Untreated Chronic Hepatitis B Patients Research Articles

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

BACKGROUND AND AIMSHepatitis 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. METHODSPatients 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. RESULTSFrom 2006 to 2021, 4,084 treatment-naïve 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 = 0.007), 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 = 0.049). In sensitivity analysis, patients with intermittent MASLD had an intermediate probability of HBsAg seroclearance. After balancing clinical and virological 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 = 0.010). CONCLUSIONSIn 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.

Comparison of architect assay and elecsys HBs Ag II assay in the quantification of hepatitis B surface antigen in chronic HBV patients

Background. Hepatitis B virus (HBV) infection is a global health concern, with an estimated 296 million chronic carriers worldwide. Quantification of hepatitis B surface antigen (HBsAg) is a crucial tool in HBV disease management, providing valuable insights into disease progression and treatment efficacy. Objective. To evaluate the comparative performance of the Abbott Architect HBsAg QT and Roche Elecsys HBsAg II assays in quantifying hepatitis B surface antigen (HBsAg) levels in patients with chronic hepatitis B (CHB). Methods. This prospective study enrolled 60 confirmed CHB patients between February 2021 and November 2021. HBsAg levels were measured using both assays and subsequently log-transformed (log10 IU/mL) for statistical analysis. Interclass correlation coefficient (ICC), Pearson correlation coefficient, and Bland-Altman analyses were employed to assess assay concordance and systematic bias. Results. A statistically significant positive correlation was observed between the Elecsys HBsAg II and Architect HBsAg QT assays for both untreated and treatment-receiving CHB patients (ICC values not specified, p <0.001). Notably, Architect consistently yielded higher HBsAg measurements compared to Elecsys. Conclusion. Both the Elecsys HBsAg II and Architect HBsAg QT assays demonstrate robust correlation in quantifying HBsAg levels in CHB patients. However, the Architect assay exhibits a systematic positive bias relative to Elecsys, which should be considered when interpreting results and making clinical decisions. Both tools provide reliable assessments for HBsAg quantification within CHB management strategies, but it is essential to be aware of potential assay-specific differences.

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

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. 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. 10,546 treatment-naïve CHB patients were included with a median follow-up of 5.1years. 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. 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.

The Impact of the Definitions of Clinical Phases on the Profiles of Grey-Zone Patients with Chronic Hepatitis B Virus Infection.

We aim to investigate the impact of different clinical phases' definitions of chronic hepatitis B (CHB) infection on the profiles of grey zone, based on HBV guidelines set by the Chinese Society of Hepatology and Chinese Society of Infectious Diseases (CSH/CSID, 2022 version) and guidelines set by the American Association for the Study of Liver Diseases (AASLD, 2018 version). We retrospectively examined untreated CHB patients enrolled in the China Registry of Hepatitis B database. Patients' clinical phases were determined as per CSH/CSID and AASLD. Liver fibrosis was estimated by FIB-4 and/or APRI. Among 3462 CHB patients, 56.9% and 41.7% fell into the grey zone based on AASLD and CSH/CSID. Compared with grey zone patients as per AASLD, those under CSH/CSID guidelines showed lower levels of median ALT (26.0 vs. 37.0 U/L, p < 0.001), AST (25.0 vs. 29.4 U/L, p < 0.001) and APRI (0.3 vs. 0.4, p < 0.001), and lower rates of advanced fibrosis estimated by APRI (7.9% vs. 11.4% p = 0.001), but comparable rates by FIB-4 (13.0% vs. 14.1%, p = 0.389). With the stepwise lowering of ALT upper limits of normal (ULN) values from 50/40 U/L for males/females to 40/40 U/L, 35/25 U/L and 30/19 U/L, the proportions of grey zone patients as per CSH/CSID declined from 46.7% to 41.7%, 34.3% and 28.8%, respectively, whereas they remained stable (55.7%, 56.2%, 56.9% and 57.0%) as per AASLD. Compared with the AASLD guidelines, CSH/CSID guidelines leave fewer and less severe patients in the grey zone. Lowering ALT ULN values reduces the number of grey zone patients as per CSH/CSID, but not under AASLD guidelines.

Comparison of kidney function decline between chronic hepatitis B patients with or without antiviral therapy.

