Effects of mu-opiate receptor engagement on microbial translocation and residual immune activation in HIV-infected, ART suppressed opioid use disorder patents initiating medication-assisted treatment
mu-阿片受体结合对 HIV 感染者、ART 抑制的阿片类药物使用障碍患者微生物易位和残余免疫激活的影响,开始药物辅助治疗
基本信息
- 批准号:10004224
- 负责人:
- 金额:$ 51.51万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-15 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AIDS/HIV problemAcquired Immunodeficiency SyndromeAcuteAdherenceAgonistAwardBehavioralBlood CirculationCaringCellsCharacteristicsChronicCitiesClinicClinicalClinical ResearchClinical TrialsClinical VirologyCounselingCountryDNADataExposure toFranceFutureGenetic TranscriptionGovernmentHIVHIV InfectionsHIV-1Harm ReductionHealthHepatitisHeroinHeroin UsersHigh PrevalenceImmunologicsIndividualIndustryInflammationInfrastructureInjecting drug userInstitutesInterdisciplinary StudyInternationalIntravenousKineticsLegal patentLinkMaintenanceMeasuresMediatingMethadoneMorbidity - disease rateNaltrexoneOpiate AddictionOpioidOpioid ReceptorOpioid userOralOutcomeOutcome StudyPatientsPennsylvaniaPeripheral Blood Mononuclear CellPersonsPharmaceutical PreparationsPhiladelphiaRNARandomizedRecoveryResearchResidual stateRiskSiteTestingThe Wistar InstituteTimeUniversitiesVietnamViraladdictionantiretroviral therapyarmbaseclinical careclinically relevantcohortimmune activationimmune reconstitutionindustry partnerintervention effectmedication-assisted treatmentmembermethadone treatmentmicrobialmortalitymu opioid receptorsoff-patentopioid useopioid use disorderprevention serviceprimary endpointprogramsrandomized trialretention ratetreatment armtreatment programtreatment servicestrial comparingviral DNAviral RNA
项目摘要
PROJECT SUMMARY
HIV infection, as well as exposure to opioids including intravenous heroin, are associated with systemic immune
activation including increased microbial translocation from the gut. The overall objective of this study is to
provide clinical evidence on the detrimental link between kinetics and characteristics of immune reconstitution
(microbial translocation, residual immune activation, retained HIV expression) in HIV-1 infected people who
inject drugs (PWIDs) and sustain interaction with the μ-opioid receptor (MOR) while on antiretroviral therapy
(ART). Defining the impact of continued MOR engagement after ART initiation is of relevance to addiction
treatment as maintenance-assisted treatment options include using a MOR agonist (methadone, MET) or a
MOR antagonist (long-acting naltrexone, XR-NTX). Notably, the effect of oral MET, which is widely used in
maintenance treatment, on ART-mediated immune reconstitution is unknown. Based on preliminary data
showing higher microbial translocation, immune activation, and active HIV transcription in ART-suppressed
PWID on MET over XR-NTR, we will test the primary hypothesis that chronic engagement of mu-opioid receptor
by a full MOR agonist (MET) while on ART will result in reduced rates and magnitude of microbial translocation,
with sustained immune activation and inflammation associated with increased levels of persistent HIV (i.e.,
integrated HIV DNA, cell-associated HIV RNA) when compared to a full MOR antagonist (XR-NTX) in spite of
viral suppression. Specifically, we will test these hypotheses in the following specific aims: Specific Aim 1.
Defining the impact of long-term MOR stimulation (MET) or blockage (XR-NTX) on the kinetics and extent of
immune reconstitution in PWID initiating ART. To this end, we will also compare 48 week changes on residual
immune activation, microbial translocation, and systemic inflammation in a cohort of PWID with chronic HIV
infection initiating ART, randomized 1:1 to either MET or XR-NTX. sCD14 level change after ART will serve as
the primary end-point variable. Specific Aim 2. Defining the clinical and virologic correlates of 48 week
treatment with MOR agonists (MET) and antagonists (XR-NTX), by studying effect of the intervention on CD4,
adherence to ART, acceptability of MAT, as well as retention in care. Changes in persistent HIV measures will
also be measured (i.e., persistence of viral RNA and DNA species in PBMC, etc.). Given the high prevalence
of HIV-infected heroin users starting ART and opioid addition therapy, Vietnam is an ideal setting to complete
the proposed study to provide generalizable proof-of-concept data in support of future long-term clinical
outcome studies. This study represents an international multi-disciplinary collaboration between the Vietnam
Ministry of Health, the Vietnam Administration of HIV/AIDS Control, the Provincial AIDS Committee, the
University of Pennsylvania, Expertise France (a French-led initiative to expand access to HIV/ Hepatitis
prevention and treatment services), the Pasteur Institute, Alkermes (industry partner), and The Wistar Institute.
