C型肝炎抗病毒治療在肝外併發症的效益

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Title:	C型肝炎抗病毒治療在肝外併發症的效益 Effectiveness of antiviral therapy for hepatitis C virus infection in extrahepatic outcomes
Authors:	許耀峻;Yao-Chun Hsu
Contributors:	臨床醫學研究所博士班
Keywords:	C型肝炎;抗病毒治療;胰島素抗性;肝外併發症;臨床效益;Hepatitis C virus;antiviral therapy;insulin resistance;extrahepatic outcomes;clinical effectiveness
Date:	2015-01-21
Issue Date:	2015-11-04 17:03:19 (UTC+8)
Publisher:	中國醫藥大學
Abstract:	背景: C型肝炎是全球重要的公共衛生問題，也戕害國人健康甚鉅。C肝病毒感染不僅是肝硬化和肝癌的主要病因，也會導致許許多多肝外併發症，以往研究已顯示C型肝炎常合併胰島素阻抗增加，冷凝蛋白血症，腎絲球炎，自體免疫疾患，心血管病變等等肝外表現，也有大量證據指出C型肝炎患者較非感染者容易罹患糖尿病，缺血性中風，動脈粥狀硬化，末期腎病，自體免疫疾病等非肝臟方面的臨床疾病。針對C型肝炎的抗病毒治療，長效型干擾素合併雷巴威林是過去十年的標準療法，因宿主28號介白素基因型的關係，在亞洲國家如台灣的療效特別好，整體病毒清除率可達七成以上。充分的資料顯示，有效的C肝抗病毒治療可減少肝臟疾病的危害，例如停滯甚至逆轉肝纖維化，預防肝癌的發生與術後再發，以及避免肝代償不全與肝病相關死亡率，然而，抗病毒藥物對於C型肝炎肝外併發症的療效，卻仍然不是很清楚，特別是能否經由治療C肝病毒來改善患者的肝臟以外臨床結果，有關文獻仍相當缺乏，有鑑於此，本研究主旨在釐清抗病毒治療是否能降低C型肝炎病人發生肝外疾病的風險。首先探討的是病毒廓清對胰島素抗性的影響，並特別考慮療程中體重變化可能扮演的因素；接著研究已罹患糖尿病的C型肝炎患者，接受抗病毒治療是否會改變腎臟和心血管方面的預後；最後，研究擴展至包含全台灣所有曾經被診斷C型肝炎的患者，分析抗病毒治療和罹患各種肝外併發症的關聯性。本研究可分成下列三個部分: 第一部分: 清除C型肝炎病毒降低胰島素抗性目的: C型肝炎感染會導致胰島素抗性；本研究擬探討C型肝炎患者在接受干擾素與雷巴威林抗病毒治療前後胰島素抗性的動態變化並且分析胰島素抗性改變和病毒廓清與否的關聯性。方法: 這個前瞻性研究募集接受長效型干擾素與雷巴威林治療的C型肝炎患者。根據治療結束24週後是否達到病毒擴清定義是否治療成功。在患者接受抗病毒治療之前，結束時，以及結束24週後，以間接方法HOMA-IR測量胰島素抗性. 結果: 本部份研究共收案65位患者，其中46人(71%) 成功達成病毒廓清。就整體而言，胰島素抗性在治療期間顯著下降，HOMA-IR中位數(四分位差)從治療前的3.7 (1.6-10.0) 下降至治療結束時的1.5 (0.8-2.9), 療程結束24週後為1.6 (0.9-3.1)。不論治療成功或失敗，停藥時的HOMA-IR都顯著比治療前低。然而，停藥24週後相較於治療前的胰島素抗性，只有在成功廓清病毒者顯著降低(p<0.0001)，中位數分別為 1.3 (0.7-2.6) 和3.6 (1.5-9.9)。對那些治療失敗者，療程結束24週後的HOMA-IR (中位數2.2; 四分位差, 1.9-4.7) 和治療前 (中位數 3.9; 四分位差, 2.2-10.0) 並無統計差異(p=0.5)。病毒成功廓清者的體重質量指數在治療前與停藥24週後並無顯著差異。結論: C型肝炎患者接受長效型干擾素合併雷巴威林的抗病毒療程後，胰島素抗性顯著改善；然而停藥24週後，只有成功廓清病毒者的胰島素抗性比治療前低。第二部分 : C型肝炎抗病毒治療改善糖尿病患者的腎臟及心血管預後目的: 根據我們和他人的研究，治療C型肝炎可改善患者的胰島素抗性並減少未來發生糖尿病的風險，但是已經罹患糖尿病的C型肝炎病人，抗病毒治療是否仍可改善臨床預後，則仍屬未知，因此本部份研究著重於糖尿病合併C型肝炎患者接受抗病毒治療對末期腎病，急性冠心症，和缺血性中風風險的影響。方法: 本研究分析台灣全民健康保險資料庫，自1997年初至2011年底，從2,267,270位糖尿病患者逐步篩檢，以特定疾病診斷與血清檢查代碼定義C型肝炎感染者，在排除癌症，肝代償不全，慢性腎病，冠狀動脈心臟病，中風，精神異常等嚴重合併症後, 依照C型肝炎有無，感染者是否曾接受抗病毒治療，先確定1,411位曾接受長效干擾素和雷巴威林治療的C肝患者(治療組), 再根據傾向分數(propensity score) 1:1比例配對1,411位罹患C肝但未治療者(未治療組), 1:4配對5,644有糖尿病但無C肝感染者(未感染組)。我們計算並比較這三組患者在末期腎病，急性冠心病，以及缺血性中風的發生風險。結果: 治療組，非治療組，非感染組末期腎臟病的8年累積發生率(95%信心區間)分別為1.1% (0.3-2.0%), 9.3% (5.9-12.7%), 和3.3% (2.3-4.3%)；缺血性中風為3.1% (1.1-5.0%), 5.3% (3.0-7.5%), 6.1% (4.8-7.4%)，急性冠心症為4.1% ( 2.1-6.1%), 6.6% (3.7-9.5%) 和7.4% (5.9-9.0%)。以多變數風險迴歸模型調整干擾因子後，抗病毒治療在末期腎病, 缺血性中風, 以及急性冠心症的風險比值,分別為0.16 (0.07-0.33 )，0.53 (0.30-0.93)，和0.64 (0.39-1.06)。結論: 慢性C型肝炎且患有糖尿病的病人，使用長效型干擾素與雷巴威林治療病毒者，有顯著較佳的腎臟與心血管臨床預後。第三部分: 抗病毒治療與C型肝炎肝外併發症的關聯性目的: C型肝炎病毒感染會導致肝外併發症，本系列研究第二部份也證實治療C型肝炎可有助於降低糖尿病患者腎臟和心血管疾病的風險，在此基礎上，本部份擬進一步釐清在整體C型肝炎患者抗病毒治療和肝外併發症的關聯性方法: 這是個全國性世代研究，自293,480位曾被診斷C型肝炎的台灣民眾篩選符合條件者，排除罹患嚴重共病症的病人。當中一共12,384位合格患者在2003年10月1日與2010年12月31日之間接受過長效型干擾素加雷巴威林抗病毒治療，此為治療組，再用傾向分數配對(propensity score-matching)法，以1:2比例找出24,768位從未接受過治療的患者，此為對照組。在調整過死亡造成的風險競爭(competing risk)效應後，本研究推算並比較兩組在末期腎病，急性冠心症，缺血性中風，與重大自體免疫疾病的累積發生率與罹病風險。結果: 到2011年12月31日止，治療組與對照組分別被追蹤了平均(± 標準差) 3.3 (± 2.5) 和3.2 (± 2.4)年。