HIV-1-infection, Methamphetamine-dependence
Conditions
Keywords
HIV, methamphetamine, viral transcription, inflammation
Brief summary
The most commonly used illicit stimulant in HIV-infected individuals is methamphetamine (MA). Prior studies demonstrate strong evidence that MA promotes increased HIV transcription as well as immune dysregulation. A challenge in achieving worldwide HIV eradication is targeting specific marginalized populations who are most likely to benefit from an HIV cure but possess poorer immune responses. For this study, HIV+ infected ART-suppressed individuals with no prior history of MA use disorder will be administered oral methamphetamine (the maximum FDA approved daily dose for the treatment of childhood obesity) to determine the effects of short-term MA exposure on residual virus production, gene expression, and inflammation. Measures of MA exposure in urine and serum will then be associated with residual virus production, gene expression, cell surface immune marker protein expression, and systemic markers of inflammation. The clinical trial data will generate advanced gene expression and immunologic data to identify potential novel targets for reversing HIV latency, reducing inflammation, and personalizing future therapies in HIV+ individuals who use MA.
Detailed description
The most commonly used illicit stimulant in HIV-infected individuals is methamphetamine (MA), and prior studies demonstrate strong evidence that MA promotes increased HIV transcription as well as immune dysregulation. HIV cure has emerged as an important clinical and research priority given evidence of ongoing immune dysfunction in HIV-infected individuals despite effective antiretroviral therapy (ART). A challenge in achieving worldwide HIV eradication is targeting specific vulnerable populations who are most likely to benefit from an HIV cure but possess poorer immune responses as a result of residual viral replication due to suboptimal ART adherence and/or direct immune dysfunction from illicit substance use. Prior non-human studies demonstrate that MA directly induces HIV production and promotes immune activation and inflammation. These preclinical findings suggest that HIV+ individuals who use MA may experience greater immune dysfunction and face additional challenges for future HIV eradication. This study will investigate the effects of short-term MA exposure in HIV+ ART-suppressed individuals without a prior history of MA use. Participants will be enrolled in an interventional study where they will be administered oral methamphetamine (the maximum FDA approved daily dose for the treatment of childhood obesity) to determine the effects of short-term MA exposure on residual virus production, gene expression, inflammation, and trace amine-associated 1 (TAAR1, a promising drug target for psychostimulant addiction) signaling. MA exposure will be quantified with multiple serum samples collected over a 24-hour monitoring period and associated with residual viral transcription, host gene and cell surface protein expression, and inflammation (plasma inflammatory cytokine levels) quantification. The proposed study will be the first human genetic study to directly evaluate the effect of MA exposure on residual viral transcription during effective ART. The overall goals of the study are to integrate a rigorous clinical study designs with high throughput 'omics data to identify novel targets for reversing HIV latency, reducing inflammation, and personalizing future therapeutic strategies specific to HIV+ ART-suppressed individuals who use MA.
Interventions
An initial 10 mg of oral methamphetamine (over-encapsulated to look similar to placebo capsule) study drug will be administered to assess tolerability, followed by a subsequent 15 mg oral dose (over-encapsulated to look similar to placebo capsule) two hours later.
OTHERPlacebo oral capsule
One placebo capsule will be administered orally on treatment day, followed by a second oral placebo capsule two hours later.
Sponsors
University of California, San Francisco
National Institute on Drug Abuse (NIDA)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The order in which participants complete the two treatment phases (i.e., oral methamphetamine and placebo) will be unknown to both the participants and the PI/study team. Both the oral methamphetamine and placebo will be prepared in identical capsules by the UCSF investigational pharmacist, out of sight of the study participant, study coordinator, and study site PI and administered to the participant to maintain double blinding. The investigational pharmacist will randomize each participant according to the methods described above. In the event that participant experiences an adverse event that requires the identity of the study drug be revealed, the PI will be able to contact the investigational pharmacist to break the blind. In the event that a participant blind is broken, the study PIs will determine the impact upon the un-blinded participant's continued participation in the study and if a replacement participant is needed on a case-by-case basis.