项目摘要
HIV 感染以及接触阿片类药物(包括静脉注射海洛因)与全身免疫有关
激活包括增加微生物从肠道的移位。 这项研究的总体目标是
提供关于免疫重建动力学和特征之间有害联系的临床证据
(微生物易位、残留免疫激活、保留 HIV 表达)在 HIV-1 感染者中
在抗逆转录病毒治疗期间注射毒品(注射吸毒者)并维持与μ阿片受体(MOR)的相互作用
(艺术)。 定义 ART 开始后持续的 MOR 参与的影响与成瘾相关
作为维持辅助治疗选择的治疗包括使用 MOR 激动剂(美沙酮,MET)或
MOR 拮抗剂(长效纳曲酮,XR-NTX)。 值得注意的是,口服 MET 的效果广泛用于
维持治疗对 ART 介导的免疫重建的影响尚不清楚。 基于初步数据
在 ART 抑制中显示出更高的微生物易位、免疫激活和活跃的 HIV 转录
PWID 上的 MET 与 XR-NTR 相比,我们将测试主要假设,即 mu-阿片受体的长期结合
在 ART 期间使用完全 MOR 激动剂 (MET) 将导致微生物易位的速率和程度降低,
持续的免疫激活和与持续性 HIV 水平升高相关的炎症(即,
与完全 MOR 拮抗剂 (XR-NTX) 相比,整合了 HIV DNA、细胞相关 HIV RNA)
病毒抑制。 具体来说,我们将在以下具体目标中测试这些假设:具体目标 1。
定义长期 MOR 刺激 (MET) 或阻断 (XR-NTX) 对动力学和程度的影响
注射吸毒者开始 ART 时的免疫重建。为此,我们还将比较 48 周残差的变化
一群患有慢性 HIV 的注射吸毒者的免疫激活、微生物易位和全身炎症
感染启动 ART,按 1:1 随机分配至 MET 或 XR-NTX。 ART 后 sCD14 水平变化将作为
主要终点变量。 具体目标 2. 定义 48 周的临床和病毒学相关性
通过研究对 CD4 的干预效果,使用 MOR 激动剂 (MET) 和拮抗剂 (XR-NTX) 进行治疗,
对 ART 的遵守、MAT 的可接受性以及护理的保留。 持续性艾滋病毒措施的改变将
也可被测量(即病毒 RNA 和 DNA 种类在 PBMC 中的持久性等)。 鉴于患病率很高
对于开始接受 ART 和阿片类药物添加治疗的 HIV 感染海洛因吸食者来说,越南是一个理想的完成环境
拟议的研究旨在提供可推广的概念验证数据,以支持未来的长期临床
结果研究。 这项研究代表了越南与越南之间的国际多学科合作
卫生部、越南艾滋病防治总局、省艾滋病防治委员会、
宾夕法尼亚大学,法国专业知识(一项由法国领导的倡议,旨在扩大艾滋病毒/肝炎的获取范围)
预防和治疗服务)、巴斯德研究所、Alkermes(行业合作伙伴)和 Wistar 研究所。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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DAVID S METZGER其他文献
DAVID S METZGER的其他文献
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{{ truncateString('DAVID S METZGER', 18)}}的其他基金
Effects of mu-opiate receptor engagement on microbial translocation and residual immune activation in HIV-infected, ART suppressed opioid use disorder patents initiating medication-assisted treatment
mu-阿片受体结合对 HIV 感染者、ART 抑制的阿片类药物使用障碍患者微生物易位和残余免疫激活的影响,开始药物辅助治疗
- 批准号:
10197865 - 财政年份:2019
- 资助金额:
$ 51.51万 - 项目类别:
Effects of mu-opiate receptor engagement on microbial translocation and residual immune activation in HIV-infected, ART suppressed opioid use disorder patents initiating medication-assisted treatment
mu-阿片受体结合对 HIV 感染者、ART 抑制的阿片类药物使用障碍患者微生物易位和残余免疫激活的影响,开始药物辅助治疗
- 批准号:
10436808 - 财政年份:2019
- 资助金额:
$ 51.51万 - 项目类别:
Effects of mu-opiate receptor engagement on microbial translocation and residual immune activation in HIV-infected, ART suppressed opioid use disorder patents initiating medication-assisted treatment
mu-阿片受体结合对 HIV 感染者、ART 抑制的阿片类药物使用障碍患者微生物易位和残余免疫激活的影响,开始药物辅助治疗
- 批准号:
10654008 - 财政年份:2019
- 资助金额:
$ 51.51万 - 项目类别:
Rapid initiation of buprenorphine/naloxone to optimize MAT utilization in Philadelphia
快速启动丁丙诺啡/纳洛酮以优化费城 MAT 的利用
- 批准号:
9896726 - 财政年份:2018
- 资助金额:
$ 51.51万 - 项目类别:
Efficacy of Drug-HIV counseling among IDU at Methadone clinics in Jakarta
雅加达美沙酮诊所注射吸毒者药物艾滋病毒咨询的效果
- 批准号:
7835556 - 财政年份:2009
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$ 51.51万 - 项目类别:
Efficacy of Drug-HIV counseling among IDU at Methadone clinics in Jakarta
雅加达美沙酮诊所注射吸毒者药物艾滋病毒咨询的效果
- 批准号:
7687184 - 财政年份:2009
- 资助金额:
$ 51.51万 - 项目类别:
Efficacy of Drug-HIV counseling among IDU at Methadone clinics in Jakarta
雅加达美沙酮诊所注射吸毒者药物艾滋病毒咨询的效果
- 批准号:
8261981 - 财政年份:2009
- 资助金额:
$ 51.51万 - 项目类别:
Efficacy of Drug-HIV counseling among IDU at Methadone clinics in Jakarta
雅加达美沙酮诊所注射吸毒者药物艾滋病毒咨询的效果
- 批准号:
8085908 - 财政年份:2009
- 资助金额:
$ 51.51万 - 项目类别:
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