前者比起後者在末期腎病，急性冠心症，缺血性中風，與重大自體免疫疾病的八年累積發生率分別為0.15% 與 1.32% (p<0.001), 2.21% 與2.96% (p=0.027), 1.31% 與 1.76% (p=0.001), 以及 0.57% 與 0.49% (p=0.816)。多變數Cox 比例風險模式顯示接受抗病毒治療者在末期腎病(風險比值, 0.15; 95% 信心區間, 0.07-0.31; p<0.001), 急性冠心症 (風險比值, 0.77; 95% 信心區間, 0.62-0.97; p=0.026), 以及缺血性中風 (風險比值, 0.62; 95% 信心區間, 0.46-0.83; p=0.001)有顯著較低的發生風險，不過抗病毒治療和重大自體免疫疾病無關。我們進一步發現治療必須至少16 週以上，這些治療有益的關聯性才成立結論: C型肝炎患者接受抗病毒治療，腎臟與循環系統併發症的風險顯著較低，但與重大自體免疫疾病無關。 Background: Hepatitis C virus (HCV) infection is an important public health problem, both globally around the world and locally in Taiwan. It is not only the major etiology of cirrhosis and hepatocellular carcinoma, but also a cause of various extrahepatic complications. Previous studies have shown that chronic hepatitis C is frequently associated with increased insulin resistance, cryoglobulinemia, glomerulonephritis, autoimmune disorder, cardiovascular disease, and so on. Also, there is a large body of evidence indicating that as compared with uninfected individuals, HCV-infected patients are exposed to higher risks of extrahepatic clinical diseases such as diabetes mellitus, ischemic stroke, atherosclerosis, end-stage renal disease, and autoimmune diseases. Pegylated interferon plus ribavirin has been the standard therapy for hepatitis C virus infection for one decade. Because the prevalent host IL28B genotype favors interferon-based treatment, this regimen achieves a high successful rate of viral eradication in Asian countries, particularly in Taiwan where more than 70% of treated patients can clear the virus. Convincing data has demonstrated that effective antiviral treatment for HCV infection is able to reduce liver-related morbidity and mortality. For example, it can halt and even reverse liver fibrosis, prevent occurrence and recurrence of hepatocellular carcinoma, and decrease hepatic decompensation and death. Nonetheless, effectiveness of antiviral therapy in extrahepatic complications of HCV infection has not been elucidated. There remains a striking paucity of literature that address whether liver-unrelated clinical outcomes can be improved by treating HCV. In order to bridge this knowledge gap, this series of researches aimed to clarify if antiviral treatment was able to attenuate the risks of extrahepatic diseases in patients with HCV infection. First of all, this study dealt with the influence of HCV viral clearance on severity of insulin resistance. The confounding effect of body weight change was taken into account. Then, diabetic patients with HCV infection were studied to clarify if their renal as well as cardiovascular outcomes would be influenced by antiviral therapy. Finally, the study was expanded to encompass all Taiwanese residents diagnosed with HCV infection to elucidate the association between treatment for the virus and extrahepatic outcomes. This study accordingly is divided into three parts: Part 1: Eradication of HCV is associated with amelioration of insulin resistance Specific aims: HCV infection can exacerbate insulin resistance, but the dynamics of insulin resistance in HCV-infected