IMPAACT P1080: Psychiatric and Antiretroviral Medication Concentrations in HIV-infected and Uninfected Children and Adolescents

P1080 is a pilot population pharmacokinetic study of HIV-1 infected and uninfected children
and adolescents who are taking methylphenidate or amphetamine/ dextroamphetamine for the
treatment of ADHD. Prescribing various psychiatric medications in combination with
antiretroviral regimens is a standard clinical practice occurring without adequate evidence
regarding benefits and risks. The goals of this study are to determine plasma concentrations
of psychiatric and antiretroviral medications in children and adolescents. Psychiatric
medication dose requirement and exposure in HIV-1 infected subjects will be compared to that
seen in uninfected children and adolescents, and antiretroviral exposure will be compared to
published studies in children and adolescents.

Inclusion Criteria for HIV-1 Infected Subjects

- Children and adolescents age ≥6 to <25 years at entry.

- Documented HIV-1 infection defined as positive test results obtained from 2 different
samples. Tests may include two of the same type OR two different types of tests
listed below, as long as they are positive test results obtained from the 2 different
samples:

- HIV-1 DNA PCR

- HIV-1 culture

- HIV-1 RNA PCR > 5,000 copies/mL

- HIV-1 p24 antigen detection

- HIV-1 antibody test (any licensed ELISA test kit, and confirmation by either
serum HIV-1 antigen test, HIV-1 antibody test done by a method that is not an
ELISA, Western blot, or plasma HIV-1 RNA)

- Subject must be taking antiretroviral medications for clinical care for at least 4
weeks prior to pharmacokinetic sampling, with no changes in drugs, doses or
formulations.

- Subject must be taking either efavirenz (EFV) OR a PI with ritonavir (RTV) OR
lopinavir/ritonavir as part of combination antiretroviral therapy. Note that RTV
dosing must be as a "booster" for the protease inhibitor. Protease inhibitors may be
any of the following: atazanavir, darunavir, fosamprenavir, indinavir, saquinavir or
tipranavir. Subjects may not be taking more than one full-dose PI. Subjects may not
be taking EFV in addition to lopinavir/ritonavir or other PI.

- Subject must be taking methylphenidate or amphetamine/ dextroamphetamine for
treatment of ADHD for at least 1 week prior to enrollment.

- Allowable methylphenidate formulations include: immediate-release (Methylin,
Ritalin or other generic, Focalin), sustained-release (Ritalin SR, Metadate ER
or generic), or biphasic (Ritalin LA, Metadate CD, Concerta, Focalin XR).

- Allowable formulations for amphetamine/ dextroamphetamine include: Adderall,
Adderall XR, Dexedrine, Liquadd, and Dexedrine Spansules(and any generic
equivalents).

- For both study arms, any dose up to the maximum FDA-approved dose by age will be
allowed.

- Subjects must be able to come in for PK sampling after at least 2 days of
consecutive, uninterrupted psychiatric and antiretroviral medication delivery.

- Parent/primary caregiver, subjects >18 years or emancipated minors must be able and
willing to provide signed informed consent. Assent of the minor subject should be
obtained where required per site procedures and IRB recommendations.

- Female subjects of reproductive potential (having reached menses, or not having
reached menopause or not having undergone hysterectomy, bilateral oophorectomy, or
tubal ligation) who engage in sexual activity that could lead to pregnancy must agree
to avoid pregnancy during the entire trial and to consistently and appropriately use
at least two of the following contraception methods: condoms, diaphragm or cervical
cap with spermicide, IUD, hormonal-based contraception. A list of acceptable methods
can be found at the FDA Birth Control Guide
(http://www.fda.gov/fdac/features/1997/babyguide.pdf).

- Note: "Female subjects of reproductive potential" is defined as girls who have
reached menarche or women who have not been post-menopausal for at least 24
consecutive months (e.g. who have had menses within the preceding 24 months), or
have not undergone a sterilization procedure (hysterectomy, bilateral
oophorectomy or salpingotomy). If the female subject is not of reproductive
potential, she is eligible without requiring contraception.

