Fibrosis-4 index stratifies risks of hepatocellular carcinoma in patients with chronic hepatitis C.

BACKGROUND AND AIMS: Risk stratification for patients with a higher risk of hepatocellular carcinoma (HCC) is crucial. We aimed to investigate the role of the Fibrosis-4 (FIB-4) index in predicting chronic hepatitis C (CHC)-related HCC. METHODS: A retrospective cohort study consecutively included treatment-naive CHC patients receiving longitudinal follow-up at the National Taiwan University Hospital from 1986 to 2014. The clinical data were collected and traced for HCC development. Multivariable Cox proportional hazard regression analysis was used to investigate the predictors for HCC. RESULTS: A total of 1285 patients in the ERADICATE-C cohort were included. The median age was 54, 56% were females, and 933 had HCV viremia. There were 33%, 38%, and 29% of patients having FIB-4 index <1.45, 1.45-3.25, and ≥3.25, respectively. After a median of 9-year follow-up, 186 patients developed HCC. Multivariable analysis revealed that older age, AFP≥20 ng/mL, cirrhosis, and a higher FIB-4 index were independent predictors for HCC. Compared with patients with FIB-4 index <1.45, those with FIB-4 1.45-3.25 had a 5.51-fold risk (95% confidence interval [CI]: 2.65-11.46), and those with FIB-4 ≥ 3.25 had 7.45-fold risk (95% CI: 3.46-16.05) of HCC. In CHC patients without viremia, FIB-4 index 1.45-3.25 and FIB-4 ≥ 3.25 increased 6.78-fold and 16.77-fold risk of HCC, respectively, compared with those with FIB-4 < 1.45. CONCLUSION: The baseline FIB-4 index can stratify the risks of HCC in untreated CHC patients, even those without viremia. The FIB-4 index should thus be included in the management of CHC.

Risk of rituximab-induced hepatitis B flare after antiviral discontinuation in rheumatic patients with chronic hepatitis B virus.

OBJECTVES: Among immunosuppressants, rituximab is most strongly associated with the risk of hepatitis B virus (HBV) reactivation in chronic HBV individuals. Current guidelines recommending antiviral prophylaxis for these patients on rituximab are predominantly based on studies in oncology. However, limited data existed for the precise risk of HBV flares, effectiveness and optimal duration of antiviral prophylaxis in rituximab-treated rheumatic patients, whose immune status and treatment regimen differ significantly from those of oncology patients. Therefore, we aimed to assess the incidence and clinical outcome of HBV reactivation in HBsAg-positive patients receiving rituximab for various autoimmune diseases who discontinue the antiviral agents. METHODS: A retrospective analysis was performed on 95 hepatitis B surface antigen (HBsAg)-positive patients treated with rituximab for autoimmune diseases in a single centre in Taiwan. HBV related hepatitis, defined as alanine aminotransferase (ALT) more than 3 times of baseline level and concurrent HBV reactivation, after anti-viral discontinuation, was the primary endpoint. Factors associated with HBV hepatitis flare and off-antiviral hepatitis flare were also analysed. RESULTS: With nucleos(t)ide analogues (NA) prophylaxis, no hepatitis flares occurred. However, without prophylaxis, 59% had flare (24.5 per 100 person-years) and 8% experienced liver decompensation. Concurrent steroid use was a dose-dependent risk factor for flare. After NA discontinuation, rituximab "retreatment" led to flares in 75% of cases and liver decompensation in 63% of patients. Stopping NAs within one-year post-rituximab, even without further rituximab treatment, resulted in a 38% flare rate. CONCLUSIONS: This study offers the direct evidence for the necessity of universal antiviral prophylaxis in rheumatic patients with chronic HBV receiving rituximab. After NA discontinuation, rituximab "retreatment" led to even higher flare rate and worse outcome. Patients who completed rituximab treatment should also keep antiviral agents for at least one more year to prevent hepatitis flare.

Pre-existing and new-onset metabolic dysfunctions increase cirrhosis and its complication risks in chronic hepatitis B.

