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Background and aim: Although antiviral treatments have been shown to affect the recurrence and long-term survival of patients with hepatocellular carcinoma (HCC) who have high viral loads, the effect of different responses to antiviral therapy on the clinical outcomes remains unclear. This study aimed to assess the effect of primary non-response (no-PR) to antiviral therapy on the survival or prognosis of patients with HCC with a high load of hepatitis B virus (HBV) DNA. Methods: A total of 493 HBV-HCC patients hospitalized at Beijing Ditan Hospital of Capital Medical University were admitted to this retrospective study. Patients were divided into two groups based on viral response (no-PR and primary response). Kaplan–Meier (KM) curves were used to compare the overall survival of the two cohorts. Serum viral load comparison and subgroup analysis were performed. Additionally, risk factors were screened and the risk score chart was created. Results: This study consisted of 101 patients with no-PR and 392 patients with primary response. In the different categories based on hepatitis B e antigen and HBV DNA, no-PR group had a poor 1-year overall survival (OS). In addition, in the alanine aminotransferase < 50 IU/L and cirrhosis groups, primary nonresponse was related to poor overall survival and progression-free survival. Based on multivariate risk analysis, primary non-response (hazard ratio (HR) = 1.883, 95% CI 1.289–2.751, P = 0.001), tumor multiplicity (HR = 1.488, 95% CI 1.036–2.136, P = 0.031), portal vein tumor thrombus (HR = 2.732, 95% CI 1.859–4.015, P < 0.001), hemoglobin < 120 g/L (HR = 2.211, 95% CI 1.548–3.158, P < 0.001) and tumor size ≥ 5 cm (HR = 2.202, 95% CI 1.533–3.163, P < 0.001) were independent risk factors for 1-year OS. According to the scoring chart, patients were divided into three risk groups (high-, medium-, and low-risk groups) with mortality rates of 61.7%, 30.5%, and 14.1%, respectively. Conclusions: The level of viral decline at 3 months post-antiviral treatment may predict the OS of patients with HBV-related HCC, and primary non-response may shorten the median survival time of patients with high HBV-DNA levels. [ABSTRACT FROM AUTHOR]

The acute‐on‐chronic liver failure (ACLF) development is highly dynamic. Currently, no satisfactory algorithm identifies patients with HBV at risk of this complication. The aim of the study was to characterize ACLF development in hospitalized HBV‐related patients without previous decompensation and to test the performance of traditional prognostic models in ruling out ACLF development within 28 days on admission we conducted a cohort study. Two multi‐center cohorts with hospitalized HBV‐related previous compensated patients were analyzed. Performances of MELD, MELD‐Na, CLIF‐C AD, and CLIF‐C ACLF‐D in ruling out ACLF development within 28 days were compared and further validated by ROC analyses. In the derivation cohort (n = 892), there were 102 patients developed ACLF within 28 days, with profound systemic inflammatory levels and higher 28‐day mortality rate (31.4% vs. 1.0%) than those without ACLF development. The MELD score (cut‐off = 18) achieved acceptable missing rate (missed/total ACLF development) at 2.9%. In the validation cohort (n = 1656), the MELD score (<18) was able to rule out ACLF development within 28 days with missing rate at 3.0%. ACLF development within 28 days were both lower than 1% (0.6%, derivation cohort; 0.5%, validation cohort) in patients with MELD < 18. While in patients with MELD ≥ 18, 26.6% (99/372, derivation cohort) and 17.8% (130/732, validation cohort) developed into ACLF within 28 days, respectively. While MELD‐Na score cut‐off at 20 and CLIF‐AD score cut‐off at 42 did not have consistent performance in our two cohorts. MELD < 18 was able to safely rule out patients with ACLF development within 28 days in HBV‐related patients without previous decompensation, which had a high 28‐day mortality. [ABSTRACT FROM AUTHOR]