patients receiving pegylated interferon plus ribavirin remain elusive. This part of study aimed to investigate the change of insulin resistance before, at the end of, and 24 weeks after the antiviral treatment for HCV infection, and to correlate the dynamics of insulin resistance with viral eradication. Methods: The prospective study enrolled HCV-infected patients who received pegylated interferon plus ribavirin. Patients were classified according to the attainment of sustained virological response (SVR). The insulin resistance was measured by homeostatic model assessment-insulin resistance (HOMA-IR). The change of HOMA-IR at baseline, the end-of-treatment, and 24-weeks after the end-of-treatment was compared in patients who achieved SVR or not. Results: A total of 65 patients participated in this study and 46 (71%) of them achieved SVR. Overall, The HOMA-IR changed significantly during antiviral therapy, with the median values (interquartile range, IQR) of 3.7 (1.6-10.0) prior to treatment, 1.5 (0.8-2.9) at the end, and 1.6 (0.9-3.1) 24 weeks after completion of therapy. However, only patients who achieved SVR had significant off-therapy reduction of HOMA-IR, with the median values of 1.3 (IQR, 0.7-2.6) 24 weeks off therapy and 3.6 (IQR, 1.5-9.9) at baseline, respectively (p<0.0001). In those without SVR, the HOMA-IR measured 24 weeks after treatment completion (median, 2.2; IQR, 1.9-4.7) did not differ from their baseline (median, 3.9; IQR, 2.2-10.0; p=0.5). Conclusion: Dual therapy with pegylated interferon plus ribavirin ameliorated IR in HCV-infected patients, but the off-therapy improvement of IR was limited to those who attained SVR. Part 2: Antiviral therapy is associated with improved renal and cardiovascular outcomes in diabetic patients with HCV infection Specific aims: According to our and others researches, HCV eradication could ameliorate insulin resistance and lower the hazard of diabetes mellitus in infected individuals. However, it remained unknown whether treatment for concomitant HCV infection was able to improve clinical outcomes in diabetic patients. Therefore, this population-based cohort study aimed to investigate whether antiviral therapy for HCV infection was associated with improved clinical outcomes related to diabetes. Methods: From the Taiwan National Health Insurance Research Database, 2,267,270 residents diagnosed with diabetes mellitus were screened. HCV infection was defined by a specific diagnosis code and measurement of serum antibody. After excluding patients with serious comorbidity, we enrolled a total of 1,411 eligible patients who received pegylated interferon plus ribavirin, and matched them 1:1 with 1,411 untreated controls by propensity scores. We also matched the treated cohort 1:4 with 5,644 diabetic patients without HCV infection. Participants were followed up for the occurrence of end-stage renal disease (ESRD), ischemic stroke, and acute coronary syndrome (ACS) after receiving antiviral treatment or the corresponding date. Results: From 2003 to 2011, the 8-year