Varied immune responses of HBV-specific B cells in patients undergoing pegylated interferon-alpha treatment for chronic hepatitis B.

BACKGROUND & AIMS: The changes of HBV-specific B-cells in chronic hepatitis B (CHB) patients underwent pegylated interferon-alfa (PEG-IFNα) treatment and achieved functional cure remain unclear. We aimed to evaluate the alterations in HBV-specific B-cells during treatment and therefore explored the mechanism of functional recovery of HBsAg-specific B-cells. METHODS: We included 39 nucleos(t)ide analogues-treated CHB patients who received sequential combination therapy with PEG-IFNα and 8 treatment-naive CHB patients. HBV-specific B-cells were characterized ex vivo using fluorescent labeled HBsAg and HBcAg. The frequency, phenotype, and subsets of HBV-specific B-cells and follicular helper T cells (Tfh-cells) were detected using flow cytometry. The functionality of HBV-specific B-cells was quantified through ELISpot assays. RESULTS: During treatment, the fraction of activated memory B-cells (MBCs) among HBsAg-specific B-cells and the expression of IgG, CXCR3, and CD38 increased. Antibody-secretion capacity of HBsAg-specific B-cell was restored after treatment only in patients with a functional cure and it showed a positive correlation with serum hepatitis B surface antibody levels. The phenotype and function of HBsAg-specific B-cells differed between patients with and without functional cure. Patients with functional cure exhibited IgG+ classical MBCs and plasmablasts in HBsAg-specific B-cells. HBcAg-specific B-cells displayed both attenuated antibody secretion with reduced IgG expression and an IgM+ atypical type of MBCs after treatment, irrespective of with and without functional cure. The number of CD40L+ Tfh-cells increased after PEG-IFNα treatment and positively correlated with HBsAg-specific B-cell activation. CONCLUSIONS: After PEG-IFNα treatment, HBsAg- and HBcAg-specific B-cells exhibit various changes in antibody secretion. Their functional differences are reflected in the alterations in phenotypes and subtypes. The presence of CD40L+ Tfh-cells is associated with the active recovery of HBsAg-specific B-cells. IMPACT AND IMPLICATIONS: HBV-related complications and hepatocellular carcinoma remain the leading causes of mortality from chronic liver disease worldwide, and a cure is rarely achieved with antiviral therapies. Elucidating the immunological mechanisms underlying the functional cure of CHB patients offers a promising therapeutic strategy for viral clearance, such as therapeutic vaccine. We analyzed the alterations in HBV-specific B-cells in patients treated with PEG-IFNα and identified novel pathways for immunotherapeutic boosting of B cell immunity.

Influence of metabolic dysfunction-associated fatty liver disease on the prognosis of patients with HBV-related acute-on-chronic liver failure.

OBJECTIVES: Metabolic-associated fatty liver disease (MAFLD) has clinical relevance in patients with acute-on-chronic liver failure (ACLF). We investigated the association between MAFLD and prognosis in patients with ACLF. METHODS: We included patients with ACLF with available clinical data who visited our hospital for nearly 9 years. We compared the prognosis of patients in the different subgroups of ACLF and predicted the incidence of adverse outcomes. Moreover, a new model based on MAFLD was established. RESULTS: Among 339 participants, 75 had MAFLD. The prognosis of patients with ACLF was significantly correlated with MAFLD. Patients with ACLF with concomitant MAFLD tended to have a lower cumulative survival rate (p = 0.026) and a higher incidence of hepatorenal syndrome (9.33% versus 3.40%, p = 0.033) than those without MAFLD. We developed an TIM2 model and the area under the ROC curve of the new model for 30-day and 60-day mortality (0.759 and 0.748) was higher than other predictive methods. CONCLUSION: The presence of MAFLD in patients with HBV-related ACLF was associated with an increased risk of in-hospital mortality. Moreover, The TIM2 model is a high-performance prognostic score for HBV-related ACLF.

Tenofovir alafenamide significantly increased serum lipid levels compared with entecavir therapy in chronic hepatitis B virus patients.

