臺灣博碩士論文加值系統

研究目的:
全口服直接抗病毒藥物(Daclatasvir加Asunaprevir)對於治療C型肝炎第1b型感染患者在全球性第三期臨床試驗(HALLMARK-DUAL1 study)與日本全國性第三期臨床試驗中獲得高的治療反應。目前已於日本、韓國等許多國家上市，臺灣也已於2016年3月上市，但目前臺灣臨床使用的經驗尚不多。本研究的目的為探究Daclatasvir加Asunaprevir對於治療臺灣C型肝炎第1b型感染患者的臨床結果與治療相關副作用分析。
研究方法及資料：
本研究收集來自中臺灣一家醫學中心及一家區域醫院，慢性C型肝炎單一感染且為基因型第1b型感染病人共五十名，取得病患同意下進行NS5A的抗藥性突變位點（resistance-associated variants, RAVs）檢測。其中五位(10%)患者因為檢測出NS5A的抗藥性突變位點（RAVs）而排除於本研究。共有二十七位患者完成共二十四週的(Daclatasvir加Asunaprevir）治療，並於治療結束後接受共二十四週的追蹤，以探討其治療效果，包括持續病毒學抑制反應與相關副作用等安全觀察。並將結果與全球性第三期臨床試驗(HALLMARK-DUAL1 study)作比較。
研究結果：
在研究族群中，平均年齡為57歲，男女比為5比4。其中63% (17/27)的人有較嚴重之肝纖維化或代償性肝硬化；56%的人曾經接受過干擾素(Interferon)加上雷巴威靈(Ribavirin)治療。治療第四週達到病毒學抑制反應的比例，本研究為89% (24/27)，全球性第三期臨床試驗為74% (477/643)。治療完成後十二週達到持續病毒學抑制反應的比例，本研究較全球性第三期臨床試驗為高。治療完成後十二週的達到持續病毒學抑制反應的比例分別為初次治療族群100% (12/12)，對干擾素加上雷巴威靈治療無法耐受族群89%(8/9)，對治療無效族群83% (5/6)。治療族群中，本身肝臟狀況較嚴重，即有較嚴重之肝纖維化或代償性肝硬化者，曾經接受過干擾素加上雷巴威靈治療者，以及有較高病毒量(HCV RNA ≥ 800,000 IU/mL)的族群，其治療完成後十二週達到持續病毒學抑制反應的比例較低。在治療中最常見的副作用為頭暈(3/27)，發熱(1/27)與疲倦(1/27)。在治療過程中，無人因為嚴重副作用而停止治療。
結論與建議：
DACLATASVIR加ASUNAPREVI對於臨床治療慢性C型肝炎第1b型感染且無NS5A的抗藥性突變之患者耐受性良好，並且可維持高的持續病毒學抑制反應。

Introduction:
All-oral direct-acting agent dual therapy with Daclatasvir plus Asunaprevir (DCV+ASV) achieved high sustained virological responses (SVR) in genotype 1b (GT-1b) HCV patients in the HALLMARK-DUAL1 study and Phase 3 Japanese study2,3. DCV + ASV is approved in several countries including Taiwan in March, 2016, Japan, Korea, and Latin America, Eastern Europe. In this study, real-world experience of DCV+ASV dual therapy in HCV GT-1b patients was reported.
Purpose:
To evaluate the efficacy and safety of DCV+ASV therapy in GT-1b HCV infected Taiwanese patients in real-world.
Method:
Fifty GT-1b HCV infection patients received dual therapy were enrolled at two hospitals in central Taiwan. Five patients (10%) were excluded due to existence of baseline resistance-associated variants (RAVs). Outcomes from 27 patients, who had received 24 weeks dual therapy and been followed up for 24 weeks after end of treatment, were recorded and analyzed. Sustained virologic response at post-treatment week 12 and week 24(SVR12/SVR24) and safety profiles were evaluated. The results were compared with those from HALLMARK-DUAL study.
Result:
In the real-world group, the mean age was 57 years old ( male/female: 5/ 4); 63% (17/27) patients had advanced liver fibrosis or compensated cirrhosis; 56% patients were treatment-experienced. Virologic response(defined as HCV RNA < LLOQ )at week 4 was 89% (24/27) in the real-world group and74% (477/643) in phase 3 clinical trial group. SVR12 rate was higher than the phase 3 clinical trial group (93 % vs. 84%). SVR12 rates were100% (12/12), 89% (8/9) and 83% (5/6)in treatment-naive, ineligible/intolerant and non-responder patients, respectively. Patients with advanced liver disease or cirrhosis, experience of previous treatment, and higher baseline viral load (HCV RNA ≥ 800,000 IU/mL) had lower SVR 12. The results were similar to those from phase 3 study. Common adverse events included dizziness ( 3/27), pyrexia ( 1/27) and fatigue ( 1/27).There were neither SAE nor AE leading to treatment discontinuation occurred.
Conclusion:
Daclatasvir plus Asunaprevir were well-tolerated and resulted in a higher SVR rate in the Taiwanese real-world GT-1b HCV patients without baseline NS5A RAVs.

壹、中文摘要 1
Abstract 4
貳、文獻綜論 6
一、前言 6
二、C型肝炎的病毒學與流行病學 6
三、慢性 C 型肝炎之治療進展...................7
四、直接抗病毒藥物對於治療C型肝炎的作用機制與發展.............10
參、研究動機與目的 13
肆、研究方法與材料 14
一、選擇研究的對象 14
二、研究的設計 14
三、用藥前基因型檢測及NS5A病毒基因突變測試(RAV) 15
四、治療前中後之病毒學反應 15
五、可能影響持續病毒學抑制反應的因子 16
六、 治療中常見副作與嚴重副作用 16
伍、研究結果 17
一、基本資料 17
二、治療前中後之病毒學反應 19
三、影響持續病毒學抑制反應的可能因子..................23
四、常見副作用與嚴重副作用 25
陸、討論 27
柒、結論 32
捌、參考文獻 33
表目錄
表1 : 病人的基本資料 18
表2 : 常見副作用與嚴重副作用 26

圖目錄
圖1 : 治療完成後十二週持續病毒學抑制反應 21
圖2 : 不同C型肝炎治療經驗對持續病毒學抑制反應的影響 21
圖3 :不同C型肝炎治療經驗在治療期間與治療後追蹤期間之病毒學反應 22
圖4 :不同肝臟狀況與共病症對持續病毒學抑制反應的影響......24

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