INTRODUCTION: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing among the chronic hepatitis B (CHB) population. This study aimed to explore the impact of metabolic dysfunction (MD) on cirrhosis and cirrhotic complication risks in CHB. METHODS: Patients with CHB were consecutively recruited between 2006-2021. The presence of MD was based on the five cardiometabolic criteria specified in the MASLD definition. Patients were categorized into MD/non-MD groups based on these criteria. RESULTS: 11,502 treatment-naïve non-cirrhotic CHB patients were included with a median follow-up of 5.3 years. Patients in the MD group (n=7314) were older and had lower HBV DNA levels than non-MD patients (n=4188). After adjustment for clinical and viral factors, MD patients had significantly higher risks of cirrhosis (adjusted hazard ratio [aHR]: 1.82, 95% confidence interval [CI]: 1.40-2.37, p<0.001) and cirrhotic complications (aHR: 1.30 per MD, 95% CI 1.03-1.63, p=0.025) in a dose-dependent manner. Furthermore, new-onset diabetes mellitus during the follow-up aggravated the risk of cirrhotic complications (aHR: 2.87, 95% CI: 1.34-6.11, p=0.006). Hepatic steatosis was associated with lower risks of cirrhosis (aHR: 0.57 within five years, 95% CI: 0.44-0.74, p<0.001) and cirrhotic complications (aHR: 0.45, 95% CI 0.23-0.88, p=0.020). Among individuals with hepatic steatosis, MASLD patients exhibited a higher cirrhosis risk than non-MD patients. CONCLUSION: Concurrent and new-onset MD increase the risks of cirrhosis and cirrhotic complications in CHB patients, independent of hepatic steatosis. Proactively investigating metabolic comorbidities in CHB is critical to stratify the risk of liver disease progression.

Serological responses to COVID-19 vaccination in patients with chronic liver diseases.

Longitudinal analysis of antibody responses following three-dose COVID-19 vaccination in patients with chronic liver disease (CLD) has been limited. From August 2021 to February 2023, sequential anti-SARS-CoV-2 spike IgG titers were determined in 45 patients with CLD who received two or three doses of COVID-19 vaccine. The geometric mean of anti-spike IgG at four weeks after the second and third doses were 1313.16 BAU/mL and 3042.29 BAU/mL, respectively, and it decreased significantly from four to 24 weeks after the second (1313.16 vs. 198.42 BAU/mL, p = 0.002) and the third (3042.29 vs. 636.71 BAU/mL, p < 0.001) dose. The anti-spike IgG titers in participants receiving prime-boost homologous mRNA vaccines (BNT162b2 or mRNA-1273) were comparable between participants with and those without significant liver fibrosis at each follow-up time point. This study demonstrated a notable decrease in anti-spike IgG after completion of the vaccination schedule in patients with CLD, highlighting the importance of additional booster doses.

Tenofovir versus entecavir on recurrence and mortality of hepatitis B virus-related hepatocellular carcinoma after curative therapy.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) and entecavir (ETV) reduce the risk of hepatocellular carcinoma (HCC) in patients of hepatitis B. This study compared the difference between ETV and TDF on risk of HCC recurrence and mortality in patients with HBV-related HCC after curative intent treatment. METHODS: Patients with HBV-related HCC who received HCC treatment (surgery or radiofrequency ablation [RFA]) and underwent long-term ETV or TDF therapy were retrospectively included. Baseline characteristics including age, sex, antiviral therapy, liver reserve, HCC stages, pathology reports and treatment modality were obtained. The risk of tumor recurrence, all-cause mortality, HCC-related mortality, and liver function were compared. RESULTS: We identified 390 HBV-related HCC patients with curative intent treatment for HCC and treated with ETV (n = 328) or TDF (n = 62) between January 2011 and December 2020. The median age was 60 years, and 90.7% patients were males. After a median follow-up of 29 months, 186 patients developed recurrent HCC and 111 died. The baseline characteristics were comparable except more ALBI grade 3 patients in TDF group (76% vs. 48%, P < 0.001). Compared to ETV group, TDF users had lower all-cause mortality (adjusted hazard ratio [aHR]: 0.38, P = 0.003), and HCC-related mortality (aHR: 0.23, P = 0.005). Lower recurrence rate was noticed in TDF users after inverse probability of treatment weighting (IPTW). TDF users had improved ALBI grade and FIB-4 index compared with ETV groups. CONCLUSIONS: TDF therapy is associated with a reduced risk of HCC-related outcomes among patients with HBV-related HCC after curative intent treatment compared with ETV usage.

Hepatitis B reactivation: A possible cause of coronavirus disease 2019 vaccine induced hepatitis.

