolic risk factors, including persistent non-MASLD, resolved MASLD, incident MASLD, and persistent MASLD, with HCC risk was evaluated using multivariable-adjusted Cox proportional hazards regression. RESULTS: Among the 5,080,410 participants with 39,910,331 person-years of follow-up, 4,801 participants developed HCC. The incidence of HCC in participants with resolved, incident, and persistent MASLD was approximately 2.2-, 2.3-, and 4.7-fold higher, respectively, than that in those with persistent non-MASLD among the Korean adult population. When stratifying the participants according to the evolutionary change in MASLD status, persistent (adjusted hazard ratio [aHR], 2.94; 95% confidence interval [CI], 2.68-3.21; P<0.001), incident (aHR, 1.85; 95% CI, 1.63-2.10; P<0.001), and resolved MASLD (aHR, 1.33; 95% CI, 1.18-1.50; P<0.001) had an increased risk of HCC compared to persistent non-MASLD. CONCLUSION: The evolutionary changes in MASLD were associated with the differential risk of HCC independent of metabolic risk factors and concomitant medications, providing additional information on the risk of HCC stratification in patients with MASLD.

Combi-Elastography versus Transient Elastography for Assessing the Histological Severity of Metabolic Dysfunction-Associated Steatotic Liver Disease.

Background/Aims: Combi-elastography is a B-mode ultrasound-based method in which two elastography modalities are utilized simultaneously to assess metabolic dysfunction-associated steatotic liver disease (MASLD). However, the performance of combi-elastography for diagnosing metabolic dysfunction-associated steatohepatitis (MASH) and determining fibrosis severity is unclear. This study compared the diagnostic performances of combi-elastography and vibration-controlled transient elastography (VCTE) for identifying hepatic steatosis, fibrosis, and high-risk MASH. Methods: Participants who underwent combi-elastography, VCTE, and liver biopsy were selected from a prospective cohort of patients with clinically suspected MASLD. Combi-elastography-related parameters were acquired, and their performances were evaluated using area under the receiver-operating characteristic curve (AUROC) analysis. Results: A total of 212 participants were included. The diagnostic performance for hepatic steatosis of the attenuation coefficient adjusted by covariates from combi-elastography was comparable to that of the controlled attenuation parameter measured by VCTE (AUROC, 0.85 vs 0.85; p=0.925). The performance of the combi-elastography-derived fibrosis index adjusted by covariates for diagnosing significant fibrosis was comparable to that of liver stiffness measured by VCTE (AUROC, 0.77 vs 0.80; p=0.573). The activity index from combi-elastography adjusted by covariates was equivalent to the FibroScan-aspartate aminotransferase score in diagnosing high-risk MASH among participants with MASLD (AUROC, 0.72 vs 0.74; p=0.792). Conclusions: The performance of combi-elastography is similar to that of VCTE when evaluating histology of MASLD.

The Predictive Value of Time-Varying Noninvasive Scores on Long-Term Prognosis of NAFLD in South Korea.

Background: This study aimed to examine whether repeated measurements on noninvasive fibrosis scores during follow-up improve long-term nonalcoholic fatty liver disease (NAFLD) outcome prediction. Methods: A cohort study of 2,280 NAFLD patients diagnosed at the Seoul National University Hospital from 2001 to 2015 was conducted. Multivariable Cox regression models with baseline and designated time-point measurements of the fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS) were used to assess the association between these scores and overall mortality, liver-related outcomes, and cardiovascular events. Results: Higher baseline NFS (high versus low probability for advanced fibrosis groups) was associated with higher risk of mortality (adjusted hazard ratio (aHR), (95% confidence interval (CI)), 2.80, [1.39-5.63]) and liver-related outcomes (3.70, [1.27-10.78]). Similar findings were observed for the association of baseline FIB-4 with mortality (2.49, [1.46-4.24]) and liver-related outcomes (11.50, [6.17-21.44]). In models considering designated time-point measurements of the scores, stronger associations were noted. For NFS, a higher time-point measurement was associated with a significantly higher risk of mortality (3.01, [1.65-5.49]) and liver-related outcomes (6.69, [2.62-17.06]). For FIB-4, higher time-point measurements were associated with significantly higher mortality (3.01, [1.88-4.82]) and liver-related outcomes (13.26, [6.89-25.53]). An annual increase in FIB-4 (2.70, [1.79-4.05]) or NFS (4.68, [1.52-14.44]) was associated with an increased risk of liver-related outcomes. No association between NFS/FIB-4 and risk of cardiovascular events was observed in both models. Conclusions: Higher aHRs describing the associations of FIB-4/NFS with overall mortality and liver-related outcomes were observed in the models that included designated time-point measurements of the scores. In addition to the baseline measurement, a routine monitoring on these scores may be important in predicting prognosis of NAFLD patients.

