人類白血球抗原對偶基因在慢性C型肝炎治病機轉所扮演的角色及其對長效型干擾素合併ribavirin治療療效的影響

Human Leukocyte Antigen Class I and II Alleles in Chronic Hepatitis C Patients: the role in the pathogenesis and response to peginterferon plus ribavirin combination therapy

林雅雲(Ya-Yun Lin)

指導教授 ： 余明隆

共同指導教授 ： 褚佩瑜(Pei-Yu Chu)

高雄醫學大學/健康科學院/生物醫學檢驗學研究所/碩士(2006年)

摘要

C 型肝炎帶原者依據WHO 推估全世界約有3％即為一億七仟萬人口。HCV急性感染後約80%的人會轉變成慢性肝炎階段，目前研究指出慢性C型肝炎導致肝細胞慢性傷害、發炎後，經過20 到30年後，約20%的患者會造成肝硬化，而且一旦肝硬化形成則每年約有1-5%會罹患肝細胞癌。
臨床上用來治療慢性C型肝炎的藥物包括利用甲型干擾素單一治療法、甲型干擾素合併ribavirin複合療法及最新利用長效型干擾素peginterferon-α（PEG-IFN-α ）合併ribavirin的複合療法。抗病毒藥物ribavirin和甲型干擾素合併使用可以明顯提高其療效至40-50%左右，而利用peginterferon合併ribavirin的複合療法其療效甚至可達65%左右。目前研究顯示治療的成功與否，包括病毒因子(基因型、血清中病毒濃度)、宿主因子（性別、年齡、肝纖維化、免疫遺傳系統）及感染時間長短亦可能影響治療效果。
人類白血球抗原(HLA) 是決定人體免疫系統功能的主要因素之一，近年有美國學者研究C型肝炎病毒之感染及其自然病程與宿主人類白血球抗原之關係的報告指出，HLA Class I及II在C型肝炎病毒感染的抗病毒免疫反應上可能扮演重要的角色。義大利學者研究健康者及慢性C肝帶原者兩個族群顯示HLA DRB1* 1601、DQB1* 0502及 HLA-DR5可能在保護人體免於受C型肝炎病毒的感染上扮演重要的角色。日本學者研究健康C肝帶原者與chronic liver disease兩個族群也顯示DRB1*1302、 DRB1*0901與C型肝炎病毒引起肝臟疾病嚴重度有關，相反的也有其他報告無類似發現。
在2003年針對台灣慢性C肝病人單獨以甲型干擾素治療療效與HLA之相關性的研究中發現為HLA-A11, B51,Cw15, DRB1*15 和Haplotype A11-DRB1*15的病患與單獨以甲型干擾素治療的持續性病毒反應（SVR）呈正相關，而HLA-A24的患者呈負相關。而針對以peginterferon合併ribavirin治療慢性C型肝炎，其治療療效與人類白血球抗原HLA之相關性目前仍無研究指出，所以我們認為宿主HLA基因多型性是否與慢性C型肝炎患者疾病進展以及利用peginterferon合併ribavirin治療效果有關是值得進一步研究探討。
本研究收集245位確診為慢性C型肝炎且有肝病理切片報告的病人，其中有208位利用PEG-IFN-α 2a合併ribavirin治療且完成療程，我們利用PCR-SSO法 (Sequence specific oligonucleotide probe hybridi- zations )測定HLA allele A、B、C、DQB、DRB對偶基因型。分析慢性C型肝炎患者的HLA allele A、B、C、DQB、DRB對偶基因型與病人嚴重肝纖維化以及對peginterferonr合併ibavirin治療療效之相關性。

