Please use this identifier to cite or link to this item:
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 virus NS5A-PKR binding domain on the effect of combination therapy with pegylated interferon and ribavirin
作者: 陳怡蘋
Chen, Yi-Ping
關鍵字: HCV;長效型干擾素;peginterferon;individualized therapy;NS5A;PKR binding domain;ISDR;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
引用: Akuta N, Suzuki F, Hirakawa M, Kawamura Y, Yatsuji H, Sezaki H, et al. A matched case-controlled study of 48 and 72 weeks of peginterferon plus ribavirin combination therapy in patients infected with HCV genotype 1b in Japan: amino acid substitutions in HCV core region as predictor of sustained virological response. J Med Virol 2009; 81:452-8. Akuta N, Suzuki F, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, et al. Predictive factors of early and sustained responses to peginterferon plus ribavirin combination therapy in Japanese patients infected with hepatitis C virus genotype 1b: amino acid substitutions in the core region and low-density lipoprotein cholesterol levels. J Hepatol 2007; 46:403-10. Akuta N, Suzuki F, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, et al. Predictors of viral kinetics to peginterferon plus ribavirin combination therapy in Japanese patients infected with hepatitis C virus genotype 1b. J Med Virol 2007; 79:1686-95. Alter MJ. Epidemiology of hepatitis C in the west. Semin Liver Dis 1995; 15:5–14. Arima N, Kao CY, Licht T, Padmanabhan R, Sasaguri Y, Padmanabhan R. Modulation of cell growth by the hepatitis C virus nonstructural protein NS5A. J Biol Chem 2001; 276:12675-84. Baek KH, Park HY, Kang CM, Kim SJ, Jeong SJ, Hong EK, et al. Overexpression of hepatitis C virus NS5A protein induces chromosome instability via mitotic cell cycle dysregulation. J Mol Biol 2006; 359:22-34. Blight KJ, Kolykhalov AA, Rice CM. Efficient initiation of HCV RNA replication in cell culture. Science 2000; 290:1972-4. Blumberg BS, Gerstley BJ, Hungerford DA, London WT, Sutnick AI. A serum antigen (Australia antigen) in Down''s syndrome, leukemia, and hepatitis. Ann Intern Med 1967; 66:924-31. Brass V, Moradpour D, Blum HE. Molecular Virology of Hepatitis C Virus (HCV): 2006 Update. Int J Med Sci 2006; 3:29-34. Chen CH, Sheu JC, Wang JT, Huang GT, Yang PM, Lee HS, Lee CZ, Chen DS. Genotypes of hepatitis C virus in chronic liver disease in Taiwan. J Med Virol 1994; 44:234-6. Chen DS. Hepatitis C virus in chronic liver disease and hepatocellular carcinoma in Taiwan. Princess Takamatsu Symp 1995; 25:27-32. Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989; 244:359-62. Cornberg M, Wedemeyer H, Manns MP. Treatment of chronic hepatitis C with pegylated interferon and ribavirin. Curr Gastroenterol Rep 2002; 4: 23-30. Cuenda A, Rousseau S. p38 MAP-kinases pathway regulation, function and role in human diseases.Biochim Biophys Acta 2007; 1773:1358-75. De Francesco R.Molecular virology of the hepatitis C virus. J Hepatol 1999; 31(Suppl.1):47-53. Durante Mangoni E, Forton DM, Ruggiero G, Karayiannis P. Hepatitis C virus E2 and NS5A region variability during sequential treatment with two interferon-alpha preparations. J Med Virol 2003; 70:62-73. Enomoto N, Sakuma I, Asahina Y, Kurosaki M, Murakami T, Yamamoto C, Izumi N, Marumo F, Sato C. Comparison of full-length sequences of interferon-sensitive and resistant hepatitis C virus 1b. Sensitivity to interferon is conferred by amino acid substitutions in the NS5A region. J Clin Invest 1995; 96:224-30. Enomoto N, Sakuma I, Asahina Y, Murakami T, Yamamoto C, Ogura Y, Izumi N, Marumo F, Sato C. Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection. N Engl J Med 1996; 334:77-81. Fattovich G, Giustina G, Degos F Diodati G, Tremolada F, Nevens F, et al Effectiveness of interferon alfa on incidence of hepatocellular carcinoma and decompensation in cirrhosis type C. European Concerted Action on Viral Hepatitis (EUROHEP). J Hepatol 1997; 27:201-5. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonçales FL Jr, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.N Engl J Med 2002; 347:975-82. Gale MJ Jr, Korth MJ, Tang NM, Tan SL, Hopkins DA, Dever TE, Polyak SJ, Gretch DR, Katze MG. Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein. Virology 1997; 230:217-27. Gale M Jr, Blakely CM, Kwieciszewski B Tan SL, Dossett M, Tang NM, Korth MJ, Polyak SJ, Gretch DR, Katze MG. Control of PKR protein kinase by hepatits C virus nonstructural 5A protein: molecular mechanisms of kinase regulation. Mol Cell Biol 1998; 18:5208-18. Griffin SD, Beales LP, Clarke DS, Worsfold O, Evans SD, Jaeger J, Harris MP, Rowlands DJ. The p7 protein of hepatitis C virus forms an ion channel that is blocked by the antiviral drug, Amantadine. FEBS Lett 2003; 535:34-8. Hadziyannis SJ, Papatheodoridis GV. Peginterferon-alpha2a (40 kDa) for chronic hepatitis C. Expert Opin Pharmacother 2003; 4:541-51. Hadziyannis SJ, Sette H Jr, Morgan TR, Balan V, Diago M, Marcellin P, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004; 140:346-55. He Y, Tan SL, Tareen SU, Vijaysri S, Langland JO, Jacobs BL, Katze MG. Regulation of mRNA translation and cellular signaling by hepatitis C virus nonstructural protein NS5A. J Virol 2001; 75:5090-8. Hope RG, Murphy DJ, McLauchlan J. The domains required to direct core proteins of hepatitis C virus and GB virus-B to lipid droplets share common features with plant oleosin proteins. J Biol Chem 2002; 277: 4261-70. Hsu CS, Liu CH, Liu CJ, Chen CL, Lai MY, Chen PJ, Chen DS, Kao JH. Factors affecting early viral load decline of Asian chronic hepatitis C patients receiving pegylated interferon plus ribavirin therapy. Antivir Ther 2009; 14:45-54. Hung CH, Chen CH, Lee CM, Wu CM, Hu TH, Wang JH, Yen YH, Lu SN. Association of amino acid variations in the NS5A and E2-PePHD region of hepatitis C virus 1b with hepatocellular carcinoma. J Viral Hepat 2008; 15:58-65. Jensen DM, Morgan TR, Marcellin P, Pockros PJ, Reddy KR, Hadziyannis SJ, Ferenci P, Ackrill AM, Willems B. Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alpha-2a (40 kd)/ribavirin therapy. Hepatology 2006; 43:954-60. Kao JH, Chen PJ, Lai MY, Yang PM, Sheu JC, Wang TH, Chen DS. Genotypes of hepatitis C virus in Taiwan and the progression of liver disease. J Clin Gastroenterol 1995; 21:233-7. Kato N, Hijikata M, Ootsuyama Y, Nakagawa M, Ohkoshi S, Sugimura T, Shimotohno K. Molecular cloning of the human hepatitis C virus genome from Japanese patients with non-A, non-B hepatitis. Proc Natl Acad Sci USA 1990; 87:9524-8. Krugman S, Giles JP, Hammond J. Infectious hepatitis. Evidence for two distinctive clinical, epidemiological, and immunological types of infection. JAMA 1967; 200:365-73 Lai CF, Chaudhary L, Fausto A, Halstead LR, Ory DS, Avioli LV, Cheng SL. Erk is essential for growth, differentiation, integrin expression, and cell function in human osteoblastic cells. J Biol Chem 2001; 276:14443-50. Lai MY. Firstline treatment for hepatitis C: combination interferon/ribavirin versus interferon monotherapy. J Gastroenterol Hepatol 2000; 15(Suppl):E130-3. Lai MY, Kao JH, Yang PM, Wang JT, Chen PJ, Chan KW, Chu JS, Chen DS. Long-term efficacy of ribavirin plus interferon alfa in the treatment of chronic hepatitis C. Gastroenterology 1996; 111:1307-12. Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med 2001; 345:41-52. Lerat H, Honda M, Beard MR, Loesch K, Sun J, Yang Y, et al. Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus. Gastroenterology 2002; 122:352-65. Lindenbach BD, Rice CM. Unravelling hepatitis C virus replication from genome to function. Nature 2005; 436:933-8. Lin HH, Kao JH, Mizokami M, Huang SC, Chen PJ, Chen DS. Serotypes, genotypes and levels of hepatitis C viremia in pregnant women in Taiwan. J Formos Med Assoc 1996; 95:429-34. Liu CH, Liu CJ, Lin CL, Liang CC, Hsu SJ, Yang SS, et al. Pegylated interferon-alpha-2a plus ribavirin for treatment-naive Asian patients with hepatitis C virus genotype 1 infection: a multicenter, randomized controlled trial. Clin Infect Dis 2008; 47:1260-9. Maekawa S, Enomoto N. Viral factors influencing the response to the combination therapy of peginterferon plus ribavirin in chronic hepatitis C. J Gastroenterol 2009; 44:1009-15. Mangia A, Minerva N, Bacca D, Cozzolongo R, Ricci GL, Carretta V, et al. Individualized treatment duration for hepatitis C genotype 1 patients: A randomized controlled trial. Hepatology 2008; 47:43-50. Manns MP, McHutchinson JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK.Peginterferon-alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001; 358:958-65. Martinot-Peignoux M, Marcellin P, Pouteau M, Castelnau C, Boyer N, Poliquin M, et al. Pretreatment serum hepatitis C virus RNA levels and hepatitis C virus genotype are the main and independent prognostic factors of sustained response to interferon alfa therapy in chronic hepatitis C. Hepatology 1995; 22:1050-6. McCaughan GW, Omata M, Amarapurkar D, Bowden S, Chow WC, Chutaputti A, et al. Asian Pacific Association for the Study of the Liver consensus statements on the diagnosis, management and treatment of hepatitis C virus infection. J Gastroenterol Hepatol 2007; 22:615-33. McHutchison JG, Manns M, Patel K, Poynard T, Lindsay KL, Trepo C,et al. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology 2002; 123:1061-9. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, Goodman ZD, Ling MH, Cort S, Albrecht JK. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 1998; 339:1485-92. Moriya K, Fujie H, Shintani Y, Tsutsumi T, Ishibashi K, Matsuura Y, Kimura S, Miyamura T, Koike K. The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. Nat Med 1998; 4:1065-67. Muñoz de Rueda P, Casado J, Patón R, Quintero D, Palacios A, Gila A, Quiles R, León J, Ruiz-Extremera A, Salmerón J. Mutations in E2-PePHD, NS5A-PKRBD, NS5A-ISDR, and NS5A-V3 of hepatitis C virus genotype 1 and their relationships to pegylated interferon-ribavirin treatment responses. J Virol 2008; 82:6644-53. Nousbaum J, Polyak SJ, Ray SC, Sullivan DG, Larson AM, Carithers RL Jr, Gretch DR. Prospective characterization of full-length hepatitis C virus NS5A quasispecies during induction and combination antiviral therapy. J Virol 2000; 