BACKGROUND AND AIMS: Coronavirus disease 2019 (COVID-19) vaccines were rapidly implemented globally and vaccine-associated immune-related hepatitis was recently reported. We aim to investigate its impact in regions endemic of chronic hepatitis B (CHB). METHODS: We retrospectively collected patients who developed hepatitis within 90 days after COVID-19 vaccination in Taiwan. The mechanisms of hepatitis included vaccine induced liver injury (VILI) and immune-related hepatitis, which are direct liver injuries defined as aspartate or alanine aminotransferase (AST or ALT) increased ≥ 5-fold upper limit of normal (ULN) and/or AST or ALT ≥ 3-fold of ULN with concurrent total bilirubin ≥ 2-fold of ULN. Indirect liver injury due to HBV reactivation was defined as HBsAg reverse seroconversion or significant rise in HBV DNA level. The demographics, clinical data, and course of hepatitis were compared statistically. RESULTS: Twenty-five patients were included with a median age of 54. The culprit vaccines were ChAdOx1 nCoV-19 (n = 9), mRNA-1273 (n = 12), and BNT162b2 (n = 4). The characteristics of hepatitis were comparable regardless of vaccine subtypes. The median onset of hepatitis was 25 days post vaccination, with a peak of 10-fold ALT-increase. The etiologies included HBV reactivation (n = 10), VILI (n = 10), and immune-related hepatitis (n = 5). HBV reactivation accounts for 90% of vaccine-induced hepatitis in patients of CHB (n = 10), and two patients died. Patients with initial AST levels >500 U/L increased 27-fold risks of liver injury greater than moderate severity compared with those without. CONCLUSION: COVID-19 vaccine induced hepatitis is a clinical significant complication, and HBV reactivation may account for a possible mechanism.

Antagonism Between Gut Ruminococcus gnavus and Akkermansia muciniphila Modulates the Progression of Chronic Hepatitis B.

BACKGROUND & AIMS: A long immune-tolerant (IT) phase lasting for decades and delayed HBeAg seroconversion (HBe-SC) in patients with chronic hepatitis B (CHB) increase the risk of liver diseases. Early entry into the immune-active (IA) phase and HBe-SC confers a favorable clinical outcome with an unknown mechanism. We aimed to identify factor(s) triggering IA entry and HBe-SC in the natural history of CHB. METHODS: To study the relevance of gut microbiota evolution in the risk of CHB activity, fecal samples were collected from CHB patients (n = 102) in different disease phases. A hepatitis B virus (HBV)-hydrodynamic injection (HDI) mouse model was therefore established in several mouse strains and germ-free mice, and multiplatform metabolomic and bacteriologic assays were performed. RESULTS: Ruminococcus gnavus was the most abundant species in CHB patients in the IT phase, whereas Akkermansia muciniphila was predominantly enriched in IA patients and associated with alanine aminotransferase flares, HBeAg loss, and early HBe-SC. HBV-HDI mouse models recapitulated this human finding. Increased cholesterol-to-bile acids (BAs) metabolism was found in IT patients because R gnavus encodes bile salt hydrolase to deconjugate primary BAs and augment BAs total pool for facilitating HBV persistence and prolonging the IT course. A muciniphila counteracted this activity through the direct removal of cholesterol. The secretome metabolites of A muciniphila, which contained small molecules structurally similar to apigenin, lovastatin, ribavirin, etc., inhibited the growth and the function of R gnavus to allow HBV elimination. CONCLUSIONS: R gnavus and A muciniphila play opposite roles in HBV infection. A muciniphila metabolites, which benefit the elimination of HBV, may contribute to future anti-HBV strategies.

Metabolic Dysfunction-Associated Steatotic Liver Disease Facilitates Hepatitis B Surface Antigen Seroclearance and Seroconversion.

