2012-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/652981摘要：目前全世界約有1億7千萬人為C型肝炎感染者，而這些患者可能會導致肝硬化，肝癌及接受肝臟移植。以長效型干擾素合併雷巴威林已成為慢性C型肝炎的標準治療，其中C型肝炎病毒基因型第一型的治療持續性病毒反應為39-79%，而C型肝炎病毒基因型第二/三型的患者則持續性病毒反應為84-91%。此外，亞洲患者較西方人有較好之持續性病毒反應，尤其在C型肝炎病毒基因型第一型之患者。然而24-32%與4-18%C型肝炎病毒基因型第一型及病毒基因型第二/三型的患者為病毒復發者，定義為治療結束時血清病毒測定不到而停藥後24週血清病毒陽性反應。由於C型肝炎病毒基因型第一型患者治療的時間為久及雷巴威林治療劑量較高，較易造成病人的不適及早期終止治療而導致成功率較低，因此吾人應針對病毒或宿主因素之研究以找出C型肝炎病毒基因型第一型患者之最適治療。此外數項臨床試驗顯示不論從未治療或是先前治療失敗患者以直接作用之C型肝炎抗病毒藥物如蛋白質抑制酶加上標準治療可以增進持續性病毒反應。近年來研究顯示位於染色體第19對上人類介白質28B基因多型性與C型肝炎自然或是治療導致之病毒清除率有關，此外以病毒動力學導向之治療方式也是相當重要。然而合併人類介白質28B基因多型性及早期病毒動力學以精準預測亞洲患者C型肝炎病毒基因型第一型患者最適治療所扮演之角色仍不清楚。另一方面，決定病患是否達到持續性病毒反應須於停藥後24週以高敏感度即時聚合酶反應決定。達到持續性病毒者於停藥超過24週後仍有持續反應。然而24週停藥觀察期為約定成俗之定義，原因是因為停藥超過24週有持續性病毒反應者鮮少病毒復發者。提早決定治療成功與否對病毒復發者是相當重要的，因為可早期讓病毒復發者早期接受新藥治療並減少因長期等待治療結果而使持續性病毒反應評估錯誤。最近兩項研究顯示以高敏感度定性或定量C型肝炎病毒檢測可於停藥超過12週早期預測治療反應。此外C型肝炎病毒復發者於停藥後4、8、及12週之C型肝炎病毒陽性檢出率為65-70%， 91%及98-99%。其中早期或晚期C型肝炎病毒復發者，定義為停藥後C型肝炎病毒陽性檢出率12週內或12週後，Zeuzem學者等人以C型肝炎病毒基因型、C型肝炎病毒量、血清中肝指數、或是否有肝硬化皆無法區別早期或晚期C型肝炎病毒復發者。因此吾人應針對病毒或宿主因素從事研究以找出區別早期或晚期C型肝炎病毒復發者之重要因子。然而人類介白質28B基因多型性在早期或晚期C型肝炎病毒復發者所扮演之角色仍不清楚。最後由於C型肝炎病毒基因型第一型患者治療的時間為久及雷巴威林治療劑量較高，較易造成病人貧血及早期終止治療而導致成功率較低，因此吾人應針對宿主因素之研究以找出C型肝炎病毒基因型第一型患者之最適治療。近年來研究顯示位於染色體第20對上人類三磷酸肌苷焦磷酸酶基因多型性與C型肝炎病患接受長效型干擾素合併雷巴威林時雷巴威林引起之貧血及治療中雷巴威林治療減量有關。然而人類三磷酸肌苷焦磷酸酶基因多型性在亞洲患者所扮演之角色仍不清楚且此基因多型性與治療持續性病毒反應之相關性仍有爭議。本研究則是針對人類介白質28B基因多型性及人類三磷酸肌苷焦磷酸酶基因多型性對慢性C型肝炎接受長效型干擾素合併雷巴威林做以下三方面之研究: (一)研究C型肝炎病毒基因型第一型病患人類介白質28B基因多型性測定結果和早期C型肝炎病毒下降幅度與治療成果比對並建立決策分析樹狀圖; (二) 針對人類介白質28B基因多型性評估是否能有效區分早期或晚期C型肝炎病毒復發者; (三) 針對類人類三磷酸肌苷焦磷酸酶基因多型性評估是否能有效區分雷巴威林引起之貧血及對治療持續性病毒反應之影響。<br> Abstract: Chronic hepatitis C virus (HCV) infection is the leading cause of cirrhosis and hepatocellular carcinoma (HCC), affecting approximately 170 million individuals worldwide. Currently, peginterferon (PEG-IFN) plus ribavirin (RBV) therapy is the standard of care (SOC) for the treatment of patients with chronic HCV infection, with an overall sustained virologic response (SVR) rates of 38% to 79% in HCV genotype 1 and 84% to 91% in HCV genotype 2/3 patients with 48 and 24 weeks of treatment, respectively. In addition, Asian patients are shown to have a better SVR rate to combination therapy than Western patients, especially for HCV genotype 1 infection. However, patients with HCV genotype 1 infection usually receive a longer duration of therapy and a higher dosage of ribavirin, causing a higher percentage of patients with premature therapy termination and thus lessen the overall treatment response. Several clinical trials showed that the addition of direct acting antivirals (DAAs) such as protease inhibitors to SOC can improve the SVR rates, either in treatment-naïve or prior treated HCV genotype 1 patients.Recent studies showed that genetic variations near the interleukin 28B (IL28B) gene (rs8099917 or rs12979860), which is located on chromosome 19 and encodes IFN λ-3, are