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研究生:詹毓哲
研究生(外文):Yu-Tse Tsan
論文名稱:慢性肝炎感染患者使用降血脂斯達汀類藥物和肝癌之風險評估
論文名稱(外文):Statins and the Risk of Hepatocellular Carcinoma in Patients with Chronic Hepatitis
指導教授:陳保中陳保中引用關係
指導教授(外文):Pau-Chung Chen
口試委員:王榮德許惠恆劉俊人于明暉
口試委員(外文):Jung-Der WangWayne Huey-Herng SheuChun-Jen LiuMing-Whei Yu
口試日期:2013-05-11
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:2013
畢業學年度:101
語文別:英文
論文頁數:93
中文關鍵詞:藥物流行病學健保資料庫B型肝炎C型肝炎斯達汀藥物肝癌
外文關鍵詞:hepatitis B virushepatitis C virushepatocellular carcinomapharmacoepidemialogymetforminNational Health Insurance Research Databasenucleoside analoguesstatinthiazolidinedione
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背景與目的:斯達汀類藥物對癌症可能有潛在的保護作用,但目前還沒有針對慢性B型與C型肝炎病毒感染的病人加以研究。本研究的目的是探討在B型與C型肝炎病毒感染的患者使用斯達汀類藥物和肝癌風險之間的關聯。同時探討糖尿病用藥與抗病毒用藥對斯達汀類藥物在使用上之交互作用。
病人與方法:第一部份我們利用台灣全民健康保險資料庫進行研究。共有33,413 B型肝癌感染患者為研究世代。每一位患者從1997年開始追蹤到2008年止以確定自1999年以來新發生的肝癌病例。隨後斯達汀類藥物,其他類降血脂藥,阿司匹林和血管緊張素轉換酶抑製劑的使用劑量亦進行分析。Cox比例風險回歸分析計算的危險比(HR)和95%信賴區間(CI)用來確認於B型肝炎感染的世代中,使用斯達汀類藥物和肝癌的發生之間的關聯性。第二部份我們擷取台灣全民健康保險資料庫診斷C型肝炎感染患者260,864為研究世代。每一位患者從1999年開始追蹤到2010年止以確定自1999年以來新發生的肝癌病例。Cox比例風險回歸併用時間依存變項模式,分析計算出危險比(HR)和95%信賴區間(CI)用來確認於C型肝癌感染的世代中,使用斯達汀類藥物和肝癌的發生之間的關聯性。第三部分同樣利用B型肝炎世代,探討糖尿病用藥與斯達汀藥物對肝癌風險之交互加成作用。第四部份利用配對的方式擷取共91,265位B型肝炎病人,配對性別,年齡,糖尿病,肝硬化,高血壓,高血脂,膽道結石,慢性腎病變,酒精性肝炎等疾病後,其中18,253位為抗病毒用藥使用者,73,012位為非使用者,去探討斯達汀藥物,抗病毒用藥與肝癌發生風險之關聯性。
結果:共有1021例肝癌由B肝病毒感染328946人年世代中發生,發病率為310.4個案於每十萬人年之中。且研究發現斯達汀類藥物的使用和肝癌的風險有劑量反應關係存在。調整後的危險比相對於為0.66(95%CI,0.44-0.99),0.41(95%CI,0.27-0.61),0.34(95%CI,0.18-0.67)於斯達汀類藥物使用28-90,91-365,和>365累計日劑量(cDDD),分別相對於沒有使用斯達汀類藥物(<28 cDDD)。共有27,883例肝癌由C肝病毒感染2,792,016.6人年世代中發生。研究發現斯達汀類藥物的使用和肝癌的風險有劑量反應關係存在。調整後的危險比相對於為0.66(95%信賴區間,0.59-0.74),0.47(0.40-0.56),0.33(0.25-0.42)於斯達汀類藥物使用28-89,90-180,和>180每年累計日劑量,分別相對於沒有使用斯達汀類藥物(<28 cDDD)。糖尿病用藥metformin和 and thiazolidinediones有降低肝癌風險之效果。抗病毒用藥與斯達汀藥物對肝癌風險降低有加成之效果。
結論:斯達汀類藥物的使用在B型與C型肝炎病毒感染的患者可能會降低肝癌的風險,且有劑量反應的關係存在。後續需要進一步的機轉研究。