cumulative incidences of ESRD in the treated, untreated, and uninfected cohorts were 1.1% (95% confidence interval [CI], 0.3-2.0%), 9.3% (95% CI, 5.9-12.7%), and 3.3% (95% CI, 2.3-4.3%), respectively (p<0.001); those of stroke were 3.1% (95% CI, 1.1-5.0%), 5.3% (95% CI, 3.0-7.5%), and 6.1% (95% CI, 4.8-7.4%), respectively (p=0.01); and those for ACS were 4.1% (95% CI, 2.1-6.1%), 6.6% (95% CI, 3.7-9.5%), and 7.4% (95% CI, 5.9-9.0%), respectively (p=0.05). As compared with the untreated cohort, antiviral treatment was associated with multivariate-adjusted hazard ratios of 0.16 (95% CI, 0.07-0.33%) for ESRD, 0.53 (95% CI, 0.30-0.93) for ischemic stroke, and 0.64 (95% CI, 0.39-1.06) for ACS, respectively. Conclusions: Antiviral treatment for HCV infection is associated with improved renal and cardiovascular outcomes in diabetic patients. Part 3: Association between Antiviral Therapy and Extrahepatic Outcomes in HCV-infected Individuals Specific aims: On the basis of the second part of this study, which demonstrated the beneficial effect of treating HCV on renal and circulatory outcomes in infected individuals with diabetes mellitus, the third part further set out to elucidate the association between extrahepatic outcomes and antiviral therapy in all Taiwanese residents with a diagnosis HCV infection. Methods: This nationwide cohort study screened totally 293,480 Taiwanese residents with HCV infection and excluded those with substantial comorbidity. The treated cohort enrolled 12,384 eligible patients who had received pegylated interferon plus ribavirin between October 1, 2003 and December 31, 2010, and were matched 1:2 with 24,768 untreated controls in the propensity score and post-diagnosis treatment-free period. The incidences of end-stage renal disease (ESRD), acute coronary syndrome (ACS), ischemic stroke, and catastrophic autoimmune diseases were calculated after adjustment for competing mortality. Results: The treated and untreated cohorts were followed up for a mean (± standard deviation) duration of 3.3 (± 2.5) and 3.2 (± 2.4) years, respectively, until December 31, 2011. The calculated 8-year cumulative incidences of ESRD, ACS, ischemic stroke, and autoimmune catastrophes between treated and untreated patients were 0.15% versus 1.32% (p<0.001), 2.21% versus 2.96% (p=0.027), 1.31% versus 1.76% (p=0.001), and 0.57% versus 0.49% (p=0.816), respectively. Multivariate-adjusted Cox regression revealed that antiviral treatment was associated with lower risks of ESRD (hazard ratio [HR], 0.15; 95% confidence interval [CI], 0.07-0.31; p<0.001), ACS (HR, 0.77; 95% CI, 0.62-0.97; p=0.026), and ischemic stroke (HR, 0.62; 95% CI, 0.46-0.83; p=0.001), but unrelated to autoimmune catastrophes. We further unraveled that these favorable associations were invalid in incompletely treated patients with duration <16 weeks. Conclusions: Antiviral treatment for HCV is associated with improved renal and circulatory outcomes, but unrelated to catastrophic autoimmune diseases.
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