Kidney function can deteriorate in patients with chronic hepatitis B (CHB). We compared the risk of kidney function decline between untreated and treated CHB patients receiving antiviral therapy. This retrospective study included 1061 untreated CHB patients and 366 tenofovir alafenamide (TAF), 190 besifovir dipivoxil maleate (BSV), and 2029 entecavir (ETV) users. The primary outcome was kidney function decline, a ≥ one-stage increase in chronic kidney disease for ≥3 consecutive months. The incidence and risk of kidney function decline were significantly higher in the 1:1 propensity score matched treated group (588 pairs) than in the untreated (2.7 per 1000 person-years [PYs] vs. 1.3 per 1000 PYs, adjusted hazard ratio [aHR] = 2.29, all p < 0.001). The matched TAF group (222 pairs) showed a similar risk for the primary outcome (aHR = 1.89, p = 0.107) despite a significantly higher incidence thereof, compared to the untreated (3.9 vs. 1.9 per 1000 PYs, p = 0.042). The matched BSV and untreated groups (107 pairs) showed no significant differences in the incidence and risk. However, ETV users (541 pairs) carried a significantly higher outcome incidence and risk than the matched untreated (3.6 vs. 1.1 per 1000 PYs, aHR = 1.05, all p < 0.001). Compared to each matched untreated group, changes in the estimated glomerular filtration rate over time were greater in the ETV group (p = 0.010), despite being similar in the TAF (p = 0.073) and BSV groups (p = 0.926). Compared with untreated patients, TAF or BSV users showed similar risk, whereas ETV users showed a higher risk of kidney function decline.

A nomogram based on HBeAg, AST, and age to predict non-minimal liver inflammation in CHB patients with ALT

Precise assessment of liver inflammation in untreated hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B virus (HBV) infection can determine when to initiate antiviral therapy. The aim of this study was to develop and validate a nomogram model for the prediction of non-minimal liver inflammation based on liver pathological injuries combined with age and alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatitis B surface antigen (HBsAg), HBeAg, and HBV DNA quantification. We retrospectively included 735 HBeAg-positive chronic hepatitis B (CHB) patients with ALT<80U/L as the primary cohort and prospectively enrolled 196 patients as the validation cohort. Multivariate logistic regression analysis identified independent impact factors. A nomogram to predict significant liver inflammation was developed and validated. Multivariate logistic regression analysis showed that HBeAg, AST, and age were independent risk factors for predicting non-minimal liver inflammation in untreated CHB patients. The final formula for predicting non-minimal liver inflammation was Logit(P) = -1.99 - 0.68 × Log10HBeAg + 0.04 × Age + 0.06 × AST. A nomogram for the prediction of non-minimal liver inflammation was established based on the results from the multivariate analysis. The predicted probability of the model being consistent with the actual probability was validated by the calibration curves, showing the best agreement in both the primary and validation cohorts. The C-index was 0.767 (95%CI=0.734-0.802) in the primary cohort and 0.749 (95%CI=0.681-0.817) in the prospective validation cohort. The nomogram based on HBeAg, AST, and age might help predict non-minimal liver inflammation in HBeAg-positive CHB patients with ALT<80U/L, which is practical and easy to use for clinicians.

The association between sPD-1 levels versus liver biochemistry and viral markers in chronic hepatitis B patients: a comparative study of different sPD-1 assays

BackgroundSoluble programmed death-1 (sPD-1) is a novel immune markers and possibly predictive of chronic hepatitis B (CHB) outcome. However, results were inconsistent by different ELISA kits. This study aims to compare the characteristics and correlations with other markers for sPD-1 measured by MyBioSource (MB) and R&D (RD) kits.MethodsA total of 254 untreated CHB patients from three sites were assayed with sPD-1 by MB and RD kits at the same time. Spearman’s correlations between the kits, and those with viral markers and ALT levels were calculated. Multivariate linear regression analysis was applied for independent factors associated with the sPD-1 levels.ResultsThere’s no correlation between sPD-1 level using MB and RD assays. sPD-1 by MB correlated profoundly with HBsAg (r = 0.8311, P < 0.0001), HBV DNA (r = 0.3896, P < 0.0001), and ALT levels (r = 0.1604, P = 0.0105) while an opposite trend by RD kit (r = − 0.0644, P = 0.3109; r = 0.2554, P < 0.0001; r = 0.4417, P < 0.0001, respectively for the 3 markers). In the multivariate linear regression analysis, HBsAg and ALT levels was the major factor associated with sPD-1 levels by MB and RD, respectively.ConclusionsThe characteristics and correlations with host/viral markers of sPD-1 by the two kits are different and leading to different associations on clinical outcomes of CHB.