Extrahepatic malignancies and antiviral drugs for chronic hepatitis B: A nationwide cohort study.

BACKGROUND/AIMS: Chronic hepatitis B (CHB) is related to an increased risk of extrahepatic malignancy (EHM), and antiviral treatment is associated with an incidence of EHM comparable to controls. We compared the risks of EHM and intrahepatic malignancy (IHM) between entecavir (ETV) and tenofovir disoproxil fumarate (TDF) treatment. METHODS: Using data from the National Health Insurance Service of Korea, this nationwide cohort study included treatment-naïve CHB patients who initiated ETV (n=24,287) or TDF (n=29,199) therapy between 2012 and 2014. The primary outcome was the development of any primary EHM. Secondary outcomes included overall IHM development. E-value was calculated to assess the robustness of results to unmeasured confounders. RESULTS: The median follow-up duration was 5.9 years, and all baseline characteristics were well balanced after propensity score matching. EHM incidence rate differed significantly between within versus beyond 3 years in both groups (P<0.01, Davies test). During the first 3 years, EHM risk was comparable in the propensity score-matched cohort (5.88 versus 5.84/1,000 person-years; subdistribution hazard ratio [SHR]=1.01, 95% confidence interval [CI]=0.88-1.17, P=0.84). After year 3, however, TDF was associated with a significantly lower EHM incidence compared to ETV (4.92 versus 6.91/1,000 person-years; SHR=0.70, 95% CI=0.60-0.81, P<0.01; E-value for SHR=2.21). Regarding IHM, the superiority of TDF over ETV was maintained both within (17.58 versus 20.19/1,000 person-years; SHR=0.88, 95% CI=0.81-0.95, P<0.01) and after year 3 (11.45 versus 16.20/1,000 person-years; SHR=0.68, 95% CI=0.62-0.75, P<0.01; E-value for SHR=2.30). CONCLUSION: TDF was associated with approximately 30% lower risks of both EHM and IHM than ETV in CHB patients after 3 years of antiviral therapy.

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.

Metabolic dysfunction-associated steatotic liver disease increases the risk of incident cardiovascular disease: a nationwide cohort study.

Background: The various subcategories under the overarching term of steatotic liver disease (SLD) have been recently proposed by the nomenclature consensus group and endorsed by international academic liver societies. Our aim was to investigate the association between each subtype of SLD and incident cardiovascular disease (CVD) in a nationwide Korean cohort. Methods: From a nationwide health screening database from Korea, 351,068 individuals aged 47-86 years between January 1, 2009 and December 31, 2010 were included and followed until December 31, 2019 for a median of 9.0 years. Individuals were categorised into no SLD, metabolic dysfunction-associated steatotic liver disease (MASLD), MASLD with increased alcohol intake (MetALD), and alcohol-related liver disease (ALD). Hepatic steatosis was defined as fatty liver index ≥60. The primary outcome was a composite CVD, which includes non-fatal and fatal myocardial infarction and stroke. The subdistribution hazard ratio (SHR) was calculated using the Fine-Gray model with treating non-CVD-related death as a competing risk. Findings: There were 199,817 male (56.9%) and 151,251 female (43.1%) with a median age of 55 years (interquartile range, 50-61). The prevalence of no SLD, MASLD, MetALD, and ALD was 44.3%, 47.2%, 6.4%, and 2.1%, respectively; and the incidence rate of CVD in each subcategory was 6.2, 8.5, 8.5, and 9.6 per 1000 person-years, respectively. MASLD (SHR, 1.19; 95% confidence interval [CI], 1.15-1.24), MetALD (SHR, 1.28; 95% CI, 1.20-1.36), and ALD (SHR, 1.29; 95% CI, 1.18-1.41) increased the risk of CVD compared to no SLD, which increment was in consecutive order (Ptrend < 0.001). Interpretation: Individuals with MASLD, MetALD, or ALD are at an increased risk of developing incident CVD. Higher risk of CVD observed in MetALD compared to MASLD suggests the additive impact of alcohol consumption in conjunction with cardiometabolic risk factors on CVD development. These findings support and validate the utility of the new consensus criteria for SLD in predicting CVD. Funding: The National Research Foundation of Korea and the Korea Centers for Disease Control and Prevention.

