Background/Aims:Tenofovir alafenamide (TAF) has emerged as a safe and effective alternative to entecavir (ETV) in the management of chronic hepatitis B (CHB). We aimed to evaluate the efficacy and safety of switching to TAF compared with maintaining ETV in patients with CHB who had achieved virologic suppression on ETV. Methods:In this multicenter, randomized, open-label, active-controlled, noninferiority clinical trial conducted at 13 Korean centers, 196 CHB patients who had experienced virologic suppression after ≥24 weeks of ETV therapy were randomized 1:1 to switch to TAF (n=95) or continue on ETV (n=101). The primary endpoint was the proportion of patients with hepatitis B virus (HBV) DNA <29 IU/mL at week 48 (per-protocol set). Secondary endpoints included alanine aminotransferase (ALT) normalization, hepatitis B surface antigen and hepatitis B e antigen serologic responses, and safety outcomes. Results:Among 188 patients in the per-protocol set (89 TAF, 99 ETV), the HBV suppression rate at week 48 was 100.0% in the TAF group and 99.0% in the ETV group (difference, 1.03%; one-sided 97.5% confidence interval, -0.96 to infinity). ALT normalization rates at week 48 were comparable between groups (55.0% in TAF vs 38.7% in ETV; p=0.26; American Association for the Study of Liver Diseases criteria). Hepatitis B e antigen seroconversion rates were also similar at week 48 (0.0% vs 12.5%; p=0.21). Safety profiles, including renal function, did not significantly differ between the two groups. Conclusions:Switching from ETV to TAF was noninferior to continuing ETV in maintaining virologic suppression, with comparable biochemical, serologic, and safety outcomes. (ClinicalTrials. gov identifier NCT06000657).

INTRODUCTION:Direct-acting antiviral agents effectively cure chronic hepatitis C (CHC), whereas curative therapy for chronic hepatitis B (CHB) is rare. We aimed to compare hepatocellular carcinoma (HCC) incidence between suppressed CHB vs cured CHC patients with cirrhosis. METHODS:We analyzed 5,773 cirrhosis patients from 43 centers in 9 countries: 1,877 with treated and suppressed CHB and 3,896 with direct-acting antiviral agents-cured CHC using inverse probability treatment weight and competing risk analysis through Fine and Gray method. RESULTS:After inverse probability treatment weight (on age, sex, ethnicity, study location, albumin, total bilirubin, creatinine, platelet, tobacco use, alcohol use, diabetes mellitus, hypertension, hyperlipidemia, cardiovascular disease, steatotic liver disease, obesity, and follow-up years), 2 study groups became similar in relevant characteristics. The 5-year cumulative HCC incidence was significantly higher in suppressed CHB compared with cured CHC (18.1% vs 7.4%, P < 0.001) with consistent findings in subgroups by sex and Model for End-Stage Liver Disease (all P < 0.021), fast CHB responders (time from treatment to viral suppression <1 year) ( P < 0.001), and CHB suppressed for <2 years ( P < 0.001), but not among CHB suppressed for ≥2 years whose HCC incidence was similar to those of cured CHC ( P = 0.954). On multivariable analysis, CHB suppression <2 years as compared with cured CHC (subdistribution hazard ratio 20.92, P < 0.001) and total bilirubin (subdistribution hazard ratio 0.71, P = 0.04) were associated with higher HCC risk. DISCUSSION:HCC risk remains high in both treated and suppressed CHB cirrhosis and cured CHC cirrhosis. However, with prolonged CHB suppression, risk of HCC can be reduced, highlighting benefits of early treatment and viral suppression in patients with CHB.