74:9028-38. Okanoue T, Itoh Y, Hashimoto H, Yasui K, Minami M, Takehara T, et al. Predictive values of amino acid sequences of the core and NS5A regions in antiviral therapy for hepatitis C: a Japanese multi-center study. J Gastroenterol 2009; 44:952-63. Park KJ, Choi SH, Lee SY, Hwang SB, Lai MM. Nonstructural 5A Protein of Hepatitis C Virus Modulates Tumor Necrosis Factor α-stimulated Nuclear Factor κB Activation. J Biol Chem 2002; 277:13122-8. Pascu M, Martus P, Höhne M, Wiedenmann B, Hopf U, Schreier E, Berg T. Sustained virological response in hepatitis C virus type 1b infected patients is predicted by the number of mutations within the NS5AISDR: a meta-analysis focused on geographical differences. Gut 2004; 53:1345-51. Paterson M, Laxton CD, Thomas HC, Ackrill AM, Foster GR. Hepatitis C virus NS5A protein inhibits interferon antiviral activity, but the effects do not correlate with clinical response. Gastroenterology 1999; 117:1187-97. Patrick M. Hepatitis C:the clinical spectrum of the disease. J Hepatol 1999; 31(Suppl.1):9-16. Pavlović D, Neville DC, Argaud O, Blumberg B, Dwek RA, Fischer WB, Zitzmann N. The hepatitis C virus p7 protein forms an ion channel that is inhibited by long-alkyl-chain iminosugar derivatives. Proc Natl Acad Sci USA 2003; 100:6104-8. Pawlotsky JM. Mechanisms of antiviral treatment efficacy and failure in chronic hepatitis C. Antiviral Res 2003; 59:1-11. Pileri P, Uematsu Y, Campagnoli S, Galli G, Falugi F, Petracca R, et al. Binding of hepatitis C virus to CD81. Science 1998; 282:938-41. Polyak SJ, Paschal DM, McArdle S, Gale MJ Jr, Moradpour D, Gretch DR. Characterization of the effects of hepatitis C virus nonstructural 5A protein expression in human cell lines and on interferon-sensitive virus replication. Hepatology 1999; 29:1262-71. Poordad F, Reddy KR, Martin P. Rapid virologic response: a new milestone in the management of chronic hepatitis C. Clin Infect Di 2008; 46:78-84. Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy group (IHIT). Lancet 1998; 352:1426-32. Ramadori G, Meier V. Hepatitis C virus infection:10 years after the discovery of the virus. Eur J Gastroenterol Hepatol 2001; 13:465-71. Reichard O, Norkrans G, Fryden A, Braconier JH, Sonnerborg A, Weiland O. Randomised, double-blind, placebo controlled trial of interferon alfa-2b with and without ribavirin for chronic hepatitis C. The Swedish Study Group. Lancet 1998; 351:83-7. Rennefahrt U, Illert B, Greiner A, Rapp UR, Troppmair J. Tumor induction by activated JNK occurs through deregulation of cellular growth. Cancer Lett 2004; 215:113-24. Roitt , Brostoff , Male.原著,王聖予翻譯。免疫學 Immunology 5 edition. Samuel CE. Antiviral actions of interferon .Clin Microbiol Rev 2001; 14:778-809. Sanger F. Determination of nucleotide sequence in DNA. Science 1981; 214:1205-10. Sarrazin C, Berg T, Lee JH Rüster B, Kronenberger B, Roth WK,Zeuzem S. Mutations in the protein kinase-binding domain of the NS5A protein in patients infected with hepatitis C virus type 1a are associated with treatment response. J Infect Dis 2000; 181:432-41. Schalm SW, Hansen BE, Chemello L, Bellobuono A, Brouwer JT, Weiland O, Cavalletto L, Schvarcz R, Ideo G, Alberti A. Ribavirin enhances the efficacy but not the adverse effects of interferon in chronic hepatitis C. Meta-analysis of individual patients data from European centers. J Hepatol 1997; 26:961-6. Schiappa DA, Mittal C, Brown JA, Mika