PNPLA3 genotypes modify the adverse effect of the total energy intake on high-risk nonalcoholic steatohepatitis development.

BACKGROUND: The relationship between diet and risk genotypes in nonalcoholic steatohepatitis (NASH) development and fibrosis progression in patients with nonalcoholic fatty liver disease (NAFLD) remains unclear. OBJECTIVE: We aimed to investigate the effects of diet on NASH development and fibrosis progression in patients with NAFLD stratified by the PNPLA3 genotype. METHODS: We performed a prospective study in a cohort of patients with biopsy-confirmed NAFLD. Histologic deterioration was obtained using serial transient elastography at every 1 or 2 y. The primary outcome was fibrosis progression, and the secondary outcome was development of high-risk NASH, defined as FibroScan-aspartate aminotransferase score ≥0.67 during the follow-up of patients with nonalcoholic fatty liver at the baseline. Dietary intake was evaluated using a semiquantitative food frequency questionnaire. RESULTS: The primary outcome was observed in 42 (29.0%) of the 145 patients during a median follow-up of 49 mo; neither the total energy intake nor each macronutrient intake significantly affected the primary outcome occurrence. Conversely, the total energy intake (HR per 1-SD: 3.03; 95% CI: 1.31, 7.01) and the PNPLA3 rs738409 genotype [HR per 1 risk allele (G): 2.06; 95% CI: 1.11, 3.83)] were independent risk factors for high-risk NASH. The significant interaction between the total energy intake and PNPLA3 genotype was noted in developing high-risk NASH (P = 0.044). As the number of PNPLA3 risk alleles decreased, the effect of the total energy intake on high-risk NASH increased; the HR per 1-SD increment in total energy intake was 1.52 (95% CI: 0.42, 5.42), 3.54 (95% CI: 1.23, 10.18), and 8.27 (95% CI: 1.20, 57.23) for the GG, CG, and CC genotypes, respectively. CONCLUSIONS: The total energy intake adversely affected the development of high-risk NASH in patients with biopsy-confirmed NAFLD. The effect was more prominent in patients without the PNPLA3 risk allele, highlighting the importance of personalized dietary interventions in NAFLD treatment.

Low-quality muscle mass rather than normal-quality muscle mass determines fibrosis progression in biopsy-proven NAFLD.

BACKGROUND AND AIMS: Sarcopaenia is associated with advanced nonalcoholic fatty liver disease (NAFLD). However, the impact of the muscle mass categorised by muscle quality on fibrosis progression remains unclear. METHODS: A total of 292 patients with biopsy-proven NAFLD who underwent serial vibration-controlled transient elastography assessments at least 1 year from baseline were selected. The skeletal muscle area (SMA) was determined on abdominal computed tomography (CT) at the third lumbar vertebra level and categorised to normal-attenuation muscle area (NAMA), low-attenuation muscle area (LAMA) and intermuscular adipose tissue (IMAT) using a muscle quality map. These SMAs were normalised by the height squared to obtain the skeletal muscle index (SMI). RESULTS: At baseline, as the histological fibrosis stage increased, SMINAMA decreased and SMILAMA increased (p for trend = 0.014 and p for trend <0.001, respectively), which was not significant after adjustment for age, sex and obesity. During a median follow-up of 41 months, fibrosis progression was detected in 48 out of 292 patients, and higher SMILAMA quartiles independently increased the risk of fibrosis progression in a dose-dependent manner (hazard ratio [HR] per quartile: 1.41; 95% confidence interval [CI], 1.04-1.91). The highest quartile of SMILAMA increased the risk of fibrosis progression by 3.25 times compared to the lowest quartile of SMILAMA (95% CI, 1.18-8.90). SMINAMA quartiles were not associated with the risk of fibrosis progression. CONCLUSION: Increased low-quality muscle mass, but not decreased normal-quality muscle mass, as assessed by a muscle quality map in CT, predicts fibrosis progression in patients with NAFLD.