BACKGROUND/AIMS:This study investigated the effectiveness of COVID-19 vaccination in decompensated cirrhosis. METHODS:This study comprised a population-based cohort of 1 583 777 patients with chronic liver disease (CLD), including decompensated cirrhosis, from the National Health Insurance Service data in South Korea. The primary outcome was the risk of COVID-19 within 6 months after vaccination between 26 February 2021 and 31 December 2021. Hospitalisation and all-cause mortality rates were also investigated. Target trial specifications with propensity score matching were used to minimise the bias between the unvaccinated and vaccinated groups. RESULTS:The mean age of patients was 54.2 years, and 54.5% were men. In total, 61 765 patients (3.9%) had decompensated cirrhosis. Compared to the unvaccinated group, the vaccinated group exhibited a lower risk of COVID-19 (hazard ratio [HR] = 0.94; 95% confidence interval [CI] = 0.91-0.97), hospitalisation (HR = 0.86; 95% CI = 0.83-0.89), and all-cause mortality (HR = 0.27; 95% CI = 0.20-0.36) in CLD. However, there was no statistical difference in the clinical outcomes among patients with decompensated cirrhosis with respect to COVID-19 vaccination. The multivariable analysis determined that COVID-19 vaccination reduced all-cause mortality in CLD (HR = 0.39; 95% CI = 0.32-0.49) and decompensated cirrhosis increased all-cause mortality in patients with COVID-19 (HR = 2.94; 95% CI = 2.15-4.02). These results were consistent during the pre-Delta and Delta-variant periods. CONCLUSIONS:COVID-19 vaccination reduced the risk of COVID-19, hospitalisation, and mortality in CLD. However, patients with decompensated cirrhosis had a poor prognosis independently of COVID-19 vaccination.

BACKGROUND:Sarcopenia and frailty are risk factors for poor prognosis in patients with liver cirrhosis. This study investigated the role of renal biomarkers in sarcopenia or frailty in patients with cirrhosis. METHODS:A total of 78 patients with liver cirrhosis and serum creatinine levels < 1.5 mg/dL were analysed for serum renal biomarkers (creatinine-to-cystatin C ratio, interleukin [IL]-18, kidney injury molecule [KIM]-1, and neutrophil gelatinase-associated lipocalin [NGAL]), sarcopenia, and liver frailty index. Sarcopenia was assessed using the skeletal muscle index of the third vertebra. We analysed the risk of sarcopenia or frailty based on various renal biomarkers of cirrhosis. RESULTS:The mean age was 59.2 years and 67.9% were men. The Child-Pugh class B score was noted in 17.9%. Sarcopenia or frailty (pre-frail and frail) was observed in 43 patients (55.1%). No significant differences in serum IL-18 (P = 0.285), NGAL (P = 0.537), or KIM-1 (P = 0.482) levels were observed according to sarcopenia or frailty. However, the creatinine-to-cystatin C ratio was significantly lower in patients with sarcopenia or frailty than in those without sarcopenia or frailty (0.73 vs. 0.83, P = 0.002). Multivariable analysis indicated that the risk factors for sarcopenia or frailty were Child-Pugh class B (odds ratio [OR], 9.04; 95% confidence interval [CI], 1.06-76.85; P = 0.044) and creatinine-to-cystatin C ratio < 0.8 (OR, 4.03; 95% CI, 1.45-11.25; P = 0.008). Serum IL-18, NGAL, and KIM-1 levels were not associated with sarcopenia or frailty. CONCLUSION:A lower serum creatinine-to-cystatin C ratio was associated with an increased risk of sarcopenia or frailty in patients with cirrhosis and favourable renal function.

Background: This study evaluated the efficacy and safety of standard-dose ursodeoxycholic acid (UDCA; fixed daily dose of 300 mg/day) compared with placebo, in patients with chronic liver disease. Methods: A multicenter, randomized, double-blind, placebo-controlled phase IV clinical trial was conducted in academic hospitals in South Korea. Patients with chronic liver disease and abnormal serum alanine aminotransferase (ALT) levels in at least two consecutive results prior to screening, persisting for at least 6 months, were randomly assigned to receive 100 mg UDCA or placebo three times daily for 8 weeks. The primary endpoint was the mean relative change in ALT levels from baseline. The secondary endpoints included changes in fibrosis and drug-related adverse events. Results: A total of 262 patients were analyzed (132 in the UDCA group and 130 in the placebo group). By week 8, there was a significantly greater reduction in serum ALT levels from baseline in the UDCA-treated patients than in the placebo group (-14.70 vs. -5.51 U/L; P = 0.010). The ALT normalization rates were higher in the UDCA group (26.52% vs. 13.08%; odds ratio, 2.60; P = 0.005). Fibrosis reduction, as assessed by the FibroTest score, was greater in the UDCA group (-0.03 vs. -0.00; P = 0.016). The frequency of adverse events in the two groups was similar, with no serious adverse events reported in the UDCA group. Conclusion: In patients with chronic liver disease, 100 mg UDCA three times daily for 8 weeks improved ALT levels and fibrosis, and had a favorable safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT06272630

