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Summary: Background: High hepatitis B surface antigen (HBsAg) level predicts hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients with low viral load. The role of longitudinal HBsAg levels in predicting HCC in HBeAg‐positive CHB patients remains unknown. Method: HBeAg‐positive CHB participants from the REVEAL‐HBV cohort with ≥2 HBsAg measurements before HBeAg seroclearance were enrolled. Group‐based trajectory modelling identified distinct HBsAg trajectory groups during a median of 11 years of HBeAg‐positive status. Cox regression models were applied for investigating independent predictors of HCC and estimating adjusted hazard ratio (HRadj) with a 95% confidence interval (CI). A p‐value less than 0.05 was considered statistically significant. Results: A total of 319 patients were enrolled and classified by HBsAg trajectory patterns as (A) persistently high group (n = 72): HBsAg persistently ≥104 IU/mL, and (B) non‐stationary group (n = 233): low HBsAg at baseline or declining to <104 IU/mL during the follow‐up. Group B had higher proportions of abnormal ALT levels, HBV genotype C and basal core mutation than group A (p < 0.05); age at entry and gender were comparable. The annual incidence of HCC in group A and group B were 0.37% and 1.16%, respectively (p = 0.03). In multivariate analysis, age >40 years (HRadj [95% CI] = 4.11 [2.26–7.48]), genotype C (HRadj [95% CI] = 4.39 [1.96–9.81]) and the non‐stationary group (HRadj [95% CI] = 3.50 [1.49–8.21]) were independent predictors of HCC. Basal core promoter mutation was the only risk factor of HCC in the persistently high HBsAg group (HRadj [95% CI] = 32.75 [5.41–198.42]). Conclusion: Patients with persistently high HBsAg levels during HBeAg‐seropositive stage represent a unique population with low risk of HCC development. [ABSTRACT FROM AUTHOR]

Gut barrier dysfunction can result in the liver being exposed to an elevated level of gut‐derived bacterial products via portal circulation. Growing evidence suggests that systemic exposure to these bacterial products promotes liver diseases including hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). However, prospective studies have not examined the association between biomarkers of gut barrier dysfunction and HCC risk in a population of hepatitis B or C viral (HBV/HCV) carriers. We investigated whether prediagnostic, circulating biomarkers of gut barrier dysfunction were associated with HCC risk, using the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer (REVEAL)‐HBV and REVEAL‐HCV cohorts from Taiwan. REVEAL‐HBV included 185 cases and 161 matched controls, and REVEAL‐HCV 96 cases and 96 matched controls. The biomarkers quantitated were immunoglobulin A (IgA), IgG, and IgM against lipopolysaccharide (LPS) and flagellin, soluble CD14 (an LPS coreceptor), and LPS‐binding protein (LBP). Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between biomarker levels and HCC were calculated using multivariable‐adjusted logistic regression. A doubling of the circulating levels of antiflagellin IgA or LBP was associated with a 76% to 93% increased risk of HBV‐related HCC (OR per one unit change in log2 antiflagellin IgA = 1.76, 95% CI: 1.06‐2.93; OR for LBP = 1.93, 95% CI: 1.10‐3.38). None of the other markers were associated with an increased risk of HBV‐related or HCV‐related HCC. Results were similar when cases diagnosed in the first 5 years of follow‐up were excluded. Our findings contribute to understanding the interplay of gut barrier dysfunction and primary liver cancer etiology. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally. The risk factors for HCC include chronic hepatitis B and C virus infections, excessive alcohol consumption, obesity, metabolic disease, and aflatoxin exposure. In addition to these viral and environmental risk factors, individual genetic predisposition is a major determinant of HCC risk. Familial clustering of HCC has been observed, and a hereditary factor likely contributes to the risk of HCC development. The familial aggregation may depend on a shared environment and genetic background as well as the interactions of environmental and genetic factors. Genome-wide association studies (GWASs) are one of the most practical tools for mapping the patterns of inheritance for the most common form of genomic variation, single nucleotide polymorphisms. This approach is practical for investigating genetic variants across the human genome, which is affected by thousands of common genetic variants that do not follow Mendelian inheritance. This review article summarizes the academic knowledge of GWAS-identified genetic loci and their association with HCC. We summarize the GWASs in accordance with various chronic hepatitis virus infection statuses. This genetic profiling could be used to identify candidate biomarkers to refine HCC screening and management by enabling individual risk-based personalization and stratification. A more comprehensive understanding of the genetic mechanisms underlying individual predisposition to HCC may lead to improvements in the prevention and early diagnosis of HCC and the development of effective treatment strategies. [ABSTRACT FROM AUTHOR]