A sequential approach using the age-adjusted fibrosis-4 index and vibration-controlled transient elastography to detect advanced fibrosis in Korean patients with non-alcoholic fatty liver disease.

BACKGROUND AND AIMS: Vibration-controlled transient elastography (VCTE) has shown good diagnostic performance in predicting fibrosis stages in patients with non-alcoholic fatty liver disease (NAFLD). However, an optimal diagnostic approach to detect advanced fibrosis in patients with NAFLD has not been established. APPROACH AND RESULTS: We prospectively collected data from 539 subjects who underwent liver biopsy at a single centre between January 2014 and December 2019. Diagnostic performance was estimated using the area under the receiver-operating characteristic curve (AUROC). Several models combining the fibrosis 4 index (FIB-4) score and liver stiffness measurement (LSM) were analysed to reduce the need for unnecessary liver biopsies. We observed significant fibrosis (≥F2), advanced fibrosis (≥F3) and cirrhosis (F4) in 173 (32.1%), 74 (13.7%) and 46 subjects (8.5%), respectively. The AUROCs (95% CI) for LSMs to diagnose ≥F2, ≥F3 and F4 were 0.82 (0.78-0.85), 0.92 (0.89-0.94) and 0.95 (0.93-0.97), respectively. Optimal LSM cut-off values were 6.7 (≥F2), 8.3 (≥F3) and 9.8 (F4) kPa. LSMs were affected by waist circumference, serum albumin and fibrosis stage (R2  = 0.315). Abdominal obesity, elevated transaminase, diabetes mellitus and high IQR/Median were associated with the discordance of ≥2 fibrosis stages between LSMs and histologic data. The sequential use of the age-adjusted FIB-4 and LSMs yielded the least uncertainty (5.3%) in classifying disease severity with the highest diagnostic accuracy (81%) among a variety of non-invasive test combinations. CONCLUSIONS: The sequential approach of age-adjusted FIB-4 and VCTE could represent a practical diagnostic strategy to detect advanced fibrosis in NAFLD (ClinicalTrials.gov #NCT02206841).

Yttrium-90 Radioembolization Is Associated with Better Clinical Outcomes in Patients with Hepatocellular Carcinoma Compared with Conventional Chemoembolization: A Propensity Score-Matched Study.

BACKGROUND: Both trans-arterial radioembolization (TARE) and conventional trans-arterial chemoembolization (TACE) can effectively control hepatocellular carcinoma (HCC) in patients who are not suitable for curative resection. This study compared the effectiveness of TARE and conventional TACE as the initial trans-arterial treatment for hepatocellular carcinoma (HCC) assessed by tumor response and clinical outcomes. MATERIAL AND METHODS: Data were retrospectively analyzed the propensity score-matched cohort for overall survival (OS), progression-free survival (PFS), and intrahepatic PFS in patients who have received TARE or TACE as the first HCC treatment from March 2012 to December 2017. RESULTS: A total of 138 patients initially treated with TARE (n = 54) or TACE (n = 84) was included in this study. Of 138 patients, median age was 59 years and the mean follow-up period was 27.6 months. TARE showed better OS (hazard ratio [HR] = 0.54, 95% confidence interval [CI] = 0.31-0.92, log-rank P = 0.02), better PFS (HR = 0.51, 95% CI = 0.36-0.97, log-rank P = 0.04), and better intrahepatic PFS (HR = 0.51, 95% CI = 0.30-0.88, log-rank P = 0.01) compared with TACE. TARE was an independent prognostic factor for OS (adjusted HR [aHR] = 0.52, 95% CI = 0.30-0.90, P = 0.02), PFS (aHR = 0.57, 95% CI = 0.35-0.94, P = 0.03), and intrahepatic PFS (aHR = 0.49, 95% CI = 0.28-0.84, P = 0.01). CONCLUSION: TARE as initial trans-arterial treatment is associated with better clinical outcomes such as longer OS compared with TACE in patients with HCC.

