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

本方案旨在研究无症状献血人群中丙型肝炎病毒（HCV）感染的自然史和流行病学，评估HCV性传播或其他经皮传播的可能性，并评估HCV感染叠加急性或慢性B病毒（HBV）感染的临床影响。 到目前为止，主要研究已招募了760名患者。在入组的760例受试者中，分析了738例受试者，包括469例重组免疫印迹试验（RIBA）阳性，52例RIBA不确定，217例RIBA阴性对照。队列的15年随访于2012年发表（JID 2012：206：654）。 有趣的流行病学研究结果包括高比例（41%）的RIBA+捐赠者承认以前（远程）静脉注射毒品，以及可卡因吸食和HCV阳性之间的强独立关联。鼻出血时共同使用的鼻吸用具，可能是病毒通过肠道外途径传播的隐蔽媒介。在抗-HCV +/RIBA阳性的献血者中，82%的人持续病毒血症，但18%的人似乎从先前的HCV感染中自发恢复。从185例（47%）慢性感染患者中获得了肝活检; 51%患有轻度慢性肝炎，44%患有中度慢性肝炎，平均感染时间为20年;只有5%患有严重炎症。在33%的活检患者中未观察到纤维化，52%的患者仅出现轻度纤维化; 15例患者出现更严重的纤维化，包括12%的桥接纤维化和2%的肝硬化。总体而言，该队列中的HCV感染通常无症状，在25年的过程中，约15%的患者进展为严重的肝脏疾病。尽管HCV与性滥交行为有关，但我们没有发现165名HCV感染者的特定伴侣发生性传播的证据。这项研究继续跟踪HCV感染的自然史，现在集中在肝活检和纤维扫描中评估的组织学进展。新的重点是对HCV的细胞介导的免疫应答、中和抗体应答、纤维化进展的预测因子的研究，包括细胞因子阵列的性能、micro-RNA和IL 28多态性的测量。现在也把重点放在治疗上。新的治疗方法与直接作用的抗病毒药物可以导致超过90%的治愈率。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。到目前为止，在144例长期随访的患者中，117例（81%）已接受基于干扰素的治疗，绝大多数患者接受了新的直接作用抗病毒药物治疗。6例患者（4.2%）进展为肝硬化，其中3例死于肝功能衰竭。 由于我们正在根据方案18-DK-0091治疗剩余的HCV患者，我们还在两项合作研究中对他们进行了随访。 1)第一项研究是完成治疗前和治疗后的miRNA分析，用于研究细胞介导的对HCV的免疫应答、中和抗体应答、纤维化进展的预测因子，包括细胞因子阵列的性能、micro-RNA和IL 28多态性的测量。 2)第二项正在进行的研究是在HCV患者中研究SICCA，观察两组患者的B细胞变化，并研究治疗后HCV患者的B细胞变化，还记录患者完成的调查，如果DAA治疗有助于他们的SICCA症状。 在本研究的当前性伴侣组中，我们招募了41名HCV感染索引病例的伴侣。所有性伴侣的初步筛查试验（EIA）和特异性HCV RNA PCR检测均为阴性。这41名伴侣中有21名（51.2%）曾检测为阴性，平均检测时间为12.8年。所有的性伴侣都与指数病例发生性行为至少1年，71%的人在性活动期间从未使用任何形式的保护措施。 自本研究的B型肝炎组获批以来，我们入组了3例HBV阳性患者。1例患者患有急性B型肝炎，并通过治疗随访其急性病程直至完全康复。第2例患者在入组时为B型肝炎表面抗原（HBsAg）和HBV DNA阳性，但不久后未经治疗转为HBV DNA阴性，但仍为HBsAg阳性。第3例患者HBsAg和B型肝炎核心抗体（抗-HBc）强阳性。进一步的检测显示，他是B e抗原（HBeAg）阴性，HBV DNA病毒载量非常低，肝功能（ALT）水平正常，提示非活动性感染。 入组的HBV阳性患者数量不足，无法进行计划的统计学比较。

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 recombinants 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 result in greater than 90% cure rates. Our goal is to treat as many patients as possible and effectively cure most of the patients in this cohort. Thus far, of 144 patients followed long-term, 117 (81%) have been treated to cure with interferon based therapies and in the vast majority with new direct acting anti-virals. Six patients (4.2%) have progressed to cirrhosis and 3 of these six have died of liver failure. As we are treating the remaining HCV patients on protocol 18-DK-0091 we are also following them on two collaborative studies. 1) The first study is to complete miRNA 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. 2) 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 of HCV infected index cases. All sexual partners 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. There were not sufficient HBV positive patients enrolled to make the planned statistical comparisons.