Background. Acute-on-chronic liver failure (ACLF) is a clinical syndrome characterized by acute deterioration of liver function and high short-term mortality. Clusterin, with biological functions similar to small heat shock proteins, can protect cells from apoptosis induced by various stressors. The aim of this study was to detect the level of serum clusterin in hepatitis B virus- (HBV-) related ACLF and to assess the predictive value of clusterin for the short-term prognosis of HBV-ACLF. Methods. We detected serum clusterin by ELISA in 108 HBV-ACLF patients, 63 HBV-non-ACLF patients, and 44 normal controls. Results. Serum clusterin was markedly lower in HBV-ACLF patients (median, 51.09 μg/mL) than in HBV-non-ACLF patients (median, 188.56 μg/mL) and normal controls (median, 213.45 μg/mL; all P < 0.05). Nonsurviving HBV-ACLF patients who died within 90 days had much lower clusterin levels than did surviving patients, especially those who died within 28 days (nonsurvival group vs. survival group: 39.82 ± 19.34 vs. 72.26 ± 43.52 , P < 0.001 ; survival time ≤ 28 vs. survival time > 28 : median 28.39 vs. 43.22, P = 0.013). The results showed that for identifying HBV-ACLF, the sensitivity of clusterin (93.7%) was similar to the sensitivities of the international normalized ratio (INR; 94.4%) and total bilirubin (TBIL; 94.8%), but its specificity (90.7%) was higher than that of prothrombin activity (PTA; 65.8%) and TBIL (69.8%) and was similar to INR (88.9%). As the concentration of clusterin increased, the mortality of HBV-ACLF patients decreased significantly from 59.3% to 7.0%. Clusterin had better ability for predicting the prognosis of HBV-ACLF patients than did the model for end-stage liver disease (MELD) score and the chronic liver failure consortium (CLIF-C) ACLF score (MELD vs. clusterin: P = 0.012 ; CLIF-C ACLF vs. clusterin: P = 0.031). Conclusion. Serum clusterin is a potential biomarker for HBV-ACLF which can be used to assess clinical severity and the short-term prognosis of patients with this disease and may help clinicians identify HBV-ACLF with greater specificity and improved prognostic accuracy than existing prognostic markers. [ABSTRACT FROM AUTHOR]

Background: Tenofovir disoproxil fumarate (TDF) imposes a high genetic barrier to drug resistance and potently inhibits replication of multidrug‐resistant hepatitis B virus. Few clinical cases with confirmed TDF‐resistance have been reported to date. Methods and Results: Here, we report viral rebound in a patient with chronic hepatitis B who underwent TDF monotherapy and harboured a quadruple mutant consisting of classic entecavir (ETV)‐resistance mutations (rtL180M/T184L/M204V) together with an rtA200V mutation in the reverse transcriptase gene. Sequencing analysis revealed that this quadruple mutant emerged as a major viral population. In vitro phenotyping demonstrated that the rtL180M/T184L/A200V/M204V mutant had moderate resistance to TDF treatment, with a 4.52‐fold higher half maximal effective concentration than that of wild‐type virus. Importantly, this patient with TDF resistance achieved virological suppression after TDF/ETV combination rescue therapy. Conclusion: An rtL180M/T184L/A200V/M204V mutant with moderate resistance to TDF monotherapy was selected during sequential nucleoside analogue (NA) treatment in a stepwise manner. ETV/TDF combination therapy effectively suppressed replication of this TDF‐resistant mutant. Our studies provide novel insights into the treatment of NA‐naïve patients as well as patients with TDF resistance. [ABSTRACT FROM AUTHOR]

Hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) is usually considered an inflammation-related cancer associated with chronic inflammation triggered by exposure to HBV and tumor antigens. T-cell exhaustion is implicated in immunosuppression of chronic infections and tumors. Although immunotherapies that enhance immune responses by targeting programmed cell death-1(PD-1)/PD-L1 are being applied to malignancies, these treatments have shown limited response rates, suggesting that additional inhibitory receptors are also involved in T-cell exhaustion and tumor outcome. Here, we analyzed peripheral blood samples and found that coexpression of PD-1 and T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) was significantly upregulated on CD4+ and CD8+ T cells from patients with HBV-HCC compared with those from patients with chronic HBV or HBV-liver cirrhosis. Additionally, PD-1+ TIGIT+ CD8+ T-cell populations were elevated in patients with advanced stage and progressed HBV-HCC. Importantly, PD-1+ TIGIT+ CD8+ T-cell populations were negatively correlated with overall survival rate and progression-free survival rates. Moreover, we showed that PD-1+ TIGIT+ CD8+ T cells exhibit features of exhausted T cells, as manifested by excessive activation, high expression of other inhibitory receptors, high susceptibility to apoptosis, decreased capacity for cytokine secretion, and patterns of transcription factor expression consistent with exhaustion. In conclusion, PD-1+ TIGIT+ CD8+ T-cell populations are associated with accelerated disease progression and poor outcomes in HBV-HCC, which might not only have important clinical implications for prognosis but also provide a rationale for new targets in immunotherapy. [ABSTRACT FROM AUTHOR]

