Effect of Methamphetamine on Residual Latent HIV Disease Study

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.

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.

Exclusion Criteria:

1. History of methamphetamine ("meth") use disorder by DSM-5 diagnostic criteria.

2. 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.

3. Current use of prescription medications containing amphetamine-type stimulants (e.g.,
Adderall®, Dexedrine®, Ritalin, etc.) within the last 1 year.

4. Sensitivity or allergy to amphetamine-type stimulants

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. Clinically significant abnormalities on physical examination or screening laboratory
values

11. History of serious adverse event or hypersensitivity to MA or corn starch (the latter
is used in the placebo).

12. 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.

13. Recent hospitalization in the last 90 days.

14. Recent infection in the last 90 days requiring systemic antibiotics.

15. Screening hemoglobin below 12.5 g/dL.

16. Prior diagnosis or abnormal screening labs consistent with a diagnosis of
hyperthyroidism or hypothyroidism.

17. Poorly controlled hypertension with systolic blood pressure > 160 on more than one
occasion.

18. History of glaucoma.

19. Significant myocardial disease (current myocarditis or reduced left ventricular
ejection fraction below the lower limit of normal) or diagnosed coronary artery
disease.

20. History of psychotic symptoms (e.g., hallucinations, delusional thinking).

21. History of bipolar disorder.

22. Significant respiratory disease requiring oxygen.

23. A history of hypersensitivity to sympathomimetic amines (e.g., epinephrine,
norepinephrine, or dopamine).

24. Diabetes or current hypothyroidism.

25. Participants of reproductive potential or breastfeeding. Women of childbearing
potential must have a negative serum pregnancy test at screening. All participants of
childbearing potential must agree to use a double-barrier method of contraception
throughout the study period and up to 90 days after the last dose of MA.

26. Exposure to any immunomodulatory drug (including maraviroc) in the 16 weeks prior to
study.

27. Prior or current use of experimental agents used with the intent to perturb the HIV-1
viral reservoir.

28. History of seizures, psychosis, abnormal electroencephalogram or brain damage with
significant persisting neurological deficit

29. Recent vaccination within the last 2 weeks prior to study baseline visit. Routine or
standard of care vaccinations (such as influenza, pneumococcal, and meningococcal
vaccinations) are allowed but must be administered greater than 14 days prior to
baseline study visit.