BACKGROUND & AIMS: Hepatitis B surface antigen (HBsAg) seroclearance is the goal of functional cure for hepatitis B virus (HBV) infection. However, the impact of metabolic dysfunction-associated steatotic liver disease (MASLD) on this favorable outcome remains unclear. METHODS: Patients with chronic hepatitis B (CHB) were consecutively recruited. MASLD was defined by the newly proposed disease criteria. Cumulative incidences and associated factors of HBsAg seroclearance/seroconversion were compared between the MASLD and non-MASLD groups. RESULTS: From 2006 to 2021, 4084 treatment-naive hepatitis B e antigen (HBeAg)-negative CHB patients were included. At baseline, CHB patients with concurrent MASLD (n = 887) had significantly lower levels of HBsAg and HBV DNA than the non-MASLD group (n = 3197). During a median follow-up of 5.0 years, MASLD was associated with a higher likelihood of HBsAg seroclearance (adjusted hazard ratio [aHR], 1.43; 95% confidence interval [CI], 1.10-1.85; P = .007), and the accumulation of individual metabolic dysfunctions additively facilitated HBsAg seroclearance. In addition, a higher rate of HBsAg seroconversion was observed in patients with MASLD versus those without MASLD (aHR, 1.37; 95% CI, 1.00-1.86; P = .049). In sensitivity analysis, patients with intermittent MASLD had an intermediate probability of HBsAg seroclearance. After balancing clinical and virologic profiles by inverse probability of treatment weighting (IPTW), MASLD was still associated with a higher HBsAg seroclearance rate (IPTW-adjusted HR, 1.41; 95% CI, 1.09-1.84; P = .010). CONCLUSIONS: In untreated HBeAg-negative CHB patients, concurrent MASLD is associated with higher rates of HBsAg seroclearance and seroconversion. Metabolic dysfunctions have additive effects on the functional cure of CHB.

Immunogenicity and safety of heterologous booster with protein-based COVID-19 vaccine (NVX-CoV2373) in healthy adults: A comparative analysis with mRNA vaccines.

BACKGROUND: Information on the protein-based severe acute respiratory syndrome (SARS-CoV-2) vaccine-NVX-CoV2373 (Novavax), as a heterologous booster remains limited. We investigated the immunogenicity and adverse events of NVX-CoV2373 as a second booster and compared them with those of mRNA vaccines in healthy adults. METHODS: Healthcare workers who had received an mRNA vaccine (mRNA-1273 or BNT-162b2) as the first booster (third dose) 12 weeks prior were recruited. Participants voluntarily received either NVX-CoV2373 or an mRNA vaccine as a second booster. Participants with a history of SARS-CoV-2 infection were excluded. The primary outcomes included serum anti-SARS-CoV-2 spike protein (SP) and neutralizing antibody titers against B.1.1.7 (Alpha), B.1.1.529 (Omicron) BA2, and BA5 variants on the 28th day after the boost. Secondary outcomes included new SARS-CoV-2 infections and adverse events reported during the study period. RESULTS: A total of 160 participants were enrolled in this study. Compared with the mRNA vaccination group (n = 59), the NVX-CoV2373 vaccination group (n = 101) had significantly lower anti-SARS-CoV-2 SP antibody titers and neutralizing antibody titers against all variants tested after the boost. During the study period, higher rates of new SARS-CoV-2 infections and a lower incidence of adverse events were observed in the NVX-CoV2373 vaccination group. No significant differences in cellular immune responses were observed between the two groups. CONCLUSION: Compared to a homologous mRNA booster vaccination, heterologous boosters with NVX-CoV2373 showed lower antibody responses, a higher incidence of new SARS-CoV-2 infections, and fewer adverse events.

HBcrAg-based risk score performs better than the HBV DNA-based scores for HCC prediction in grey zone patients who are HBeAg-negative.

Background & Aims: Risk scores have been designed to predict the development of hepatocellular carcinoma (HCC) in treatment-naive patients with chronic hepatitis B (CHB). However, little is known about their predictive accuracy in HBeAg-negative patients in the grey zone (GZ). We aimed to develop a HBcrAg-based HCC risk score and explore whether it outperforms other risk scores in GZ patients. Methods: Two retrospective cohorts of HBeAg-negative patients with American Association for the Study of Liver Diseases-defined GZ were established for derivation and validation (Taiwanese, N = 911; Japanese, N = 806). All of them were non-cirrhotic at baseline and remained treatment-naive during the follow-up. The primary endpoint was HCC development. Results: In a median follow-up period of 15.5 years, 85 patients developed HCC in the derivation cohort. We found that age, sex, alanine aminotransferase, platelet count, and HBcrAg, but not HBV DNA levels, were independent predictors and a 20-point GZ-HCC score was developed accordingly. The 10-year and 15-year area under the ROC curve (AUROC) ranged from 0.83 to 0.86, which outperformed the HBV DNA-based HCC risk scores, including REACH-B and GAG-HCC scores (AUROC ranging from 0.66 to 0.74). The better performance was also validated in EASL- and Asian Pacific Association for the Study of the Liver-defined GZ patients. These findings remained consistent in the validation cohort. Finally, the low-risk and high-risk GZ patients (stratified by a score of 8) had an HCC risk close to inactive CHB and immune-active CHB patients, respectively, in both cohorts. Conclusions: The HBcrAg-based GZ-HCC score predicts HCC better than other HBV DNA-based risk scores in GZ patients who are HBeAg-negative patients, which may help optimise their clinical management. Impact and implications: We have developed a risk score based on HBcrAg, which has shown better predictive ability for HCC compared with other risk scores based on HBV DNA. Using a score of 8, GZ patients can be classified into low- and high-risk groups, which can guide follow up and early treatment, respectively. This validated risk score is a valuable tool for optimising the management of GZ patients who are HBeAg-negative.

