摘要:一、B型肝炎預防接種計畫時施後幼兒仍帶原之原因及實務可行之解決方法探討依據過去研究顯示,目前之B型肝炎疫苗政策下,仍有約10%的HBsAg (+)/HBeAg(+)母親所生小孩成為慢性B型肝炎帶原; 另外HBsAg (+)/HBeAg(-)母親所生小孩,感染率雖低於1%,然而可能造成嬰兒急性及致死之猛暴性肝炎;在目前疫苗政策下,為了進一步減少B型肝炎感染率及疾病,針對此一特殊族群周產期感染之危險因子做詳細的了解,是未來預防及治療的重要參考資料。近年小型的前瞻性研究,已收集母子之血清做病毒分析,研究顯示,母子感染可能在嬰兒期發生嚴重度不等的肝炎,這些病例過去可能被忽視,而帶原母親中,哪些是造成疫苗失敗感染的更高危險群,也亟待釐清;對於懷孕母親,以及生育年齡之婦女之健康管理及照顧也是很重要的資訊。因此需要一個較大規模,長期前瞻性的研究來提供正確資訊,已期達到疾病之預防及治療的最大效益。本研究為三年之前瞻性研究,為本國多中心之合作計畫,預計收集600 對母子血清,包括台大醫院400 對母子,及合作醫院200對母子;為了解母親之病毒濃度以及母親在周產期時產生e抗原陰轉 (HBeAg seroconverion) 對出生嬰兒的影響,我們將抽取母親在周產期及產後4~6個月內血清,檢測HBeAg,anti-HBe,轉氨酵素,及病毒量;嬰兒在出生後3天內,4~6個月分別抽血,測定轉氨酵素及HBsAg,anti-HBs titer,及anti-HBc; 同時為探討宿主因素是否影響感染率,我們亦將抽取母子血液DNA,分析可能之宿主基因變異和母子感染之關係。我們將利用即時定量PCR的方法測定母親懷孕期間的病毒量,並比較嬰兒感染者與未感染者之母親病毒量之差異;若嬰兒受到感染,則將測定嬰兒與母親的病毒量、基因型、以及母子的表面抗原”a determinant”突變;嬰兒若有肝功能上升,則需每1~3個月追蹤其肝功能及B型肝炎表面抗原及e抗原狀態。以上之資料以統計分析,找出母子傳染之高危險群。第二部份將以回溯性方式分析過去造成母子傳染而引起嬰兒急性或猛暴性肝炎之嬰兒病例共40名,分析其臨床因子及預後,以及分析已留存之母子配對血清15對,測定其病毒量,基因型及危險因子,以釐清嬰兒感染B型肝炎並早期發病之最高危險族群之發病因子,進一步探討控制感染之對策。本計畫第三部分將統計全國性急性及猛暴性肝炎及嬰兒肝炎死亡率之統計調查,利用衛生署之資料庫,比較全國1994,1999,2004,及2009之死亡統計,有關一歲以下急性B型肝炎個案數,以及因肝炎而死亡之嬰兒死亡率,以了解我國嬰兒肝炎所造成之影響長期影響及趨勢。本計畫之成果,以長期前瞻性的研究,以及過去所收集珍貴病例之血清資料,經由病毒學及統計學分析提供正確資訊,將可提出達到實務可行之預防方法建議。二、孕婦於懷孕期間採取降低母體血液HBV等預防措施對於降低垂直感染風險之效果與可行性評估研究我國自1984年開始實施全國新生兒B型肝炎疫苗接種計畫,使B型肝炎帶原率由15-20%, 降至<1%。然而接種疫苗後仍感染B型肝炎,甚或發生肝癌,猛暴性肝炎之病例仍有所見,近年我們探討疫苗接種後兒童發生B型肝炎感染,絕大多數為B型肝炎帶原母親之子女;尤其母親為e抗原陽性個案,其子女帶原率近10%,相當於每年全國仍有400名新增B肝帶原人口,為了進一步降低B型肝炎帶原率,針對高危險群做B肝防治乃必要之措施。過去之研究施打疫苗後仍發生B型肝炎感染之原因,包括子宮內感染,母親高病毒量,宿主HLA typing,病毒突變株等因素,針對降低母親病毒量曾有小規模研究,發現使用孕婦產前使用lamivudine(category C)可降低子女帶原率; 然而在孕婦使用抗病毒藥物,對於母胎之安全性,降低感染率之效益仍不明確,近年新抗病毒藥物陸續發展,選用對母親及胎兒安全有效,能達到降低母子感染率之藥物,是將來確實可行之降低B肝感染方法。本研究目的,在評估孕產婦對於藥物治療之接受度; 發展高危險群母親之快速篩檢方法; 並進行臨床試驗,利用抗病毒藥物telbivudine (category B)來降低母親病毒量,評估降低母子傳染率之效果,並追蹤B肝帶原母親在孕期及產後之B型肝炎狀況。 本研究為三年之前瞻性,本國多中心研究,包括生產年齡及孕婦之B肝帶原者問卷調查,孕產婦及生育年齡女性對於以藥物降低母子傳染之接受度,以及利用HBsAg及HBeAg效價預測母親病毒量; 進一步,我們將在懷孕20-26周篩檢800名B型肝炎帶原孕婦,年齡20-50歲,其中HBeAg 陽性,並同意參與本研究只,進行病毒量分析,預估約100 名孕婦病毒量大於>105 copies/mL者,其中60名自懷孕28-31周(第三孕期) 起投與每日telbivudine 600mg治療,至生產完一個月止; 另有40名孕婦不接受藥物治療為對照組;所生之子女均接受例行之HBIG及三劑B型肝炎疫苗;我們將分別在使用藥物(1個月後),生產時,及產後3-6個月追蹤母親之肝功能及病毒量;以監測母親B型肝炎病毒量及肝炎之發生狀況;所生之子女將在產後0,3-6 及12個月抽血檢驗HBsAg及 anti-HBs以確定是否受到感染,以及是否產生具保護性抗體。臨床上母子之任何不良反應,以及出生嬰兒之先天異常,疾病等狀況亦將追蹤記錄。 本研究之結果將對防治高危險群母親之B型肝炎嬰兒提供確實可行之方法,並評估此方法擴大實施之可能性;對於我國根除B型肝炎之目標,為重要之指標研究。三、慢性B肝患者感染危險因子和自然病程進展病毒及宿主因子之研究慢性肝炎危害國民健康眾所皆知。台灣之慢性肝炎主要經由肝炎病毒感染所造成。過去研究已知我國病毒性肝炎之主要致病原為B型肝炎病毒,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或2歲前嬰幼兒之水平傳染,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25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。從過去對自然病史之研究得知,在台灣,大部分的慢性B型肝炎感染的患者,都是在2歲之前得到感染。其自然病史的分期,可以依據病毒和宿主之間的交互作用,分為三期。第一期是免疫耐受期:大部分的孩童及年輕人皆屬於這個時期,其臨床表現為血清中e抗原呈陽性且病毒量高,但ALT數值卻是正常或是輕微的上升,肝臟中病毒大量的複製,但宿主對B型肝炎病毒的免疫反應,卻相當有限。到了20至40歲間,會進入第二個時期,稱之為免疫廓清期:之前沒有症狀的帶原者,會開始有一些急性發作的症狀,同時血清中的ALT也會反覆的上升,在肝臟中,肝細胞會因為宿主免疫反應而遭破壞,在經過一段時期肝臟反覆的發炎之後,病人的e抗原會被清除,e抗體會出現,吾人稱之為e抗原的血清轉換,同時病人血清中的病毒量也會隨之下降。之後的病人會進入第三個時期,稱之為低複製期(low replication)或不活動帶原狀態(inactive carrier state),在這個時期,血清中的病毒量通常較低,ALT數值正常,在肝臟中,病毒的複製會被抑制,同時肝臟細胞也不再遭到破壞。由於病毒的複製僅被抑制,但未被清除,故病人血清中的表面抗原仍為陽性。這群病人在長期追蹤後,每年有1-2%的會發生表面抗原血清轉換。然而有20-30%的不活動帶原者,會以每年2.2-3.3%的機會,產生B型肝炎病毒的再活化,也就是進入再活化期(reactivation phase)或是e抗原陰性慢性B型肝炎:這些病人的臨床表徵包括血清中病毒量上升、ALT數值上升,以及肝臟細胞再次受到免疫系統的破壞。目前已知e抗原陽性和陰性之慢性B肝患者,有較高機會發展成肝硬化和肝癌,因此需要監測病情進展或給予抗病毒藥物治療。除早期感染外,青少年階段以後藉由血液和體液交換之水平傳染亦扮演某些角色,亟需加以釐清並研擬相關防治策略作阻斷,使B型肝炎的消除成為可能。