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研究生： 郭淑蕙
Kuo, Shu-Hui
論文名稱： 以長效型干擾素及Ribavirin治療慢性C型肝炎導致藥物不良事件之研究
The Study on Adverse Events Induced by Pegylated Interferon Alpha plus Ribavirin in Chronic Hepatitis C
指導教授： 林嘉音
Lin, Chia-Ying
張定宗
Chang, Ting-Tsung
蔡瑞真
Tsai, Jui-Chen
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： 132
中文關鍵詞： 藥物不良事件 、長效型干擾素 、C型肝炎
外文關鍵詞： Ribavirin, Pegylated interferon alpha, adverse event, hepatitis C virus (HCV)
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    • 研究背景：
    根據世界衛生組織估計，全世界約有一億七千萬人感染C型肝炎，若未進一步治療，20%病患可能會二、三十年後演變為肝硬化，一旦進展至該階段，每年又將1-4%被診斷為肝癌，所以防治慢性C型肝炎為公共衛生關注課題。長效型干擾素(Pegylated interferon)與Ribavirin合併療法為目前C型肝炎標準治療方式，在台灣中央健保局已於2003年10月開始給予健保給付。療效方面，目前研究已證實，干擾素與Ribavirin的組合確實優於單獨使用干擾素，但也較易產生藥物不良反應，為了避免副作用，常需要在治療過程中調整藥物劑量，繁瑣的處置同時構成臨床上困擾。

    研究目的：
    本研究主要重點在於呈現長效型干擾素（Peginterferon alpha-2a or Peginterferon alpha-2b）及Ribavirin治療國人慢性C型肝炎療程中，發生藥物不良事件之型態，進而分析其發生相關因子，希望藉此瞭解以提升病患用藥安全，並降低醫療資源支出。

    研究方法：
    本研究類型屬於回溯型研究，研究對象為台灣南部三家醫療機構（國立成功大學醫學院附設醫院、嘉義基督教醫院、慈濟大林分院），於2003年10月起至2005年10月底止，符合『全民健康保險加強慢性C型肝炎治療試辦計畫』條件，接受長效型干擾素及Ribavirin治療之患者。主要之研究工具，是藉由電話問卷與病歷回顧，完成相關資料與檢驗數值記錄。

    研究結果：
    與國外前瞻性研究相比，雖然本研究接受C型肝炎用藥導致不良事件之發生率較高，如：虛弱無力（88%），疲勞（88%），食慾不振（82%），體重減輕（83%），發燒（82%），肌肉痠痛、關節痛（77%），掉頭髮（77%），焦慮（76%），發冷、發抖（69%），失眠（67%），頭暈（66%），頭痛（61%），容易生氣（60%），運動一會兒就喘（59%），皮膚癢（54%），噁心、嘔吐（45%），心悸、心跳變快（42%），注射部位反應（40%），咳嗽（38%），憂鬱（34%），視力模糊（34%），皮膚起紅疹（32%），腹瀉（26%）、便秘（24%），但收納310位患者中，完成治療仍有93%患者。在分析治療完成之患者發現：僅1.4%之患者治療後白血球檢驗值未減少，而血紅素檢驗值則1.7%之患者未受影響，況且一旦白血球數值下降到3.0K/mm3以下，與疲勞、體重減輕、皮膚搔癢之不良事件，統計上顯示有相關性；而當Hb下降小於12g/dl時，與噁心嘔吐、心悸、體重減輕…等之不良事件亦顯示統計上有相關性。另外本研究觀察到未完成治療之患者與完成治療之患者間，就人口學特徵與過去病史比較，統計結果未具差異。至於C型肝炎藥物劑量維持率而言，在288位完成治療之患者中，78.8%能維持長效型干擾素之初始劑量至結束療程，75%能維持Ribavirin之初始劑量至結束療程，其中年齡大於五十歲之患者，較無法維持Ribavirin初始劑量至結束療程。

    結論：
    由本研究結果建議：未來治療C型肝炎時，對患者出現血液異常驗數值應更小心監測，除避免不良事件發生，亦可減少醫療資源支出，並提昇患者生活品質。

    BACKGROUND:
    According to the estimate by the Word Health Organization, 170 million people are infected with the Hepatitis C virus (HCV). Unfortunately, the patients over 20-30 years, 20% turn into the cirrhosis. Once they caused cirrhosis, 1-4% will get hepatocellular carcinoma every year. Hence, the prevention of the chronic hepatitis C has become an important issue in public health. The current standard therapy for hepatitis C is a combination of Pegylated interferon and Ribavirin. Since October 2003, the Bureau of National Health Insurance in Taiwan enforced Hepatitis C trial treatment program and reimburse for the combination therapy. With respect to the efficacy the combination therapy, studies have proved it is better than interferon alone, but it causes adverse reactions frequently. To avoid that, dose reduction during the course of treatment is commonplace. The tedious handling processes also bring inconveniences to the clinical practice.

    OBJECTIVE:
    The major purpose of this study is to investigate the types of the adverse events during the treatment of hepatitis C, using Pegylated interferon alpha-2a or alpha-2b in combination with Ribavirin. By the analysis of its related risk factors, we may understand how to improve the drug safety and lower the expenses of medical resources.

    METHODS:
    Patients who participated in Enforcing Hepatitis C Trial Treatment Program of Bureau of National Health Insurance and received Pegylated interferon and Ribavirin in National Cheng Kung University Hospital, Chia-Yi Christian Hospital, and Buddhist Dalin Tzu Chi Hospital between October 2003 and October 2005 were enrolled in this retrospective study. The first part of the study was to collect data and laboratort values of the patients from medical chart review, and the other part was questionnaires survey from telephone interview.

