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標題: C型肝炎病毒之NS5A-PKR結合區域突變對長效型干擾素和雷巴威林合併療法的影響評估
Evaluation of mutations in hepatitis C virusNS5A-PKR binding domain on the effect of combination therapy with pegylatedinterferon and ribavirin
作者: 陳怡蘋
Chen, Yi-Ping
關鍵字: HCV;C型肝炎病毒;peginterferon;individualized therapy;NS5A;PKR binding domain;ISDR;長效型干擾素;個人化治療;NS5A;蛋白激酶;接受器結合區域;干擾素敏感決定區
出版社: 生命科學院碩士在職專班
C型肝炎病毒感染是一導致肝硬化或肝癌的主因,雖然長效型干擾素(peginterferon)和雷巴威林(ribavirin)合併治療可達至少50%的持續病毒反應(sustained virological response, SVR),但為了避免對一些個人和治療不足的病人過度治療,使用個人化反應率可使治療更有效進行。合宜地個人化治療(individualized therapy)對所有的慢性C型肝炎病患並非完全有效,C型肝炎病毒NS5A蛋白之蛋白激酶接受器結合區域(protein kinase receptor binding domain, PKRBD;codons 2209-2274)內含干擾素敏感決定區(interferon sensitivity determining region, ISDR;codons 2209-2248)可能藉阻斷干擾素(interferon, IFN)誘導蛋白激酶(protein kinase, PKR)調解各方面的抗病毒作用而影響基礎干擾素療法的反應。因此,我們針對HCV-1b的患者於當代個人化治療下,探討其PKR binding domain包括干擾素敏感決定區(ISDR)及其下游鄰近26個胺基酸之突變對治療的影響。有37個病人根據基礎病毒量結合快速及早期病毒反應給予量身訂做、合宜地治療方針,而有23個病人則無依照治療方針或以次合宜的療法治療,藉由聚和酶連鎖反應及定序分析決定病患治療前血清C型肝炎病毒PKR binding domain的胺基酸序列。整體來說,接受合宜個人化治療病人的持續病毒反應為78.4%,較優於接受次合宜治療病人的持續病毒反應(47.8%,p=0.015),而多變項分析顯示合宜地個人化療法(p=0.019)和80/80/80 adherence(p=0.006)對整個研究世代是獨立預測因子,進一步次分析個人化治療之預測因子,結果顯示在ISDR下游的26個胺基酸是唯一持續病毒反應的預測因子(p=0.024)。故ISDR下游的26個胺基酸突變仍可作為當代合宜地個人化治療時持續病毒反應的預測因子。

Hepatitis C virus (HCV) infection, a leading cause of end-stage liver disease such as cirrhosis or hepatocellular carcinoma. Although therapy with peginterferon and ribavirin will achieve at least a 50% chance of sustained virological response(SVR), individual response rate can be further optimized in order to avoid overtreatment in some individuals and undertreatment in others. Optimally individualized therapeutic approach is not effective in all chronic hepatitis C patients. The NS5A of HCV-1b with a wild-type interferon sensitivity determining region (ISDR) sequence (codons 2209-2248) within protein kinase R (PKR)-binding domain (codons 2209-2274) has the potential to block the interferon (IFN)-induced PKR that mediates various aspects of the antiviral effect, which may therefore influence the response to interferon based therapies. We investigated whether the substitutions in PKR binding domain (PKRBD), including the interferon sensitivity-determine region (ISDR) and 26 additional downstream amino acids from ISDR, would have effects upon chronic HCV-1b infected patients in the era of individualized therapy. Thirty-seven patients were treated with optimally tailored therapy guided by baseline viral load combined with rapid and early virological responses while 23 patients were treated without guidance and/or assigned suboptimal treatment duration. The amino acid sequences of the PKRBD were determined by PCR and sequencing. The overall SVR rate of patients who received optimally individualized therapy was 78.4%, which was better than the SVR rate of patients who received suboptimal therapy (47.8%, P = 0.015). Multivariate analysis showed that optimally individualized therapy (P = 0.019) and 80/80/80 adherence (P = 0.006) were independent favorable predictors of SVR in the entire cohort. Further sub-analysis of the predictive factors of SVR in patients treated with optimally individualized therapy showed that mutations in the 26-amino acid downstream from the ISDR (P = 0.024) was the only independent predictor of SVR. Mutations in 26-amino acid downstream portion from the ISDR remained a prognosticator of SVR in the era of optimally tailored therapy.
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