慢丙肝抗病毒治疗中依从性和疗效的关系及CD24预测病毒清除的价值

发布时间：2018-05-18 17:56

本文选题：丙型肝炎 + 治疗　；参考：《吉林大学》2014年博士论文

【摘要】：全球范围内每年有30,000,000-40,000,000人新发丙型肝炎病毒(Hepatitis C virus，HCV)感染，我国新发HCV感染病例也呈逐年上升趋势。HCV感染后，约75-80%的病人不能自发清除HCV而发展成慢性感染。目前干扰素联合利巴韦林的标准治疗方案只能使约一半的病人治愈，其余不能清除HCV的病人将可能进展为肝硬化、肝癌，这也成为西方国家肝移植的主要原因。用药依从性对抗HCV疗效起重要作用，未用药何以产生疗效？虽然治疗慢性疾病中药物依从性的重要性已有报道，但真实的临床实践中，难免有病人因各种原因存在一定的不依从，因此，不依从程度与疗效之间的关系及提高依从性的方法值得深入分析。宿主对丙型肝炎的免疫反应是病毒清除和肝脏疾病发生发展的重要因素。CD24在炎症和免疫反应中起着重要的作用，且CD24的单核苷酸多态性（SNP）与慢性乙型肝炎的发生风险和进展密切相关，但CD24对自发及抗病毒治疗诱导的HCV清除的研究，目前国内外尚无相关报道。本研究将对真实的临床实践中慢性HCV感染病人依从性的变化及其对疗效的影响进行深入研究，同时分析另一重要的宿主免疫分子CD24对慢性丙型肝炎的抗病毒治疗疗效的影响。因此本研究第一部分采用经济而有效的重组普通IFN-α2b5MU每周3次皮下注射联合利巴韦林900mg/日口服，疗程48周，治疗结束后随访24周的方案进行抗HCV治疗。对参与治疗的353例病人进行治疗前横断面研究，，包括患者一般信息、基线的肝脏病毒学、生化学及影像学评估，并对患者进行HCV及其治疗知识的普及。纵向随访研究包括开始治疗后2周、4周、12周、24周、48周、72周进行回访并发放、计数药物，监测HCV RNA载量、肝脏生化学、影像学变化及用药依从性、不良反应及相应的治疗。第一部分实验结果如下：意向性（ITT）分析和符合方案（PP）分析表明抗病毒治疗反应在治疗开始后第24周达最高，随后出现轻度下降；在开始治疗后的前12周，两种抗病毒药物的依从性均很高，随着治疗的进行，两种药物的服药依从性均呈下降趋势，利巴韦林尤其明显；早期病毒学应答（EVR）和持续病毒学应答（SVR）随着利巴韦林用药依从性的增加而增加，利巴韦林依从性≥60%患者的应答率明显高于利巴韦林依从性60%的患者。利巴韦林依从性对病毒学应答的影响在HCV基因型1B的患者较2A型患者更为明显；每个12周的治疗间隔中利巴韦林依从性≥60%的患者均比利巴韦林依从性60%的患者会获得明显高的SVR率。本部分研究尚对较差依从性产生的原因进行了总结分析，期望给医务人员以提示，加强对病人不依从的监督，以取得好的疗效。结果表明药物不良反应（乏力、周身酸痛、血小板降低、白细胞降低、头晕、甲低、甲减、皮疹、贫血、精神抑郁）和其他非药物原因（出差、农忙、外伤）是导致较差依从性的主要原因。本研究第二部分采用采用焦磷酸测序法，对544例慢性HCV感染（CHC）病人、78例自发HCV清除（SHC）病人和215例健康对照者，进行共刺激分子CD24-P534,P170, P1527位点和IFNL3rs12979860位点的基因变异的检测。在慢性HCV感染组，362人参与了重组干扰素α2b联合利巴韦林48周的抗HCV治疗并与治疗结束后随访24周。外周血单个核细胞及其亚群表面CD24蛋白表达水平采用流式细胞术进行检测。第二部分实验结果如下：与慢性HCV感染组相比，自发HCV清除组的P170CT和CT/TT基因型表达明显增高，CT型在慢性HCV感染组和自发HCV清除组的百分比分别为62.8%比47.2%；CT/TT型在慢性HCV感染组和自发HCV清除组的百分比分别为75.6%比60.3%。多元素回归分析结果表明，P170(CD24Ala57Val)多态性是自发HCV清除的独立预测因素，对CT基因型校正后的OR=2.11,95%CI=1.19-3.73, P=0.010；对CT/TT基因型，校正后的OR=2.01,95%CI=1.15-3.49, P=0.014。 Cox回归分析和秩和检验发现CD24单核苷酸多态性和治疗诱导的HCV清除之间无相关性。携带CT/TT基因型的病人较CC基因型的病人有更高的T细胞表面CD24表达。综上所述，治疗依从性随着抗病毒治疗的进行而逐渐降低，利巴韦林表现得更明显；利巴韦林更高的依从性会导致更高的早期和持续病毒学应答，这种影响对HCV基因1B型的患者更明显；在中国汉族人群中CD24Ala57Val多态性及其相应的CD24表达水平的变化是自发HCV清除的重要的预测因素，但对抗病毒药物治疗诱导的HCV清除无影响。
[Abstract]:There are 30000000-40000000 new hepatitis C virus (Hepatitis C virus, HCV) infected every year in the world, and the new HCV infection cases in our country are also increasing year by year,.HCV infection, about 75-80% patients can not spontaneously remove HCV and develop into chronic infection. The standard treatment scheme of interferon combined with Go Leigh Ba Velin can only be made about the same. Half of the patients are cured, and the rest of the patients who are unable to remove HCV will probably advance to liver cirrhosis and liver cancer, which is also the main cause of liver transplantation in the western countries. Drug compliance plays an important role in the response to the efficacy of HCV. Why does not use drugs to produce therapeutic effects? Although the importance of drug compliance in the treatment of chronic diseases has been reported, the true clinical reality In practice, it is unavoidable that there are certain non compliance for various reasons. Therefore, the relationship between the non compliance and the curative effect and the way to improve the compliance should be deeply analyzed. The immune response of the host to hepatitis C is an important factor in the development of virus clearance and liver disease,.CD24 plays an important role in the inflammation and immune response. CD24's single nucleotide polymorphism (SNP) is closely related to the risk and progress of chronic hepatitis B, but there is no relevant report on the study of HCV clearance induced by spontaneous and antiviral therapy at home and abroad. This study will affect the compliance of patients with chronic HCV infection in real clinical practice and the effect on the efficacy of CD24. We conducted in-depth study and analyzed the effect of another important host immune molecule CD24 on antiviral therapy for chronic hepatitis C.