本計畫擬於三年內,延續吾人過去之研究,探究慢性B型肝炎患者之自然病史,以及產生肝硬化或肝癌之致病機轉之探討。主要探討的族群,可分為e抗原陽性,e抗原陰性,肝硬化,潛伏性B型肝炎感染(occult HBV infection),以及合併B型及C型肝炎感染之患者。藉由大規模之問卷調查和長期追蹤,完成以下的研究:(1)B肝帶原者可能感染途徑之調查;(2)e抗原陽性患者發生肝硬化及肝癌之病毒及宿主危險因子;(3) e抗原陽性患者產生e抗原血清轉換之病毒學和宿主機轉; (4) e抗原陽性患者產生e抗原血清轉換後,發生肝炎急性發作,肝硬化及肝癌之發生率以及病毒和宿主危險因子;(5) e抗原陰性患者,發生表面抗原消失,或是肝炎急性發作,肝硬化及肝癌之發生率以及病毒和宿主危險因子;(6) B型肝炎肝硬化患者,發生肝衰竭及肝癌之病毒和宿主危險因子;(7) B肝疫苗接種者,隱性B型肝炎之盛行率及長期預後探討(8) 慢性B型及C型肝炎合併感染患者之長期預後以及病毒和宿主危險因子。藉由這些大規模族群的長期追蹤,吾人希望達成下列目的:(1)瞭解除垂直傳染外,其他水平傳染途徑之比例;(2)瞭解慢性B型肝炎患者,於各個時期的臨床表現及預後;(3)探討慢性B型肝炎患者,在各個時期追蹤後,產生不良預後之病毒和宿主危險因子;(4) 探討慢性B型肝炎患者進展至不同時期的致病機轉;(5) 探討慢性B型及C型肝炎合併感染患者產生不良預後之病毒和宿主危險因子。四、健保給付慢性B型肝炎治療藥物之療效和效益評估慢性肝炎危害國民健康眾所皆知。台灣之慢性肝炎主要經由肝炎病毒感染所造成。過去研究已知我國病毒性肝炎之主要致病原為B型肝炎病毒,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25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。慢性B型肝炎的治療,在最近的10年內,進展相當迅速。對於e抗原陽性的患者,吾人希望藉由治療,達到e抗原血清轉換,以長期降低病毒的複製;對於e抗原陰性的患者,吾人希望藉由治療達到長期病毒消失;同時藉由治療,達成減少肝硬化、肝癌及死亡的最終目標。目前在台灣,除了有屬於免疫調節劑的短效型及長效型兩種干擾素之外,有另外4種核苷酸相似物(nucleos(t)ide analog),用來抑制病毒複製的的口服抗病毒藥物,包括干安能(lamivudine),干適能(adefovir dipivoxil),貝樂克(entecavir)以及喜必福(telbivudine)的上市。而我國健保體系,也自民國92年10月1日起,陸續將以上的藥物,納入健保給付的範疇。本計畫擬探究慢性B型肝炎患者,接受各式抗病毒藥物治療,其短期及長期追蹤的效果和效益評估。我們將聯合台灣北,中,南區等醫院,包括台大醫院,國泰醫院,臺北市立聯合醫院仁愛院區,亞東醫院,慈濟醫院台北分院,台中榮民總醫院,以及高雄醫學大學附設醫院一起共同合作。主要探討以下幾個主題: (1) e抗原陽性患者接受長效型干擾素治療,產生e抗原血清轉換以及表面抗原消失之發生率以及病毒和宿主因子的影響; (2) e抗原陽性患者接受貝樂克治療,產生e抗原血清轉換之病毒和宿主因子的探討;(3) e抗原陽性患者接受喜必福治療,產生e抗原血清轉換之病毒和宿主因子的探討; (4) e抗原陰性患者接受長效型干擾素治療,產生表面抗原消失之病毒和宿主因子。(5) 長效型干擾素、貝樂克及喜必福治療的成本效益分析。藉由長期追蹤的這群接受治療的慢性B型肝炎患者,我們希望達成下列目的:(1)瞭解慢性B型肝炎患者,接受各式治療的療效;(2) 探討慢性B型肝炎e抗原陽性的患者,接受各式治療後產生e抗原血清轉換之病毒和宿主因子的影響;(3) 探討慢性B型肝炎的患者,接受治療停藥後,長期追蹤的預後;(4) 瞭解各種治療的成本效益。唯有藉由以上的研究,才能有效且全面的評估現階段治療B型肝炎的政策,已作為日後調整治療政策的參考。
Abstract: 一、Breakthrough hepatitis B virus infection in infants born to carrier mother: the risk factor, early prognosis, and strategies to interrupt mother-to-infant transmissionPrevious studies have shown that under our universal vaccination program for hepatitis B virus (HBV) infection, about 10% of children born to HBsAg (+)/HBeAg(+) mopthers still became HBsAg positive carrier; on the other hand, children born to HBsAg (+)/HBeAg(-) mothers had much lower rate of infection below 1%. However, cases of acute and fulminant hepatitis may occur in infants born to HBsAg (+)/HBeAg(-) mothers. The efficacy of current vaccination program has reached its limitation. To further reduce the mother-to-infant transmission of HBV, careful investigation of this high risk group is mandatory.Our recent prilimiary study has collected mother-infant paired serum for HBV viral marker analysis, and found tht high viral load is most likely the cause to breakthrough infection of infant received vaccination. For those infants infected, asymptomatic hepatitis occurred during the first year of life, which could be overlooked without prospective study. Little is known about the natural course and risk of development more severe hepatitis, and long-term outcome in these children with breakthrough infection. For pregnant women and women of child-bearing age, the strategy for treating chronic HBV infection, and the treatment for interrupting mother-to-infant infections are lacking. A prospective, larger scale study for more accurately identifying high risk mothers for mother-to-infant HBV infections are very