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
• 负责人: DAVID S METZGER
• 金额: $ 165.25万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436808
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Acute; Adherence; Agonist; Award; Behavioral; Blood Circulation; Caring; Cells; Characteristics; Chronic; Cities; Clinic; Clinical; Clinical Research; Clinical Trials; Counseling; Country; DNA; Data; Exposure to; France; Future; Genetic Transcription; Government; HIV; HIV Infections; HIV-1; Harm Reduction; Health; Hepatitis; Heroin; Heroin Users; High Prevalence; Immunologics; Immunotherapy; Individual; Industry; Inflammation; Infrastructure; Injecting drug user; Institutes; Interdisciplinary Study; International; Intravenous; Kinetics; Legal patent; Link; Maintenance; Measures; Methadone; Morbidity - disease rate; Naltrexone; Opiate Addiction; Opioid; Opioid Receptor; Oral; Outcome; Outcome Study; Patients; Pennsylvania; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Philadelphia; RNA; Randomized; Recovery; Research; Residual state; Risk; Site; Testing; The Wistar Institute; Time; Universities; Vietnam; Viral; addiction; antagonist; antiretroviral therapy; arm; base; clinical care; clinically relevant; cohort; immune activation; immune reconstitution; industry partner; intervention effect; medication-assisted treatment; member; methadone treatment; microbial; mortality; mu opioid receptors; opioid use; opioid use disorder; opioid user; prevention service; primary endpoint; programs; randomized trial; retention rate; systemic inflammatory response; treatment arm; treatment program; treatment services; trial comparing; viral DNA; viral RNA

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.

项目总结