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
艾滋病毒感染以及暴露于阿片类药物(包括静脉注射海洛因)与全身免疫相关。
激活,包括增加肠道微生物移位。本研究的总体目标是
为免疫重建的动力学和特征之间的有害联系提供临床证据
(微生物易位,残留免疫激活,保留HIV表达)的HIV-121感染者,
注射药物(PWID),并在抗逆转录病毒治疗时维持与μ-阿片受体(莫尔)的相互作用
定义ART启动后持续莫尔参与的影响与成瘾相关
作为维持的治疗--美沙酮辅助治疗选择包括使用莫尔激动剂(美沙酮,MET)或
莫尔拮抗剂(长效纳洛酮,XR-10 NTX)。
维持治疗对ART-1介导的免疫重建的影响尚不清楚。
显示ART-抑制组的微生物易位、免疫激活和HIV转录活性更高,
PWID对MET超过XR-β NTR的影响,我们将检验主要假设,即μ阿片受体的慢性参与
通过完全莫尔激动剂(MET)同时进行ART将导致微生物易位的速率和幅度降低,
持续的免疫激活和炎症与持续性HIV水平的增加有关(即,
尽管如此,与完整的莫尔受体拮抗剂(XR-α NTX)相比,整合的HIV DNA、细胞相关的HIV RNA)
病毒抑制。具体而言,我们将在以下具体目标中测试这些假设: 具体目标1。
定义长期莫尔刺激(MET)或阻断(XR-MOR NTX)对
PWID中的免疫重建启动ART。为此,我们还将比较48周的残留变化,
慢性HIV感染者PWID队列中的免疫激活、微生物易位和全身炎症
感染启动ART,1:1随机分配至MET或XR-NTX。
主要的端点变量。 明确48周妊娠的临床和病毒学相关因素
用莫尔激动剂(MET)和拮抗剂(XR-MOR NTX)治疗,通过研究干预对CD 4的影响,
坚持抗逆转录病毒治疗,MAT的可接受性,以及保持护理。持续艾滋病毒措施的变化将
也被测量(即, PBMC中病毒RNA和DNA种类的持续存在等)。 鉴于高发病率
对于开始ART和阿片类药物添加治疗的艾滋病病毒感染的海洛因使用者来说,越南是完成
本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研究
结果研究。这项研究代表了越南和美国之间的国际多学科合作,
卫生部、越南艾滋病毒/艾滋病控制局、省艾滋病委员会、
宾夕法尼亚大学,法国专家(法国领导的扩大艾滋病毒/肝炎获得机会的倡议)
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
- 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:
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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