Background: Statins may have protective effects against cancer, but no studies have focused on their effects in patients with chronic hepatitis B and C virus infection. The prevalence rates of viral hepatitis are very high in Taiwan. The reimbursement database of National Health Insurance (NHI) in Taiwan provided an opportunity for surveillance. We conducted our study for four objectives; (1) to investigate whether statin use is associated with the reduction of hepatocellular carcinoma (HCC) incidence in hepatitis B virus (HBV) infected carriers; (2) to investigate whether statin use is associated with the reduction of HCC incidence in hepatitis C virus (HCV) infected patients; (3) to determine if there is a synergistic effect of statins, metformin, and thiazolidinediones (TZDs) on risk reduction of HCC in patients with HBV and/or diabetes; (4) to investigate the association between the use of nucleoside analogues (NAs), statins and the risk of HCC in HBV-infected patients.
Methods: First part: we conducted a population-based cohort study from the Taiwan National Health Insurance Research Database. A total of 33,413 HBV-infected patients were included as the study cohort. Each subject was individually tracked from 1997 to 2008 to identify incident cases of HCC since 1999. Subsequent use of statin, other lower-lipid agents, aspirin, and angiotensin-converting enzyme inhibitors were identified. Cox proportional hazard regressions were employed to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between the use of statins and the occurrence of HCC in the HBV-infected cohort. Second part: a population-based cohort study of 260,864 HCV-infected patients enrolled in the Taiwan National Health Insurance Research Database since January 1, 1999, and followed through December 31, 2010. Cox proportional hazards regression with time-dependent covariates for drug exposures was employed to evaluate the association between statin use and HCC risk. Third part: we conducted a population-based cohort study from the Taiwan National Health Insurance Research Database. A total of 33,413 HBV-infected patients were included as the study cohort. Each subject was individually tracked from 1997 to 2008 to identify incident cases of HCC since 1999. The diabetic prescriptions of medications that potentially could confound the association between statin use and cancer risk were also added, such as metformin and TZDs. Two Cox proportional hazard models were conducted with adjustment for different potential confounders to examine the association between HCC and the amounts of metformin and TZDs used. Forth part: A population-based matched cohort study of 91,265 HBV-infected patients enrolled in the Taiwan National Health Insurance Research Database since October, 2003 and December, 2010. 18,253 patients with NAs use were 1:4 matched as 73,012 patients without NAs use according to index date, age, sex, diabetes, liver cirrhosis, hypertension, hyperlipidemia, biliary tract stones, chronic renal injury, alcohol related diseases, and COPD. Cox proportional hazards regression model for drug exposures was employed to evaluate the association between NAs, statin use and HCC risk.
Results: First part provides additional information on the use of statin, with the finding that statin use may reduce the risk for HCC in HBV-infected patients in a dose-dependent manner. Second part provides additional information on the use of statin, with the finding that statin use may reduce the risk for HCC in HCV-infected patients in a dose-dependent manner. Third part provides additional information on the use of statin, with the finding that there is a protective effect on HCC risk reduction of metformin and TZD use. Forth part provides clinical information on the use of NAs and statin, with the finding if there is a synergistic effect on HCC risk reduction in HBV-infected patients in Taiwan.
Discussion: Statin use is dose-dependently associated with reduced risk for hepatocellular carcinoma in the presence of hepatitis B and hepatitis C viral infection. Statin use is an additional, convenient and acceptable strategy for preventing HCC in persons infected with hepatitis B and hepatitis C virus. The role of NAs and statins in cancer prevention continues to be an avenue for further investigation. A large-scale study is needed to clarify the association between HCC and the use of NAs, statin, metformin, and TZDs. Future studies should take into account the impact of these classes of pharmacological agents on reducing HCC risk, and adjust for them as potential confounders, even in clinical setting.

口試委員會審定書 iii
誌謝 vi
中文摘要 vii
Abstract ix
Chapter 1 Introduction 1
Background 1
1.1 Viral hepatitis and hepatocellular carcinoma 1
1.2 Antiviral treatment 1
1.3 Chemopreventive effect of statins 2
1.4 Mechanism of anticarcinogenic properties for statins 4
1.5 Synergistic effect on HCC risk reduction of metformin or thiazolidinediones 5
1.6 The database of National Health Insurance 6
Objectives 8
Aim I 8
Aim II 8
Aim III 8
Aim IV 8
Chapter 2 Materials and Methods 9
2.1 Data sources 9
2.1 Identification of study sample 9
2.2 Definition of hepatocellular carcinoma 11
2.3 Exposure to Statins 12
2.4 Potential Confounders 13
2.5 Statistical Analyses 14
Chapter 3 Results 20
3.1 Association between statin use and risk of HCC in HBV-infected patients 20
3.2 Association between statin use and risk of HCC in HCV-infected patients 21
3.3 Synergistic effect on HCC risk reduction of metformin or TZDs 23
3.4 Association between the use of NAs, statins and the risk of HCC in HBV-infected patients 24
Chapter 4 Discussion 26
4.1 Statins and risk of HCC in HBV-infected patients 26
4.2 Statins and risk of HCC in HCV-infected patients 31
4.3 Synergistic effect on HCC risk reduction of metformin or TZDs 35
4.4 The use of NAs, statins and the risk of HCC in HBV-infected patients 36
Chapter 5 Conclusion 38
Reference 39
Tables and Figures 47
Table 1 47
Table 2. 48
Table 3. 50
Table 4. 52
Table 5. 54
Table 6. 57
Table 7. 59
Table 8. 60
Table 9. 62
Table 10. 64
Table 11. 65
Figure 1. Study design flowchart of statin use and HCC in HCV cohort. 66
Figure 2.Study design flowchart of NAs, statins use, and risk of HCC in HBV cases. 67
Figure 3. Cumulative Incidence of Hepatocellular Carcinoma by Cumulative Defined Daily Dose (cDDD) of Statin Use during the Follow-up Period in the HBV-infected Cohort. 68
Figure 4. Cumulative rates of HCC events according to duration of statin use under different yearly time-weighted mean (TWM) cDDD in the HCV cohort. 69
Figure 5. Cumulative Incidence of Hepatocellular Carcinoma of NAs and Statin Uses during the Follow-up Period in the HBV-infected Cohort. 70
Appendix 71



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