BACKGROUND:This study investigated the role of the albumin-bilirubin (ALBI) grade as a predictive factor for mortality in patients with favorable liver function undergoing transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). METHODS:A total of 251 HCC patients with Child-Pugh class A and a model for end-stage liver disease (MELD) score < 10 who received TACE as initial treatment were analyzed. Predictive factors for overall survival were assessed. RESULTS:The mean age was 61.5 years, and the median follow-up was 10.3 years. A high ALBI grade (ALBI score > -2.60) was observed in 147 patients (59%). Multivariable analysis showed that mortality was significantly associated with Barcelona Clinic Liver Cancer (BCLC) stage B (hazard ratio [HR] 2.21, 95% confidence interval [CI] 1.24-3.93, p = 0.007), BCLC stage C (HR 4.80, 95% CI 2.76-8.34, p < 0.001), presence of ascites (HR 2.28, 95% CI 1.31-3.97, p = 0.003), progressive disease (PD) of tumor response (HR 2.95, 95% CI 1.76-4.93, p < 0.001), and high ALBI grade (Grade ≥ 2) (HR 1.96, 95% CI 1.20-3.21, p = 0.008). Overall survival differed significantly by ALBI grade: the 3-, 6-, 9-, and 12-year survival rates were 80.4%, 78.7%, 76.2%, and 65.5% in the low ALBI group (Grade 1) and 61.3%, 42.8%, 35.7%, and 35.7% in the high ALBI group (Grade ≥ 2) (p < 0.001). CONCLUSIONS:High ALBI grade (Grade ≥ 2) is associated with increased mortality in patients with Child-Pugh class A and low MELD score undergoing TACE for HCC. ALBI grade may serve as a predictor of survival in patients with preserved liver function receiving TACE.

BACKGROUND & AIMS:This study aimed to investigate the impact of serious infection on mortality of patients with chronic liver disease (CLD). METHODS:This study was conducted on 1,699,159 patients with CLD from the Korean National Health Insurance Service between 2009 and 2021. Serious infection was defined as acute meningitis, acute osteomyelitis, bacteremia, pneumonia, pyelonephritis, serious gastrointestinal infection, skin and soft tissue infections, spontaneous bacterial peritonitis, or COVID-19 infection. The primary outcome was all-cause mortality stratified by serious infection episodes (0, 1, and ≥2). RESULTS:The mean age of patients was 57.4 years, with 55.6% being men. Among them, the proportion of CLD without cirrhosis, compensated cirrhosis, and decompensated cirrhosis was 77.5% (n = 1,317,468), 17.5% (n = 296,617), and 5.0% (n = 85,074), respectively. During follow-up, there were 336,602 episodes of serious infections, with pneumonia being the most common, followed by serious gastrointestinal infection, pyelonephritis, and bacteremia. Mortality rates were 3.94, 41.58, and 114.03 per 1000 person-years in patients with 0, 1, and ≥2 serious infections, respectively. Multivariable analysis indicated that adjusted hazard ratios (aHRs) for mortality were 6.04 (95% confidence interval [CI], 5.96-6.13) for 1 infection and 13.40 (95% CI, 13.20-13.60) for ≥2 infections, compared with no infections. Compared with CLD without cirrhosis, the development of serious infection was higher in compensated cirrhosis (aHR, 1.99; 95% CI, 1.97-2.02) and decompensated cirrhosis (aHR, 3.31; 95% CI, 3.26-3.37). CONCLUSIONS:Patients with CLD exhibited a trend of increased mortality dependent on the number of serious infections and the degree of disease severity of CLD, ranging from CLD without cirrhosis, compensated cirrhosis, and decompensated cirrhosis. Decompensated cirrhosis has more than a 3-fold risk of infection than CLD without cirrhosis.