important to develop further strategies in interrupting all mother-to-infant infecionts. The present study is a multi-centered, three-year prospective study. A total of 600 mother-infant pairs will be recruited, including 400 pairs in National Taiwan University Hospital, and 200 pairs from 3-5 collaborating hospitals. To investigate the impact of maternal viral load and HBeAg seroconversion during perinatal periods in mothers, we will test the maternal blood at perinatal period and 4-6 months after delivery for HBeAg, anti-HBe, transaminase levels, and viral load. The infant will be tested within 3 day and 4-6 months after delivery for HBsA, anti-HBs titer, and anti-HBc. For infants with breakthrough infection, viral load, genotype, a determinant in surface antigen of the infants and their mothers will be tested. Infected children will be followed every 1-3 months for liver function and close moniter occurrence of clinical hepatitis. The risk factors for mother-to-infant infection will be analyzed after data collecting.Because the cases of infantile acute/fulminant hepatitis in prospective study may be small. We will futhre analyzed the clinical data and paired mother-infant sera retrospectively, of our patients with acute/fulminant hepatitis B in the past 20 years. Because these infants had the worst outcome after HBV infection including mortality, we will elucidate the highest risk groups from this part of study.The third part will be epidemiology data from National Mortality Registry, and data from the Department of Health, comparing the incidence and cases of acute hepatitis B in infancy, and infantile mortality due to hepatitis in year 1994, 1999, 2004, and 2009, to elucidate the long-term impact of universal vaccination and trend of changing epidemiology in HBV related disease in Taiwan.The present project will provide important data from prospective and retrospective studies, and provide extensive and detailed clinical and virological data about high-risk group mother-to-infant transmission of HBV. The results will provide solid base for our further strategies in further reducing HBV infection rate in our population.二、The effectiveness and feasibility of using antiviral therapy in pregnant women to reduce mother-to-infant transmission of hepatitis B virusSince the implementation of universal vaccination in 1984,the chronic HBV carrier rate in our general population reduced from 15-20%,down to < 1% in the post-vaccination population。However, even receiving full vaccine protection,cases of chronic HBV carrier,even hepatocelular carcinoma and fulminant hepatitis still exist。In recent years we have studied the children born to HBV carrier mothers,and found that HBV infection often occurred in children born to HBeAg positive mothers。In this population the HBsAg carrier rate is as high as 10%。Annually there are 400 new cases of chronic HBV carrier in Taiwan。To further reduce the HBV infection in our people,strategies in reducing infection rate in this high risk group are mandatory。Previous studies have suggested many causes of vaccine failure,including intrauterine infection, high maternal viral load,host HLA typing,mutations of surface antigen,etc.。Small scale studies using lamivudine treatment in pregnant woman in the third trimester has proved effective in reducing children infection rate。