Intervention model description
This is a phase IV randomized, double-blinded, placebo-controlled crossover study. A placebo treatment arm will be assigned to participants in a randomized crossover design. HIV+ ART-suppressed individuals with no prior history of MA use disorder will be administered 10mg oral methamphetamine hydrochloride, followed by 15 mg methamphetamine hydrochloride two hours later, for a total of 25mg in one 24-hour period (the maximum FDA approved daily dose for the treatment of childhood obesity). Participants will complete the study twice (once on a placebo treatment arm and once with the oral methamphetamine treatment arm). Which treatment arm occurs first will be randomly assigned and will include a 31-day washout period between the two phases.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Willing and able to provide written informed consent 2. Male or female, age ≥ 18 and ≤ 65 years 3. HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen or plasma HIV-1 RNA viral load. 4. Continuous therapy with a Department of Health and Human Services (DHHS) recommended/alternative combination ART for least 24 months (at least 3 agents) at study entry with no regimen changes in the preceding 12 weeks 5. Maintenance of undetectable plasma HIV-1 RNA (\<40 copies/ml) for at least 12 months. Episodes of single HIV plasma RNA 50-500 copies/ml will not exclude participation if subsequent HIV plasma RNA is \<40 copies/ml. 6. No plans to modify ART during the study period (146 days, or approximately 5 months) 7. Screening CD4+ (cluster of differentiation 4) T-cell count ≥ 350 cells/mm3 8. Screening hemoglobin ≥ 12.5 g/dL 9. No current or prior history of methamphetamine (MA) use disorder by DSM-5 diagnostic criteria. Participants may have a prior history of taking prescription medications containing amphetamines-type stimulants such as Adderall® or Dexedrine® or Ritalin for the treatment of conditions such as attention deficit hyperactivity disorder as long as the participant has not taken these medications in the last 12 months or plans to take these medications during the entire study period. 10. Willingness to use two forms of contraception throughout the study period as well as up to 30 days after the last day of study completion. 11. Ability and availability to participate in the full 146 days of the study (approximately 5 month) and maintain the inclusion/
Exclusion criteria
.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HIV Transcription (Cell-associated HIV RNA) in Peripheral Blood | 4 hours | The change in HIV reservoir size (as measured by cell-associated HIV RNA levels) over a 4 hour study period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Systemic Inflammation (Plasma Pro-inflammatory Cytokine Levels) | 4 hours | The change in plasma pro-inflammatory interleukin (IL)-1B levels over a 4 hour study period. |
| Change in the Frequency of Non-classical Monocyte Cells, as Measured With Flow Cytometry | 4 hours | The change in frequency of non-classical monocyte cells (CD3nCD14nCd16p) in peripheral blood (peripheral blood mononuclear cells - PBMCs), as measured by flow cytometry over a 4-hour study period following drug or placebo administration. |
| Trace Amine Receptor 1 (TAAR1) Signaling Metabolite Levels in in Peripheral Blood | 4 hours | The change in tyramine (TAAR1 signaling metabolite) levels over a 4 hour study period. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORSulggi A Lee, MD PhD
University of California, San Francisco
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Oral Methamphetamine, Then Placebo Oral Capsule Participants will be randomized to oral methamphetamine first then placebo oral capsule using a random number generator. When oral methamphetamine is administered, an initial 10 mg of oral methamphetamine study drug will be administered to assess tolerability, followed by a subsequent 15 mg oral dose two hours later. Then the participant will receive the placebo oral capsule for their second treatment phase starting at approximately Day 77. For the placebo treatment, one placebo capsule will be administered orally on treatment day, followed by a second oral placebo capsule two hours later.