    RESULTS:
    Compared with some prospective studies conducted in other countries, the incident rates of the adverse events were higher in this study, for example: weakness (88%), fatigue (88%),anorexia (82%), weight loss (83%), fever (82%), the arthralgia and myalgia (77%), alopecia (77%), anxious (76%), chilly and shiver (69%), insomnia (67%), dizziness (66%), headache (61%), irritability (60%), short of breath after a while in sport (59%), the pruitus (54%), nausea and vomitting (45%), tachycardia (42%), injection site reaction (40%) , cough (38%), depression (34%), blurred vision (34%), skin rash (32%), diarrhea (26%), constipation (24%). Despite high incidence of the adverse events, 93% of the 310 patients enrolled completed the treatment. Of those patients who completed the treatment, only 1.4% of the patients maintained their values of White Blood Count (WBC) and 1.7% of the patients maintained their values of hemoglobin (Hb). In addition, when WBC declined to <3.0K/mm3, significant incidences of fatigue, weight loss and pruritus were found. When hemoglobin (Hb) declined to <12g/dl, significant incidences of related adverse events such as, nausea, vomiting, tachycardia, weigh loss were found. In this study, the medical histories and demographic features between the patients who completed and those who did not complete the treatment were not significantly different. With respect to the dosage of the medications used among 288 patients who completed the treatment, 78% of them did not adjust the dosage of the Pgylated interferon throughout the treatment, 75% of them did not adjust the dosage of Rivavirin throughout the treatment. The dosage maintenance rate was significantly different between patients who were older and younger than 50 years.

    CONCLUSIONS:
    The studies suggest that greater care must be given to the patients to advoid adverse events when their laboratory values of hematologic are abnormal. As a consequence, we may lower the medical expenses and improve life quality for those patients.

    中文摘要 I Abstract IV 誌謝 VII 目錄 VIII 表目錄 XII 圖目錄 XIV 第一篇 以長效型干擾素及Ribavirin治療慢性C型肝炎導致藥物不良事件之研究 第一章 研究背景 1 第二章 文獻回顧 3 第一節 C型肝炎病毒之簡介 3 第二節 C型肝炎之流行病學 4 第三節 C型肝炎之自然病史 5 第四節 慢性C型肝之藥物治療 6 4.1治療對象 6 4.2治療藥物發展史與臨床療效之介紹 6 4.2.1傳統型干擾素單一療法 6 4.2.2 Ribavirin單一療法 8 4.2.3傳統型干擾素與Ribavirin 9 4.2.4長效型干擾素單一療法 10 4.2.5長效型干擾素與Ribavirin合併療法 10 第五節 C型肝炎藥物治療之安全性 15 5.1干擾素 15 5.1.1類似感冒症狀 15 5.1.2精神症狀 16 5.1.3自體免疫功能失調 17 5.1.4血液檢驗數值異常 18 5.1.5心血管疾病 19 5.1.6腎臟疾病 20 5.1.7肝臟毒性 20 5.1.8呼吸道副作用 20 5.1.9胃腸道副作用 20 5.1.10眼科副作用 21 5.1.11致畸胎性 21 5.2 Ribavirin 22 第六節 C型肝炎治療藥物劑量調整規範 24 6.1 血液檢驗值異常 24 6.1.1 絕對嗜中性球 24 6.1.2 血小板 24 6.1.3 血紅素 24 6.2 腎功能異常 25 6.3 肝功能異常 25 第三章 研究目的 26 第四章 研究方法 27 第一節 研究設計 27 1.1 研究類型 27 1.2 研究期間與對象 27 1.3 收納標準 27 1.4 排除標準 28 1.5 研究分組定義 28 第二節 研究流程 30 2.1 研究樣本數 30 2.2 申請人體試驗委員會審核 30 2.3 蒐集研究病患基本資料 30 2.4 彙整資料 31 2.4.1電話問卷調查 31 2.4.2回溯性評估病歷記載 32 第三節 評估指標與定義 35 3.1 評估指標 35 3.2 評估指標之定義 35 第四節 統計方法 38 4.1 統計模式設定 38 4.2資料分析方法 38 4.3 資料管理軟體及統計分析軟體 38 第五章 研究結果 40 第一節 研究對象 40 第二節 藥物不良事件其他相關因素之探討 63 第三節 維持C型肝炎藥物治療劑量比率之分析 78 第六章 討論 80 第一節 研究對象 80 第二節 藥物不良事件與其他相關因素之探討 83 第三節 研究限制 85 第四節 未來研究方向 86 第七章 結語 87 第二篇 臨床藥事服務 第一章 目的 89 第二章 方法 90 第一節 建立電腦警訊系統藥物交互作用配對資料庫 90 第二節 藥物交互作用臨床監測指標 95 第三節 建構「電腦警訊藥物交互作用系統」疑義處方照會作業流程 96 第三章 記錄方式 97 第一節 建立電腦警訊系統藥物交互作用配對資料庫 97 第二節 藥物交互作用臨床監測指標 98 第三節 建構「電腦警訊藥物交互作用系統」疑義處方照會作業流程 99 第四章 結果 100 第一節 建立電腦警訊系統藥物交互作用配對資料庫 100 第二節 藥物交互作用臨床監測指標 101 第三節 建構「電腦警訊藥物交互作用系統」疑義處方照會作業流程 102 第五章 未來展望與建議 103 參考文獻 122 附錄一、人體試驗委員會同意臨床試驗證明書 129 附錄二、以長效型干擾素及Ribavirin 治療慢性C 型肝炎電話問卷調查 130

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