Effects of Mu-opiate Receptor Engagement on Microbial Translocation and Residual Immune Activation in HIV-infected, ART Suppressed Opioid Use Disorder Patients Initiating Medication-assisted Treatment
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 225
- 试验地点
- 2
- 主要终点
- Change in sCD14
研究概览
简要总结
HIV infection, as well as exposure to opioids (including heroin), are associated with systemic immune activation including increased microbial translocation from the gut. The overall objective of this study is to define the impact of long-term mu-opiate receptor stimulation or blockage with medication for opiate use disorder (i.e, methadone, buprenorphine/naloxone, or extended-release naltrexone) on the kinetics and extent of immune reconstitution on HIV-1 infected people who inject opiate and initiating antiretroviral therapy.
详细描述
The use of intravenous opioids (e.g., heroin) has been shown to impair the immune reconstitution outcomes of combined antiretroviral therapy (cART) in HIV-1-infected individuals. People who inject opioid drugs (PWID) have lower CD4 count recovery and sustained cellular activation and inflammation compared to non-opioid users. The pathogenesis of this phenomenon remains understudied. Notably, the effect of oral μ-opioid receptor (MOR) full agonists (e.g., methadone) or partial agonist (e.g., buprenorphine), which are widely used as medications for opioid use disorder treatment, on cART-mediated immune reconstitution is also unknown, limiting the information available to healthcare providers on immune or viral outcomes associated with MOR agonists or antagonists (e.g., naltrexone) in HIV-infected PWIDs. The primary objective of this proposal is to establish the extent and pathogenesis of residual immune activation/inflammation, levels of immune reconstitution, and HIV measures in HIV-1-infected PWID who start cART concomitant with medication for opioid use disorder in an addiction clinic with three strategies: a) integrated treatment program (ITP) with oral methadone maintenance, or b) ITP with oral buprenorphine, or c) ITP with extended-release naltrexone.
The primary hypothesis is that PWIDs receiving MOR agonists (i.e. methadone maintenance) will have impaired cART-mediated immune reconstitution outcomes and/or higher levels of systemic immune activation and cell-associated HIV as compared to PWIDs receiving MOR partial agonist (i.e., buprenorphine/naloxone) or antagonist (i.e., extended-release naltrexone).
The investigators will test these hypotheses in the following specific aims:
Specific Aim 1: To define the impact of sustained MOR stimulation on the kinetics and extent of immune reconstitution and activation in HIV-1-infected PWID who are starting cART. To this end, the investigators will compare long-term changes in immune activation and senescence, systemic inflammation, and biological immune reconstitution parameters in a cohort of PWID with chronic HIV infection initiating ART, randomized 1:1:1 to either methadone, buprenorphine/naloxone or extended-release naltrexone.
Specific Aim 2: To define the clinical and virological correlates of long-term treatment with MOR full agonist (methadone), partial agonist (buprenorphine/naloxone) and antagonist (extended-release naltrexone), by analysis of clinical outcomes (CD4 count), adherence to ART, and retention in care. Viral measures will focus on the changes in persistent HIV reservoir measures on ART (i.e., characterization of cell-associated viral RNA and DNA species in PBMC).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Meet DSM-5 criteria for moderate to severe opiate use disorder (as determined by DSM-5 checklist)
- •Opiate use with a positive urine drug screen for heroin or other opiates (other than methadone, buprenorphine, buprenorphine/naloxone) at screening visit
- •Documented HIV-1 infection with CD4 less than 350 cells/ μL and VL more than 10,000 copies/mL
- •cART-naïve or or on cART no longer than 3 months if already started
- •Willingness to receive cART or on cART no longer than 3 months if already started
- •Willingness to be randomized to either daily methadone, buprenorphine/naloxone or monthly injection of extended-release naltrexone treatment
- •Ability to understand and complete study procedures
- •Provision of adequate locator information that lists all contact information a participant agrees that the research staff may use to reach him/her
- •All participants must be able to comprehend the purpose of the study and to provide informed consent
- •Is, in the opinion of the study physician, in stable health as determined by pre-study physical examination, medical history, ECG, and laboratory evaluations and is likely to complete the study.
- •Has a total body weight of more than 50 kg (110 pounds) and a body mass index (BMI) of more than 20 at screening.