GPR, King's Score and S-Index are superior to other non-invasive fibrosis markers in predicting the liver fibrosis in chronic Hepatitis B patients.

In this study, we investigated the efficacy of nine non-invasive fibrosis markers in the assessment of the degree of fibrosis in patients with chronic Hepatitis B (CHB) in comparison with liver biopsy. A total of 1454 untreated CHB patients from two different centers who underwent liver biopsy were included in the study. Laboratory results of patients were reviewed retrospectively and the pathology slides were re-evaluated in accordance with the Ishak score. Degree of fibrosis ≥ 3 was accepted as "significant fibrosis", ≥ 4 as "advanced fibrosis", and ≥ 5 as cirrhosis. The diagnostic performance of the markers Aspartate aminotransferase to Platelet Ratio Index (APRI), Fibrosis-4 score (FIB-4), Aspartate aminotransferase to Alanine aminotransferase Ratio (AAR), AAR to Platelet Ratio Index (AAPRI), Gamma-glutamyl transpeptidase to Platelet Ratio (GPR), King's Score, Fibro quotient (Fibro-Q), S Index and Platelet to Lymphocyte Ratio (PLR) were evaluated with ROC analysis. In detecting significant fibrosis, APRI, GPR, King's Score and S Index had AUROC values over 0.70. For advanced fibrosis, all of the models except AAPRI; and for cirrhosis, all of the models had AUROC values over 0.70. In accordance with the chosen staging system, GPR, King's Score and S Index had high diagnostic efficacy whereas APRI, FIB-4, FibroQ and PLR had moderate diagnostic efficacy, AAR and AAPRI had low diagnostic efficacy. GPR, King's Score and S Index had moderate diagnostic performance in detecting significant fibrosis and advanced fibrosis, and high diagnostic performance in detecting cirrhosis.

Diagnostic performance of elastography on liver fibrosis in antiviral treatment-naive chronic hepatitis B patients: a meta-analysis.

BackgroundThis study aimed to assess the performance of transient elastography (TE), two-dimensional shear wave elastography (2D-SWE), and magnetic resonance elastography (MRE) for staging significant fibrosis and cirrhosis in untreated chronic hepatitis B (CHB) patients.MethodsPubmed, Embase, Web of Science, and Cochrane Library were searched for terms involving CHB, TE, 2D-SWE, and MRE. Other etiologies of chronic liver disease, previous treatment in patients, or articles not published in SCI journals were excluded. Hierarchical non-linear models were used to evaluate the diagnostic accuracy of TE, 2D-SWE, and MRE. Heterogeneity was explored via analysis of threshold effect and meta-regression.ResultsTwenty-eight articles with a total of 4,540 untreated CHB patients were included. The summary areas under the receiver-operating characteristic curves (AUROCs) using TE, 2D-SWE, and MRE for predicting significant fibrosis (SF) were 0.84, 0.89, and 0.99, respectively. The AUROC values of TE, 2D-SWE, and MRE for staging cirrhosis were 0.9, 0.94, and 0.99, respectively. Based on the meta-analysis of studies with head-to-head comparison, 2D-SWE is superior to TE (0.92 vs 0.85, P < 0.01) in staging significant fibrosis.ConclusionTE, 2D-SWE, and MRE express acceptable diagnostic accuracies in staging significant fibrosis and cirrhosis in untreated CHB patients. 2D-SWE outperforms TE in detecting significant fibrosis in treatment-naive people with hepatitis B virus.

Low eligibility for hepatitis B treatment in the Brazilian public health system.

