摘要:慢性肝炎危害國民健康眾所皆知。過去研究已知我國肝炎之主要致病原為B型肝炎病毒,其長期感染後,會產生如肝硬化和肝細胞癌等後遺症,目前仍是國人健康的大敵。而其最重要的感染途徑乃由母親傳給新生兒之周產期傳染,故我國政府自民國73年起展開全面性的B型肝炎疫苗預防接種,至今已屆滿30年且有相當理想的效果。然而仍約有6%因故未能接種疫苗或10% e抗原陽性或是高病毒量孕婦之新生兒,因疫苗/免疫球蛋白接種無效而可能變為慢性帶原者,再加上原有約300萬的成人B型肝炎帶原者,故往後三十年間,慢性B型肝炎病毒感染之後遺症如肝硬化和肝細胞癌仍舊是國人健康的大敵。此外, 特殊族群病毒性肝炎之流行病學近年來也有所改變,因此本3年計畫主題為”特殊族群病毒性肝炎之流行病學、孕婦B型肝炎S抗原濃度檢驗應用與孕婦抗病藥物治療之母嬰安全性評估” 。子計畫1著重於孕婦抗病毒藥物治療之母嬰安全性評估, 研究目的在於追蹤孕婦於懷孕期間短期服用TDF,對母親及子女所造成的長期影響,包括其子女的骨骼生長發育、B型肝炎抗體的濃度以及發生水平傳染的機率;母親B肝病程的發展,包括肝功能及e抗原的變化、是否接受抗病毒藥物治療或是下一胎懷孕狀況等,此外我們也將持續收案高病毒量B肝孕婦服用TDF,並增添開始投藥以及停藥的時機之彈性,以提高個案參與意願。第一部份將收案80-100對曾經參與過孕期投以 TDF治療或控制組的母子進行追蹤,追蹤期間為產後2-5年(小孩2-5歲),檢測母親肝功能、B肝標記、病毒量;子女的部份將會進行抽血,檢測B肝標記、骨質代謝標記,視情況允許安排骨密度檢查 (DEXA),並記錄身高體重等成長發育狀況。我們將觀察服藥組及對照組母子之長期追蹤結果是否有差異,以了解孕婦於孕期使用TDF治療的安全性及影響;第二部份將收案40-60名B肝雙陽性並且病毒量大於106 IU/mL之孕婦,其中2/3人於懷孕26-30週起投以TDF 300mg治療,並於產後0-2週停藥,另外1/3相同狀況但不接受藥物治療為對照組,兩組母親及所生子女都將進行定期抽血追蹤,母親將追蹤肝、腎功能以及病毒量至產後一年,子女將追蹤確認有無感染以及肝功能至一歲,並確認有無產生保護性抗體。子計畫2著重於評估孕婦B型肝炎篩檢以B肝表面抗原定量分析,作為預測病毒量濃度與e抗原定性檢驗之可行性, 因應未來孕產婦B肝帶原率及e抗原陽性率的世代變化,擬以B肝表面抗原定量(HBsAg levels)來評估母親病毒量高低及e抗原陽性的可行性,並研究以母親B肝表面抗原定量預測子女B肝周產期感染及子宮內感染的有效性。其目的是想探討:母親生產時的血清B肝表面抗原定量(HBsAg)與e抗原陽性及病毒量之間的關係,以及可否作為預測其小孩得到B肝病毒感染的指標。研究方法以跨院合作方式,母親於產前(第三孕期)或生產當時抽血檢驗B型肝炎表面抗原濃度、病毒濃度;其子女於出生時、4-6個月大及12-18個月大時,抽血檢驗B肝表面抗原,了解是否受到B肝病毒感染。針對B肝帶原母親預計收案200組B肝帶原母親及嬰兒,第一年收集B肝表面抗原為陽性的母親100對母子;第二年收集B肝表面抗原為陽性的母親100對母子;第三年持續追蹤至母親產後及子女出生12-18個月大時之B肝血清學標記,並利用「B型肝炎病毒子宮內母子感染之危險因子探討」計劃中200對B肝帶原母親血清進行表面抗原濃度測定及各項實驗室檢驗報告,進行統計與分析。子計畫3著重於急性病毒性肝炎對於慢性B型肝炎患者的流行病學、臨床重要性及預後之探討, 第一部份之研究預計向臺大醫院安全衛生室及感控中心申請全院(包括台大醫院雲林、新竹及金山分院)醫師、護理人員、醫技人員及醫療廢棄物清理人員等同仁B型肝炎帶原資料,尖銳物品扎傷事件事件及急性B、C型肝炎感染的比率,藉此建立醫護人員B及C型肝炎的流行病學資料,以瞭解醫護人員實際暴露在病毒性肝炎的風險,及慢性B型肝炎感染且從事易接觸傳染的侵入性醫療處置的醫護人員的比率,以提供醫院安衛室進一步追蹤。另外也要探討針扎事件後感染急性B、C型肝炎的比率,及醫護人員在醫院中感染急性B及C型肝炎且在院內通報個案之發生率及危險因子。第二部分之研究將探討急性A型肝炎及急性E型肝炎對於慢性B型肝炎患者短期及長期的影響。在第一年的研究,我們將探討150位沒有肝硬化的慢性B型肝炎患者,發生過急性A型肝炎,急性D型肝炎,急性E型肝炎的比例; 在第二年的研究,我們將接著分析150位肝硬化的慢性B型肝炎患者,發生過急性A型肝炎,急性D型肝炎及急性E型肝炎的比例,對比於第一年的資料,我們可以了解急性A型肝炎及急性E型肝炎是否對慢性B型肝炎發生肝硬化有所影響。而在第三年的研究,我們將探討150 位慢性B型肝炎患者合併嚴重急性發作或是肝臟代償不全者,由急性A型肝炎,急性D型或是急性E型肝炎所造成的比例。藉由這項3年計畫,我們將了解急性A型肝炎, 急性D型肝炎及急性E型肝炎對對於慢性B型肝炎患者的影響。這些資料,也將幫助我們了解相關流行病學及臨床資訊,並進一步幫助我們預防急性A型肝炎, 急性D型肝炎及急性E型肝炎對於慢性B型肝炎患者的影響。
Abstract: Hepatitis B virus (HBV) infection is endemic in Taiwan. After the implementation of universal hepatitis B vaccination, there is significant reduction of HBsAg seropositivity and HBV-related hepatocellular carcinoma (HCC) incidence in children, teenagers and young adults. However, the incidence of HBV-related HCC in adults remains high. For example, since the implementation of universal vaccination in 1984, the chronic HBV carrier rate in our general population reduced from 10-20%, down to < 1% in the post-vaccination population. However, approximately 30-40% of chronic HBV infections cannot be prevented by vaccination. To further reduce the HBV infection in our population, treatment with antiviral agents in highly viremic mothers may decrease infants HBV infection rate, and is currently under investigation in many countries.The aims of subproject 1 are to follow-up the growth and bone development of the children of high risk pregnant women who have received TDF or control group during pregnancy, to monitor the rates of horizontal and occult HBV infection, and vaccine-induced antibody (anti-HBs) titers of children, and to follow-up the long-term outcome (disease flare, antiviral therapy, and subsequent pregnancy) of the high risk mothers after TDF treatment or control group. In addition, we will continue to conduct clinical trail of TDF therapy during pregnancy. We will provide flexible range of time to start and stop the TDF therary, and may reflect the real-life practice in the future. The current study will be conducted