- •Female subjects: Cannot be pregnant, Cannot be lactating, Must be unable to conceive (i.e., surgically sterilized, sterile, or post-menopausal defined as 1 year without bleeding or spotting) OR must agree to use an acceptable method of birth control (e.g., birth control pills, intrauterine device [IUD], or a double barrier method of birth control (condoms and spermicide together; or diaphragm, condom and spermicide together)
排除标准
- •Current cognitive impairment, schizophrenia, paranoid disorder, bipolar disorder not compatible with study procedure (assessed by the medical director of the study)
- •Known neurological, cardiovascular, renal, or other significant medical disorder that is likely to impair or make the individual's participation hazardous Active Tuberculosis or other symptomatic infectious disease AIDS-defining illness
- •Current cancer or other malignancies
- •Advanced liver disease (FibroScan® METAVIR score F3-F4, liver elasticity more than10kPa)
- •Use of immunomodulators
- •Meet DSM-5 criteria for any other substance use disorder (except nicotine)
- •Engagement in opiate medication treatment at baseline (methadone, buprenorphine, buprenorphine/naloxone, naltrexone)
- •Pending legal charges with likely incarceration within next 6 months
- •Currently participating in another clinical trial
研究组 & 干预措施
Methadone
Participants in this arm will receive a 48-week integrated treatment program for opiate use disorder with daily directly observed oral methadone (MET) and antiretroviral therapy (cART).
干预措施: Methadone (Drug)
Buprenorphine/naloxone
Participants in this arm will receive a 48-week integrated treatment program for opiate use disorder with daily directly observed oral buprenorphine/naloxone and antiretroviral therapy (cART).
干预措施: Buprenorphine/naloxone (Drug)
XR-Naltrexone
Participants in this arm will receive a 48-week integrated treatment program for opiate use disorder with monthly injection extended-release naltrexone (XR-NTX) and antiretroviral therapy (cART).
干预措施: XR-Naltrexone (Drug)
结局指标
主要结局
Change in sCD14
时间窗: Baseline, Week-4, -8, -12, -24, -36, -48
Change in plasma sCD14 concentration over 48 weeks
次要结局
- Marker of immune activation: Change in CD38(baseline, Week-4, -8, -12, -24, -36 and -48)
- Marker of inflammation: Change in Plasma hr-CRP(baseline, Week-4, -8, -12, -24, -48)
- Marker of immune activation: HLA-DR(baseline, Week-4, -8, -12, -24, -36 and -48)
- Marker of immune activation: Change in sCD163(baseline, Week-4, -8, -12, -24, -36 and -48)
- Marker of immune activation: Change in Type-I IFN(baseline, week -12, -24, -36 and -48)
- Marker of bacterial translocation: Change in endo-CAB(Baseline, Week-48)
- Marker of bacterial translocation: Change in bacterial butyryl-coA-coA(Baseline, Week-48)
- Marker of immune activation: Change in PD1(baseline, Week-4, -8, -12, -24, -36 and -48)
- Marker of immune activation: Change in CD169(baseline, Week-4, -8, -12, -24, -36 and -48)
- Marker of inflammation: Change in d-dimer(baseline, Week-4, -8, -12, -24, -48)
- Marker of inflammation: Change in sTNFR-1(baseline, Week-4, -8, -12, -24, -48)
- Marker of bacterial translocation: Change in Zonulin-1(Baseline, Week-48)
- Addiction clinical outcomes: Medication for opioid use disorder (MOUD)(Week 48)
- Marker of bacterial translocation: Change in LPB(Baseline, Week-48)
- Retention in care(Baseline to Week-48)
- HIV-related outcomes: Change in CD4 counts(baseline, Week-4, -8, -12, -24, -36 and -48)
- Addiction clinical outcomes: Change in Drug use(Baseline, Week-4, -8, -12, -16, -20, -24, -28, -32, -36, -40, -44, and -48)
- Marker of bacterial translocation: Change in s16 rDNA(Baseline, Week-48)
- Marker of inflammation: Change in Interleukins IL-6 and IL-10(baseline, Week-4, -8, -12, -24, -48)
- Marker of inflammation: Change in TGF-beta(baseline, Week-4, -8, -12, -24, -48)
- Marker of bacterial translocation: Change in LPS(Baseline, Week-48)
- Marker of bacterial translocation: Change in Intestinal fatty acid-binding protein (I-FABP)(Baseline, Week-48)
- HIV-related outcomes: cART adherence(baseline, Week-4, -8, -12, -24, -36 and -48)
- HIV-related clinical outcomes: Viral load(baseline, Week-12, -24, and -48)