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系統識別號 U0026-0209201310021100
論文名稱(中文) 慢性B型肝炎自然病程中和接受抗病毒藥物後的病毒動力學和演化
論文名稱(英文) Viral Kinetics and Evolution in Chronic Hepatitis B Patients during the Nature Course and after Antiviral Therapy
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 101
學期 2
出版年 102
研究生(中文) 吳毅晉
研究生(英文) I-Chin Wu
學號 s98951047
學位類別 博士
語文別 英文
論文頁數 101頁
口試委員 指導教授-張定宗
指導教授-楊孔嘉
口試委員-蕭璦莉
口試委員-王憲威
口試委員-盧勝男
口試委員-戴嘉言
中文關鍵字 干適能  慢性B型肝炎  抗藥性  貝樂克  演化  B型肝炎e抗原  B型肝炎病毒  干安能  核苷類似物  核苷酸類似物  血清轉換  病毒動力學  病毒準種 
英文關鍵字 adefovir dipivoxil  chronic hepatitis B  drug resistance  entecavir  evolution  hepatitis B e antigen  hepatitis B virus  lamivudine  nucleoside analogues  nucleotide analogues  seroconversion  viral kinetics  viral quasispecies 
學科別分類
中文摘要 慢性B型肝炎是重要的健康問題。目前已有數種核苷類似物可以用來治療慢性B型肝炎,但需要長期服用,且抗藥性會在一到數年之後發生。先前的研究顯示病毒動力學在抗病毒治療的早期有其重要性且病毒準種的演化和慢性病毒感染的致病機轉有密切關係。本論文的目的在探討慢性B型肝炎自然病程中和接受抗病毒藥物後的病毒動力學和演化,我們共執行4個研究以達到此目標。在第一個研究,我們於B型肝炎e抗原陽性的慢性B型肝炎病人的自然病程中定義了3種病毒動力學型態。下降型的病人有較好的臨床結果,起伏型的病人有較差的臨床結果。這樣的發現表示連續測量B型肝炎病毒量可以使我們對B型肝炎疾病活性有更精確的評估。在第二個研究,我們發現達到B型肝炎e抗原血清轉換後如接受較長的抗病毒藥物治療則能增加維持B型肝炎e抗原血清轉換的機會,而那些接受較久抗病毒藥物治療後才達到B型肝炎e抗原血清轉換的病人可能需要較長時間的鞏固治療。然而,在維持B型肝炎e抗原血清轉換的病人中,有一半的病人血中可以測到病毒,這些可以測到病毒的病人中,大部分有有核前區或基礎核心促進子突變株,而且這些核前區或基礎核心促進子突變株通常在開始服用抗病毒藥物治療前即已存在。這些突變株在接受抗病毒藥物治療的病人身上的臨床意義有待大型的臨床試驗來釐清。在第三個研究,我們觀察到B型肝炎e抗原陰性病人接受貝樂克治療時,不論其基準ALT,均有相當好的療效。然而對於B型肝炎e抗原陽性病人,貝樂克在ALT輕微上升的病人具有療效,但沒有像在ALT大於正常值上限兩倍的病人那麼好。這個結果可以供臨床醫師治療這類病人時參考。在第四個研究,我們發現接受干安能治療後較快得到病毒突破的病人有可能比較容易在連續接受干安能和貝樂克治療後產生貝樂克抗藥性。實驗組比起對照組有較高的基準丙胺酸轉胺酶,於貝樂克抗藥性發生前在反轉錄酶區段和核前/核心區段也有較高的病毒演化速率。病毒演化速率可以當作監測抗病毒治療時的新指標。總結來說,慢性B型肝炎病人身上不同的病毒動力學和演化型態代表了獨特的臨床意義和免疫表現。我們將會研究不同病期和接受抗病毒藥物後慢性B型肝炎病人的T細胞免疫反應以進一步釐清慢性B型肝炎的致病機轉。
英文摘要 Chronic hepatitis B virus infection is an important health problem. Several nucleoside analogues could be used as antiviral therapy, but long-term therapy is necessary and drug resistance develops one or several years later. Previous studies showed that viral kinetics was important during the early phase of their antiviral treatment and viral quasispecies evolution was important in the pathogenesis of chronic viral disease. The aim of this thesis is to investigate viral kinetics and evolution in chronic hepatitis B patients during the nature course and after antiviral therapy. Four studies were conducted to achieve this goal. In study 1, three patterns of viral kinetics during the natural course of HBeAg-positive chronic hepatitis B were defined and had distinct clinical significance. The declining pattern had a better clinical outcome and the wavering pattern had the worse outcome. The finding implies serial measurement of serum HBV DNA could help to assess disease activity more accurately in patients with chronic HBV infection. In study 2, prolonged antiviral therapy after HBeAg seroconversion appeared to increase sustained HBeAg seroconversion, and longer duration of antiviral therapy might be needed in patients who experience seroconversion late after initiation of