Summary: Background: Hepatitis B surface antigen (HBsAg) seroclearance is the most important milestone indicating favourable clinical outcomes in patients with chronic hepatitis B (CHB). However, it is difficult to achieve due to the impaired HBV‐specific immunity, such as programmed cell death 1 (PD‐1)‐associated T cell exhaustion. We assessed soluble PD‐1 (sPD‐1) as a novel seromarker for predicting spontaneous HBsAg loss. Methods: Serial serum levels of sPD‐1 were evaluated in 1046 untreated hepatitis B e antigen (HBeAg)‐seronegative individuals who had achieved undetectable serum HBV DNA. Multiple regression analyses were applied to assess associations among baseline and subsequent sPD‐1 levels, HBsAg decline during follow‐up, and spontaneous HBsAg seroclearance. Results: A total of 390 individuals achieved spontaneous HBsAg seroclearance during 6464.4 person‐years of follow‐up. Baseline sPD‐1 levels were inversely associated with baseline HBsAg levels (qHBsAg) as well as a greater decline in qHBsAg during follow‐up. Incidence rates of HBsAg seroclearance were 11.5, 61.7, 96.7 and 151.0 per 1000 person‐years for sPD‐1 levels of ≥4000, 536‐3999, 125‐535 and <125 pg/mL, respectively (Ptrend < 0.0001). Compared with baseline sPD‐1 levels ≥4000 pg/mL, the rate ratio (95% CI) of HBsAg seroclearance was 2.1 (1.1‐3.9), 3.0 (1.6‐5.5) and 5.1 (2.8‐9.5), for baseline sPD‐1 levels of 536‐3999, 125‐535 and <125 pg/mL, respectively, after adjustment for sex, age and serum alanine aminotransferase and HBsAg levels. Conclusion: sPD‐1 level is a novel marker which independently predicts spontaneous HBsAg seroclearance of HBeAg‐negative inactive CHB patients with undetectable HBV DNA. (word count: 234, <250). [ABSTRACT FROM AUTHOR]

Background: Diversity in the HLA genes might be associated with disease outcomes-the heterozygote advantage hypothesis. We tested this hypothesis in relation to hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC).Methods: We utilized DNA from > 10 000 Taiwanese individuals with current or past HBV infection to examine the association between HLA diversity and critical natural history steps in the progression from HBV infection to HCC. Individuals were classified as homozygotes at a given locus when imputed to carry the same 4-digit allele for the 2 HLA alleles at that locus.Results: Increase in number of homozygous HLA class II loci was associated with an increased risk of chronic HBV infection (Ptrend = 1.18 × 10-7). Among chronic HBV carriers, increase in number of homozygous HLA class II loci was also associated with an increased risk of HBV-associated HCC (Ptrend = .031). For individual HLA loci, HLA-DQB1 homozygosity was significantly associated with HCC risk (adjusted hazard ratio = 1.40; 95% confidence interval, 1.06-1.84). We also found that zygosity affects risk of HCC through its ability to affect viral control.Conclusions: Homozygosity at HLA class II loci, particularly HLA-DQB1, is associated with a higher risk of HBV-associated HCC. [ABSTRACT FROM AUTHOR]

Summary: Background: Chronic hepatitis B virus (HBV) infection is a great health burden with geographical variations. Aims: To explore genetic variants associated with chronic HBV infection. Methods: The study included 15 352 participants seropositive for HBV core antibodies in Taiwan Biobank. Among them, 2591 (16.9%) seropositive for HBV surface antigen (HBsAg) were defined as having chronic HBV infection. All participants were examined for whole‐genome genotyping by Axiom‐Taiwan Biobank Array. The human leucocyte antigen (HLA) imputation was performed after identification of the variants within the region. Logistic regressions were used to estimate odds ratios (ORs) with 95% confidence intervals. Correlations of different HLA allele frequencies with HBsAg seroprevalence were evaluated across worldwide populations by Pearson correlation coefficients. Epitope prediction was performed for HLA alleles using NetMHCIIpan method. Results: Located within a cluster of 450 single nucleotide polymorphisms in HLA class II, rs7770370 (P = 2.73 × 10−35) was significantly associated with HBV chronicity (Pcorrected < 8.6 × 10−8). Imputation analyses showed that HLA‐DPA1*02:02 and HLA‐DPB1*05:01 were associated with chronic HBV, with adjusted ORs of 1.43 (1.09‐1.89) and 1.61 (1.29‐2.01). These allele frequencies were positively correlated with global HBsAg seroprevalence, with R of 0.75 and 0.62 respectively (P < 0.05). HLA‐DRB1*13:02, HLA‐DQA1* 01:02 and HLA‐DQB1*06:09 associated with HBV chronicity negatively, with adjusted ORs of 0.31 (0.17‐0.58), 0.70 (0.56‐0.87) and 0.33 (0.18‐0.63). These HLA alleles had various binding affinities to the predicted epitopes derived from HBV nucleocapsid protein. Conclusions: HLA class II variants are relevant for chronicity after HBV acquisition. [ABSTRACT FROM AUTHOR]

