Anti-retroviral Therapy, Medications for Opioid Use Disorder, Opioids and HIV Infection - Study 1 (AMOHI-1)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Inflammation; Opioid-use Disorder; HIV-1-infection; Immune Activation; Buprenorphine; Methadone; Naltrexone; Antiretroviral Treatment
• Intervention / Treatment: Drug: Methadone; Drug: Buprenorphine/naloxone; Drug: XR-Naltrexone

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Estimated): 225
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: David S Metzger, PhD; Phone Number: 2157467346; Email: dsm@pennmedicine.upenn.edu
• Study Contact Backup: Name: Cecile M Denis, PhD; Phone Number: 2158981825; Email: cdenis@pennmedicine.upenn.edu

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Active, not recruiting
      • University of Pennsylvania
• Vietnam
  • Ho Chi Minh City, Vietnam
    • Recruiting
    • Go Vap Clinic
    • Contact: Thuy Huynh Thu, MD, MSc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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)

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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).	Drug: Methadone; Participants will receive a 48-week integrated treatment program for opiate use disorder with daily directly observed oral methadone syrup (MET), structured counseling sessions (BDRC-based) weekly for the first 3 months and monthly thereafter, and antiretroviral therapy.
Experimental: 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).	Drug: Buprenorphine/naloxone; Participants will receive a 48-week integrated treatment program for opiate use disorder with daily directly observed oral buprenorphine/naloxone tablets (Suboxone(R)), structured counseling sessions (BDRC-based) weekly for the first 3 months and monthly thereafter, and antiretroviral therapy.; Other Names: Suboxone
Experimental: 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).	Drug: XR-Naltrexone; Participants will receive a 48-week integrated treatment program for opiate use disorder with monthly extended-release naltrexone (Vivitrol(R)), structured counseling sessions (BDRC-based) weekly for the first 3 months and monthly thereafter, and antiretroviral therapy.; Other Names: Vivitrol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in sCD14	Change in plasma sCD14 concentration over 48 weeks	Baseline, Week-4, -8, -12, -24, -36, -48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Marker of immune activation: Change in CD38	Change in CD38 concentration over 48 weeks	baseline, Week-4, -8, -12, -24, -36 and -48
Marker of immune activation: HLA-DR	Change in HLA-DR concentration over 48 weeks	baseline, Week-4, -8, -12, -24, -36 and -48
Marker of immune activation: Change in PD1	Change in PD1 expression in C8+ T cells over 48 weeks	baseline, Week-4, -8, -12, -24, -36 and -48
Marker of immune activation: Change in CD169	Change in CD169 expression in monocytes over 48 weeks	baseline, Week-4, -8, -12, -24, -36 and -48
Marker of immune activation: Change in sCD163	Change in plasma sCD163 concentration over 48 weeks	baseline, Week-4, -8, -12, -24, -36 and -48
Marker of immune activation: Change in Type-I IFN	Change in type-I IFN signature over 48 weeks	baseline, week -12, -24, -36 and -48
Marker of inflammation: Change in Plasma hr-CRP	Change in plasma hr-CRP concentration over 48 weeks	baseline, Week-4, -8, -12, -24, -48
Marker of inflammation: Change in d-dimer	Change in plasma d-dimer concentration over 48 weeks	baseline, Week-4, -8, -12, -24, -48
Marker of inflammation: Change in sTNFR-1	Change in plasma sTNFR-1 concentration over 48 weeks	baseline, Week-4, -8, -12, -24, -48
Marker of inflammation: Change in Interleukins IL-6 and IL-10	Change in plasma IL-6 and IL-10 concentration over 48 weeks	baseline, Week-4, -8, -12, -24, -48
Marker of inflammation: Change in TGF-beta	Change in plasma TGF-beta concentration over 48 weeks	baseline, Week-4, -8, -12, -24, -48
Marker of bacterial translocation: Change in LPB	Change in plasma LPB concentration at 48 weeks	Baseline, Week-48
Marker of bacterial translocation: Change in LPS	Change in plasma LPS concentration at 48 weeks	Baseline, Week-48
Marker of bacterial translocation: Change in endo-CAB	Change in plasma endo-CAB concentration at 48 weeks	Baseline, Week-48
Marker of bacterial translocation: Change in Intestinal fatty acid-binding protein (I-FABP)	Change in plasma I-FABP concentration at 48 weeks	Baseline, Week-48
Marker of bacterial translocation: Change in Zonulin-1	Change in plasma Zonulin-1 concentration at 48 weeks	Baseline, Week-48
Marker of bacterial translocation: Change in s16 rDNA	Change in s16rDNA concentration at 48 weeks	Baseline, Week-48
Marker of bacterial translocation: Change in bacterial butyryl-coA-coA	Change in bacterial butyryl-coA-coA concentration at 48 weeks	Baseline, Week-48
Retention in care	Percentage of completed medication visits over 48 weeks	Baseline to Week-48
HIV-related outcomes: Change in CD4 counts	Change in CD4 counts over 48 weeks	baseline, Week-4, -8, -12, -24, -36 and -48
HIV-related outcomes: cART adherence	Number of prescription refills over 48-weeks	baseline, Week-4, -8, -12, -24, -36 and -48
HIV-related clinical outcomes: Viral load	Percentage of participants with a suppressed viral load at Week-12, -24, and -48	baseline, Week-12, -24, and -48
Addiction clinical outcomes: Medication for opioid use disorder (MOUD)	Comparison of percentage of participants who completed the treatment in each group	Week 48
Addiction clinical outcomes: Change in Drug use	Change in percentage of monthly drug use over 48 weeks	Baseline, Week-4, -8, -12, -16, -20, -24, -28, -32, -36, -40, -44, and -48

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Collaborators: National Institute of Drug Abuse; The Wistar Institute; Ho Chi Minh City CDC; Institute of Applied Medicine and Epidemiology (IMEA)
• Investigators: Principal Investigator: Luis J Montaner, DVM, D.Phil, The Wistar Institute

Study record dates

Study Major Dates

• Study Start (Actual): January 30, 2023
• Primary Completion (Estimated): June 30, 2024
• Study Completion (Estimated): June 30, 2024

Study Registration Dates

• First Submitted: July 1, 2020
• First Submitted That Met QC Criteria: July 17, 2020
• First Posted (Actual): July 21, 2020

Study Record Updates

• Last Update Posted (Actual): July 10, 2023
• Last Update Submitted That Met QC Criteria: July 6, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: HIV; Antiretroviral therapy; Immune activation; Opioid use disorder; Medication for Opioid Use Disorder
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Pathologic Processes; Narcotic-Related Disorders; Substance-Related Disorders; Inflammation; Infections; Opioid-Related Disorders; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Narcotic Antagonists; Respiratory System Agents; Alcohol Deterrents; Antitussive Agents; Buprenorphine; Naltrexone; Naloxone; Buprenorphine, Naloxone Drug Combination; Methadone
• Other Study ID Numbers: R01DA048728 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes