摘要:在大多數國家,有慢性病毒的肝炎的病患通常只有單一C 型肝炎病毒(HCV)或者B型肝炎病毒(HBV)感染。但是在HBV 或HCV 感染盛行國家例如台灣,雙重HBV 和HCV 感染病患不在少數。而且,有雙重HBV 和HCV 感染病患比單一C 型病毒(HCV)或者B型肝炎病毒(HBV)感染病患有更嚴重的肝疾病和肝細胞癌(HCC)發生的危險,因此應該被更積極治療。台灣一向是全球肝病療法的指標,對於各種肝炎之治療皆有相當成效,唯獨罹患慢性B、C 型肝炎雙重感染者一直令醫界束手無策。有感於全球有百萬慢性B、C 型肝炎雙重感染病患亟待治療,我們在長達兩年的台灣多中心臨床試驗中,使用長效型干擾素(peginterferon alfa-2a, 珮格西施PEGASYS®)合併雷巴威林(ribavirin)療法,針對三百餘名患者進行治療追蹤。本研究共收案321 人,其中有161 位慢性B、C 型肝炎雙重感染與160 位單純慢性C型肝炎感染的病患接受治療,目前皆已完成治療及追蹤24 週以上。結果發現超過75%患者可以達到C 型肝炎持續性病毒學反應的治療目標。我們的結果證實針對慢性B、C型肝炎雙重感染者,長效干擾素合併使用雷巴威林(ribavirin),是有效的根治C 型肝炎病毒的治療方法。此外,使我們驚奇的是其中10%雙重HBV 和HCV 感染患者經治療後血清HBsAg 轉變成陰性,這是一般慢性HBV 患者經抗病毒治療後的最終、最理想治療標的。相對地,自然病程或者治療後引起的HBsAg 消失比率,在慢性HBV 單一感染病患裡每年只有大約0-3%。例如,長庚朱嘉明教授最近報告HBsAg 轉變成陰性的累積發生率在10 年追蹤期為8.1%。目前被推薦用於治療慢性B 型肝炎的藥物中,經一年核苷酸類似物(如lamivudine, adefovir dipivoxil, or entecavir)治療後HBsAg 消失比率<1%,經一年長效型干擾素治療後HBsAg 消失比率在亞洲患者也是<1%。因此驗証雙重B 型和C 型肝炎患者經治療後會出現10%HBsAg 消失比率是相當好的成效,也值得進一步探討HBsAg消失的相關機制。以前的報告指明HBsAg 消失與收錄患者時的年齡、肝炎的嚴重度、男性、和肝硬變的存在等因素有相關。病毒因子,例如HBV 基因型B 或者有急性HCV 重覆感染,也已經被證實與HBsAg 的消失有關。不過,幾個關鍵的問題仍有待釐清。病毒性肝炎事實上是宿主和病毒交互作用的結果,而決定療效的因素,有一大部分是由於被感染者本身體質(宿主基因體特性)以及個體內病毒的基因體特性所致。因此除了病毒因子以外,決定內科療法成效的宿主因子也相當重要。但是宿主的基因體非常龐大,如何找到關鍵基因為極具挑戰性的問題。本計劃擬由藥物基因體學的觀點切入,利用此一治療族群,尋找宿主關鍵基因、基因多型性以及肝臟基因表現對於治療反應的影響。為了釐清這些問題,我們假設宿主因子能夠在雙重感染C 型和B 型肝炎的病患身上影響HBsAg 的消失。利用此一治療族群,我們希望在基因變異以及基因表現的各個層級探討(1)是否宿主基因多型性影響HBsAg 的消失,(2)是否宿主肝臟基因表現形態影響HBsAg 的消失,(3)是否宿主附基因修飾(epigenetic modifications)影響HBsAg 的消失,和(4)治療前後miR-122 動態變化以及此變化對HBsAg 消失方面的影響。關於慢性HBV 感染,HBsAg 消失是一個關鍵的事件,通常代表著肝炎活性降低和長期良好的預後。雖然如此,自然病程或者經治療引起的HBsAg 消失仍不常見。而且,HBsAg消失的機制基本上仍未知。我們意外發現大約10%雙重感染病患在治療之後失去HBsAg。如果我們能在這群病患裡釐清HBsAg 消失的機制,能為將來的治療提供研發方向,使病患減少罹患HBV 相關肝疾。這些結果預期將在了解、預測個別肝炎患者的自然病史,以及為每位患者量身訂製最合適的治療策略上有重大效益,並提昇本國肝炎研究之卓越。
Abstract: In most countries, patients with chronic viral hepatitis usually have single hepatitis Cvirus (HCV) or hepatitis B virus (HBV) infection. However, in areas where HBV infection isendemic such as Southeast Asia, Far East and southern Europe, subjects infected with bothhepatitis C and B are substantial. We have treated hepatitis C and B dually infected patients ina pilot study by using standard IFN in combination with ribavirin for 6 months. We found thata sustained HCV virologic clearance rate (SVR) in hepatitis C and B dually infected patientscould be achieved to an extent comparable to that in simple hepatitis C. After a follow-up of>2 years, HCV RNA remained undetectable in 89% of patients with sustained clearance ofserum HCV RNA 6 months post-treatment. To our surprise, 21% of them lost serum HBsAg,which is the ultimate endpoint of antiviral therapy for chronic HBV infection. A recentnationwide multicenter clinical trial in Taiwan using peg-interferon alfa plus ribavirindemonstrated that the HCV SVR can be further increased to be around 75%, and consistentlythe HBsAg clearance could be obtained in 10% of the treated patients. In contrast, thespontaneous or treatment-induced HBsAg clearance rate is only around 0-3% annually inpatients with chronic