A Prospective Study Of Anti-hepatitis C Virus Positive Blood Donors

抗丙型肝炎病毒阳性献血者的前瞻性研究

• 批准号: 10019263
• 负责人: Valeria de Giorgi
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10019263
• 关键词: Acute; Acute Hepatitis; Aftercare; Antibodies; Antibody Response; Antiviral Agents; B-Lymphocytes; Biological Assay; Biopsy; Blood Donations; Blood donor; Chronic; Chronic Hepatitis; Chronic Hepatitis B; Cirrhosis; Clinical; Cocaine; Development; Enrollment; Epidemiology; Epistaxis; Fibrosis; Genetic Polymorphism; Goals; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B Virus; Hepatitis B e Antigens; Hepatitis C; Hepatitis C Transmission; Hepatitis C virus; Histologic; Individual; Infection; Inflammation; Interferons; Liver Fibrosis; Liver diseases; Measurement; Measures; Messenger RNA; MicroRNAs; Natural History; Outcome; Patients; Performance; Population; Prospective Studies; Protocols documentation; Publishing; Recombinants; Recovery; Sex Behavior; Sexual Partners; Sexual Transmission; Surveys; Symptoms; Testing; Time; United States National Institutes of Health; Viral Load result; Virus Diseases; anti-hepatitis C; arm; base; cell mediated immune response; co-infection; cohort; cytokine; design; follow-up; indexing; intravenous drug use; liver biopsy; liver function; neutralizing antibody; novel therapeutics; recombinant virus; screening; sexually active; viral DNA; viral RNA; viral transmission

This protocol is designed to study the natural history and epidemiology of hepatitis C virus (HCV) infection in an asymptomatic blood donor population, to assess the potential for sexual transmission or other percutaneous transmission of HCV and to assess the clinical impact of acute or chronic hepatitis B virus (HBV) infection superimposed on HCV infection. To date, the primary study has enrolled 760 patients. Of those 760 enrolled, 738 subjects have been analyzed, including 469 recombinant immunoblot assay (RIBA) positives, 52 RIBA indeterminates, and 217 RIBA-negative controls. The 15 year follow-up of the cohort was published in 2012(JID 2012:206:654). Interesting epidemiologic findings include the high proportion (41 percent) of RIBA+ donors who admitted to prior (remote) intravenous drug use and the strong independent association between cocaine snorting and HCV positivity. Shared paraphernalia for snorting accompanied by epistaxis, may serve as a covert vehicle for parenteral viral transmission. Among anti-HCV+/RIBA-positive donors, 82 percent were persistently viremic, but 18 percent appeared to have spontaneously recovered from prior HCV infection. A liver biopsy has been obtained from 185(47%) patients who were chronically infected; 51% had mild chronic hepatitis and 44% had moderate chronic hepatitis over a mean duration of infection of 20 years; only 5% had severe inflammation. No fibrosis was observed in 33% of biopsied patients and 52% had only mild fibrosis; 15 had more severe fibrosis including 12% with bridging fibrosis and 2% with cirrhosis. Overall, HCV infection in this cohort was generally asymptomatic and over the course of 25 years progressed to severe liver disease in approximately 15%. Despite an association of HCV with sexually promiscuous practices, we found no evidence for sexual transmission to the specific partners of 165 HCV-infected individuals. The study continues to follow the natural history of HCV infection and is now focusing on histologic progression as assessed in liver biopsies and fibroscans. New emphasis is being placed on studies of cell-mediated immune responses to HCV, neutralizing antibody responses, predictors of fibrosis progression, including performance of cytokine arrays, micro-RNAs and measurement of IL28 polymorphisms. Emphasis is now also being placed on treatment.New treatments with direct acting antivirals can effect greater than 90% cure rates, but the new drugs are expensive and not readily available. Our goal is to treat as many patients as possible and effectively cure most of the patients in this cohort. Thus far,128 patients in this study have been treated to cure either with interferon based therapies or with new direct acting anti-virals. As we are treating the remaining HCV patients on protocol 18-DK-0091 we are also following them on two collaborative studies. The first study is to complete mRNA analysis pre and post treatment for studies of cell-mediated immune responses to HCV, neutralizing antibody responses, predictors of fibrosis progression, including performance of cytokine arrays, micro-RNAs and measurement of IL28 polymorphisms The second ongoing study is studying SICCA in HCV patients looking at changes in B Cells for both groups of patients and studying the B Cell changes in HCV patients after treatment and also documenting with patient completed surveys if treatment with a DAA helps their SICCA symptoms. In the current sexual partner arm of this study, we have enrolled 41 partners all of whom tested negative by both the initial screening test (EIA) and the specific HCV RNA PCR test. Twenty-one (51.2%) of those 41 partners had previously tested negative with an average duration between testing of 12.8 years. All partners were sexually active with index cases for at least 1 year and 71% never used any form of protective measure during sexual activity. Since approval of the hepatitis B arm of this study, we have enrolled 3 HBV positive patients. One patient had acute hepatitis B and was followed through her acute course to full recovery with treatment. The second patient was hepatitis B surface antigen (HBsAg) and HBV DNA positive at enrollment, but soon after became HBV DNA negative without treatment, but continues to be HBsAg positive. The third patient was strongly positive for HBsAg and for hepatitis B core antibody (anti-HBc). Further testing revealed that he was hepatitis B e antigen (HBeAg) negative and had very low level HBV DNA viral load and normal liver function (ALT) levels suggesting inactive infection.