BP. Relationship of hepatitis C genotype 1 NS5A sequence mutations to early phase viral kinetics and interferon effectiveness. J Infect Dis 2002; 185:868-77. Schröter M, Zöllner B, Schäfer P, Laufs R, Feucht HH. Quantitative detection of hepatitis C virus RNA by light cycler PCR and comparison with two different PCR assays. J Clin Microbiol 2001, 39:765-8. Sen GC, Lengyel P. The interferon system. A bird’s eye view of its biochemistry. J Biol Chem 1992; 267:5017-20. Sen GC, Ransohoff RM. Interferon-induced antiviral actions and their regulation. Adv Virus Res 1993; 42:57-102. Simmonds P. Genetic diversity and evolution of hepatitis C virus--15 years on. J Gen Virol 2004; 85:3173-88. Sun CA,Chen HC,Lu SN,Chen CJ,Lu CF,You SL,and Sin SH.Presistent hyperendemicity of hepatitis C virus infection in Taiwan. J Med Virol 2001; 65:30-4. Sy T, Jamal MM. Epidemiology of hepatitis C(HCV)infection. Int J Med Sci 2006; 3:41-6. Tan SL, Katze MG. How hepatitis C virus counteracts the interferon response: the jury is still out on NS5A. Virology 2001; 284:1-12. The French METAVIR Cooperative Study Group. Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. Hepatology 1994; 20:15-20. Torres-Puente M, Cuevas JM, Jiménez-Hernández N, Bracho MA, García-Robles I, Wrobel B, et al. Genetic variability in hepatitis C virus and its role in antiviral treatment response. J Viral Hepat 2008; 15:188-99. Yen YH, Hung CH, Hu TH, Chen CH, Wu CM, Wang JH, Lu SN, Lee CM. Mutations in the interferon sensitivity-determining region (nonstructural 5A amino acid 2209-2248) in patients with hepatitis C-1b infection and correlating response to combined therapy of pegylated interferon and ribavirin. Aliment Pharmacol Ther 2008; 27:72-9. Yu ML, Chuang WL, Chen SC, Dai CY, Hou C, Wang JH, et al. Genotype distribution of hepatitis C virus infection in Taiwan. J Med Virol 1994; 44:74-9. Yu ML, Chuang WL, Chen SC, Dai CY, Hou C, Wang JH, et al. Changing prevalence of hepatitis C virus genotypes: molecular epidemiology and clinical implications in the hepatitis C virus hyperendemic areas and a tertiary referral center in Taiwan. J Med Virol 2001; 65:58-65. Yu ML, Dai CY, Huang JF, Chiu CF, Yang YH, Hou NJ, et al. Rapid virological response and treatment duration for chronic hepatitis C genotype 1 patients: a randomized trial. Hepatology 2008; 47:1884-93. Zein NN. Clinical significance of hepatitis C virus genotypes. Clin Microbiol Rev 2000; 13:223-35. Zeuzem S, Berg T, Moeller B, Hinrichsen H, Mauss S, Wedemeyer H, Sarrazin C, Hueppe D, Zehnter E, Manns MP. Expert opinion on the treatment of patients with chronic hepatitis C. J Viral Hepat 2009; 16: 75-90. Zeuzem S. Heterogeneous virologic response rates to interferon-based therapy in patients with chronic hepatitis C:who responds less well? Ann Intern Med 2004; 140:370-81. Zeuzem S,Yoshida EM, Benhamou Y, Bain VG, Shouval D, Pianko S, et al. Sustained virologic response rates with albinterferon alfa-2b plus ribavirin treatment in IFN naive chronic hepatitis C genotype 1 patients. Hepatology 2007; 46(Suppl):317A. 胡秀蓉.隱形殺手-C型肝炎的治療.長庚藥學學報2003; 10:1-4. 廖運範.B型肝炎的傳染.當代醫學2009; 434:936-41 謝佩真,郭行道,卓文春.C型肝炎病毒基因分型及其臨床重要性. 內科學誌2009; 20:309-19.
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.
其他識別: U0005-0302201010512100
Appears in Collections:生命科學系所

Show full item record

Google ScholarTM


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.