2015-08-012024-05-18https://scholars.lib.ntu.edu.tw/handle/123456789/712324Chronic hepatitis B (CHB) is an important disease in Taiwan and the subsequent liver cirrhosis and hepatocellular carcinoma pose a great threat in public health. There are five oral nucleos(t)ide analogues available, the lamivudine, adefovir, entecavir, telbivudine and tenofovir. According to current guideline, for HBeAg-positive chronic hepatitis B patients, antiviral therapy may be discontinued after HBeAg seroconversion and undetectable HBV DNA levels on two consecutive occasions, with at least 6-month intervals. For HBeAg-negative patients, the therapy may be discontinued if undetectable HBV DNA levels have been established on three separate occasions, with 6 months apart. The Bureau of National Health Insurance of Taiwan extended the reimbursement of anti-HBV treatment to 36 months since November 1, 2009. Therefore, growing patients face to discontinue anti-HBV therapy from now on. Nevertheless, even after a consolidation therapy, virological relapse still occurred in 42-90% of HBeAg-positive patients and in 47% HBeAg-negative patients. At present, the frequency, clinical outcome and predictive markers of HBV relapse after discontinuation of potent anti-HBV agents (ie. entecavir, telbivudine and tenofovir) are still unclear. The possible mechanism of virological relapse after prolonged viral suppression was also uncertain. From previous studies, pre-treatment and end-of-treatment virological factors (eg. HBV DNA, quantitative serum HBsAg, HBV genotype), host factors (age) and treatment-related factors (duration of consolidation therapy) are potential factors to predict virological relapse. After discontinuation of treatment, the resurge of HBV would break the balance between virus and host and T cells play a major role. Therefore, we believe host factors regarding immunity are important to the virological relapse. The aim of this study is to investigate the viral and host factors associated with virological/clinical relapse after discontinuation of anti-HBV therapy. We plan to establish a cohort of 300 CHB patients to discontinue entecavir, telbivudine or tenofovir and follow their post-treatment clinical outcomes in 3 years. By using this prospective cohort, we would like to collect their serum and peripheral blood mononuclear cells at various time points and investigate the viral, host and therapy-related factors associated with virological relapse. In addition to the quantitative HBsAg, we would like to include several novel predictive biomarkers (ie. total anti-HBc, HBeAg titer and pre core/basal core promoter mutation quantification) for virological/clinical relapse. In addition, we would like to collect the genomic DNA of patients for certain single nucleotide polymorphism (especially the HLA DP and DR regions) and the serum IP-10 protein concentration for comparison between the relapsers with the sustained responders. We would also like to test the T cell functional change at end-of-treatment and relapse and to investigate the programmed cell death protein-1, a negative regulator of T cell function. This study is clinically important because we can identify high risk patients of hepatitis relapse after discontinuation of anti-HBV therapy. This study is also biologically important because by the investigation of virological relapse, it is a good chance to investigate the immunopathogenesis of hepatitis B and host-viral interactions. By doing so, we are able to prevent fulminant of fatal hepatitis flare after anti-HBV therapy discontinuation.entecavirtelbivudinetenofovirviral loadhepatitis B surface antigenhepatitis B core antibodyhepatitis B e antigenpyrosequencinghuman leukocyte antigenT cellprogrammed death-1single nucleotide polymorphismIP-10 protein