Evaluation of mutations in hepatitis C virusNS5A-PKR binding domain on the effect of combination therapy with pegylatedinterferon and ribavirin

• Main Authors: Yi-Ping Chen, 陳怡蘋
• Other Authors: 周寬基
• Format: Others
• Language: zh-TW
• Published: 2009
• Online Access: http://ndltd.ncl.edu.tw/handle/98017660255216741801

碩士 === 國立中興大學 === 生命科學院碩士在職專班 === 98 === 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.