HBV infection alone. Thus it is interesting to clarify the mechanismsassociated with the clearance of HBsAg in this treatment cohort with dual hepatitis B and C.Previous observations suggest that the probability of HBsAg seroclearance correlatedpositively with age at entry, sustained remission of hepatitis, marginally significantly withmale gender, and the presence of liver cirrhosis. Viral factors such as HBV genotype B orsuperinfection with acute HCV infection have also been shown to correlate with the clearanceof HBsAg. However, several critical issues remain to be resolved in patients with dual chronichepatitis C and B. Chronic hepatitis B is an infectious disease, thus three mechanistic factorsmay account for the post-treatment loss of HBsAg in dually infected patients, including hostfactors, viral factors, or the interaction between both viruses. HBV and HCV may infect thesame hepatocyte, then HCV structure or functional proteins may directly influence thereplication of HBV and the expression of HBsAg. However, two recent studies justdemonstrated that there is no direct viral interaction between HBV and HCV in vitro. The roleof viral factors in the loss of HBsAg has been addressed in previous studies. In contrast,whether any host genomic factor or its expression can influence the clearance of HBsAg indually infected patients is not studied well.To address this issue, we hypothesize that host genomic factor or its expression caninfluence the clearance of HBsAg in patients dually infected with hepatitis C and B. Takingadvantage of the treatment cohort, we aim to (1) clarify whether host genomic factorsinfluence HBsAg clearance, (2) clarify whether host gene expression profiles correlate withHBsAg clearance, (3) clarify whether epigenetic mechanisms influence HBsAg clearance, and(4) study the kinetics and predictive value of miR-122 on the clearance of HBsAg.In our treatment cohort, we have already collected the dually infected patients who lostHBsAg after treatment. We have also collected the serial serum samples, PBMC samples,and/or liver biopsy specimens of these cases and matched controls. Besides, in the past wehave developed certain genomic techniques for the study of host genome and HBV viralgenome. In this project, we will develop genomic assays for candidate gene SNPs, hostepigenomic changes and expression miRNAs either by ourselves or through the cooperationwith private companies. Through the collection of clinical cases with clear clinical phenotypesand sample bank, and through the development of host epigenetic/genomic/liver geneexpression assays, we are confident that we can clarify the genotype-phenotype relationshipregarding the loss of HBsAgHBsAg loss is a critical event and usually indicates remission ofhepatitis activity and a favorable long-term outcome. If we can clarify the underlyingmechanisms of HBsAg loss in this group of patients, we may provide directions for futuretreatment development.