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

该方案旨在研究无症状献血人群中丙型肝炎病毒(丙型肝炎病毒)感染的自然病史和流行病学，评估性传播或其他经皮传播丙型肝炎病毒的可能性，并评估急性或慢性乙肝病毒感染叠加丙型肝炎病毒感染的临床影响。 到目前为止，这项初步研究已经招募了760名患者。在760名登记的受试者中，738名受试者进行了分析，其中469名重组人免疫印迹试验(RIBA)阳性，52名RIBA不确定者，217名RIBA阴性对照。该队列的15年后续行动于2012年公布(JID 2012：206：654)。有趣的流行病学发现包括RIBA+捐赠者中承认以前(远程)静脉吸毒的高比例(41%)，以及吸食可卡因和丙型肝炎病毒阳性之间强烈的独立关联。共用的打喷嚏用具伴随着鼻出血，可能是非肠道病毒传播的秘密媒介。在抗-丙型肝炎病毒+/RIBA阳性的献血者中，82%的人持续感染病毒，但18%的人似乎已经从先前的丙型肝炎病毒感染中自发恢复。185名(47%)慢性感染患者进行了肝脏活检；51%的患者患有轻度慢性肝炎，44%的患者患有中度慢性肝炎，平均感染时间为20年；只有5%的患者患有严重炎症。33%的活检患者没有观察到纤维化，52%的患者只有轻微的纤维化；15例有更严重的纤维化，包括12%的桥性纤维化和2%的肝硬变。总体而言，该队列中的丙型肝炎病毒感染总体上是无症状的，在25年的过程中，大约有15%的人进展为严重的肝病。尽管丙型肝炎病毒与性乱行为有关，但我们没有发现证据表明，在165名丙型肝炎病毒感染者中，性传播给特定的伴侣。这项研究继续跟踪丙型肝炎病毒感染的自然历史，现在重点关注肝活检和纤维扫描评估的组织学进展。新的重点正被放在对丙型肝炎病毒的细胞介导的免疫反应、中和抗体反应、纤维化进展的预测因素的研究上，包括细胞因子阵列的性能、微RNA和IL28基因多态性的测量。现在还将重点放在治疗上。使用直接作用的抗病毒药物的新疗法可以导致90%以上的治愈率。我们的目标是治疗尽可能多的患者，并有效地治愈这一队列中的大多数患者。到目前为止，在144名长期随访的患者中，117名(81%)接受了以干扰素为基础的治疗，绝大多数接受了新的直接作用的抗病毒药物治疗。6名患者(4.2%)进展为肝硬变，其中3名死于肝功能衰竭。 当我们用18-DK-0091方案治疗剩余的丙型肝炎患者时，我们也在跟踪他们进行两项合作研究。 1)第一项研究是完成治疗前后的miRNA分析，用于研究丙型肝炎病毒的细胞免疫应答、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、microRNA和IL28基因多态性的测量。 2)正在进行的第二项研究是研究丙型肝炎患者的SICCA，观察两组患者的B细胞变化，研究治疗后丙型肝炎患者的B细胞变化，并记录患者完成的DAA治疗是否有助于他们的SICCA症状。 在目前的性伴手臂这项研究中，我们已经招募了41例性伴侣感染丙型肝炎病毒的指标病例。所有性伴在初次筛查试验(EIA)和特异的丙型肝炎病毒RNA聚合酶链式反应试验(EIA)中均呈阴性。在这41个合作伙伴中，有21个(51.2%)以前检测为阴性，两次检测之间的平均持续时间为12.8年。所有性伴都有至少一年的性行为活跃，71%的人在性行为期间从未使用过任何形式的保护措施。 自从这项研究的乙肝分支机构获得批准以来，我们已经招募了3名乙肝病毒阳性患者。一名患者患有急性乙型病毒性肝炎，并通过治疗随访其急性病程直至完全康复。第二例患者入院时乙肝表面抗原(HBs Ag)和HBVdna均阳性，但不久未经治疗转为HBVdna阴性，但仍为HBs Ag阳性。第三例患者的乙肝表面抗原和乙肝核心抗体(抗-HBc)呈强阳性。进一步的检测显示，他是HBe抗原(HBeAg)阴性，HBVDNA病毒载量很低，肝功能(ALT)正常，表明感染不活跃。没有足够的乙肝病毒阳性患者入选进行计划的统计比较。

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.