as two parts in 2015-2018. Part one, a total of 80-100 mother-infant pairs whose mothers have received TDF or control from 30 weeks of gestation to 4 weeks postpartum, are invited to join this followed-up study at 2- 5 years after delivery of the child. Maternal viral loads, HBV markers and ALT levels are tested during this study. HBV markers, bone markers and bone mineral density (DEXA), body weight, body length are tested in children. We will compare the differences between TDF and control group to see the long-term safety and effect of short-term TDF treatment in pregnant women upon mothers and children. In part two study, an estimated 40-60 pregnant women with high HBV viral load (>106 IU/mL), will be recruited in the study, including 20-30 subjects treated with TDF 300 mg daily starting from 26-30 weeks of gestation (2rd to 3rd trimester) and continued to 0-2 weeks after delivery, and 20-30 pregnant women are enrolled as controls with no drug given to the mother. Maternal viral loads and ALT levels are tested before TDF treatment, 1 month after treatment, at the time of delivery, and during 1,2,4,6 to 12 months after delivery. HBV DNA and HBsAg are tested in the children. The aims of subproject 2 are to collect maternal blood samples prior to or at delivery and will be tested for HBsAg levels, HBeAg and HBV DNA levels. Infants born to these HBsAg-positive mothers will be asked to test for HBsAg at 0, 4-6 months and at 12-18 months of age. We plan to enroll 100 mother-infant pairs in the first year, enroll another 100 mother-infant pairs in the second year, and follow-up the infants till 12-18 months of age and perform laboratory work in the third year. In addition, store serum samples of 200 mother-children pairs from previous studies will also be tested and analyzed.The aims of subproject 3 are (1) to collect the HBV infection profiles from the Occupational Safety & Health Office from all HCPs at the National Taiwan University Hospital (NTUH) and its branch at Yun-Lin, Hsin-Chu, and Jin-Shan. The events of needle-stick injury and acute hepatitis B and C infection reported by NTUH will be collected. We can subsequently establish the epidemiological data for the risk of HBV and HCV infection in HCPs of NTUH. We will also investigate the rate of HCPs who performs the exposure-prone invasive procedures. In addition, the rate of acute HBV or HCV infection after needle-stick or sharp injury will be investigated. Finally, the incidence and risk for HCPs to get acute HBV and HCV infection will be further evaluated. The aims of Part 2 study are to explore how acute HAV or acute HEV infection affects short-term and long-term outcomes of HBV carriers by using cross-sectional and longitudinal studies. (1) First year: we will determine the prevalence rate of HAV, HDV, HEV infection in 150 HBV carriers without cirrhosis; (2) Second year: we will enroll another 150 HBV-related cirrhosis patients and determine their HAV, HDV, HEV infection status. These data will be compared with 150 non-cirrhotic HBV patients to evaluate whether HAV, HDV or HEV superinfection affects the development of cirrhosis in HBV carriers; (3) Third year: we will explore whether the uperinfection of HAV, HDV, or HEV causes severe acute hepatitis or hepatic decompensation in 150 HBV carriers. With this 3-year project, we will understand more about whether the superinfection of HAV, HDV or HEV plays a role in affecting the short-term and long-term outcomes of HBV carriers. These data will surely provide meaningful epidemiological and clinical information to improve the prevention and management of HBV carriers with HAV, HDV or HEV superinfection in Taiwan.