However,larger scale studies on the efficacy and safety to mother and fetus is lacking。 Recently there are emerging new antiviral drugs; these drugs are promising to be used in preganant woman。 he aims of the present study are to evalute the acceptance of pregnant women in receiving antiviral drugs in Taiwan; to develop a rapid method for screening high-viral load mother; and to conduct a clinical trial in using telbivudine (category B) to reduce mother-to-infant transmission,and to monitor the hepaitits B viral status and mother hepatitis occurrence。This is a three-year study。Firstly we will assess the acceptability of pregnant women and child-bearing age women with positive HBsAg by questionnaire。We will also test 100 HBsAg carrier mothers,and correlated their HBsAg and HBeAg titers with HBV viral load for further application in large population。The clinical trials will screen 800 cases of HBsAg positive pregnant women aged 20 to 50 years at gestational at 20-26 weeks。They will be tested for HBsAg and HBeAg。 In whom both markers are positive,HBV viral load will be tested。An estimated 100 pregnant women with high HBV viral load (>105 copies/mL),will be recruited in the study; including 60 subjects treated with telbivudine 600 mg daily starting from 28-31 weeks of gestation (3rd trimester) and continued to 1 month after delivery;and 40 pregnant women are enrolled as controls with no drug given to the mother。The newborn babies are given with HBIG within 24 hours after delivery,and HBV vaccines at 0,1,and 6 months。 Maternal viral loads and ALT levels are tested before telbivudine treatment,1 month after treatment,at the time of delivery,and between 3-6 months after delivery。HBV DNA and HBsAg are tested in the children at day 1,3-6 moths,and 1 year after birth。The primary outcome is reduction of the HBsAg carrier rate of the children。The secondary outcome is the liver function and HBeAg reduction in pregnant mother。Any adverse reactions in the mother,fetus,or infants;the occurrence of any congenital anomalies,and newborn diseases will be recorded。 The results of the present study will provide potentially applicable methods for reducing HBV carrier rate,to develop a rapid method for screening high-risk mothers that can be applied in large scale practice。The results will be important in the effort toward eradication of HBV infection in our country。 三、Studies on the transmission routes and the impact of viral and host factors on disease progression in hepatitis B carriersHepatitis B virus (HBV) infection is a global health problem, especially in the endemic area like Taiwan. The clinical manifestations of HBV infection include acute/fulminant hepatitis or various forms of chronic infection. Chronic HBV infection may lead to inactive carrier state, chronic hepatitis, cirrhosis or hepatocellular carcinoma (HCC). In Taiwan, the most important transmission route of HBV infection is perinatal transmission, which has been effectively blocked by universal hepatitis B vaccination with or without hepatitis B immune globulin (HBIG) since 1984. However, there are still newly-developed HBV carriers, including 6% unvaccinated population and 10% neonates born to hepatitis B e antigen (HBeAg)-positive or high viremic carrier mothers with vaccination/HBIG