The risk of recurrence after resection of hepatocellular carcinoma (HCC) is high. Apart from nucleos(t)ide analogues therapy, population-based studies suggest statin, nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin have chemopreventive effect on recurrence. The role of those drugs on HCC recurrence should be delineated. Consecutive 430 hepatitis B surface antigen (HBsAg)-positive patients undergoing curative resection of HCC were enrolled. The detailed medical records including the use of statin, NSAID and aspirin were reviewed. All the patients had regular image study surveillance after the surgery. Predictors associated with recurrence were analyzed by Cox's proportional hazards models. There were 58.8% patients in Barcelona Clinic Liver Cancer (BCLC) stage A, and 37.6% had severe liver fibrosis or cirrhosis. Of them, 47 (10.9%) patients had received potential chemoprophylactic agents either at the time of HCC diagnosis or before their HCC recurrence. During a median 50.3 months of follow-up, 54.7% patients experienced recurrence. The median time to recurrence was 15.4 months. In the univariate analysis, aspirin and statins use were significantly associated a low risk of recurrence (hazard ratio [HR]: 0.18; p = 0.016, and HR: 0.50; p = 0.031, respectively). After adjusting competing factors, large tumor size, severe liver fibrosis, and high alpha-fetoprotein (AFP) level were significantly associated with recurrence. Importantly, aspirin use was found to significantly decrease the risk for HCC recurrence with the adjusted HRs of 0.22–0.24 based on the models. Aspirin use may have chemo-preventive effect on recurrence of hepatitis B virus-related HCC after curative resection. [ABSTRACT FROM AUTHOR]

Background and Aim: Noninvasive fibrosis indices can predict the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). Modified FIB‐4 (mFIB‐4) is a promising noninvasive index for predicting liver fibrosis. To investigate the predictive accuracy of several extant noninvasive fibrosis indices, including mFIB‐4, for HCC incidence in CHB patients receiving long‐term entecavir therapy. Methods: We enrolled 1325 nucleos(t)ide analogue‐naïve CHB patients (noncirrhotic 844; cirrhotic 481) treated with entecavir. Baseline clinical features and fibrosis indices were collected and evaluated for predicting HCC risk through univariate and multivariate Cox regression analyses. Results: Of the 1325 patients, 105 (7.9%) developed HCC during a median follow‐up period of 4.1 years. Age (hazard ratio [HR], 1.039; 95% confidence interval [CI], 1.020–1.059; P < 0.0001), diabetes mellitus (DM) (HR, 1.902; 95% CI, 1.185–3.052; P = 0.0077), and mFIB‐4 (HR, 4.619; 95% CI, 1.810–11.789; P = 0.0014) were independent predictors of HCC in all patients (mFIB‐4 ≥ 1.5 for the noncirrhotic cohort; DM and mFIB‐4 ≥ 2.0 for the cirrhotic cohort). A combination of mFIB‐4 and the DM status stratified the cumulative risk of HCC into three subgroups in all patients (high: mFIB‐4 ≥ 1.5/DM; intermediate: mFIB‐4 ≥ 1.5/non‐DM; and low: mFIB‐4 < 1.5, P < 0.0001) and in the cirrhotic cohort (high: mFIB‐4 ≥ 2.0/DM; intermediate: mFIB‐4 ≥ 2.0/non‐DM; and low: mFIB‐4 < 2.0, P = 0.0007). An mFIB‐4 cutoff value of 1.5 stratified the cumulative risk of HCC in the noncirrhotic cohort (P = 0.015). Conclusions: The mFIB‐4 index alone or in combination with DM is the optimal noninvasive predictor of HCC risk in CHB patients receiving entecavir therapy. [ABSTRACT FROM AUTHOR]

