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Predictive value of serum ALT and T-cell receptor beta variable chain for HBeAg seroconversion in chronic hepatitis B patients during tenofovir treatment.

ABSTRACT: Effective antiviral therapy plays a key role in slowing the progression of chronic hepatitis B (CHB). Identification of serum indices, including hepatitis B e antigen (HBeAg) expression and seroconversion, will facilitate evaluation of the efficacy of antiviral therapy in HBeAg-positive CHB patients. The biochemical, serological, virological parameters, and the frequency of circulating CD4CD25 regulatory T cell (Treg) in 32 patients were measured at baseline and every 12 weeks during 96 weeks of tenofovir disoproxil fumarate (TDF) treatment. The relationship between the hepatitis B virus (HBV) deoxyribonucleic acid (DNA) and Treg and alanine aminotransferase (ALT) levels was analyzed, respectively. The molecular profiles of T-cell receptor beta variable chain (TRBV) were determined using gene melting spectral pattern. For the seroconverted 12 patients, ALT declined to normal levels by week 24 and remained at this level in subsequent treatment; moreover, the predictive cutoff value of ALT for HBeAg seroconversion (SC) was 41.5?U/L at week 24. The positive correlation between HBV DNA and Treg and ALT was significant in SC patients, but not in non-SC patients. Six TRBV families (BV3, BV11, BV12, BV14, BV20, and BV24) were predominantly expressed in SC patients at baseline. The decline of ALT could be used to predict HBeAg seroconversion for CHB patients during TDF treatment. In addition, the profile of Tregs and TRBVs may be associated with HBeAg seroconversion and could also be a potential indicator for predicting HBeAg SC and treatment outcome for CHB patients.

SUBMITTER: Yang J

PROVIDER: S-EPMC5348167 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Predictive value of serum ALT and T-cell receptor beta variable chain for HBeAg seroconversion in chronic hepatitis B patients during tenofovir treatment.

Yang Jiezuan J Yan Dong D Guo Renyong R Chen Jiajia J Li Yongtao Y Fan Jun J Fu Xuyan X Yao Xinsheng X Diao Hongyan H Li Lanjuan L

Medicine 20170301 10

Effective antiviral therapy plays a key role in slowing the progression of chronic hepatitis B (CHB). Identification of serum indices, including hepatitis B e antigen (HBeAg) expression and seroconversion, will facilitate evaluation of the efficacy of antiviral therapy in HBeAg-positive CHB patients. The biochemical, serological, virological parameters, and the frequency of circulating CD4CD25 regulatory T cell (Treg) in 32 patients were measured at baseline and every 12 weeks during 96 weeks of ...[more]

PMID: 28272219

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Project description:Background:Patients with chronic hepatitis B virus (HBV) infection who are hepatitis B virus e antigen (HBeAg) positive are increasingly being treated with nucleos(t)ide analogs (NUCs). However, the predictive value of serum hepatitis B virus core antibody (HBcAb) levels for HBeAg seroconversion among patients with high viral load remains unclear. Methods:This study consisted of 74 patients with high viral load (HBV DNA >1 × 107 copies/mL) enrolled in a multicenter, randomized, controlled trial, treated with lamivudine and adefovir (N = 32) or entecavir (N = 42) for up to 96 weeks. Serum HBV DNA, quantitative hepatitis B virus surface antigen (HBsAg), HBeAg, and HBeAb was tested at each visit. Quantitative HBcAb evaluation was conducted for all the available samples in the trial, by using a newly developed double-sandwich anti-HBc immunoassay. Results:Serum HBcAb levels were significantly higher in patients with a serum alanine aminotransferase (ALT) level more than five times the upper limit of normal (ULN) compared with patients with ALT levels within 5 × ULN (4.25 ± 0.61 vs. 3.94 ± 0.47 log10 IU/mL, P = 0.0345). Patients with HBeAg seroconversion were associated with a higher level of HBcAb at baseline, compared with those without HBeAg seroconversion (4.38 ± 0.54 vs. 4.02 ± 0.58 log10 IU/mL, P = 0.029). The area under receiver operating characteristic curve of baseline HBcAb for HBeAg seroconversion was 0.71 (95% CI: 0.55-0.86, P = 0.013). When the baseline HBcAb level was >4.375 log10 IU/mL, the sensitivity and specificity to predict HBeAg seroconversion at week 96 were 62.5% and 74.2%, and the positive likelihood ratio (LR) and negative LR were 2.42 and 0.51, respectively. The multivariate analysis result indicated that baseline serum HBcAb level was the only independent predictor for HBeAg seroconversion at week 96, with an odds ratio of 4.78. Conclusion:Baseline serum HBcAb level >4.375 log10 IU/mL could satisfactorily predict HBeAg seroconversion among patients with high viral load treated with NUC.

Project description:Background & aimsCurrent therapies for chronic hepatitis B virus (HBV) infection control viral replication but do not eliminate the risk of progression to hepatocellular carcinoma. HBV-specific CD8 T cells are necessary for viral control, but they are rare and exhausted during chronic infection. Preclinical studies have shown that blockade of the PD-1:PD-L1 axis can restore HBV-specific T cell functionality. The aim of this study was to analyze how the clinical and treatment status of patients impacts the ability of HBV-specific T cells to respond to PD-L1 blockade.MethodsExpression patterns of the PD-1:PD-L1/PD-L2 axis were analyzed in healthy donors and chronically infected patients in different clinical phases of disease. A functional assay was performed to quantify baseline HBV-specific T cell responses in chronically infected patients. Baseline responses were then compared to those attained in the presence of an anti-PD-L1 monoclonal antibody (MEDI2790).ResultsChronically infected patients were characterized by the upregulation of PD-1 within the T cell compartment and a concomitant upregulation of PD-L1 on myeloid dendritic cells. The upregulation was maximal in HBV e antigen (HBeAg)-positive patients but persisted after HBeAg negativization and was not restored by long-term treatment. HBV reactivity, measured as frequency of HBV-specific T cells, was significantly higher in HBeAg-negative patients with lower HBV DNA levels, independently of HBV surface antigen or alanine aminotransferase levels. Anti-PD-L1 blockade with MEDI2790 increased both the number of IFN-γ-producing T cells and the amount of IFN-γ produced per cell in 97% of patients with detectable HBV reactivity, independently of patients' clinical or treatment status.ConclusionPatients with lower levels of HBV DNA and the absence of HBeAg have more intact HBV-specific T cell immunity and may benefit the most from PD-L1 blockade as a monotherapy.Lay summaryHepatitis B virus (HBV)-specific T cell responses during chronic infection are weak due to the upregulation of inhibitor molecules on the immune cells. In this study we show that the inhibitory PD-1:PD-L1 axis is upregulated during chronic HBV infection and successful antiretroviral therapy does not restore normal levels of PD-1 and PD-L1 expression. However, in HBV e antigen-negative patients, treatment with an anti-PD-L1 antibody can increase the functionality of HBV-specific T cell responses by an average of 2-fold and is a promising new therapy for patients with chronic HBV infection.

Dataset Information

Predictive value of serum ALT and T-cell receptor beta variable chain for HBeAg seroconversion in chronic hepatitis B patients during tenofovir treatment.

Publications

Predictive value of serum ALT and T-cell receptor beta variable chain for HBeAg seroconversion in chronic hepatitis B patients during tenofovir treatment.

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