failure. Together with the already existing 3 million adult chronic hepatitis B patients in Taiwan, HBV-related liver cirrhosis and HCC is still an important health issue in the next 30 years. In Taiwan, HBV infection occurs predominantly during the perinatal period or early childhood. The natural course of chronic HBV infection acquired early in life can be divided into three phases. The first is immune tolerance phase, which is characterized by active replication of HBV, positivity for HBeAg, and normal-to-low levels of alanine aminotransferase (ALT) levels. The second is immune clearance phase when HBeAg-positive patients have raised ALT levels. In the third phase, HBeAg seroconverts to its antibody (anti-HBe). Most patients are the inactive carriers and experience prolonged low ALT and viral replication whereas 20-30% of them have HBV reactivation and designated HBeAg-negative chronic hepatitis B, presenting with fluctuating ALT and high viral replication. From prior studies, the annual reactivation of HBeAg-negative chronic hepatitis has been reported to be 2.2%-3.3%. The persistent liver inflammation, either caused by prolonged immune clearance phase or HBeAg-negative chronic hepatitis, has been documented to be closely associated with the development of cirrhosis and HCC. Therefore, these at-risk patients need close monitoring of clinical course and prompt anti-viral therapy if indicated. In addition to infection in early life, horizontal transmission of HBV in teenagers and young adults may play some role in existing HBV carriers and thus needs to be investigated. These data will provide preventive strategies to further reduce the risk of HBV infection. In this 3-year proposal, we aim to extend our previous observations and investigate natural history of chronic hepatitis B and virus as well as host-related mechanisms of cirrhosis and HCC development in HBV carriers. The populations to be investigated include HBeAg-positive, HBeAg-negative, cirrhosis, occult HBV infection and chronic hepatitis B and C dual infection. With the aid of large-scale and long-term follow-up populations, we anticipate to accomplish the following studies:(1) Surveillance of possible HBV transmission routes in HBV carriers; (2) host and viral factors of cirrhosis and HCC development in HBeAg-positive patients;(3) mechanisms of HBeAg seroconversion; (4) the probability and host/viral factors of hepatitis flare, cirrhosis and HCC development in HBeAg seroconverters;(5) the probability and host/viral factors of HBsAg seroclearance, hepatitis flare, cirrhosis and HCC development in HBeAg-negative HBV carriers;(6) host and viral factors of hepatic decompensation development in HBV-related cirrhosis patients;(7) prevalence of occult HBV infection in vaccinated population and their long-term outcomes; (8) prognosis and host/viral risk factors of chronic hepatitis B and C dually infected patients. With long-term follow-up of the large-scale cohort, we wish to: (1) understand the proportion of horizontal transmission routes in Taiwanese HBV carriers; (2) understand the clinical course of chronic hepatitis B patients in different disease stages; (3) investigate the viral/host risk factors of adverse outcome in chronic hepatitis B patients with different disease stages; (4) investigate the mechanisms of disease progression in chronic hepatitis B patients; (5) investigate the host/viral risk factors of adverse outcome in chronic hepatitis B and C dually infected patients.