BACKGROUND & AIMS: It is unclear if there may be sex differences in response to nucleos(t)ide analogs including virologic response (VR), biochemical response (BR), complete response (CR), and hepatocellular carcinoma (HCC) incidence among hepatitis B patients. We compared nucleos(t)ide analog treatment outcomes by sex. METHODS: We performed a retrospective cohort study of 3388 treatment -naive adult hepatitis B patients (1250 female, 2138 male) from the Real -World Evidence from the Global Alliance for the Study of Hepatitis B Virus consortium who initiated therapy with either entecavir or tenofovir from 22 sites (Argentina, Korea, Japan, Taiwan, and the United States). We used propensity -score matching to balance background characteristics of the male and female groups and competing -risks analysis to estimate the incidence and subdistribution hazard ratios (SHRs) of VR, BR, CR, and HCC. RESULTS: Females (vs males) were older (52.0 vs 48.6 y); less likely to be overweight/obese (49.3% vs 65.7%), diabetic (9.9% vs 13.1%), or cirrhotic (27.9% vs 33.0%); and had a lower HBV DNA level (5.9 vs 6.0 log10 IU/mL) and alanine aminotransferase level (91 vs 102 IU/L) (all P < .01). However, after propensity -score matching, relevant background characteristics were balanced between the 2 groups. Females (vs males) had similar 5 -year cumulative VR (91.3% vs 90.3%; P = .40) and HCC incidence rates (5.1% vs 4.4%; P = .64), but lower BR (84.0% vs 90.9%; P < .001) and CR (78.8% vs 83.4%; P = .016). Males were more likely to achieve BR (SHR, 1.31; 95% CI, 1.17-1.46; P < .001) and CR (SHR, 1.16; 95% CI, 1.03-1.31; P = .016), but VR and HCC risks were similar. CONCLUSIONS: Sex differences exist for treatment outcomes among hepatitis B patients. Male sex was associated with a 16% higher likelihood of clinical remission and a 31% higher likelihood of biochemical response than females, while virologic response and HCC incidence were similar between the 2 groups.

Background: Chronic hepatitis B virus (HBV) infection is associated with a reduced risk of dyslipidaemia. Using a human faecal transplant mouse model, we compared changes in gut microbiota and lipid profiles in mice transplanted with human faeces from HBV-infected and non-infected individuals. Methods: A total of 19 mice received human faecal microbiota transplantation (FMT) from four HBV-infected individuals and were categorised into the HBV-positive mice group, while 20 mice received FMT from four HBV-non-infected individuals and were categorised into the HBV-negative mice group. Serial changes in the gut microbiota and lipid levels were compared between the two subgroups during 6 weeks of post-FMT period. Results : In the analysis of gut microbiota in FMT mice, we observed a robust increase in alpha diversity and abundance of taxa related to lipid metabolism, including Akkermansia muciniphila in HBV-positive mice, compared to that in HBV-negative mice. Functional inference analysis revealed that the pathways involved in glycerolipid metabolism were more enriched in HBV-positive mice. At 5 weeks of post-FMT, the reduced triglyceride (TG) level was predominantly observed in HBV-positive mice, compared to that in HBV-negative mice. Conclusions: In the experimental FMT mouse model, we found that altered gut microbiota accompanied by HBV infection was associated with a robust increase in alpha diversity and butyrate producers, which resulted in areduced level of TG at 5 weeks post-FMT. This indicates that the reduced risk of dyslipidaemia in chronic HBV infection may be due to the altered gut microbiota accompanied by HBV infection.