该方案旨在研究无症状的献血者人群中丙型肝炎病毒（HCV）感染的自然病史和流行病学，以评估HCV性传播或其他经皮传播的潜力，并评估急性或慢性肝炎病毒（HBV）对HCV感染的急性或慢性肝炎病毒（HBV）的临床影响。 迄今为止，这项主要研究已招募了760名患者。 在这760名招募的人中，已经分析了738名受试者，包括469个重组免疫印迹测定（RIBA）阳性，52个RIBA不确定性和217个RIBA阴性对照。该队列的15年随访于2012年发布（JID 2012：206：654）。有趣的流行病学发现包括接受先验（远程）静脉吸毒的RIBA+供体的高比例（41％），以及可卡因鼻涕与HCV阳性之间的强烈独立关联。共同的用鼻子鼻子的用具，可以作为肠胃外病毒传播的秘密工具。在抗HCV+/RIBA阳性供体中，有82％的人持续病毒，但似乎有18％的人从先前的HCV感染中自发恢复。从185例（47％）的患者中获得了肝活检。 51％的慢性肝炎患有轻度的慢性肝炎，而44％的慢性肝炎在平均20年的平均感染期内；只有5％的炎症严重。在33％的活检患者中未观察到纤维化，而52％的纤维化只有轻度纤维化。 15具有更严重的纤维化，其中包括桥接纤维化的12％和肝硬化的2％。总体而言，该队列中的HCV感染通常是无症状的，在25年的时间里，大约15％的肝病发展为严重的肝病。尽管HCV与性滥交的实践有关联，但我们没有发现向165个HCV感染者的特定伴侣进行性传播的证据。该研究继续遵循HCV感染的自然史，现在正关注肝活检和纤维镜中评估的组织学进展。新的重点是对细胞介导的对HCV的免疫反应的研究，中和抗体反应，纤维化进展的预测指标，包括细胞因子阵列的性能，微RNA和IL28多态性的测量。现在，重点也放在治疗上。直接作用抗病毒药的新疗法可能会影响90％的治疗率，但新药很昂贵且不容易获得。我们的目标是治疗尽可能多的患者并有效治愈该队列中的大多数患者。迄今为止，这项研究中的128例患者已接受治疗基于干扰素的疗法或新的直接作用抗病毒病。 当我们在协议18-DK-0091上处理其余的HCV患者时，我们也在对他们进行两项协作研究。 第一项研究是完成mRNA分析，用于研究细胞介导的对HCV的免疫反应，中和抗体反应的免疫反应，纤维化进展的预测因子，包括细胞因子阵列的性能，微RNA和IL28多晶型的IL28多态性研究的第二次研究的患者在HCV患者中进行了b细胞的研究，并研究了HCV患者的研究。并记录患者完成的调查，如果使用DAA治疗有助于其SICCA症状。 在本研究的当前性伴侣部门中，我们已经招募了41个合作伙伴，他们通过初始筛选测试（EIA）和特定的HCV RNA PCR测试进行了阴性测试。 在这41个伙伴中，有21个（51.2％）先前已经测试了阴性，在12。8年之间的平均持续时间为阴性。 所有合作伙伴至少对指数案件进行性活动至少1年，而71％的伴侣在性活动期间从未使用任何形式的保护措施。 自从这项研究的丙型肝炎B部门批准以来，我们已经招募了3名HBV阳性患者。 一名患者患有急性乙型肝炎，并通过急性治疗进行治疗完全康复。 第二名患者是乙型肝炎表面抗原（HBSAG）和HBV DNA呈阳性，但不久后变成了HBV DNA阴性，但无需治疗，但仍然是HBSAG阳性。第三名患者对HBSAG和乙型肝炎核心抗体（抗HBC）的呈阳性。 进一步的测试表明，他是丙型肝炎抗原（HBEAG）阴性，HBV DNA病毒载量非常低，肝功能正常（ALT）水平表明不活跃感染。