Effect of Methamphetamine on Residual Latent HIV Disease Study

NCT03825536 | Completed Phase 4 Results DMC FDA Drug

• 2 other identifiers: 18-267651R61DA047024-01
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

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.

Conditions

HIV-1-infection; Methamphetamine-dependence

Keywords

HIV; methamphetamine; viral transcription; inflammation

Outcome Measures

Primary Outcomes (1)

• 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.

  4 hours

Secondary Outcomes (3)

• Systemic Inflammation (Plasma Pro-inflammatory Cytokine Levels)

  4 hours

• Change in the Frequency of Non-classical Monocyte Cells, as Measured With Flow Cytometry

  4 hours

• Trace Amine Receptor 1 (TAAR1) Signaling Metabolite Levels in in Peripheral Blood

  4 hours

Study Arms (2)

Oral methamphetamine, then Placebo oral capsule

EXPERIMENTAL

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.

Drug: Oral Methamphetamine; Other: Placebo oral capsule

Placebo oral capsule, then Oral methamphetamine

EXPERIMENTAL

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.

Drug: Oral Methamphetamine; Other: Placebo oral capsule

Interventions

Placebo oral capsule OTHER

One placebo capsule will be administered orally on treatment day, followed by a second oral placebo capsule two hours later.

Also known as: Placebo

Oral methamphetamine, then Placebo oral capsule; Placebo oral capsule, then Oral methamphetamine

Oral Methamphetamine DRUG

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.

Also known as: Desoxyn

Oral methamphetamine, then Placebo oral capsule; Placebo oral capsule, then Oral methamphetamine

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Willing and able to provide written informed consent
• Male or female, age ≥ 18 and ≤ 65 years
• 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.
• 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
• 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.
• No plans to modify ART during the study period (146 days, or approximately 5 months)
• Screening CD4+ (cluster of differentiation 4) T-cell count ≥ 350 cells/mm3
• Screening hemoglobin ≥ 12.5 g/dL
• 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.
• 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.

You may not qualify if:

• History of methamphetamine ("meth") use disorder by DSM-5 diagnostic criteria.
• Evidence of MA use other than due to the administered oral methamphetamine study drug, based on urine, hair, or serum MA measurements collected at baseline and follow-up study visits.
• Current use of prescription medications containing amphetamine-type stimulants (e.g., Adderall®, Dexedrine®, Ritalin, etc.) within the last 1 year.
• Sensitivity or allergy to amphetamine-type stimulants
• Current use of any other "psychoactive" drug within the last 1 year. These include cocaine, ecstasy, lysergic acid diethylamide (LSD), mushrooms, or other recreational drugs - but nicotine or caffeine use is ok.
• Marijuana use in the last 30 days; marijuana may influence the interpretation of the study drug's effect on viral transcription, inflammation, and/or gene expression.
• Current use of opioids (heroin, methadone) or prescription opioid agonists such as hydrocodone (Norco®), buprenorphine/naloxone (Suboxone®), oxycodone (Oxycontin®), hydromorphone (Dilaudid®) within the last 1 year by self-report and/or urine qualitative screening.
• Current use of alcohol use disorder (DSM-5 criteria) within the last 1 year as this might put patient at risk of withdrawal during the study.
• Significant physical or psychiatric illness that might impair the ability to safely complete the study or that might be complicated by the study drugs, including prior seizures (after age 8) or other active neurological disease.
• Clinically significant abnormalities on physical examination or screening laboratory values
• History of serious adverse event or hypersensitivity to MA or corn starch (the latter is used in the placebo).
• Recent use within the last month of the following medications given potential interactions with oral methamphetamine: acebrophylline, iobenguane, isocarboxazid, methylene blue, moclobemide, phenelzine, procarbazine, rasagiline, safinamide, selegiline, tranylcypromine, asunaprevir, buproprion, topical cocaine, fluoxetine, iohexol, linezolid, paroxetine, potassium citrate, quinidine, sodium bicarbonate, sodium citrate, sodium lactate, tipranavir, and tromethamine.
• Recent hospitalization in the last 90 days.
• Recent infection in the last 90 days requiring systemic antibiotics.
• Screening hemoglobin below 12.5 g/dL.

Sponsors & Collaborators

• University of California, San Francisco: lead
• National Institute on Drug Abuse (NIDA): collaborator

Study Sites (1)

San Francisco General Hospital

San Francisco, California, 94110, United States

Location

Related Publications (17)

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  PMID: 27660234 BACKGROUND

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• Centers for Disease Control and Prevention (CDC). Increasing morbidity and mortality associated with abuse of methamphetamine--United States, 1991-1994. MMWR Morb Mortal Wkly Rep. 1995 Dec 1;44(47):882-6.

  PMID: 7476843 BACKGROUND

• Marquez C, Mitchell SJ, Hare CB, John M, Klausner JD. Methamphetamine use, sexual activity, patient-provider communication, and medication adherence among HIV-infected patients in care, San Francisco 2004-2006. AIDS Care. 2009 May;21(5):575-82. doi: 10.1080/09540120802385579.