ABSTRACTBackground: Chronic hepatitis B (CHB) affects 257 million people worldwide. However, the proportion of patients eligible for treatment in the public health system has not been established. This study describes the clinical and laboratory profiles of untreated CHB patients and estimates the eligibility rate for antiviral therapy in accordance with the Brazilian Clinical Protocol and Therapeutic Guidelines. Methods: Records of 670 CHB patients were collected from May 2012 to September 2013 in Minas Gerais. Data from each patient were analyzed by hepatitis B virus (HBV) management. Results: 461 CHB patients were treatment-naive. Of these, 23 were HBeAg-positive, 352 were HBeAg-negative, and 14 were clinically diagnosed with cirrhosis. Periodic monitoring was performed in only three patients. However, 9.3% of untreated patients met the eligibility criteria for HBV treatment. Conclusions: Few CHB patients were active carriers and eligible candidates for antiviral therapy. This study revealed inadequate pre-treatment conduct in the Brazilian public health system, emphasizing the need for regular laboratory follow-up for patients initially not eligible for treatment. Such information may indirectly subsidize the planning and improvement of actions and services related to optimal HBV management in the public sphere.

ALT Levels in Treatment-Naive, Chronic Hepatitis B Patients with Concurrent Fatty Liver Disease: A US Nationwide Study

Introduction: Treatment criteria for chronic hepatitis B (CHB) relies on ALT, which can be impacted by concurrent nonalcoholic fatty liver disease (NAFLD), but ALT data on patients with CHB and NAFLD are limited. We aimed to characterize ALT distribution in untreated CHB patients with NAFLD. Methods: We retrospectively analyzed untreated US adults with CHB (533 with NAFLD, 3,172 without NAFLD) using the Clinformatics^™ Data Mart Database (2003–2019). The main outcome was ALT elevation (>1× upper limit of normal, 35/25 U/L for men/women, respectively). Secondary outcomes were advanced fibrosis (via FIB-4 index) and factors associated with fibrosis. Results: The majority of patients were Asian (61.0%) and hepatitis B e-antigen (HBeAg)-negative (90.4%). Patients with CHB and NAFLD were older (57.2 vs. 49.5 years, p < 0.001), more likely male (59.3% vs. 46.2%, p < 0.001), with higher percentages of advanced fibrosis (3.6% vs. 2.6%, p < 0.001) than those with CHB alone. CHB-NAFLD patients were more likely to have elevated ALT than those with CHB only, but this difference was only significant among those with low hepatitis B virus (HBV) DNA (38.1% vs. 25.6%, p < 0.001), not those with higher HBV DNA (>2,000 IU/mL). After adjusting for HBeAg, HBV DNA, and diabetes, NAFLD was not independently associated with advanced fibrosis (odds ratio 1.18, 95% confidence interval: 0.30–4.59, p = 0.81). Discussion: CHB-NAFLD patients with HBV DNA below treatment threshold were more likely to have elevated ALT but not those with higher HBV DNA, suggesting that ALT threshold does not need to be raised for antiviral eligibility for CHB with NAFLD.

Prediction models for development of hepatocellular carcinoma in chronic hepatitis B patients.

Chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC) is a major health problem in Asian-Pacific regions. Antiviral therapy reduces, but does not completely prevent, HCC development. Thus, there is a need for accurate risk prediction to assist prognostication and decisions on the need for antiviral therapy and HCC surveillance. A few risk scores have been developed to predict the occurrence of HCC in CHB patients. Initially, the scores were derived from untreated CHB patients. With the development and extensive clinical application of nucleos(t)ide analog(s) (NA), the number of risk scores based on treated CHB patients has increased gradually. The components included in risk scores may be categorized into host factors and hepatitis B virus factors. Hepatitis activities, hepatitis B virus factors, and even liver fibrosis or cirrhosis are relatively controlled by antiviral therapy. Therefore, variables that are more dynamic during antiviral therapy have since been included in risk scores. However, host factors are more difficult to modify. Most existing scores derived from Asian populations have been confirmed to be accurate in predicting HCC development in CHB patients from Asia, while these scores have not offered excellent predictability in Caucasian patients. These findings support that more relevant variables should be considered to provide individualized predictions that are easily applied to CHB patients of different ethnicities. CHB patients should receive different intensities of HCC surveillance according to their risk category.

Assessing risk scores for predicting hepatocellular carcinoma in Thai patients with chronic hepatitis B.

