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研究生:楊曜旭
研究生(外文):Yao-Hsu Yang
論文名稱:B型、C型肝炎患者藥物使用與病程發展之關連性
論文名稱(外文):The association between drug use and disease progression among patients with hepatitis B virus or hepatitis C virus infection
指導教授:陳保中陳保中引用關係
口試日期:2017-05-18
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:職業醫學與工業衛生研究所
學門:醫藥衛生學門
學類:公共衛生學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:英文
論文頁數:112
中文關鍵詞:小柴胡湯史他汀肝硬化肝癌健保資料庫長庚醫學研究資料庫
外文關鍵詞:Xiao-chai-hu-tangstatincirrhosishepatocellular carcinomaNational Health Insurance Research Database (NHIRD)Chang Gung Research Database (CGRD)
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截至目前為止對於B型肝炎與C型肝炎之治療仍以干擾素或抗病毒藥物為主,可以大幅的減少肝癌與肝硬化等病程發展。除了傳統的治療方式以外,也有不少的藥物具有chemoprevntion之作用,本研究之主要分析藥物有statin跟中藥小柴胡湯兩種。台灣的健保資料庫是全世界唯一有包含中醫藥使用之資料庫,而長庚醫學研究資料庫除了藥物處置等紀錄以外,還有檢查結果、檢驗報告等資料。透過分析健保資料庫跟長庚醫學研究資料庫,我們可以提供更多statin與小柴胡湯對於B型肝炎與C型肝炎治療療效的實證。
A. Statin
目前許多研究已證實statin可以降低B型肝炎與C型肝炎患者罹患肝癌之風險,本研究之目的是使用健保資料庫跟長庚醫學研究資料庫分析statin是否可以降低B型肝炎與C型肝炎患者發展到肝硬化之風險。
健保資料庫的分析指出,根據受試者的Statin使用量將C型肝炎患者分為四組:小於28-83個藥物耗用標準化之定義每日劑量(defined daily dose, DDD) 84-365DDD跟大於365DDD,未達28DDD的患者當作對照組。相對於對照組,各組別罹患肝硬化的風險比值分別為28-83DDD: 0.33 (95% CI:0.31-0.36)、 84-365DDD: 0.24 (95% CI:0.22-0.25)、>365DDD:0.13 (95% CI:0.12-0.15)。
長庚醫學研究資料庫的分析指出根據B型肝炎患者的Statin使用量將患者分為四組:小於28-83個DDD、84-365DDD跟大於365DDD,未達28DDD的患者當作對照組。相對於對照組,各組別罹患肝硬化的風險比值分別為28-83DDD: 0.65 (95% CI, 0.53 to 0.80)、 84-365DDD: 0.53 (95% CI, 0.45 to 0.63)、>365DDD: 0.42 (95% CI, 0.34 to 0.51)。

B. 小柴胡湯
先前的研究指出小柴胡湯對於B型肝炎與C型肝炎的患者也有其保護作用。日本有小型的臨床試驗研究證實小柴胡湯可以降低肝硬化病患罹患肝癌之風險。目前對於小柴胡湯之療效鮮少有臨床資料提供相關資料,本計畫擬使用健保資料庫跟長庚醫學研究資料庫分析B型肝炎之小柴胡湯使用與肝癌風險。
從健保資料庫1997-2010年的資料中挑選出89,466位肝硬化且有B型肝炎之病患當作研究族群,資料分析指出,根據B型肝炎患者的小柴胡湯使用量將患者分為四組:35-69g、70-139g跟大於140g,並以用量於35g的病患當作對照組。各組別罹患肝癌的風險比值分別為0.79 (95% CI, 0.65 to 0.97), 0.73 (95% CI, 0.57 to 0.94), and 0.67 (95% CI, 0.52 to 0.86)。
Both hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are well-known etiological factors of Hepatocellular carcinoma (HCC) and cirrhosis. This study investigated the association between the use of statin and xiao-chai-hu-tang(XCHT) and the disease progression in patients with HBV or HCV infection. There are two parts of this research:
A. Statin
Recently, statins have been investigated for their antiproliferative, antiangiogenic, antiinflammatory, and antineoplastic effects. Several animal studies have shown that statins can inhibit the progression of cirrhosis; however, few clinical studies have been conducted. This study investigated the association between the use of statin and the risk of cirrhosis development in patients with HBV or HCV infection by analyzing the data from Taiwan National Health Insurance Research Database (NHIRD) and Chang Gung Research Database (CGRD).
