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研究生： 陳宜芝
Chen, Yi-chih
論文名稱： 慢性C型肝炎病人肝臟纖維化的嚴重程度與Pegylated Interferon Alfa-2b倂用Ribavirin療效之相關性
The Association of Liver Fibrosis with Effectiveness of Pegylated Interferon Alfa-2b Plus Ribavirin for Chronic Hepatitis C
指導教授： 鄭斌男
Cheng, Pin-nan
莊善安
Chuang, Shan-an
高雅慧
Yang, Yea-Huei Kao
學位類別： 碩士
Master
系所名稱： 醫學院 - 臨床藥學研究所
Institute of Clinical Pharmacy
論文出版年： 2007
畢業學年度： 95
語文別： 中文
論文頁數： 142
中文關鍵詞： 血液學副作用 、長效型干擾素 、肝臟纖維化 、C型肝炎
外文關鍵詞： pegylated interferon alfa-2b, HCV, ribavirin, adverse effect of hematology
相關次數： 點閱：133  下載：2 
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    • 研究背景：
    根據世界衛生組織的統計，全球大約有一億七千萬的人口(全世界人口的百分之三)感染C型肝炎病毒，而台灣C型肝炎的帶原者大約有四十萬人。政府為了積極治療慢性C型肝炎，中央健保局自民國九十二年十月一日起推動「全民健康保險加強慢性C型肝炎治療試辦畫」。目前臨床慢性C型肝炎的標準治療方式為長效型干擾素與Ribavirin的合併療法。在臨床研究中發現，一些宿主本身的因素或是病毒的因子都與藥物治療的反應率有相關性，這些因子包括：年齡、性別、C型肝炎病毒基因型、治療前的病毒量、在治療過程中早期發生病毒清除、肝臟纖維化及發炎的程度和體重等。根據目前有限的文獻中發現，肝硬化或肝纖維化嚴重程度與慢性C型肝炎治療之相關性呈現分歧的結果；另一方面，肝硬化或肝纖維化嚴重者，因為副作用而降低劑量或是停藥的比例則是偏高的，但是否因此影響療效值得評估。
    研究目的：
    本研究是以南部某醫學中心中參與「全民健康保險加強慢性C型肝炎治療試辦計畫」的病患為研究對象，評估其肝臟切片檢查中肝臟纖維化的嚴重程度是否與長效型干擾素與Ribavirin的合併療法的療效及血液學副作用有相關性。
    研究方法：
    本研究為回溯性世代觀察研究(cohort study)，以民國九十二年十月一日至九十五年九月三十日於國立成功大學醫學院附設醫院之腸胃內科參與「全民健康保險加強慢性C型肝炎治療試辦計畫」之病患為研究對象，以病例回顧為研究工具。這些研究對象以METAVIR system將其肝纖維化依嚴重程度分成肝門脈區纖維化（F1）、少數門脈或橋連纖維化（F2）、多數門脈或橋連纖維化(F3)、肝硬化（F4）四組，再分別去評估治療結束時(第24週)和治療結束後觀察6個月(第48週)這兩個時段其病毒學反應和生化學反應，並且記錄這四組發生血液學副作用(血小板減少症、嗜中性白血球減少症、貧血)的比例和程度；此外亦分析因血液學副作用調整藥物劑量之比例和程度。
    研究結果：
    共有154位病人納入分析，其各組人數如下：F1組有10人，F2組有56人，F3組有53人，F4組有35人。結果發現在治療結束時(第二十四週)，達到生化學反應的比率會隨著肝臟纖維化的程度愈嚴重其數值愈小(80% vs. 70.9% vs. 52.8% vs. 48.6%)，但沒有統計學上的差異(p=0.059)；在治療結束後觀察6個月(第四十八週)發現，達到生化學反應的比率與肝臟纖維化的嚴重程度之間無相關性(p=0.062)。若將研究對象重新分組成輕微肝纖維化(F1,F2)和嚴重肝纖維化(F3,F4)兩組，則在治療結束時和結束後觀察六個月，輕微纖維化這組病人達到生化學反應的比率明顯地比嚴重纖維化這組病人高且有統計學上的意義(72.3% vs. 51.1%, p=0.008; 83.3% vs. 62.3%, p=0.01)。但在病毒學反應上則無此相關性。而血小板低下症和貧血的發生率會隨著肝臟纖維化程度愈嚴重，其發生率就愈高，但只有血小板低下症有統計學上的差異(0% vs.10.7% vs.2.6% vs.34.3%, p=0.016)。
    結論：
    輕微肝臟纖維化的病患在治療結束時和治療結束後觀察6個月確實比嚴重纖維化的病患有較好的生化學反應，但是在病毒學反應方面並未觀察到相同的結果。另外本研究同時也觀察到血小板低下症與貧血等副作用較易發生在嚴重肝纖維化的病患身上進而導致在治療過程中peginterferonα-2b需停藥的比率較高和ribavirin劑量降低的程度也較多。