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• Wires ES, Alvarez D, Dobrowolski C, Wang Y, Morales M, Karn J, Harvey BK. Methamphetamine activates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and induces human immunodeficiency virus (HIV) transcription in human microglial cells. J Neurovirol. 2012 Oct;18(5):400-10. doi: 10.1007/s13365-012-0103-4. Epub 2012 May 22.

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• Liang H, Wang X, Chen H, Song L, Ye L, Wang SH, Wang YJ, Zhou L, Ho WZ. Methamphetamine enhances HIV infection of macrophages. Am J Pathol. 2008 Jun;172(6):1617-24. doi: 10.2353/ajpath.2008.070971. Epub 2008 May 5.

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• Toussi SS, Joseph A, Zheng JH, Dutta M, Santambrogio L, Goldstein H. Short communication: Methamphetamine treatment increases in vitro and in vivo HIV replication. AIDS Res Hum Retroviruses. 2009 Nov;25(11):1117-21. doi: 10.1089/aid.2008.0282.

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• Jiang J, Wang M, Liang B, Shi Y, Su Q, Chen H, Huang J, Su J, Pan P, Li Y, Wang H, Chen R, Liu J, Zhao F, Ye L, Liang H. In vivo effects of methamphetamine on HIV-1 replication: A population-based study. Drug Alcohol Depend. 2016 Feb 1;159:246-54. doi: 10.1016/j.drugalcdep.2015.12.027. Epub 2016 Jan 4.

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• Saito M, Yamaguchi T, Kawata T, Ito H, Kanai T, Terada M, Yokosuka M, Saito TR. Effects of methamphetamine on cortisone concentration, NK cell activity and mitogen response of T-lymphocytes in female cynomolgus monkeys. Exp Anim. 2006 Oct;55(5):477-81. doi: 10.1538/expanim.55.477.

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• Harms R, Morsey B, Boyer CW, Fox HS, Sarvetnick N. Methamphetamine administration targets multiple immune subsets and induces phenotypic alterations suggestive of immunosuppression. PLoS One. 2012;7(12):e49897. doi: 10.1371/journal.pone.0049897. Epub 2012 Dec 5.

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• Carrico AW, Flentje A, Kober K, Lee S, Hunt P, Riley ED, Shoptaw S, Flowers E, Dilworth SE, Pahwa S, Aouizerat BE. Recent stimulant use and leukocyte gene expression in methamphetamine users with treated HIV infection. Brain Behav Immun. 2018 Jul;71:108-115. doi: 10.1016/j.bbi.2018.04.004. Epub 2018 Apr 18.

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• Jing L, Li JX. Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction. Eur J Pharmacol. 2015 Aug 15;761:345-52. doi: 10.1016/j.ejphar.2015.06.019. Epub 2015 Jun 16.

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• Pei Y, Asif-Malik A, Hoener M, Canales JJ. A partial trace amine-associated receptor 1 agonist exhibits properties consistent with a methamphetamine substitution treatment. Addict Biol. 2017 Sep;22(5):1246-1256. doi: 10.1111/adb.12410. Epub 2016 May 19.

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• Uhl GR, Drgon T, Liu QR, Johnson C, Walther D, Komiyama T, Harano M, Sekine Y, Inada T, Ozaki N, Iyo M, Iwata N, Yamada M, Sora I, Chen CK, Liu HC, Ujike H, Lin SK. Genome-wide association for methamphetamine dependence: convergent results from 2 samples. Arch Gen Psychiatry. 2008 Mar;65(3):345-55. doi: 10.1001/archpsyc.65.3.345.

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• Breen MS, Uhlmann A, Nday CM, Glatt SJ, Mitt M, Metsalpu A, Stein DJ, Illing N. Candidate gene networks and blood biomarkers of methamphetamine-associated psychosis: an integrative RNA-sequencing report. Transl Psychiatry. 2016 May 10;6(5):e802. doi: 10.1038/tp.2016.67.

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• Li MD, Wang J, Niu T, Ma JZ, Seneviratne C, Ait-Daoud N, Saadvandi J, Morris R, Weiss D, Campbell J, Haning W, Mawhinney DJ, Weis D, McCann M, Stock C, Kahn R, Iturriaga E, Yu E, Elkashef A, Johnson BA. Transcriptome profiling and pathway analysis of genes expressed differentially in participants with or without a positive response to topiramate treatment for methamphetamine addiction. BMC Med Genomics. 2014 Dec 12;7:65. doi: 10.1186/s12920-014-0065-x.

  PMID: 25495887 BACKGROUND

MeSH Terms

Conditions

Inflammation

Interventions

Methamphetamine

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Amphetamines; Phenethylamines; Ethylamines; Amines; Organic Chemicals

Results Point of Contact

• Title: Sulggi A. Lee
• Organization: University of California, San Francisco

sulggi.lee@ucsf.edu

415-735-5127

Study Officials

• Sulggi A Lee, MD PhD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: January 28, 2019
• First Posted: January 31, 2019
• Study Start: January 1, 2021
• Primary Completion: January 11, 2023
• Study Completion: January 11, 2023
• Last Updated: April 9, 2026
• Results First Posted: April 8, 2025

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)