Current practice and recommendations for management of hepatitis B virus in people living with HIV in Asia.

BACKGROUND: The prevalence of HIV and hepatitis B virus (HBV) co-infection is higher in Asia than in Europe and North America and varies significantly between different regions within Asia. Important routes of transmission of both these infections include high-risk unprotected sexual contact, intravenous drug use, and transmission of maternal infection perinatally or in early childhood. While life expectancy among people living with HIV has been extended with effective antiretroviral therapy (ART), HBV-induced liver injury and complications have emerged as a leading cause of morbidity and mortality in people living with HIV. OBJECTIVES: This article describes the prevalence of co-infection, current clinical practice, and recommendations for the management of people living with HIV-HBV co-infection in Asia. RESULTS AND CONCLUSIONS: Screening for HBV should occur at the time of HIV diagnosis; however, HBV screening rates in people living with HIV in Asia vary widely by region. Similarly, people with HBV should be screened for HIV before initiation of HBV antiviral therapy. People with HIV-HBV co-infection should be assessed for liver damage and risk factors for liver disease and be monitored regularly for liver complications and HBV DNA. Medical treatment with ART is lifelong and includes tenofovir and lamivudine or emtricitabine, unless intolerant or contraindicated, as these are active against both HIV and HBV. HBV vaccination programmes are effective in reducing co-infection rates. Mother-to-child transmission can be prevented through measures such as vaccination, antenatal screening, and treatment of pregnant women who are infected.

Association of vaccine-specific regulatory T cells with reduced antibody response to repeated influenza vaccination.

Repeated annual influenza vaccinations have been associated with reduced vaccine-induced antibody responses. This prospective study aimed to explore the role of vaccine antigen-specific regulatory T (Treg) cells in antibody response to repeated annual influenza vaccination. We analyzed pre- and postvaccination hemagglutination inhibition (HI) titers, seroconversion rates, seroprotection rates, vaccine antigen hemagglutinin (HA)-specific Treg cells, and conventional T (Tconv) cells. We compared these parameters between vaccinees with or without vaccine-induced seroconversion. Our multivariate logistic regression revealed that prior vaccination was significantly associated with a decreased likelihood of achieving seroconversion for both H1N1(adjusted OR, 0.03; 95% CI, 0.01-0.13) and H3N2 (adjusted OR, 0.09; 95% CI, 0.03-0.30). Furthermore, individuals who received repeated vaccinations had significantly higher levels of pre-existing HA-specific Treg cells than those who did not. We also found that vaccine-induced fold-increases in HI titers and seroconversion were negatively correlated with pre-existing HA-specific Treg cells and positively correlated with the ratio of Tconv to Treg cells. Overall, our findings suggest that repeated annual influenza vaccination is associated with a lower vaccine-induced antibody response and a higher frequency of vaccine-specific Treg cells. However, a lower frequency of pre-existing Treg cells correlates with a higher postvaccination antibody response.

High PIVKA-II level and ASAP score predict 1-year risk of hepatocellular carcinoma in non-cirrhotic chronic hepatitis B patients.