四、Efficacy and Cost-Effectiveness Analyses of BNHI-reimbursed anti-HBV Treatments Chronic viral hepatitis is well known to have a great health impact in Taiwan, and hepatitis B virus (HBV) infection is the major cause of liver disease worldwide. Perinatal transmission of HBV from carrier mothers to infants plays an important role in spreading the virus. Taiwan has launched a universal hepatitis B vaccination program to interrupt prenatal HBV transmission since 1984 with a great success in these 25 years. However, 6% of newborn still fail to complete vaccination and 10% of newborn born to HBeAg-positive mothers with high viral load become persistent HBV infection due to HBIG or vaccination failure. These newborn HBV carriers along with the existing 3 million adult carriers still at risk of developing HBV-related complications, such as cirrhosis and hepatocellular carcinoma in the coming 30 years.The treatment of chronic hepatitis B is revolutionized in recent 10 years. For HBeAg-positive patients, the treatment endpoint is to achieve a durable HBe seroconversion with undetectable serum HBV DNA. For HBeAg-negative patients, the endpoint is to permanently suppress viral replication. In addition, the ultimate goal of HBV therapy is to improve the health outcomes, such as reduction or prevention of cirrhosis, hepatocellular carcinoma and liver-related mortality. In Taiwan, two immunomodulators-conventional and pegylated inferferon, and four nucleos(t)ide analogues including lamivudine, adefovir dipivoxil, entecavir and telbivudine are approved for the treatment of chronic hepatitis B. The Bureau of National Health Insurance (BNHI) launched the reimbursement program to include these medications since October, 2003. To investigate the short-term and long-term therapeutic effects and cost-effectiveness of anti-HBV treatments, we will collaborate with several hospitals, including National Taiwan University Hospital, Cathy General Hospital, Ren-Ai branch of Taipei City Hospital, Far Eastern Memorial Hospital, Taipei branch of Buddhist Tzu Chi General Hospital, Taichung Veterans General Hospital, and Kaohsiung Medical University Chung-Ho Memorial Hospital. By using a long-term follow-up of chronic hepatitis B patients treated with different agents, we will study (1) The viral and host factors associated with HBeAg and HBsAg seroconversion of HBeAg-positive chronic hepatitis B patients with pegylated interferon, entecavir and telbivudine; (2) The viral and host factors associated with HBsAg seroconversion of HBeAg-negative chronic hepatitis B patients with pegylated interferon; (3) The cost effectiveness of pegylated interferon, entecavir and telbivudine therapy. With these data, we will understand more about individual therapeutic outcomes of various anti-HBV agents; the viral and host factors contributing to treatment-induced HBe seroconversion; the long-term outcomes following effective treatment and the cost effectiveness of different treatment regimens. Afterwards, we can evaluate current BNHI practice guidelines for the treatment of chronic hepatitis B and make further recommendations.