Background: The effect of newer oral anti-hepatitis B virus (HBV) medication, tenofovir disoproxil (TDF), on liver-related outcomes among Asians is limited. We examined the effect of TDF on the incidence of hepatocellular carcinoma (HCC) in an Asian population with chronic hepatitis B (CHB).Methods: This was a retrospective cohort study of 6914 adults with chronic HBV monoinfection and no history of transplantation who were recruited from 6 US referral, community medical centers and a community based Taiwan cohort for a total of 774 patients who received TDF and 6140 who were not treated. Propensity score matching (PSM) for age, sex, HBV e antigen status, HBV DNA level, alanine aminotransferase (ALT) level, baseline cirrhosis status, and follow-up time was performed to balance the groups, resulting in 591 treated individuals and 591 untreated individuals. Kaplan-Meier analysis was used to estimate the cumulative risk of HCC. Cox proportional hazards models were run to estimate the HCC risk between groups.Results: The 8-year cumulative HCC incidence was significantly higher in the PSM untreated group (20.13% vs 4.69%; P < .0001). Cirrhosis was a significant predictor for HCC (adjusted hazard ratio [aHR], 5.36; 95% confidence interval [CI], 2.73-10.51; P < .001). On multivariate analysis adjusted for age, sex, HBV DNA level, ALT level, and study site, TDF was associated with a 77% reduction in the risk of HCC (aHR, 0.23; 95% CI, .56-.92) in patients with cirrhosis and a 73% reduction (aHR, 0.27; 95% CI, .07-.98) in patients without cirrhosis.Conclusions: Among cirrhotic and noncirrhotic Asian patients with CHB, TDF therapy was significantly associated with a reduction in the 8-year HCC cumulative incidence rate. [ABSTRACT FROM AUTHOR]

The relation between aflatoxin B1 (AFB1) and cirrhosis in chronic carriers of hepatitis B virus (HBV) remains inconclusive. This case-control study nested in a large community-based cohort aimed to assess the effect of AFB1 exposure on cirrhosis and HCC in chronic HBV carriers. Serum AFB1-albumin adduct levels at study entry were measured in 232 cirrhosis cases, 262 HCC cases and 577 controls. Multivariate-adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) were estimated using logistic regression. Among all chronic HBV carriers, the time intervals between study entry and diagnosis of HCC, cirrhosis, cirrhotic HCC, and non-cirrhotic HCC were all significantly ( p < 0.0001) shorter in participants with high serum levels of AFB1-albumin adducts than those with low/undetectable levels. There were significant dose-response relations with serum AFB1-albumin adduct level at study entry for cirrhosis ( p-trend = 0.0001) and cirrhotic HCC ( p-trend < 0.0001) newly diagnosed within 9 years after entry as well as non-cirrhotic HCC ( p-trend = 0.021) newly diagnosed within 4 years after entry. The aORs (95% CIs) for high versus undetectable serum AFB1-albumin adduct levels were 2.45 (1.51-3.98) for cirrhosis ( p = 0.0003), 5.47 (2.20-13.63) for cirrhotic HCC ( p = 0.0003), and 5.39 (1.11-26.18) for non-cirrhotic ( p = 0.0368) HCC, respectively. There remained a significant dose-response relation between serum AFB1-albumin adduct level and HCC risk ( p-trend = 0.0291) in cirrhosis patients, showing an aOR (95% CI) of 3.04 (1.11-8.30) for high versus undetectable serum levels ( p = 0.0299). It is concluded that AFB1 exposure may increase the risk of cirrhosis and HCC in a dose-response manner among chronic HBV carriers. [ABSTRACT FROM AUTHOR]