Therefore, the first part of this study uses an economic and effective recombinant IFN- alpha 2b5MU 3 subcutaneous injection combined with Leigh Bhave Lin 900mg/ day oral administration for 48 weeks, and a 24 week follow-up of 24 weeks after treatment for anti HCV treatment. A cross-sectional study before treatment for 353 patients involved in the treatment, including patient general information, baseline liver Virology, biochemistry and imaging evaluation, and the popularization of HCV and treatment knowledge for patients. Longitudinal follow-up studies included 2 weeks, 4 weeks, 12 weeks, 24 weeks, 48 weeks, 72 weeks, counting drugs, monitoring the load of HCV RNA, liver biochemistry, imaging changes and medication compliance, side effects and corresponding treatment.
The first part of the experiment is as follows:
ITT analysis and coincidence analysis (PP) analysis showed that the antiviral therapy response reached the highest level at twenty-fourth weeks after treatment, followed by a slight decrease.
In the first 12 weeks after the treatment, the compliance of the two antiviral drugs was very high. With the treatment, the compliance of the two drugs showed a downward trend, especially in Leigh Bhave Lin.
The early virological response (EVR) and the sustained virological response (SVR) increased with the increase of Leigh Bhave Lin's medication compliance. The response rate of the patients with Leigh Bhave Lin compliance more than 60% was significantly higher than that of the patients with Leigh Bhave Lin compliance 60%.
The effect of Leigh Bhave Lin compliance on virological response was more obvious in patients with HCV genotype 1B than in 2A patients.
In each 12 week treatment interval, patients with Leigh Bhave Lin compliance greater than 60% had a significantly higher SVR rate than those with Leigh Bhave Lin's compliance rate of 60%.
In this part, the reasons for the poor compliance were summarized and analyzed in order to give the medical staff a hint to strengthen the supervision of the patients, and to achieve good curative effect. The results showed that the adverse drug reactions (fatigue, body and pain, thrombocytopenia, leukocyte decrease, dizziness, hypothyroidism, hypothyroidism, rash, anemia, depression) and its His non drug reasons (travel, farming, trauma) are the main causes of poor compliance.
In the second part of this study, we used pyrosequencing method to examine 544 cases of chronic HCV infection (CHC), 78 cases of spontaneous HCV clearance (SHC) and 215 healthy controls, to detect the genetic variation of CD24-P534, P170, P1527 and IFNL3rs12979860 loci of CO stimulators. In chronic HCV infection group, 362 people were involved in recombinant interferon alpha 2b. The anti HCV treatment combined with Leigh Bhave Lin 48 weeks was followed up for 24 weeks after the treatment. The expression of CD24 protein on the surface of peripheral blood mononuclear cells and its subsets was detected by flow cytometry.
The second part of the experiment results are as follows:
Compared with the chronic HCV infection group, the expression of P170CT and CT/TT genotypes in the spontaneous HCV scavenging group was significantly higher, the percentage of the CT type in the chronic HCV infection group and the spontaneous HCV clearance group was 62.8% to 47.2%, and the percentage of CT/TT type in the chronic HCV infection group and the spontaneous HCV clearance group was 75.6% to 60.3%., respectively.
Multielement regression analysis showed that P170 (CD24Ala57Val) polymorphism was an independent predictor of spontaneous HCV clearance, OR=2.11,95%CI=1.19-3.73, P=0.010, CT/TT genotypes, OR=2.01,95%CI=1.15-3.49, P=0.014. after CT genotypes.
Cox regression analysis and rank sum test showed no correlation between CD24 single nucleotide polymorphisms and treatment induced HCV clearance. Patients carrying CT/TT genotype had higher CD24 expression on the surface of T cells than those of the CC genotype patients.
In summary, treatment compliance gradually decreases with the progression of antiviral therapy, and Leigh Bhave Lin is more evident; Leigh Bhave Lin's higher compliance leads to a higher early and sustained virological response to the HCV gene 1B patients; the CD24Ala57Val polymorphism and its corresponding CD2 in Chinese Han population 4 the change of expression level is an important predictor of spontaneous HCV clearance, but it has no effect on HCV clearance induced by viral treatment.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R512.63

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