therapy. However, half of patients with sustained HBeAg seroconversion had viremia and most of them had precore/basal core promoter mutants which usually had existed prior to adefovir dipivoxil therapy. The clinical outcome of these patients needs to be illustrated in the future. In study 3, HBeAg-negative patients with mildly elevated ALT have treatment responses to entecavir that are similar to the responses for those with ALT greater than 2 x ULN. For HBeAg-positive patients with mildly elevated ALT, entecavir had lower efficacy than for those with ALT greater than 2 x ULN. The findings demonstrate the treatment responses that can be expected should clinicians choose to initiate entecavir treatment in accordance with the current treatment guidelines. In study 4, the patients who get virologic breakthrough sooner after lamivudine therapy might be easier to get entecavir resistance after sequential lamivudine and entecavir therapy. The case group had higher baseline ALT levels and higher viral evolutionary rates of reverse transcriptase region and precore/core region before development of entecavir resistance, as compared with the control group. Viral evolutionary rates may serve as a new parameter to monitor antiviral treatment. In conclusion, different viral kinetic and evolutionary patterns in patients with chronic hepatitis B implicate distinct clinical significance and immunologic perspective. We will study T cell-mediated immune responses in chronic hepatitis B patients at different disease stages and after antiviral therapy to further elucidate the pathogenesis of chronic hepatitis B.
論文目次 English Abstract i
Chinese Abstract iii
Acknowledgments v
Abbreviations vi
Table of Contents vii
List of Tables ix
List of Figures xi
Chapter 1. Introduction 1
1.1 Hepatitis B Virus 1
1.2 Clinical Manifestations of Chronic HBV Infection 2
1.3 Treatment for Chronic Hepatitis B 3
1.4 Thesis Aims 3
Chapter 2. Viral Kinetics in the Natural Course of Chronic hepatitis B 5
2.1 Background and Aims 5
2.2 Patients and Methods 7
2.3 Results 10
2.4 Discussion 13
2.5 Tables and Figures 16
Chapter 3. Durability after Discontinuation of Antiviral Therapy 23
3.1 Background and Aims 23
3.2 Patients and Methods 25
3.3 Results 28
3.4 Discussion 30
3.5 Tables and Figures 33
Chapter 4. Efficacy of Entecavir in Chronic Hepatitis B Patients with Mildly Elevated ALT 39
4.1 Background and Aims 39
4.2 Patients and Methods 41
4.3 Results 43
4.4 Discussion 45
4.5 Tables and Figures 48
Chapter 5. Evolution of Hepatitis B Virus during Sequential Nucleoside Analogues Therapy 53
5.1 Background and Aims 53
5.2 Patients and Methods 56
5.3 Results 60
5.4 Discussion 63
5.5 Tables and Figures 66
Chapter 6. General Discussion, Conclusions, and Prospects 78
6.1 Coevolution in Chronic HBV Infection 78
6.2 T cell-mediated Immune Response in Chronic HBV Infection 78
6.3 Conclusions and Prospects 79
Bibliographies 80
Publications 99
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