From NHIRD, A dose-response relationship between statin use and cirrhosis risk was observed among HCV infected patients. The adjusted hazard ratios were 0.33 (95% CI, 0.31 to 0.36), 0.24 (95% CI, 0.22 to 0.25), and 0.13 (95% CI, 0.12 to 0.15) for statin use of 28 to 83, 84 to 365, and more than 365 cDDD, respectively, relative to no statin use (< 28 cDDD).
The adjusted hazard ratios of cirrhosis were 0.65 (95% CI, 0.53 to 0.80), 0.53 (95% CI, 0.45 to 0.63), and 0.42 (95% CI, 0.34 to 0.51) for statin use of 28 to 83, 84 to 365, and more than 365 cDDD, respectively, relative to no statin use (< 28 cDDD) among HBV infected patients recruited from CGRD .


B. XCHT
We conducted a population-based cohort study by using the Taiwan National Health Insurance Research Database. A total of 89,466 HBV-infected patients with cirrhosis were included as the study cohort. Each patient was individually tracked from 1997 to 2010 to identify incident cases of HCC. A Cox proportional hazards regression with time-dependent covariates for drug exposure was employed to evaluate the association between XCHT use and HCC risk.
A dose–response relationship between XCHT use and HCC risk was observed. The adjusted hazard ratios were 0.79 (95% CI, 0.65 to 0.97), 0.73 (95% CI, 0.57 to 0.94), and 0.67 (95% CI, 0.52 to 0.86) for patients using 35 to 69, 70 to 139, and ≧140 grams per year, respectively, relative to less than 35 g.
致謝 1
一、中英文摘要: 2
(一)中文摘要 2
(二)英文摘要 4
Introduction 6
Background 6
Statin 7
Xiao-chai-hu-tang 7
National Health Insurance Research Database (NHIRD) 9
Chang Gung Research Database (CGRD) 10
Objectives 12
Reference 13
Part I: Statin use and the risk of cirrhosis development in patients with hepatitis C virus infection. 17
Table 1. Patient demographics and clinical characteristics of study cohort and matched cohort. 41
Table 2. Adjusted hazard ratios (HRs) of cirrhosis development associated with statin use during the follow-up period in study cohort and matched cohort. 45
Figure1 Flowchart of the patient enrollment process of study cohort and matched cohort. 48
Figure 2 Cumulative incidence of cirrhosis development by cumulative defined daily dose (cDDD) of statin use during the follow-up period from the study (a) and matched (b) cohorts. 49
Part II: Statin use and the risk of cirrhosis development in patients with hepatitis B virus infection: a hospital based cohort study 50
Table1 Patient demographics and clinical characteristics of study cohort . 73
Table 2. Adjusted hazard ratios (HRs) of cirrhosis development associated with statin use during the follow-up period. 75
Table 3. Subgroup analysis of adjusted hazard ratios (HRs) for cirrhosis development associated with statin use during the follow-up period. 76
Supplement Table1 Patient demographics and clinical characteristics of NHIRD cohort and CGRD cohort. 78
Supplement Table 2. Adjusted hazard ratios (HRs) of cirrhosis development associated with statin use during the follow-up period in NHIRD cohort and CGRD cohort. 81
Part III: Xiao-chai-hu-tang and the risk of hepatocellular carcinoma in patients with hepatitis B virus-related cirrhosis 84
Table1 Patient demographics and clinical characteristics of study cohort. 104
Table2 Adjusted hazard ratios (HRs) of Xiao-chai-hu-tang use in reduction of HCC risk in HBV-related cirrhosis cohort by cox proportional hazards models with time-dependent covariates for drug exposure. 106
Figure1 Flowchart of the patient enrollment process of study cohort. 107
Figure 2 Cumulative incidence of hepatocellular carcinoma development by Xiao-chai-hu-tang use during the follow-up period of all patients (a) and subgroup analysis of sex (b,c), age (d,e), and severity of cirrhosis (f,g). 108
Figure 3 Sensitivity analyses and subgroup analyses for Xiao-chai-hu-tang use and the risk of hepatocellular carcinoma by cox proportional hazards models without time-dependent covariates for drug exposure. 112
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