Chronic hepatitis B (CHB) infection-associated hepatocellular carcinoma (HCC) is a major health problem in Asian countries. Several HCC risk prediction models have been developed using either treated or untreated CHB patients. However, there is limited validation of these risk scores in a treated and untreated mixed CHB patient cohort. This study analysed and validated HCC risk scores among 2208 CHB patients who enrolled in the HCC surveillance programme in Thailand during July 2010. The baseline clinical and radiologic data of these CHB patients were applied to calculate various HCC risk scores. There were 20 patients (0.9%) with HCC development at the 5.9-year follow-up. The areas under the receiver operating characteristic curves (AUROCs) predicting HCC risk at 5years were 0.80 (0.68-0.91), 0.73 (0.60-0.85), 0.79 (0.67-0.91), 0.70 (0.58-0.82), 0.72 (0.59-0.85), 0.76 (0.63-0.87) and 0.77 (0.64-0.89) for the GAG-HCC, CU-HCC, REACH-B, PAGE-B, mPAGE-B, CAMD and AASL scores, respectively. The overall HCC risk scores were accurate and comparable. However, the subgroup analysis revealed better HCC-risk-predictive performance in the treated patients, while performance was less helpful in those not fulfilling criteria for antiviral therapy. Clinicians should be aware of these data when using the HCC risk score in untreated CHB patients.

Natural History and Hepatocellular Carcinoma Risk in Untreated Chronic Hepatitis B Patients With Indeterminate Phase

Many patients with chronic hepatitis B (CHB) may not conform to any of the defined phases and hence are classified as indeterminate. We aimed to characterize the baseline prevalence of indeterminate patients and their natural history, phase transition, and hepatocellular carcinoma (HCC) risk. This was a retrospective cohort study of 3366 adult untreated noncirrhotic CHB patients seen at 5 US clinics and 7 Taiwanese townships who had at least 1 year of serial laboratory data before enrollment with a mean follow-up period of 12.5 years. Patients' clinical phases were determined at baseline and through serial data during follow-up evaluation, based on the American Association for the Study of Liver Diseases 2018 guidance. At baseline, 1303 (38.7%) patients were in the indeterminate phase. By up to year 10 of follow-up evaluation, 686 patients (52.7%) remained indeterminate, while 283 patients (21.7%) became immune active. Compared with patients who remained inactive, patients who remained indeterminate had a higher 10-year cumulative HCC incidence (4.6% vs 0.5%; P < .0001) and adjusted hazard ratio for HCC of 14.1 (P= .03). Among patients who remained indeterminate, age 45 years and older (adjusted hazard ratio, 18.4; P= .005) was associated independently with HCC development. Nearly 40% of patients had indeterminate CHB phase. Of these, half remained indeterminate and one-fifth transitioned to the immune active phase. HCC risk in persistently indeterminate CHB was 14 times higher than inactive CHB. Among persistently indeterminate CHB patients, age 45 years and older was associated with an 18 times higher risk for HCC development. Further studies are needed to evaluate the potential benefit of antiviral therapy for indeterminate patients, especially in the older subgroup.

Combination of quantitative hepatitis B core antibody (qHBcAb) and aspartate aminotransferase (AST) can accurately diagnose immune tolerance of chronic hepatitis B virus infection based on liver biopsy

Background and aimsImmune tolerance is defined as HBeAg positive, high hepatitis B virus load (HBV), persistent normal alanine aminotransferase (ALT), no or slight inflammation or fibrosis in liver histology. However, it is still unclear the threshold of high hepatitis B virus load and how to predict histology without liver biopsy. The aim of this study was to predict immune tolerance in HBeAg positive, alanine aminotransferase -normal populations with non-invasive indicators. MethodsTwo multi-center prospective cohort study recruited 907 treatment-naïve chronic hepatitis B (CHB) patients who had undergone liver biopsy in mainland China from August 2013 to September 2016 and April 2018 to June2019. Quantitative hepatitis B core antibody, AST and HBV DNA were investigated using commercial diagnostic assays and histological grading and staging was assessed by the Ishak scoring system. ResultsOne hundred and thirteen untreated CHB patients with HBeAg-positive, normal alanine aminotransferase (ALT) and high level of HBV DNA (≥5log10 IU/mL) were enrolled in this study. The area under the receiver operating characteristic curves (AUROCs) of qHBcAb, AST, HBV DNA and qHBcAb-AST index were 79.6%, 80.5%, 76.4% and 87.7%. Our novel qHBcAb-AST index, which combined qHBcAb and AST showed better performance with higher sensitivity (88.6% [95% confidence interval (CI) 72.3% – 96.3%]) and negative predictive value (NPV) (93.8% [95% CI 84.2% - 98.0%]). ConclusionsThe combination of qHBcAb and AST can more accurately predict the immune tolerance of people with HBeAg-positive, normal alanine aminotransferase (ALT).