    Background
    Hepatitis C virus (HCV) infection is a world-wide health problem. It was estimated that nearly 170 million people, including 420,000 subjects in Taiwan, were infected with HCV. Chronic HCV infection could lead to development of liver cirrhosis and even hepatocellular carcinoma. Combination therapy of pegylated interferon plus ribavirin is the current standard treatment that achieve about 54% to 56% of sustained virologic response (SVR). Several host or viral factors have been investigated to correlate with treatment response. These factors included gender, ethnic, ages, genotype, early clearance of virus during therapy, baseline viral load, body weight, and degree of liver fibrosis. Among them, only few reports addressed the relationship between degree of liver fibrosis and treatment response and revealed controversial results.
    Objective
    To assess the association between degree of liver fibrosis and the effectiveness and hematological adverse effects of peginterferon alfa-2b plus ribavirin combination treatment for chronic hepatitis C in Taiwan.
    Methods
    This is a retrospective cohort study and conducted by way of reviewing the medical records of included patients. The study period was from October 2003 to September 2006. And patients who participated in Enforcing Hepatitis C Trial Treatment Program of Bureau of National Health Insurance in National Cheng-Kung University Hospital were enrolled. Biochemical and virologic parameters were recorded. We allocated patients into 4 groups according to the various degree of liver fibrosis classified by METAVIR system. The primary outcomes were to compare the biochemical and virologic response of peginterferonα-2b and ribavirin at the 24th and 48th week between 4 groups. The secondary outcome was to assess the incidence rates of hematological adverse events such as neutropenia, thrombocytopenia and anemia of the 4 groups.
    Results
    One hundred and fifty-four patients with chronic hepatitis C who participated the Enforcing hepatitis C trial treatment program of Bureau of National Health Insurance were included in this study. They were allocated into four groups by METAVIR system including 10 patients in fibrosis stage 1 (portal fibrosis, F1), 56 patients in stage 2 (few bridging fibrosis, F2), 53 patients in stage 3 (many bridging fibrosis, F3) and 35 patients in stage 4 (cirrhosis, F4). At the end of treatment, the biochemical response decreased as the severity of liver fibrosis increased (80% vs. 70.9% vs. 52.8% vs. 48.6%) without significant difference (p=0.059). The sustained biochemical response was not associated with the severity of liver fibrosis (p=0.062). If we regrouped these patients into the mild fibrosis (F1,F2) and severe fibrosis(F3,F4), biochemical response rate was significantly higher in mild fibrotic patients than severe fibrotic patients at the end of treatment and 24 weeks after treatment(72.3% vs. 51.1%, p=0.008; 83.3% vs. 62.3%, p=0.01). In contrast, the virologic response did not demonstrate the similar association. Among the hematologic adverse effects during treatment, the incidence rates of thrombocytopenia and anemia were increased as the severity of liver fibrosis worsened, but only thrombocytopenia event exhibited significant difference (0% vs. 10.7% vs. 22.6% vs. 34.3%, p=0.016).
    Conclusion
    Patients with mild fibrosis had better biochemical response, but not virologic response, than those with severe fibrosis at the end of treatment and 24 weeks after treatment. Patients with severe fibrosis have higher incidence of thrombocytopenia and anemia events which resulted in higher rates of peginterferonα-2b discontinuation and higher extent of ribavirin dose reduction.

    第一篇 慢性C型肝炎的病人肝臟纖維化的嚴重程度與Pegylated Interferon Alfa-2b倂用Ribavirin療效之相關性 1 第一章 研究背景 1 第二章 文獻回顧 5 第一節 C型肝炎病毒之簡介 5 第二節 C型肝炎之流行病學 6 第三節 C型肝炎之自然病史 8 第四節 C型肝炎之診斷與評估 10 4.1 C型肝炎抗體 10 4.2 C型肝炎病毒核醣核酸 11 4.3 血清丙氨酸轉胺酶 13 4.4 C型肝炎病毒基因型 13 4.5 肝臟切片檢查 15 第五節 慢性C型肝炎之治療 18 5.1 治療對象 18 5.2 治療反應的定義 20 5.3 藥物治療的發展史 22 5.4 治療藥物簡介 22 5.5 藥物治療之臨床療效 26 5.6 藥物治療之副作用及處理方式 29 第六節 影響藥物療效之相關因子 38 6.1 療效預估因子 38 6.2 肝臟纖維化的嚴重程度對藥物治療之影響 42 6.3 結語 44 第三章 研究目的 49 第四章 研究方法 50 第一節 研究設計 50 1.1 研究類型 50 1.2 研究時間及研究對象 50 1.3 納入標準 51 1.4 排除標準 51 1.5 研究分組定義 52 第二節 研究流程 52 第三節 評估指標與定義 55 3.1 主要評估指標 55 3.2 次要評估指標 55 第四節 統計方法 57 4.1 統計模式設定 57 4.2 資料分析方法 57 4.3 資料管理軟體及統計分析軟體 57 第伍章 研究結果 58 第一節 病患基本資料 58 第二節 主要評估指標 64 第三節 次要評估指標 71 3.1 血液學副作用之發生率 71 3.2 血球降低的程度 71 3.3停藥或降低劑量的發生率 72 3.4 劑量降低的程度 73 3.5 平均血球變化的情形 73 第陸章 討論 83 第一節 研究對象 83 第二節 病患基本資料 85 第三節 肝臟纖維化的嚴重程度對於藥物療效之影響 87 3.1 生化學反應 87 3.2 病毒學反應 87 3.3 病毒學與生化學療效不一致 89 3.4 療效預估因子 90 第四節 肝臟纖維化的嚴重程度對於藥物安全性之影響 93 4.1 嗜中性白血球 93 4.2 血小板 94 4.3 血色素 95 第五節 Ribavirin減低劑量對療效之影響 100 第六節 國內慢性C型肝炎治療之探討與建議 102 第七節 研究限制 104 第八節 未來研究方向 105 第柒章 結論 106 第二篇 臨床藥事服務 107 第一章 認識慢性C型肝炎治療用藥~問卷調查 107 第一節 背景 107 第二節 目的 108 第三節 臨床服務進行方式 108 第四節 臨床服務執行結果 110 第五節 討論與結語 114 第二章 護理人員用藥講座—藥物磨粉停看聽 116 第一節 背景 116 第二節 目的 117 第三節 講座進行方式 117 第四節 結果 118 第五節 討論與結語 125 參考文獻 127

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