Elevated serum gamma-glutamyl transferase (GGT) levels are associated with chronic hepatitis B (CHB)-related hepatocellular carcinoma. However, their role in predicting mortality in patients with CHB treated with nucleotide/nucleoside analogs (NAs) remains elusive. Altogether, 2843 patients with CHB treated with NAs were recruited from a multinational cohort. Serum GGT levels before and 6 months (Month-6) after initiating NAs were measured to explore their association with all-cause, liver-related, and non-liver-related mortality. The annual incidence of all-cause mortality was 0.9/100 person-years over a follow-up period of 17,436.3 person-years. Compared with patients who survived, those who died had a significantly higher pretreatment (89.3 vs. 67.4 U/L, p = 0.002) and Month-6-GGT levels (62.1 vs. 38.4 U/L, p < 0.001). The factors associated with all-cause mortality included cirrhosis (hazard ratio [HR]/95% confidence interval [CI]: 2.66/1.92-3.70, p < 0.001), pretreatment GGT levels (HR/CI: 1.004/1.003-1.006, p < 0.001), alanine aminotransferase level (HR/CI: 0.996/0.994-0.998, p = 0.001), and age (HR/CI: 1.06/1.04-1.07, p < 0.001). Regarding liver-related mortality, the independent factors included cirrhosis (HR/CI: 4.36/2.79-6.89, p < 0.001), pretreatment GGT levels (HR/CI: 1.006/1.004-1.008, p < 0.001), alanine aminotransferase level (HR/CI: 0.993/0.990-0.997, p = 0.001), age (HR/CI: 1.03/1.01-1.05, p < 0.001), and fatty liver disease (HR/CI: 0.30/0.15-0.59, p = 0.001). Pretreatment GGT levels were also independently predictive of non-liver-related mortality (HR/CI: 1.003/1.000-1.005, p = 0.03). The results remained consistent after excluding the patients with a history of alcohol use. A dose-dependent manner of <25, 25-75, and >75 percentile of pretreatment GGT levels was observed with respect to the all-cause mortality (trend p < 0.001). Pretreatment serum GGT levels predicted all-cause, liver-related, and non-liver-related mortality in patients with CHB treated with NAs.

Background and Aim; The benefits of entecavir (ETV) versus tenofovir disoproxil fumarate (TDF) in reducing the development of chronic hepatitis B (CHB)-related hepatocellular carcinoma remain controversial. Whether mortality rates differ between patients with CHB treated with ETV and those treated with TDF is unclear. Methods; A total of 2542 patients with CHB treated with either ETV or TDF were recruited from a multinational cohort. A 1:1 propensity score matching was performed to balance the differences in baseline characteristics between the two patient groups. We aimed to compare the all-cause, liver-related, and non-liver-related mortality between patients receiving ETV and those receiving TDF. Results: The annual incidence of all-cause mortality in the entire cohort was 1.0/100 person-years (follow-up, 15 757.5 person-years). Patients who received TDF were younger and had a higher body mass index, platelet count, hepatitis B virus deoxyribonucleic acid levels, and proportion of hepatitis B e-antigen seropositivity than those who received ETV. The factors associated with all-cause mortality were fibrosis-4 index > 6.5 (hazard ratio [HR]/confidence interval [CI]: 3.13/2.15-4.54, P < 0.001), age per year increase (HR/CI: 1.05/1.04-1.07, P < 0.001), alanine aminotransferase level per U/L increase (HR/CI: 0.997/0.996-0.999, P = 0.003), and gamma-glutamyl transferase level per U/L increase (HR/CI: 1.002/1.001-1.003, P < 0.001). No significant difference in all-cause mortality was observed between the ETV and TDF groups (log-rank test, P = 0.69). After propensity score matching, no significant differences in all-cause, liver-related, or non-liver-related mortality were observed between the two groups. Conclusions: Long-term outcomes of all-cause mortality and liver-related and non-liver-related mortality did not differ between patients treated with ETV and those receiving TDF.

No information is available regarding the influence of besifovir (BSV), a new nucleotide analogue, on the occurrence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). This study evaluated the reduced risk of HCC in patients undergoing BSV treatment. A total of 188 patients with CHB were treated with BSV for up to 8 years. We prospectively assessed the incidence of HCC compared with the risk from prediction models. During the follow-up, 5 patients developed HCC: 1 of 139 patients with non-cirrhotic CHB, and 4 of 49 patients with liver cirrhosis. We compared the HCC incidence in non-cirrhotic and cirrhotic patients with the predicted number derived from the REACH-B (risk estimation for HCC in CHB) model and GAG-HCC (guide with age, gender, HBV DNA, core promotor mutation, and cirrhosis) model, respectively. The standardized incidence ratio (SIR) was 0.128 (p = 0.039) at 7 years in non-cirrhotic CHB patients, and the SIR was 0.371 (p = 0.047) at 7.5 years in cirrhotic patients, suggesting a significantly decreased HCC incidence in both groups. HCC prediction was available for BSV-treated patients using existing models. In conclusion, BSV decreased the risk of HCC in patients with CHB, and prediction models were applicable. Clinical trial registry website and trial number: ClinicalTrials.gov no: NCT01937806.