Risk Scores for Hepatocellular Carcinoma in Chronic Hepatitis B: A Promise for Precision Medicine.

In the past 10 years, there have been over a dozen risk scores to predict the occurrence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). Many of the scores were derived in untreated CHB patients, while others were based on patients receiving antiviral therapy. In review of a total of 17 prediction scores, the variables included in these scores may be categorized into three groups: (1) liver fibrosis and cirrhosis, (2) hepatitis activities, and (3) host factors including comorbid conditions. HCC scores in untreated patients tended to include variables from all three categories, whereas of those derived in patients on therapy, few included variables representing hepatitis activities. Some variables which are well accepted as significant risk factors for HCC, such as family history, are not included in the majority of the scores. While the effects on HCC development of variables that represent hepatitic and inflammatory activities are relatively easily controlled by antiviral therapy, impact of fibrosis/cirrhosis as well as host and comorbidity factors are more difficult to modify. More work is needed for precision scores that comprehensively consider all of the relevant variables and provide individualized prediction which then may be applied to broad CHB populations. In the meantime, the existing scores are helpful for the clinician to counsel their patients of their risk of HCC, to determine candidacy for surveillance and to strategize to mitigate the risk of HCC by intervening in modifiable factors such as controlling viral/hepatitic activities and optimizing medical management of comorbidity.

Association among cytokine profiles of innate and adaptive immune responses and clinical-virological features in untreated patients with chronic hepatitis B

BackgroundComplete clearance of intracellular viruses depends on effector cells of innate and adaptive immune systems. This study aimed to identify the relationships among antiviral cytokines produced by natural killer (NK) and T cells and clinical-virological characteristics in untreated chronic hepatitis B (CHB) patients.MethodsWe measured antiviral cytokines interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-2 (IL-2) produced by T, NK and natural killer T (NKT) cells, respectively, in a cohort with chronic hepatitis B virus (HBV) infection (CHB). We also correlated these cytokines with clinical-virological characteristics using a linear regression model.Resultslevels of IFN-γ+ and TNF-α+ CD4+ and CD8+ T cells were significantly higher in immune active (IA) phase than in other phases. Immune tolerant (IT) patients showed the lowest expression of IFN-γ by NK and NKT cells, and TNF-α by NK cells. IFN-γ+, TNF-α+ and IL-2+ CD4+ and CD8+ T cells frequencies were similar between IA and gray zone (GZ) phases. Principal component analysis based on cytokines confirmed that most IT patients significantly differed from inactive carriers (IC) and IA patients, while GZ patients were widely scattered. Multivariate analysis showed both T and NK cells producing IFN-γ and TNF-α, but not IL-2, had significant association with serum alanine aminotransferase (ALT). Moreover, IFN-γ+ NKT cells were associated with HBV DNA, while IFN-γ+ CD4+ and CD8+ T cells were correlated with age.ConclusionHBV clinical phases are characterized by distinct cytokine signatures, which showed relationship to viral features in these untreated CHB patients.

Tenofovir disoproxil fumarate reduces hepatocellular carcinoma, decompensation and death in chronic hepatitis B patients with cirrhosis.

Lamivudine and entecavir reduce hepatic events and death in chronic hepatitis B (CHB) patients with cirrhosis, but the impact of tenofovir disoproxil fumarate (TDF) is less well studied. To investigate the effectiveness of TDF therapy in CHB patients with cirrhosis. We studied TDF-treated and untreated CHB patients with cirrhosis from three tertiary centres. TDF cohort included consecutive patients who received TDF for ≥12months while the untreated cohort were historical controls receiving routine clinical care prior to the availability of anti-viral therapy. The primary outcome was 5-year cumulative probability of hepatocellular carcinoma (HCC) with secondary outcomes being hepatic decompensation and death or liver transplantation (LT). A total of 1088 (291 untreated and 797 TDF-treated) patients were included in the study. Five-year cumulative probabilities in untreated vs TDF-treated cohorts were 14.9% vs 9.8% for HCC (P=.07), 22.3% vs 5.9% for decompensation (P<.01) and 13.1% vs 1.1% for death or LT (P<.01) respectively. On multivariable Cox regression, TDF treatment was independently associated with reduced risks of HCC (adjusted hazard ratio [aHR] 0.46, P<.01), decompensating events (aHR 0.28, P=.01) and death or LT (aHR 0.06, P<.01). On sensitivity analyses, these risk reductions with TDF treatment were consistently demonstrated regardless of severity of liver disease and prior anti-viral treatment. TDF treatment led to sustained improvements in most validated prognostic scores for predicting HCC, decompensation and death. Compared to untreated patients, TDF treatment reduces the risks of HCC, hepatic decompensation and death in CHB patients with cirrhosis at 5years.