highly associated with spontaneous or treatment-induced HCV clearance. Furthermore, response-guided therapy based on HCV early virokinetics is also important for appropriate therapy. However, combined IL28B genetic variations and early HCV viral kinetics to predict treatment response in HCV genotype 1 Asian patients with PEG-IFN plus RBV remain largely unknown.In clinical practice, the determination of SVR or not is to test serum HCV RNA level at 24 weeks after the completion of therapy by using the sensitive polymerase chain reaction (PCR)-based method. Patients who achieve SVR have durable viral suppression beyond 24 weeks of off-therapy follow-up.15-17 However, the 24-week off-therapy observation rule is arbitrarily defined, probably because the reappearance of viremia beyond 24 weeks is rarely observed. Earlier determination of treatment outcomes is important for viral relapsers because they can receive new antiviral agents in time, and also for viral responders to avoid underestimation of SVR when they have drop-outs during the off-therapy follow-up period. Two studies indicated that by using sensitive qualitative or quantitative HCV RNA assays, 98% to 100% of viral responders could be accurately determined at 12 weeks off-therapy. Furthermore, rates of serum HCV RNA reappearance in viral relapsers were 65%-70%, 91%, and 98%-99% at 4, 8 and 12 weeks off-therapy, respectively. Among early or late viral relapsers, defined as reappearance of viremia at < 12 or ≥ 12 weeks off therapy, Zeuzem et al. failed to discriminate patients with early versus late relapse by baseline factors, including HCV genotype, HCV RNA levels, ALT levels and status of cirrhosis. Therefore, further studies are needed to identify host and viral factors associated with early or late viral relapse. However, the role of IL28B genetic variations in predicting early or late viral relapse in HCV patients treated with PEG-IFN plus RBV remains largely unknown.Recent studies showed that inosine triphosphate pyrophosphatase (ITPA) genetic variations (rs1127354), which is located on chromosome 20, are highly associated with ribavirin-induced anemia and ribavirin dose reduction due to anemia. However, the role of ITPA genetic variations in Asian HCV patients remained largely elusive, and the role to predict treatment response with PEG-IFN plus RBV remains controversial.The aims of the study were focused on three parts: (1) To define the role of IL28B genetic polymorphism and early viral decline and tried to make decision tree in patients with combination therapy; (2) To define and validate viral, treatment, and host factors associated with early or viral relapse, with the special emphasis on the role of IL28B genetic variations; (3) To define the association of ITPA genetic variations with ribavirin-induced anemia and SVR in HCV genotype 1 patients with combination therapy