Effectiveness of Transarterial Chemoembolization-First Treatment for Advanced Hepatocellular Carcinoma: A Propensity Score Matching Analysis.

BACKGROUND: Still in real-world practice, advanced hepatocellular carcinoma (HCC) patients are treated with transarterial chemoembolization (TACE). This study compared the therapeutic effectiveness of initial TACE treatment and initial sorafenib treatment in advanced HCC patients. PATIENT AND METHODS: Advanced HCC patients initially treated with sorafenib or TACE were included in this study. Treatment crossover due to an unfavorable response to initial treatment was allowed. Propensity score (PS) matching was applied for balancing baseline characteristics. The primary outcome was overall survival (OS) and the secondary outcomes included tumor response. RESULTS: A total of 554 patients were included in this study: 85 were initially treated with sorafenib (the sorafenib-first group) and 469 with TACE (the TACE-first group). In the entire cohort, the TACE-first group was associated with lower risk of death [adjusted hazard ratio (HR)=0.75, P=0.04]. In the PS-matched cohort (85 patients per group), the TACE-first group showed longer OS than the sorafenib-first group in both univariable (HR=0.68, P=0.02) and multivariable analyses (adjusted HR=0.58, P=0.002). Specifically, within both the entire and the PS-matched cohorts, the TACE-first group showed longer OS in subgroups with major portal vein tumor thrombosis (HR=0.72, P=0.048; HR=0.52, P=0.003) or infiltrative HCC (HR=0.42, P<0.001; HR=0.30, P=0.004, respectively). The objective response rate was higher in the TACE-first group (29.3% vs 14.7%, P=0.03) within the PS-matched cohort. CONCLUSION: For advanced HCC, initial TACE leads to longer OS with a more favorable tumor response than initial sorafenib treatment. Intrahepatic tumor control with initial locoregional therapy may be a potent strategy for advanced HCC.

Effectiveness of nivolumab versus regorafenib in hepatocellular carcinoma patients who failed sorafenib treatment.

BACKGROUND/AIMS: Several treatment options are currently available for patients with hepatocellular carcinoma (HCC) failing previous sorafenib treatment. We aimed to compare the effectiveness of regorafenib and nivolumab in these patients. METHODS: Consecutive HCC patients who received regorafenib or nivolumab after failure of sorafenib treatment were included. Primary endpoint was overall survival (OS) and secondary endpoints were time to progression, tumor response rate, and adverse events. Inverse probability of treatment weighting (IPTW) using the propensity score was conducted to reduce treatment selection bias. RESULTS: Among 150 study patients, 102 patients received regorafenib and 48 patients received nivolumab. Median OS was 6.9 (95% confidence interval [CI], 3.0-10.8) months for regorafenib and 5.9 (95% CI, 3.7-8.1) months for nivolumab (P=0.77 by log-rank test). In multivariable analysis, nivolumab was associated with prolonged OS (vs. regorafenib: adjusted hazard ratio [aHR], 0.54; 95% CI, 0.30-0.96; P=0.04). Time to progression was not significantly different between groups (nivolumab vs. regorafenib: aHR, 0.82; 95% CI, 0.51-1.30; P=0.48). HRs were maintained after IPTW. Objective response rates were 5.9% and 16.7% in patients treated with regorafenib and nivolumab, respectively (P=0.04). CONCLUSION: After sorafenib failure, the use of nivolumab may be associated with improved OS and better objective response rate as compared to using regorafenib.