Background and Aims Most studies on risk predictors of hepatocellular carcinoma (HCC) among cirrhotic chronic hepatitis B patients do not confirm the date at cirrhosis diagnosis. We examined HCC risk and predictors in chronic hepatitis B patients with newly diagnosed cirrhosis. Methods 4155 HBsAg seropositive participants were followed every 6-12 months with seromarker testing. Cirrhosis was ascertained through abdominal ultrasonography and computerized linkage with national health insurance profiles. Predictors included in Cox proportional hazards models were age, HBeAg serostatus, serum levels of HBsAg, alanine aminotransferase (ALT), alpha-fetoprotein (AFP), and ALDH2 rs671 genotypes. Results A total of 301 patients developed cirrhosis, 76 of whom later developed HCC after 2462 person-years, showing an average annual incidence of 3.1%. The 15-year cumulative HCC risk among cirrhotics was 39.8% with a lifetime (30-80 years old) HCC risk of 78.5%. The adjusted HR's (95% CI, P-value) were 14.26 (3.17-64.08, P = 0.0005) for age at cirrhosis diagnosis of ≥60 years ( vs 30-39 years), 2.85 (1.49-5.46, P = 0.0015) for HBeAg seropositivity ( vs HBeAg seronegativity with HBsAg levels <1000 IU/mL), 0.35 (0.20-0.59, P < 0.0001) for AA/AG genotypes of rs671 ( vs GG genotype), 3.68 (1.70-7.99, P = 0.0010) for ALT levels >45 U/L ( vs <15 U/L), 3.52 (1.78-6.93, P = 0.0003) for AFP levels >20 ng/mL ( vs <10 ng/mL), and 2.64 (1.38-5.07, P = 0.0035) for HBsAg levels ≥1000 IU/mL ( vs <1000 IU/mL among HBeAg seronegatives). Conclusions Older age, GG genotype of ALDH2 rs671, HBeAg seropositivity, and elevated serum levels of ALT, AFP, and HBsAg at cirrhosis diagnosis were HCC risk predictors in cirrhotic chronic hepatitis B patients. [ABSTRACT FROM AUTHOR]

Background & Aims: Seroclearance of hepatitis B surface antigen (HBsAg) is the most ideal end point in the treatment of chronic hepatitis B. This study develops a predictive scoring system to assess whether the addition of serum levels HBsAg may improve the predictability of HBsAg loss. Methods: This study included 2491 untreated participants with genotype B or C HBV infection, who were HBsAg-seropositive, HBeAg-seronegative, anti-HCV-seronegative, and cirrhosis free at study entry. Regression coefficients of predictors in Cox Regression models were converted into integer scores for predicting HBsAg seroclearance. Predictive accuracy was assessed with area under the receiver operating characteristic curves (AUROC), and predictive accuracies of models with and without serum HBsAg levels were compared. Results: Low serum levels of both HBsAg and HBV DNA were the strongest predictors of spontaneous HBsAg seroclearance. Compared to baseline serum HBsAg levels ⩾1000IU/ml, the multivariate adjusted rate ratio of spontaneous HBsAg seroclearance was 10.96 (7.92–15.16) for those with baseline serum HBsAg levels <100IU/ml. The predictive ability of HBsAg levels was modified by HBV viral load, showing a weaker effect in those with higher viral loads, and the strongest effect among those with undetectable viral loads. The inclusion of serum HBsAg levels greatly improved the AUROC for predicting HBsAg seroclearance at the fifth (from 0.79 [0.787–0.792] to 0.89 [0.889–0.891]) and tenth year (from 0.73 [0.728–0.732] to 0.84 [0.839–0.841]) after study entry. Conclusions: Incorporated into an easy-to-use scoring system, HBV viral load and quantitative serum HBsAg levels can accurately predict HBsAg seroclearance. [Copyright &y& Elsevier]

LINKED CONTENT This article is linked to Huang et al and Hoek papers. To view these articles, visit https://doi.org/10.1111/apt.15887 and https://doi.org/10.1111/apt.15960 [ABSTRACT FROM AUTHOR]

Noninvasive fibrosis indices can help stratify the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) receiving nucleos(t)ide analogue (NA) therapy. We investigated the predictive performance of on-treatment changes in FIB-4 (△FIB-4) and 1-year FIB-4 values (FIB-4 12M) for HCC risk in patients with CHB receiving entecavir therapy. We included 1325 NA-naïve patients with CHB treated with entecavir, retrospectively, from January 2007 to August 2012. A combination of △FIB-4 and FIB-4 12M was used to stratify the cumulative risk of HCC into three subgroups each in the noncirrhotic and cirrhotic subgroups with p < 0.0001 by using the log-rank test (noncirrhotic: the highest risk (n = 88): FIB-4 12M ≥ 1.58/△FIB-4 ≥ 0 (hazard ratio (HR): 40.35; 95% confidence interval (CI): 5.107–318.7; p <0.0001) and cirrhotic: the highest risk (n = 89): FIB-4 12M ≥2.88/△FIB-4 ≥0 (HR: 9.576; 95% CI: 5.033–18.22; p < 0.0001)). Patients with noncirrhotic CHB treated with entecavir who had a FIB-4 12M < 1.58 or FIB-4 12M ≥ 1.58/△FIB-4 < 0 exhibited the lowest 5-year HCC risk (0.6%). A combination of on-treatment changes in FIB-4 and 1-year FIB-4 values may help identify patients with CHB receiving entecavir therapy with the lowest risk of HCC. [ABSTRACT FROM AUTHOR]