Acute-on-chronic liver failure (ACLF) is a clinical syndrome associated with high short-term mortality in patients with chronic liver disease. Chronic hepatitis B is the main cause of ACLF (HBV-ACLF) in China and other Asian countries. To improve disease management and survival for patients with ACLF, we aimed to discover novel biomarkers to enhance HBV-ACLF diagnosis and prognostication. We performed a metabolomics profiling of 1,024 plasma samples collected from patients with HBV-related chronic liver disease with acute exacerbation at hospital admission in a multi-year and multi-center prospective study (367 ACLF and 657 non-ACLF). The samples were randomly separated into equal halves as a discovery set and a validation set. We identified metabolites associated with 90-day mortality in the ACLF group and the progression to ACLF within 28 days in the non-ACLF group (pre-ACLF) using statistical analysis and machine learning. We developed diagnostic algorithms in the discovery set and used these to assess the findings in the validation set. ACLF significantly altered the plasma metabolome, particularly in membrane lipid metabolism, steroid hormones, oxidative stress pathways, and energy metabolism. Numerous metabolites were significantly associated with 90-day mortality in the ACLF group and/or pre-ACLF in the non-ACLF group. We developed algorithms for the prediction of 90-day mortality in patients with ACLF (area under the curve 0.87 and 0.83 for the discovery set and validation set, respectively) and the diagnosis of pre-ACLF (area under the curve 0.94 and 0.88 for the discovery set and validation set, respectively). To translate our discoveries into practical clinical tests, we developed targeted assays using liquid chromatography-mass spectrometry. Based on novel metabolite biomarkers, we established tests for HBV-related ACLF with higher accuracy than existing methods. NCT02457637 and NCT03641872. Acute-on-chronic liver failure (ACLF) is a clinical syndrome associated with high short-term mortality affecting 25% of patients hospitalized with cirrhosis. Chronic hepatitis B is the main etiology of ACLF in China and other Asian counties. There is currently no effective therapy. Early diagnosis and accurate prognostication are critical for improving clinical outcomes in patients with ACLF. Based on novel metabolite biomarkers, we developed liquid chromatography-mass spectrometry tests with improved accuracy for the early diagnosis and prognostication of HBV-related ACLF. The liquid chromatography-mass spectrometry tests can be implemented in clinical labs and used by physicians to triage patients with HBV-related ACLF to ensure optimized clinical management. [Display omitted] • Metabolomics uncovered profound metabolic perturbations associated with HBV-related ACLF in patient plasma. • We identified novel metabolite biomarkers that can be used to enhance ACLF prognostication and early diagnosis. • We developed and validated LCMS-based clinical tests with improved accuracy for ACLF prognostication and early diagnosis. [ABSTRACT FROM AUTHOR]

Background & Aims The important pathophysiological role of immune dysfunction, especially innate immune dysfunction in patients with acute-on-chronic liver failure ( ACLF), has been investigated in recent years, but dysregulation of adaptive immunity remains poorly elucidated. The aim of this study was to (i) determine the CD3+ T-lymphocyte count and the balance between CD4+ regulatory T (Tregs) and conventional T cells (Tconv) in hepatitis B virus ( HBV)-related ACLF patients; (ii) analyse the frequencies of Tregs subpopulations; and (iii) assess the suppressive potency of CD4+ Tregs and each fraction. Methods We enrolled 20 HBV- ACLF patients, 10 septic shock subjects, 20 chronic hepatitis B ( CHB) patients and 20 healthy volunteers ( HC). Based on flow cytometry, we performed the absolute counting of circulating T lymphocytes and phenotyping of CD4+ Tregs and quantified the effects of Tregs and each subpopulation on Tconv proliferation by CFSE staining. Results Compared with CHB patients and HC, we observed an equal reduction in peripheral T subsets in HBV- ACLF and septic shock subjects; the number of CD4+ Tregs remained unchanged and the Tconv count declined, promoting elevation of the Treg-to-Tconv ratio. The frequencies of Treg-II and -III were elevated in HBV- ACLF. Functional studies showed that the suppressive capacity of Tregs was preserved in the HBV- ACLF group and Treg-II came first. Conclusions Similar to septic shock subjects, in HBV- ACLF patients there exists a reduction in CD4+ T lymphocytes, predominantly CD4+ Tconv, and the development of suppressive CD4+ Tregs greatly prevails over Tconv, constituting important characteristics of adaptive immune dysfunction of HBV- ACLF. [ABSTRACT FROM AUTHOR]