High risk of clinical events in untreated HBeAg-negative chronic hepatitis B patients with high viral load and no significant ALT elevation.

It remains unknown whether antiviral treatment for HBeAg-negative chronic hepatitis B (CHB) patients having high viral loads without significant elevation of alanine aminotransferase (ALT) levels would reduce the risks of clinical events. To compare clinical outcomes of high viral load CHB patients untreated for normal or mildly elevated ALT vs those treated for ALT≥2 upper limit of normal (ULN). This historical cohort study included 5414 HBeAg-negative CHB patients without cirrhosis at a tertiary hospital in Korea from 2000 to 2013. Inactive phase was defined as serum hepatitis B virus [HBV] DNA<2000IU/mL and persistently normal ALT (n=3572). High viral load (HBV DNA≥2000IU/mL) patients were classified into three phases by ALT levels: Replicative (persistently normal ALT, n=900); Mildly active (ALT 1-2ULN, n=396); and Active (ALT≥2ULN, n=546) phases. All Active phase patients were treated with nucleos(t)ide analogues. The mean age of the patients was 47years without a significant difference among the groups. Compared with the treated Active phase group, the untreated Replicative phase group showed a significantly higher risk of hepatocellular carcinoma (HCC; HR 1.76; 95% CI 1.00 - 3.10, P = 0.05) and death/transplantation (HR 2.14; 5% CI 1.09 - 4.21, P = 0.03) by propensity score-matched analysis. The untreated mildly active phase patients had further increase in risk of HCC and death/transplantation compared with the treated Active phase group by unadjusted, PS-matched, competing risks, and multivariable-adjusted analyses. Untreated high viral load HBeAg-negative CHB patients without significant ALT elevation had higher risks of clinical events than treated Active phase patients with elevated ALT.

Chronic hepatitis B: The interplay between intrahepatic lymphocyte population and viral antigens in relation to liver damage.

In Chronic hepatitis B (CHB) infection, virus and immune response interplay is thought to be responsible for pathogenesis. Yet, the impact of each immune cell population and viral protein expression in liver damage is still unknown. Our aim was to study the interplay between intrahepatic immune response and viral activity in relation to CHB liver damage. Immunostaining was performed in 29 liver biopsies from untreated CHB patients to characterize liver infiltrate [Th (CD4+), CTL (CD8+), Treg (FoxP3+), Th17 (IL-17A+) and Th1 (T-bet+)] and viral antigen expression (HBsAg and HBcAg). Inflammatory activity and fibrosis were assessed using the HAI and METAVIR scoring system. All studied populations were identified in the portal-periportal (P-P) areas with a CD4+ lymphocyte predominance, while only CD8+ and FoxP3+ cells were observed in the intralobular area. Both P-P CD4+ and intralobular CD8+ cell frequencies were increased among severe hepatitis cases. Concerning HBsAg and HBcAg expression, a mutually exclusive pattern was observed. HBcAg was mainly detected among HBeAg-positive patients and was associated with hepatitis severity and higher frequency of P-P FoxP3+, intralobular CD8+ and FoxP3+ cells. HBsAg was identified among HBeAg-negative cases with less severe hepatitis grade and lower frequency of P-P CD4+ and intralobular FoxP3+ lymphocytes. In conclusion, the HBV antigen profile expression seen during CHB infection may be reflecting different stages of viral replication which impacts the host immune response and liver damage process. While HBcAg might be an inducer of a regulatory microenvironment, the intralobular CTL population seemed to have a key role in hepatitis severity.