BACKGROUND: Tenofovir alafenamide (TAF) has a serum lipid-raising effect in patients with HIV; however, its effect on serum lipids and nonalcoholic fatty liver disease (NAFLD) risk in patients with chronic hepatitis B (CHB) is unclear. AIM: To compare the effects of TAF and entecavir (ETV) on serum lipid levels in patients with CHB. METHODS: In this retrospective cohort study, the data including the clinical features, serum lipids, and metabolic factors of patients with CHB at baseline and approximately 1 year after TAF or ETV treatment were collected and analyzed. We used propensity score-matched models to assess the effects on high-density lipoprotein, low-density lipoprotein, triglycerides, and total cholesterol (TCHO). RESULTS: A total of 336 patients (75.60% male) were included; 63.69% received TAF and 36.31% received ETV. Compared with the ETV group, the TAF group had significantly higher TCHO levels after treatment (4.67 ± 0.90 vs 4.36 ± 1.05, P = 0.006). In a propensity score-matched model for body mass index, age, sex, smoking, drinking, presence of comorbidities such as NAFLD, cirrhosis, diabetes mellitus, and hypertension, TAF-treated patients had significantly increased TCHO levels compared to that at baseline (P = 0.019). There was no difference for the ETV group. Body mass index, sex, hypertension, baseline TCHO, and creatine kinase-MB isoenzyme levels were significantly associated with elevated TCHO levels in logistic regression analysis. However, 1-year TAF treatment did not increase the incidence of NAFLD. CONCLUSION: A greater increase in TCHO was observed in patients with CHB receiving TAF compared to those receiving ETV. However, TAF-induced dyslipidemia did not increase the incidence of NAFLD.

Clinical value of predictive models based on liver stiffness measurement in predicting liver reserve function of compensated chronic liver disease.

BACKGROUND: Assessment of liver reserve function (LRF) is essential for predicting the prognosis of patients with chronic liver disease (CLD) and determines the extent of liver resection in patients with hepatocellular carcinoma. AIM: To establish noninvasive models for LRF assessment based on liver stiffness measurement (LSM) and to evaluate their clinical performance. METHODS: A total of 360 patients with compensated CLD were retrospectively analyzed as the training cohort. The new predictive models were established through logistic regression analysis and were validated internally in a prospective cohort (132 patients). RESULTS: Our study defined indocyanine green retention rate at 15 min (ICGR15) ≥ 10% as mildly impaired LRF and ICGR15 ≥ 20% as severely impaired LRF. We constructed predictive models of LRF, named the mLPaM and sLPaM, which involved only LSM, prothrombin time international normalized ratio to albumin ratio (PTAR), age and model for end-stage liver disease (MELD). The area under the curve of the mLPaM model (0.855, 0.872, respectively) and sLPaM model (0.869, 0.876, respectively) were higher than that of the methods for MELD, albumin-bilirubin grade and PTAR in the two cohorts, and their sensitivity and negative predictive value were the highest among these methods in the training cohort. In addition, the new models showed good sensitivity and accuracy for the diagnosis of LRF impairment in the validation cohort. CONCLUSION: The new models had a good predictive performance for LRF and could replace the indocyanine green (ICG) clearance test, especially in patients who are unable to undergo ICG testing.

Effect of type 2 diabetic mellitus in the prognosis of acute-on-chronic liver failure patients in China.

BACKGROUND: Acute-on-chronic liver failure (ACLF) patients have a high short-term mortality rate, and the severity evaluation of ACLF is necessary for prognostication. Therefore, it was meaningful to evaluate the association between type 2 diabetic mellitus (DM) and ACLF and further explore the feasibility of using DM as a prognostic indicator in ACLF patients. The association between type 2 DM and the prognosis of patients with severe liver disease remains unclear. AIM: To examine the effect of type 2 DM on the prognosis of patients with ACLF. METHODS: Clinical data from 222 ACLF patients were collected and analyzed. The patients were categorized into two groups depending on whether they had DM or not, and the clinical data of ACLF patients were measured within 48 h after admission. Complications of ACLF were documented during treatment, such as hepatic encephalopathy, hepatorenal syndrome, acute upper gastrointestinal hemorrhage, and spontaneous peritonitis (SBP). Values of laboratory parameters, complication rates, and hospital mortality rates were compared between two groups. RESULTS: Among 222 ACLF patients, 38 cases were categorized into DM groups, the mean age was 56.32 years and 73.68% were male. The prognosis of ACLF patients was significantly correlated with DM in univariate [hazard ratio (HR) = 2.4, 95% confidence interval (CI) =1.5-3.7, P < 0.001] and multivariable analysis (HR = 3.17, 95%CI =1.82-5.523, P < 0.001). The incident of SBP (34.21% vs 13.59%, P = 0.038) and other infections like lung, urinary, blood, and cholecyst (44.74% vs 28.26%, P = 0.046) were higher in DM patients than non-DM counterparts. In addition, the ACLF patients with DM tended to have a high mortality rate (P < 0.001). Cumulative survival time was also significantly shorter in the ACLF patients with DM than non-DM. CONCLUSION: A significant association between DM and the prognosis of ACLF patients was found in China. The ACLF patients with DM had higher incidence of hospital mortality and infection than those without DM.