Oral Methamphetamine: An initial 10 mg of oral methamphetamine (over-encapsulated to look similar to placebo capsule) study drug will be administered to assess tolerability, followed by a subsequent 15 mg oral dose (over-encapsulated to look similar to placebo capsule) two hours later.
Placebo oral capsule: One placebo capsule will be administered orally on treatment day, followed by a second oral placebo capsule two hours later. | 5 |
| Placebo Oral Capsule, Then Oral Methamphetamine Participants will be randomized to a placebo oral capsule first, then oral methamphetamine using a random number generator. For the placebo treatment, one placebo capsule will be administered orally on treatment day, followed by a second oral placebo capsule two hours later. Then the participant will receive the oral methamphetamine capsule for their second treatment phase starting at approximately Day 77. When oral methamphetamine is administered, an initial 10 mg of oral methamphetamine study drug will be administered to assess tolerability, followed by a subsequent 15 mg oral dose two hours later.
Oral Methamphetamine: An initial 10 mg of oral methamphetamine (over-encapsulated to look similar to placebo capsule) study drug will be administered to assess tolerability, followed by a subsequent 15 mg oral dose (over-encapsulated to look similar to placebo capsule) two hours later.
Placebo oral capsule: One placebo capsule will be administered orally on treatment day, followed by a second oral placebo capsule two hours later. | 5 |
| Total | 10 |
Baseline characteristics
| Characteristic | Oral Methamphetamine, Then Placebo Oral Capsule | Placebo Oral Capsule, Then Oral Methamphetamine | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 5 Participants | 10 Participants |
| Age, Continuous | 45.6 years STANDARD_DEVIATION 9.5 | 44.4 years STANDARD_DEVIATION 9.34 | 45 years STANDARD_DEVIATION 8.91 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 3 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 5 Participants | 8 Participants |
| Region of Enrollment United States | 5 participants | 5 participants | 10 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 14 |
| other Total, other adverse events | 1 / 14 | 0 / 14 |
| serious Total, serious adverse events | 0 / 14 | 0 / 14 |
Outcome results
Primary
HIV Transcription (Cell-associated HIV RNA) in Peripheral Blood
The change in HIV reservoir size (as measured by cell-associated HIV RNA levels) over a 4 hour study period.
Time frame: 4 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Oral Methamphetamine, Then Placebo Oral Capsule | HIV Transcription (Cell-associated HIV RNA) in Peripheral Blood | 10.45 copies/million cells |
| Placebo Oral Capsule, Then Oral Methamphetamine | HIV Transcription (Cell-associated HIV RNA) in Peripheral Blood | 57.38 copies/million cells |
Secondary
Host Gene Expression (RNA Sequencing) in Peripheral Blood
The change in host gene expression as measured by RNA-seq over a 4 hour study period
Time frame: 4 hours
Secondary
Systemic Inflammation (Plasma Pro-inflammatory Cytokine Levels)
The change in plasma pro-inflammatory IL-1B levels over a 4 hour study period.
Time frame: 4 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Oral Methamphetamine, Then Placebo Oral Capsule | Systemic Inflammation (Plasma Pro-inflammatory Cytokine Levels) | 0.875 pg/uL |
| Placebo Oral Capsule, Then Oral Methamphetamine | Systemic Inflammation (Plasma Pro-inflammatory Cytokine Levels) | 0.054 pg/uL |
Secondary
Trace Amine Receptor 1 (TAAR1) Signaling Metabolite Levels in in Peripheral Blood
The change in tyramine (TAAR1 signaling metabolite) levels over a 4 hour study period.
Time frame: 4 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Oral Methamphetamine, Then Placebo Oral Capsule | Trace Amine Receptor 1 (TAAR1) Signaling Metabolite Levels in in Peripheral Blood | -215.901 ug |
| Placebo Oral Capsule, Then Oral Methamphetamine | Trace Amine Receptor 1 (TAAR1) Signaling Metabolite Levels in in Peripheral Blood | -171.506 ug |