Effects of Treatment With Aprepitant (Emend®) in HIV Infected Individuals. 375 mg Dose

DESIGN

Randomized, placebo controlled, double blind study to determine the safety and antiviral
activity of aprepitant by comparing the change in HIV RNA viral load after 2 weeks of
aprepitant monotherapy.

DURATION

42 days.

SAMPLE SIZE and POPULATION

18 HIV infected males and females ≥ 18 years old who have early infection with CD4 cell
counts ≥ 350 cells/mm3.

REGIMEN

Subjects will be randomized 1:1 to receive aprepitant (Emend®) or placebo.

Arm A: Aprepitant placebo Arm B: Aprepitant 375 mg QD

HYPOTHESIS AND STUDY OBJECTIVES

Hypothesis : Aprepitant is safe, tolerable, and has antiviral activity in HIV infected
individuals.

Primary Objectives:

To assess the safety and tolerability of 375 mg aprepitant for 2 weeks To assess the
response of plasma HIV-1 RNA to 375 mg of aprepitant compared with baseline.

Secondary Objectives:

To investigate the course and duration of antiretroviral response 375 mg of aprepitant given
over a 14-day period.

To evaluate the dose-response and pharmacokinetic and pharmacodynamic relationship between
viral RNA change and aprepitant plasma levels.

To evaluate aprepitant effects on CD4+ and CD8+ T-cell counts, circulating SP levels,
natural killer cell number and function and CCR5 expression in peripheral PBMCs.

To evaluate the effects of aprepitant in the viral tropism and envelope sequence of the main
HIV-1 population of the participants.

To assess viral drug susceptibility in conjunction with baseline coreceptor tropism
phenotype and changes in coreceptor phenotype after the exposure to aprepitant.

To evaluate aprepitant effects on fasting plasma glucose, insulin, HDL, free fatty acids,
and triglyceride concentrations after 14 days of treatment.

To provide preliminary description of any change from baseline in sleep quality, anxious
mood, depressed mood and neurocognitive measures after 2 weeks of aprepitant therapy.

Inclusion Criteria:

- HIV-1 infection, as documented by a rapid HIV test or any FDA-Approved HIV-1 Enzyme
or Chemiluminescence Immunoassay (E/CIA) test kit and confirmed by Western blot at
any time prior to study entry.

- CD4+ cell count >= 350/mm3 obtained within 90 days prior to study entry

- Plasma HIV-1 RNA of >=2,000 copies/mL as measured by any standard assay and performed
within 90 days prior to study entry.

- CCR5 tropic virus exclusively as determined by the Monogram tropism assay (PhenoSense
Entry™) to be performed within 90 days of study entry.

- Laboratory values obtained within 30 days prior to study entry, as follows:

- Absolute neutrophil count (ANC) >= 750/mm3

- Hemoglobin >= 10.0 g/dL

- Platelet count >= 100,000/mm3

- Creatinine <= 2 x ULN

- AST (SGOT), ALT (SGPT), and alkaline phosphatase <= 2 x ULN

- Total bilirubin <= 2.5 x ULN

- Albumin >= 3 g/dL

- Female subjects of reproductive potential must have a negative spot urine pregnancy
test result (with a sensitivity of at least 50 mIU/mL) performed at entry, prior to
starting initial study treatment.

- All subjects must agree not to participate in a conception process while on study
drug and for 30 days after stopping the medication.

- Karnofsky performance score >= 80 within 30 days prior to study entry.

- Men and women > 18 years of age.

- Ability and willingness of subject to give written informed consent.

- Willing to return for a follow-up visit on day 42.

- Subjects taking any precautionary concomitant medications must be on stable doses for
>8 weeks prior to study entry and have no plans to change medications or doses for
the duration of the study.

Exclusion Criteria:

- Receipt of antiretroviral treatment within the 16 weeks prior to study entry or
intent to initiate antiretroviral therapy within 60 days after entry.

- Diabetes requiring treatment with oral hypoglycemics or insulin therapy.

- Pregnancy within 90 days prior to study entry.

- Breast-feeding.

- Use of drugs that are inhibitors or inducers of metabolism by the cytochrome P450
CYP3A4 or CYP2C9 (such as warfarin and phenytoin) within 7 days of study entry.

- Use of systemic corticosteroids or hormonal agents within 90 days prior to study
entry.

- Use of any immunomodulator, HIV vaccines, or investigational therapy within 90 days
prior to study entry.

- Any vaccination within 30 days prior to study entry.

- Use of systemic cytotoxic chemotherapy within 90 days prior to study entry.

- History of allergy to aprepitant or its formulations.

- Active drug or alcohol use or dependence that, in the opinion of the investigator,
would interfere with adherence to study requirements.

- History of chronic active hepatitis B or C infection or severe hepatic dysfunction
(Child-Pugh score > 9) regardless of etiology

- Serious illness requiring systemic treatment and/or hospitalization until subject
either completes therapy or is clinically stable on therapy, in the opinion of the
investigator, for at least 14 days prior to study entry.

- Weight < 40 kg or 88 lbs. within 90 days prior to study entry.

- History of severe psychiatric comorbidities, such as depression, schizophrenia,
mania, psychosis.