Protein induced by Vitamin K absence or antagonists-II (PIVKA-II) is a diagnostic marker of hepatocellular carcinoma (HCC). We aimed to investigate the predictive role of PIVKA-II and ASAP score for development of HCC in 1 year among untreated patients of chronic hepatitis B (CHB). We conducted this case-control study to include untreated CHB patients followed at the National Taiwan University Hospital and grouped into HCC and matched non-HCC groups. Their archived serum samples were assayed for PIVKA-II levels 1 year before HCC, at HCC or their last serum sample. A total of 69 HCC cases and 102 non-HCC controls were recruited. Baseline PIVKA-II level was significantly higher in the HCC group than in the control group and it could predict HCC development in 1 year with an area under the receiver operating characteristic curve of 0.76. Multivariable analysis adjusting age, sex, liver function and alpha-fetoprotein level showed that baseline PIVKA-II ≥31 mAU/mL (vs. <31 mAU/mL) increased 12.5-fold risk (95% CI: 4.9-31.7) of HCC in 1 year, and even in patients with normal alpha-fetoprotein levels. The ASAP score, a combination of age, sex, alpha-fetoprotein and PIVKA-II, increases the predictability for HCC in 1 year. We concluded that both high PIVKA-II level and ASAP score may predict HCC development in 1 year in untreated CHB patients, especially in patients with normal alpha-fetoprotein level.

Serial increase and high alpha-fetoprotein levels predict the development of hepatocellular carcinoma in 6 months.

AIM: Alpha-fetoprotein (AFP) checkup with abdominal ultrasonography for hepatocellular carcinoma (HCC) surveillance remains controversial. We evaluated a serial AFP-increase and high AFP levels in the prediction of HCC. METHODS: At-risk patients with chronic liver disease underwent HCC surveillance with trimonthly AFP measurement were included and categorized into HCC and non-HCC groups. Their AFP levels at 12, 9, and 6 months (-6M) before the outcome date were evaluated. Group-based trajectory analysis and multivariable regression analysis were performed to identify AFP trajectories as risk predictors for HCC. RESULTS: Overall, 2776 patients were included in the HCC (n = 326) and non-HCC (n = 2450) groups. Serial AFP levels were significantly higher in the HCC than the non-HCC groups. Trajectory analysis identified AFP-increase group (11%) increased 24-fold risks of HCC compared with the AFP-stable (89%) group. Compared with patients without the AFP-increase, a serial 3-month AFP-increase ≥10% elevated HCC risk by 12.1-fold (95% CI: 6.5-22.4) in 6 months, and the HCC risks increased 13-60 fold in patients with cirrhosis, hepatitis B, or C receiving antiviral therapy, or AFP levels <20 ng/ml. Combining serial AFP-increase ≥10% and AFP ≥20 ng/ml at -6M significantly increased 41.7-fold (95% CI: 13.8-126.2) HCC risks. In patients who underwent biannual AFP checkups, those with both 6-month AFP-increase ≥10% and AFP ≥20 ng/ml increased 22.1-fold (95% CI: 12.52-39.16) HCC risks in 6 months. Most HCCs were detected at an early stage. CONCLUSIONS: Serial 3-6-month AFP-increase of ≥10% previously and AFP level of ≥20 ng/ml significantly increased HCC risks in 6 months.

Diversity and composition of gut microbiota in healthy individuals and patients at different stages of hepatitis B virus-related liver disease.

BACKGROUND: Hepatitis B virus (HBV) causes chronic hepatitis B (CHB), liver cirrhosis, and hepatocellular carcinoma. The evolution of human gut microbiota during the progression of HBV-related liver diseases remains unclear. Therefore, we prospectively enrolled patients with HBV-related liver diseases and healthy individuals. Through 16S ribosomal RNA amplicon sequencing, we characterized the gut microbiota of the participants and predicted the functions of microbial communities. RESULTS: We analyzed the gut microbiota of 56 healthy controls and 106 patients with HBV-related liver disease [14 with resolved HBV infection, 58 with CHB, and 34 with advanced liver disease (15 with liver cirrhosis and 19 with hepatocellular carcinoma)]. Patients with HBV-related liver disease exhibited a higher degree of bacterial richness (all P < 0.05) than did healthy controls. Beta diversity analyses revealed a distinct clustering pattern between healthy controls and patients with HBV-related liver disease (all P < 0.05). The composition of bacteria (from the phylum level to the genus level) varied across the stages of liver disease. Linear discriminant analysis effect size revealed multiple taxa that differ significantly in abundance between healthy controls and patients with HBV-related liver disease; however, fewer differences were observed among patients with resolved HBV infection, those with CHB, and those with advanced liver disease. The ratio of Firmicutes to Bacteroidetes was increased in all three patient groups compared with the ratio in healthy controls (all P < 0.001). The analysis of the sequencing data by using PICRUSt2 revealed the changes in microbial functions with disease progression. CONCLUSIONS: The diversity and composition of gut microbiota appear to vary significantly between healthy controls and patients at different stages of HBV-related liver disease. The understanding of gut microbiota may provide novel therapeutic options in these patients.