Inclusion Criteria for HIV Uninfected Subjects

- Children and adolescents age ≥6 to <25 years at entry.

- Subject is not known to be HIV-1 infected.

- Note: For perinatally-exposed subjects, definitive exclusion of HIV-1 infection
in a non-breastfed infant is based on two or more negative virologic tests, with
one obtained at age ≥1 month and one at ≥4 months, or two negative HIV-1
antibody tests from separate specimens obtained at age ≥6 months. Per current
CDC guidelines, uninfected subjects ≥13 years will be screened for HIV-1. A
documented negative HIV-1 antibody screening test or negative HIV-1 RNA or DNA
PCR within the past year will be accepted to fulfill this criterion.

- Subject must be taking methylphenidate or amphetamine/ dextroamphetamine for
treatment of ADHD for at least one week prior to enrollment.

- Allowable methylphenidate formulations include: immediate-release (Methylin,
Ritalin or other generic, Focalin), sustained-release (Methylin ER, Ritalin SR,
Metadate ER or generic), or biphasic (Ritalin LA, Metadate CD, Concerta and
Focalin XR.

- Allowable formulations for amphetamine/ dextroamphetamine include: Adderall,
Adderall XR, Dexedrine, Liquadd, and Dexedrine Spansules (and any generic
equivalents).

- For both arms, any dose up to the maximum FDA-approved dose by age will be
allowed.

- Subjects must be able to come in for PK sampling after at least 2 days of
consecutive, uninterrupted psychiatric medication delivery.

- Parent/primary caregiver, subjects >18 years or emancipated minors must be able and
willing to provide signed informed consent. Assent of the minor subject should be
obtained where required per site procedures and IRB recommendations.

- Female subjects of child bearing potential (having reached menses, or not having
reached menopause or not having undergone hysterectomy, bilateral oophorectomy, or
tubal ligation) who engage in sexual activity that could lead to pregnancy must agree
to avoid pregnancy during the entire trial and to consistently and appropriately use
at least two of the following contraception methods: condoms, diaphragm or cervical
cap with spermicide, IUD, hormonal-based contraception. A list of acceptable methods
can be found at the FDA Birth Control Guide
(http://www.fda.gov/fdac/features/1997/babyguide.pdf).

- Note: "Female subjects of child bearing potential" is defined as girls who have
reached menarche or women who have not been post-menopausal for at least 24
consecutive months (e.g. who have had menses within the preceding 24 months), or
have not undergone a sterilization procedure (hysterectomy, bilateral
oophorectomy or salpingotomy). If the female subject is not of child bearing
potential, she is eligible without requiring contraception.

Exclusion Criteria for All Study Subjects

- A positive urine test at screening for use of the following disallowed drugs:
methamphetamine; methadone, barbiturates; benzodiazepines; opiates; phencyclidine; or
propoxyphene.

- Note: If propoxyphene is not part of the routine screening panel at the site, it
is not required. If propoxyphene is part of the routine screening panel at the
site, the results should be recorded on the appropriate CRF.

- Chemotherapy for malignancy within three months prior to study screening.

- Pregnancy or breastfeeding an infant.

- Any clinically significant diseases (other than HIV-1 infection) or clinically
significant findings during the screening medical history or physical examination
that, in the investigator's opinion, would compromise the outcome of this study.

- Study drugs prescribed above the FDA-recommended maximum dose by age.

- Known or demonstrated hypersensitivity or intolerance to Dextromethorphan.

- Subjects taking a disallowed medication.

- For HIV-1 Infected Subjects Only: Presence of an active CDC Stage C (per 1994 Revised
Classification System for Human Immunodeficiency Virus Infection in Children Less
Than 13 Years of Age, or 1993 Revised Classification System for HIV Infection Among
Adolescents and Adults) opportunistic infection or serious bacterial infection
requiring therapy within two weeks prior to screening.