Programmed death 1 expression during antiviral treatment of chronic hepatitis B: Impact of hepatitis B e-antigen seroconversion.

UNLABELLED: Hyperexpression of the programmed death 1 (PD-1) molecule is a hallmark of exhausted T-cells, having a negative impact on T-cell activation and function. We studied longitudinally 18 hepatitis B e antigen (HBeAg)-positive patients undergoing treatment with direct antivirals (telbivudine or lamivudine) to determine the relationship between treatment-induced viremia reduction and HBeAg seroconversion with respect to PD-1 levels and T-cell reactivity. PD-1 expression was assessed by (1) flow cytometry and (2) quantitative real-time polymerase chain reaction; hepatitis B virus (HBV)-specific CD8+ T-cells were quantitated by pentamer staining; T-cell reactivity to HBV antigens was determined by interferon gamma (IFNgamma) and interleukin 10 (IL-10) enzyme-linked immunosorbent spot (ELISPOT) assays; and central/effector memory phenotypes were defined by phenotypic markers. PD-1 expression correlated closely with viremia levels. On therapy, PD-1 decreased significantly on total CD8+ T-cells, HBV-specific CD8+ T-cells, and CD3+/CD8- T-cells both as the percentage of positive cells (P < 0.01) and as the mean fluorescent intensity (P < 0.05), and this was paralleled by a marked reduction of PD-1 messenger RNA levels (P = 0.001). HBeAg serocoversion (in 6/18 patients) resulted in a further PD-1 decrease with a 50% reduction in the frequency of PD-1+/CD8+ T-cells, which was not observed in patients remaining HBeAg-positive. The decrease in PD-1 expression was associated with increased frequencies of IFNgamma-producing T-cells and decreased frequencies of IL-10 producing T-cells. At baseline, PD-1 expression correlated directly with the frequency of hepatitis B core antigen (HBcAg) central and effector memory phenotypes, whereas an inverse correlation was observed between PD-1 expression and HBcAg-specific effector phenotypes. CONCLUSION: These results demonstrate that in chronic HBV infection, both viremia levels and HBeAg drive PD-1 expression and resulting T-cell impairment. Treatment-induced suppression of HBV replication reduces PD-1 expression; however, additional immunotherapeutic interventions are needed for restoration of T-cell functions.

Late magnetic resonance surveillance of repaired coarctation of the aorta.

OBJECTIVE: Coarctation of the aorta has often been described as a simple form of congenital heart disease. However, rates of re-coarctation reported in the literature vary from 7% to 60%. Re-coarctation of the aorta may lead to worsening systemic hypertension, coronary artery disease and/or congestive cardiac failure. We aimed to describe the rates of re-coarctation in subjects who had undergone early coarctation repair (<2 years of age) and referred for clinically indicated or routine magnetic resonance (MR) surveillance. METHODS: We retrospectively identified 50 consecutive subjects (20.2+/-6.9 years post-repair) imaged between 2004 and 2008. Patient characteristics, rates of re-coarctation and LV/aortic dimensions were examined. RESULTS: Forty percent of subjects had bicuspid aortic valves (BAV). There were 40 cases of end-to-end repair and 10 cases of subclavian flap repair. Re-intervention with balloon angioplasty or repeat surgery had been performed in 32% of subjects. The MRI referrals were clinically indicated in 34% and routine in 66% of patients. Re-coarctation was considered moderate or severe in 34%, mild in 34% and no re-coarctation was identified in 32% of patients. There was no significant difference in the number of cases of re-coarctation identified in the clinically indicated versus routine referrals for MR imaging (p=0.20). There were no cases of aortic dissection or aneurysm formation identified amongst the subjects. The mean indexed left ventricular mass and ejection fraction was 72+/-16g/m(2) and 66+/-6%, respectively. Amongst those subjects with BAV there were larger aortic sinus (30+/-1mm vs 27+/-1mm, p=0.03) and ascending aortic (27+/-1mm vs 23+/-1mm, p=0.01) dimensions when compared to subjects with morphologically tricuspid aortic valves. CONCLUSIONS: We demonstrate that many years after early repair of coarctation of the aorta, MR surveillance detects significant rates of re-coarctation. These findings were independent of whether or not there was a clinical indication for imaging. Those patients with BAV disease had larger ascending aortic dimensions and may require more frequent non-invasive surveillance.