Aim This study developed and validated a non-invasive scoring model to predict 1-year hepatitis B e antigen (HBeAg) seroconversion in response to nucleos(t)ide analog (NA) treatment in NA-naïve patients with HBeAg-positive chronic hepatitis B (CHB). Methods Baseline data from 1014 patients visiting the outpatient and inpatient clinics of Beijing Ditan Hospital, Capital Medical University, China between October 2008 and April 2015 were included. These patients received NAs for HBeAg-positive CHB. The patients were assigned randomly to the derivation ( n = 710) and validation ( n = 304) cohorts in a 7:3 ratio. A prediction scoring model was established based on univariate and multivariate Cox proportional hazards regression analyses to identify independent prediction factors. In the derivation cohort, the odds ratio of the predictors were converted to integer risk scores by rounding the quotient from dividing the odds ratio, and the final score was the sum of these values. The predictive accuracy of the scoring model was further assessed using Harrell’s concordance index (C-index). Results The 1-year cumulative HBeAg seroconversion rates were 11.83% and 8.55% in the derivation and validation cohorts, respectively. In the derivation cohort, baseline pretreatment alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), globulin (GLO), and quantitative HBeAg (qHBeAg) levels were independently associated with HBeAg seroconversion and were included in the scoring system. The model had good discrimination in the derivation and validation cohorts (C-index = 0.750, 95% confidence interval 0.694–0.806 and C-index = 0.776, 95% confidence interval 0.698–0.855, respectively). The prediction scores ranged from 0 to 4; scores of 0–1 and 2–4 identified patients with lower and higher levels of HBeAg seroconversion, respectively. Kaplan–Meier analysis was used to determine the 1-year cumulative HBeAg seroconversion rates in the two groups (scores of 0–1 and 2–4) of the primary cohort, and log-rank tests revealed a significant difference (4.87% vs. 20.9%, p < 0.0001). Conclusions The 1-year prediction scoring model based on baseline levels of ALT, GGT, GLO, and qHBeAg offered a reliable predictive value for the response to NA therapy in a Chinese cohort. [ABSTRACT FROM AUTHOR]

• We developed a prognostic nomogram for 30-day mortality in patients with OHE. • MELD and NLR provided risk stratification for patient outcomes. • Patients with MELD ≥ 23 and NLR ≥ 4 have a high mortality rate. Overt hepatic encephalopathy (OHE) is a serious complication of liver disease. We aimed to develop a dynamic nomogram for estimating the probability of 30-day transplant-free mortality in patients with OHE and hepatitis B-related cirrhosis (HBC). We identified 402 patients with OHE and HBC at the Beijing Ditan Hospital between January 2011 and July 2016. Independent risk factors were determined using multivariate Cox proportional hazards regression analysis. A dynamic nomogram was established to predict the probability of 30-day transplant-free mortality. The discrimination and clinical usefulness of the nomogram were estimated using the area under the receiver operating characteristic (AUC) and calibration curves, and decision curve analysis. A prospective cohort of 208 patients was enrolled for validation. The model for end-stage liver disease (MELD) score and neutrophil-to-lymphocyte ratio (NLR) were independently associated with the 30-day transplant-free mortality. The AUC values of the nomogram were 0.881 and 0.879 in the derivation and validation cohorts, respectively, and the discrimination ability was superior to that of the established models. The calibration plot fitted the predicted survival and observed probabilities well. The incidence of mortality was 2.0% (3/151) in patients with MELD scores < 23 and NLR < 4, and 55.4% (41/92) in those with MELD scores ≥ 23 and NLR ≥ 4. The dynamic nomogram can predict the risk of 30-day transplant-free mortality in patients with OHE and HBC. Patients with MELD scores ≥ 23 and NLR ≥ 4 have a high mortality rate and should be admitted to intensive care. [ABSTRACT FROM AUTHOR]