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Immune correlates of long-term success with DAA therapy in HCV/HIV infected people who inject drugs

DAA 治疗 HCV/HIV 感染注射吸毒者长期成功的免疫相关性

基本信息

批准号：
9928694
负责人：
Shyamasundaran Kottilil
金额：
$ 7.67万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9928694
关键词：
Address American Antiviral Agents Baltimore CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Caring Chronic Hepatitis C Clinical Cytometry Data Defect Development Disease Progression District of Columbia Effectiveness Epidemic Evaluation Flow Cytometry Goals HIV HIV Infections HIV Seropositivity HIV/HCV Hepatic Hepatitis C Hepatitis C Incidence Hepatitis C Prevalence Hepatitis C Therapy Hepatitis C Transmission Hepatitis C co-infection Hepatitis C virus High Prevalence Immune Immune System Diseases Immunity Immunophenotyping Impairment Individual Infection Inflammation Injecting drug user Interferons Interruption Intervention Investigation Knowledge Liver Liver Failure Liver Fibrosis Liver diseases Longitudinal Studies Lymphocyte Maintenance Malignant neoplasm of liver Measures Mediating Mission Morbidity - disease rate Natural History New Agents Opioid replacement therapy Outcome Patients Peripheral Pharmaceutical Preparations Plasma Population Prevention Prevention strategy RNA Recovery Recurrence Regimen Relapse Research Technics Retreatment Role Route T cell response T-Lymphocyte Treatment Effectiveness Viral Viral hepatitis Virus Work activation product adaptive immunity adverse outcome base co-infection cost design exhaustion high risk high risk population immune activation improved inflammatory marker injection drug use innovation insight interest intrahepatic medication-assisted treatment mortality novel opioid use prevent progenitor public health relevance response success therapeutic immunization therapeutic vaccine transcriptome sequencing transmission process treatment response treatment strategy virology

项目摘要

Abstract An estimated 3 million Americans have chronic Hepatitis C (HCV) infection, and of those, up to 25% are co- infected with HIV. Of the new HCV infections, 80% occur in people who inject drugs (PWID) and successful treatment strategies for this core group are required to break this epidemic. Directly acting antiviral agents (DAAs) are new non-immune based therapies to treat HCV and are effective in treating HCV with HIV co-infection; still individuals with co-infection have more rapid progression of hepatic fibrosis and worse clinical outcomes than those with HCV mono-infection. PWID with HIV infection have significantly higher rates of re-infection and liver disease progression even after achieving sustained virologic response (SVR). It is critical to investigate the long- term durability of SVR in these high-risk populations in order to identify probable factors that contribute to HCV recurrence. Our group has been studying HCV treatment responses (including HIV positive PWID patients) in Baltimore and District of Columbia. We showed that in patients achieving SVR with DAA therapy, HCV specific T cell immunity is recovered in contrast to those with relapse of HCV. We are seeking to identify immune correlates of successful treatment response, especially in high-risk groups, with the goal of identifying persistent defects in virus specific immune recovery that may hamper durability of SVR. In this proposal, we will seek to 1) investigate the improvement in liver disease with SVR and HCV re-infection rates post SVR in HIV/HCV co- infected patients with or without current injection drug use 2) explore the impact of HIV/HCV co-infection and current injection drug use on recovery and maintenance of HCV-specific peripheral CD4 and CD8 T- cell responses after DAA therapy and 3) characterize the persistence of hepatic immune defects after SVR in HIV/HCV co-infected high-risk patient groups. Through these specific aims, we will elucidate the immune mechanisms and factors that drive re-infection in HIV/HCV co-infected PWID. We hypothesize that DAA-based eradication of HCV will result in augmentation of virus specific adaptive immunity, the lack of which may be associated with adverse outcomes in HIV/HCV co-infected patients and current PWID. We will employ standard and novel research techniques, including measuring soluble and cellular markers of inflammation and immune activation, conventional flow cytometry and novel mass cytometry for immunophenotyping diverse lymphocyte populations in periphery and liver and hepatic transcriptome sequencing to quantify HCV-specific immunity in these patients. Our proposal will provide valuable insights in protective immunity against HCV in HIV/HCV co- infected PWID who are at highest risk of reinfection and disease progression and are at the core of HCV epidemic. This will help us identify patients that may require additional intervention, and pave the way for development of innovative preventive strategies targeting HIV infected PWID enabling us to disrupt the ongoing HCV epidemic.

摘要据估计，有300万美国人患有慢性丙型肝炎（HCV）感染，其中高达25%的人是共同感染者。感染了艾滋病病毒在新的HCV感染中，80%发生在注射毒品（PWID）和成功注射毒品的人中。需要为这一核心群体制定治疗战略，以遏制这一流行病。直接作用抗病毒剂（DAA）是治疗HCV的新的非免疫基础疗法，并且在治疗HCV与HIV合并感染中有效; 合并感染的个体肝纤维化进展更快，临床结局更差， HCV单一感染者。PWID合并HIV感染者有明显较高的再感染率和肝脏即使在达到持续病毒学应答（SVR）后，疾病也会进展。关键是要调查长期以来- 在这些高危人群中进行SVR的长期持久性，以确定导致HCV的可能因素复发我们小组一直在研究HCV治疗反应（包括HIV阳性PWID患者），巴尔的摩和哥伦比亚特区。我们发现，在DAA治疗达到SVR的患者中，HCV特异性与HCV复发的患者相比，T细胞免疫恢复。我们正在寻找免疫的成功治疗反应的相关因素，特别是在高危人群中，目的是确定持续的病毒特异性免疫恢复的缺陷可能会妨碍SVR的持久性。在本建议中，我们将寻求1）调查HIV/HCV共感染者中SVR后肝脏疾病和HCV再感染率的改善情况，有或无当前注射药物使用的感染患者2）探索HIV/HCV合并感染的影响，当前注射药物对HCV特异性外周血CD 4和CD 8 T细胞恢复和维持的作用 DAA治疗后的反应和3）表征SVR后肝脏免疫缺陷的持续性， HIV/HCV合并感染的高危患者群体。通过这些具体的目标，我们将阐明免疫 HIV/HCV共感染PWID中驱动再感染的机制和因素。我们假设基于DAA的 HCV的根除将导致病毒特异性获得性免疫的增强，缺乏这种免疫可能会导致与HIV/HCV合并感染患者和当前PWID的不良结局相关。我们将采用标准和新的研究技术，包括测量可溶性和细胞标志物的炎症和免疫活化、常规流式细胞术和新型质谱细胞术用于免疫分型不同淋巴细胞外周人群和肝脏及肝脏转录组测序，以量化HCV特异性免疫，这些病人。我们的建议将提供有价值的见解，在保护性免疫对丙型肝炎病毒的艾滋病毒/丙型肝炎病毒共- 感染的PWID，其再感染和疾病进展的风险最高，并且是HCV的核心疫情这将有助于我们识别可能需要额外干预的患者，并为制定针对艾滋病毒感染的PWID的创新预防战略，使我们能够破坏正在进行的 HCV流行。