Effects of Hepatitis B Surface Antigen on Virus-Specific and Global T Cells in Patients With Chronic Hepatitis B Virus infection.

BACKGROUND & AIMS: Chronic hepatitis B virus (HBV) infection is characterized by the presence of defective viral envelope proteins (hepatitis B surface antigen [HBsAg]) and the duration of infection-most patients acquire the infection at birth or during the first years of life. We investigated the effects of these factors on patients' lymphocyte and HBV-specific T-cell populations. METHODS: We collected blood samples and clinical data from 243 patients with HBV infection (3-75 years old) in the United Kingdom and China. We measured levels of HBV DNA, HBsAg, hepatitis B e antigen, and alanine aminotransferase; analyzed HBV genotypes; and isolated peripheral blood mononuclear cells (PBMCs). In PBMCs from 48 patients with varying levels of serum HBsAg, we measured 40 markers on nature killer and T cells by mass cytometry. PBMCs from 189 patients with chronic infection and 38 patients with resolved infections were incubated with HBV peptide libraries, and HBV-specific T cells were identified by interferon gamma enzyme-linked immune absorbent spot (ELISpot) assays or flow cytometry. We used multivariate linear regression and performed variable selection using the Akaike information criterion to identify covariates associated with HBV-specific responses of T cells. RESULTS: Although T- and natural killer cell phenotypes and functions did not change with level of serum HBsAg, numbers of HBs-specific T cells correlated with serum levels of HBsAg (r = 0.3367; P < .00001). After we performed the variable selection, the multivariate linear regression model identified patient age as the only factor significantly associated with numbers of HBs-specific T cells (P = .000115). In patients younger than 30 years, HBs-specific T cells constituted 28.26% of the total HBV-specific T cells; this value decreased to 7.14% in patients older than 30 years. CONCLUSIONS: In an analysis of immune cells from patients with chronic HBV infection, we found that the duration of HBsAg exposure, rather than the quantity of HBsAg, was associated with the level of anti-HBV immune response. Although the presence of HBs-specific T cells might not be required for the clearance of HBV infection in all patients, strategies to restore anti-HBV immune responses should be considered in patients younger than 30 years.

Bayesian splines versus fractional polynomials in network meta-analysis.

BACKGROUND: Network meta-analysis (NMA) provides a powerful tool for the simultaneous evaluation of multiple treatments by combining evidence from different studies, allowing for direct and indirect comparisons between treatments. In recent years, NMA is becoming increasingly popular in the medical literature and underlying statistical methodologies are evolving both in the frequentist and Bayesian framework. Traditional NMA models are often based on the comparison of two treatment arms per study. These individual studies may measure outcomes at multiple time points that are not necessarily homogeneous across studies. METHODS: In this article we present a Bayesian model based on B-splines for the simultaneous analysis of outcomes across time points, that allows for indirect comparison of treatments across different longitudinal studies. RESULTS: We illustrate the proposed approach in simulations as well as on real data examples available in the literature and compare it with a model based on P-splines and one based on fractional polynomials, showing that our approach is flexible and overcomes the limitations of the latter. CONCLUSIONS: The proposed approach is computationally efficient and able to accommodate a large class of temporal treatment effect patterns, allowing for direct and indirect comparisons of widely varying shapes of longitudinal profiles.