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

University of Pennsylvania

Status and phase: Enrolling; Phase 2

Conditions: Naltrexone; Inflammation; Antiretroviral Treatment; HIV-1-infection; Opioid-use Disorder; Immune Activation; Buprenorphine; Methadone

Treatments: Drug: Methadone; Drug: Buprenorphine/naloxone; Drug: XR-Naltrexone

Study type: Interventional

Funder types: Other; Other U.S. Federal agency

Identifiers

NCT04480554

R01DA048728

Details and patient eligibility

About

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.

Full 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).

Enrollment: 225 estimated patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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225 participants in 3 patient groups

Methadone

Experimental group

Description:

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).

Treatment:

Drug: Methadone

Buprenorphine/naloxone

Experimental group

Description:

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).

Treatment:

Drug: Buprenorphine/naloxone

XR-Naltrexone

Experimental group

Description:

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).

Treatment:

Drug: XR-Naltrexone