Distinct effects of hepatic steatosis and metabolic dysfunction on the risk of hepatocellular carcinoma in chronic hepatitis B.

OBJECTIVE: Chronic hepatitis B (CHB) and metabolic dysfunction-associated fatty liver disease (MAFLD) are the leading causes of hepatocellular carcinoma (HCC). We aim to explore the impact of concurrent MAFLD on the risk of HCC in CHB. METHODS: Patients with CHB were consecutively recruited from 2006 to 2021. MAFLD was defined by steatosis and either obesity, diabetes mellitus, or other metabolic abnormalities. The cumulative incidence of HCC and associated factors were compared between the MAFLD and non-MAFLD groups. RESULTS: 10,546 treatment-naïve CHB patients were included with a median follow-up of 5.1 years. CHB patients with MAFLD (n = 2212) had fewer hepatitis B e antigen (HBeAg)-positivity, lower HBV DNA levels, and Fibrosis-4 index compared with the non-MAFLD group (n = 8334). MAFLD was independently associated with a 58% reduced risk of HCC (adjusted hazard ratio [aHR] 0.42, 95% confidence interval [CI] 0.25-0.68, p < 0.001). Furthermore, steatosis and metabolic dysfunction had distinct effects on HCC. Steatosis was protective against HCC (aHR 0.45, 95% CI 0.30-0.67, p < 0.001), while a greater burden of metabolic dysfunction increased the risk (aHR 1.40 per dysfunction increase, 95% CI 1.19-1.66, p < 0.001). The protective effect of MAFLD was further confirmed in analysis with inverse probability of treatment weighting (IPTW), patients who had undergone antiviral therapy, those with probable MAFLD, and after multiple imputation for missing data. CONCLUSIONS: Concurrent hepatic steatosis is independently associated with a lower risk of HCC, whereas the increasing burden of metabolic dysfunction aggravates the risk of HCC in untreated CHB patients.

Pre-operative gamma-glutamyl transferase levels predict outcomes in hepatitis B-related hepatocellular carcinoma after curative resection.

BACKGROUND: Surgical resection is a curative therapy for early-stage hepatocellular carcinoma (HCC); however, HCC recurrence is not uncommon. Identifying outcome predictors helps to manage the disease. Gamma-glutamyl transferase (GGT) may predict the development of HCC, but its role to predict the outcomes after surgical resection of HCC was unclear. This study aimed to investigate pre-operative GGT levels for outcome prediction in patients with hepatitis B virus (HBV)-related HCC. METHODS: We conducted a retrospective cohort study to include patients with HBV-related HCC receiving surgical resection. Clinical information, HCC characteristics and usage of antiviral therapy were collected. A time-dependent Cox proportional hazard regression analysis were used to predict HCC recurrence and survival. RESULTS: A total of 699 consecutive patients with HBV-related HCC who received surgical resection with curative intent between 2004 and 2013 were included. After a median of 4.4 years, 266 (38%) patients had HCC recurrence. Pre-operative GGT positively correlated with cirrhosis, tumor burden and significantly increased in patients to develop HCC recurrence. Multivariable analysis demonstrated that pre-operative GGT ≥38 U/L increased 57% risk (hazard ratio [HR]: 1.57, 95% confidence interval [CI]: 1.20-2.06) of recurrent HCC after adjustment for confounding factors. Specifically, pre-operative GGT ≥38 U/L predicted early (<2 years) HCC recurrence (HR: 1.94, 95% CI: 1.30-2.89). Moreover, pre-operative GGT ≥38 U/L predicted all-cause mortality (HR: 1.73, 95% CI: 1.06-2.84) after surgery. CONCLUSION: Pre-operative GGT levels ≥38 U/L independently predict high risks of HCC recurrence and all-cause mortality in HBV-related HCC patients receiving surgical resection.