本研究結果顯示嚴重肝纖維化與年齡因素有相關，與任單一個HLA並無相關，而分析各個HLA allele 連鎖不平衡(linkage disequilibrium, LD)與嚴重肝纖維化，我們發現將年齡因素控制後病患嚴重肝纖維化與haplotype HLA B*51-Cw*15呈正相關。
針對208位慢性C型肝炎患者分析探討C型肝炎患者接受PEG-IFN-α 2a合併ribavirin治療療效與病患治療前血清病毒濃度、基因型和嚴重肝纖維化有關係。治療療效與HLA alleleA、B、C、DQB、DRB對偶基因型之間的相關性，發現HLA-B*40與治療療效呈負相關。而有HLA- A*24與持續性病毒反應（SVR）呈正相關。而分析HLA allele 連鎖不平衡(linkage disequilibrium, LD)發現，haplotype HLA B*40-DRB1*03、B*46-DRB1*09、Cw*01-DQB1*03、Cw*01-DRB1*09與持續性病毒反應（SVR）呈負相關。
我們的結果顯示宿主之HLA allele在慢性C型肝炎之致病機轉與抗病毒藥物之反應可能扮演重要之角色。未來C型肝炎的治療可能可以藉由不同的病毒因素及HLA型態而規劃不同的療程，以達到最大的治療效應。

關鍵字

甲型干擾素 ； 長效型干擾素 ； 人類白血球抗原

並列摘要

Hepatitis C virus (HCV) is an enveloped positive-stranded RNA virus classified in the Flaviviridae family. An estimated 170 million individuals are infected with HCV worldwide.
While current therapeutic strategies against HCV infection rely mainly on either naked interferon or pegylated alpha interferon (PEG-IFN-α) alone or in combination with ribavirin. The current studies pointed out the therapeutic regimen of pegylated alpha IFN (PEG-IFN-α) and ribavirin provides substantially improved highly rates of sustained viral clearance. The pathogenesis of HCV and the effectiveness of treatment depend on both viral factors such as HCV genotype, viral load and the duration of infection and the host immune responses.
Human leukocyte antigens (HLA) are the determinant factors of immune function. Some reports had shown the association between nature course and infection of HCV and HLA Class II gene typing.
The purpose of our study is to investigate HLA class I and II genotypes frequency at chronic hepatitis C patients in Taiwan, and association between HLA allies and role of immunogenetics on the pathogenesis of chronic hepatitis C, and the influence of HLA alleles in the response to PEG-IFN-α 2a plus ribavirin combination therapy.
In this study, we plan to enroll total 245 chronic hepatitis C patients who were proved histopathologically. The association between HLA Class allies and the severity of liver disease caused by chronic HCV infection in chronic hepatitis C patients. Our results show that the presence of the haplotype B*51- Cw*15（P=0.048;OR,4.892;95％CI,1.011－23.666）is associated with a increased risk for the development of HCV induced end stage liver disease.
The influence of HLA Class allies on the response to combination therapy with PEG-IFN-α 2a plus ribavirin in 208 chronic hepatitis C patients , which was significantly correlated to liver cirrhosis, pretreatment serum hepatitis C virus (HCV) RNA levels and genotype 1b. After correcting for the number of alleles tested, the differences were no longer apparent. Further adjustment for potential confounders (cirrhosis, HCV RNA levels, and genotype).The frequency of B40 significantly lower [p=0.045; OR=0.475], while the frequency of A24 was significantly higher [p=0.023, odds ratio (OR) = 2.525] in the sustained responders than in the non-responders. The haplotype HLA B*40-DRB1*03、B*46-DRB1*09、Cw*01-DQB1*03 and Cw*01- DRB1*09 frequency of significantly lower [p=0.045,OR=0.170； p=0.049,OR=0.304；p=0.046,OR=0.429；p=0.037, OR=0.316, respectively. ]in the sustained responders than in the non-responders.
This suggests may play a crucial role for a complex host immunogenetic interplay in the response to combination therapy with PEG-IFN-α 2a and ribavirin in chronic hepatitis C patients in chronic hepatitis C because it is a key protein in antigen presentation to T-helper (Th) cells by antigen-presenting cells.

並列關鍵字

Interferon-alpha ； Pegylated-Interferon ； Human Leucocyte Antigens

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