摘要:在B型肝炎病毒(HBV)好發地區,慢性感染主要始於嬰幼兒期。 HBV慢性感染者血中B肝表面抗原(HBsAg)消失,被認為具清除病毒之趨勢。雖然表面抗原消失在成人帶原者通常反映狀況良好(除了肝硬化者),但在兒童之意義、機轉和影響因子仍有待釐清。HBV DNA測不到之低量病毒帶原者,HBsAg定量比HBV DNA定量更能反應其感染狀況。本三年研究計畫目標為探討影響自發性HBsAg清除之因子:(1)415名自兒童期開始接受長期追蹤之慢性 HBV感染者自發性HBsAg血清清除狀況;(2)其HBsAg陰轉前,HBsAg濃度及最初HBV DNA量之系列性變化;(3)在HBsAg清除前HBV之S基因序列之變化;(4)宿主基因對HBsAg清除的影響,尤其細胞激素IL 2, IL4, IL10, IL12, IL27, TNF-α及IFN-γ之單一核苷酸多型性(SNP)。計畫第一年,將研究自發性HBsAg清除年齡及年清除率。比較HBsAg已清除者和未清除者之性別、長期追蹤ALT最高值、感染途徑、HBV基因型,最初HBV DNA量, HBV之S表面基因突變狀況與HBV疫苗史等。第二年,持續追蹤病人並探討其在HBsAg清除前系列血清HBsAg濃度,與其臨床資料作相關分析探討其影響因子。並採宿主周邊血球DNA供細胞激素SNP分析。第三年,持續追蹤病人,並將繼續收集HBsAg已清除者及未清除之帶原者,以及另100名非帶原者但感染過B型肝炎者之DNA檢體,分析其IL-2, IL-4, IL-10, IL-12, IL-27,TNF-α和 IFN-γ之SNP。分析SNP所得「與HBsAg血清清除相關之細胞激素」,並測量其血清濃度。
Abstract: Chronic hepatitis B virus (HBV) infection is a world wide health problem. In endemic areas of HBVinfection, chronic infection begins mainly in infancy or early childhood. Once chronic HBV infection is established, it is not easy to recover spontaneously. Loss of serum hepatitis B surface antigen (HBsAg) is generally considered as having the possibility or trend of HBV eradication. Spontaneous HBsAg seroclearance/ seroconversion during chronic HBV infection seems an uncommon event. Although its occurrence generally reflecting a favorable event in adults with some exception in those with liver cirrhosis, the significance, mechanism, and affecting factors in children and adolescents remain to be elucidated.The specific aim of this three year project is to investigate factors affecting the spontaneous HBsAg clearance/seroconversion during chronic HBV infeciton since childhood by (1) analyzing the rates of spontaneous HBsAg seroclearance/seroconversion in the natural course of chronic HBV infection during long term follow-up since childhood ; (2) studying the serial changes of HBsAg titer before HBsAg seroclearance and initial HBV DNA levels during long term follow-up since childhood; (3)analyzing the serial changes of HBV surface gene sequences before clearance of HBsAg during long term follow-up in those with HBsAg seroclearance, and correlate with the vaccination status ; (4) analyzing host genetic factors favoring HBsAg seroconversion (by conducting single nucleotide polymorphism analysis of cytoines IL 2, IL4, IL10, IL12, IL27, TNF-α, and IFN-γ) on HBsAg clearance.Totally 415 children with chronic HBV infection who were enrolled at < age 15 will be followed up for liver function profiles and HBV markers every 6 months. During the 1st year of the project, the annual rates of spontaneous HBsAg clearance / HBsAg seroconversion will be obtained. The age at HBsAg serconversion, gender, peak ALT levels, transmission route, initial HBV DNA levels, HBV genotypes will be compared between those who clear HBsAg versus those who remain persistently HBsAg seropositive. Serial HBV surface gene mutation status will be analyzed and correlated with the HBV vaccination status.During the 2nd year of the project, serial quantitation of HBsAg titers before HBsAg seroclearnce will be determined, and correlated with clinical data, and compare with that among those without HBsAg clearance. The host DNA extracted from PBMC from of 17 patients who clear serum HBsAg and 170 patients without HBsAg seroclearance and 50 control non-carrier subjects who recovered from HBV in fection and with positive anti-HBs will be performed and subjected for the analysis of single nucleotide polymorphism (SNP) analysis for cytokine genes.During the 3rd year of the project, the host host DNA extracted from the PBMC from 18 patients with HBsAg seroclearance, 180 patients without HBsAg seroclearance, and 100 control non-carrier subjects who recovered from HBV infection and with positive anti-HBs will be subjected for the assay of SNP for IL-2, IL-4, IL-10, IL-12, IL-27, TNF-α,and IFN-γ genes. Host serum levels of the selected candidate cytokines will be measured and correlated with the results of SNP analysis and clinical course.