Dipyridamole for Immune Activation in HIV

Background:

- Since HIV-infected individuals started taking anti-HIV medications, illnesses from AIDS
have decreased, but other serious diseases have increased. Researchers think this may be
caused by an increase in activity of the immune system that fights infection, leading to
inflammation. Inflammation is a normal body reaction to any infection. However, if
inflammation lasts a long time, like in HIV infection, it may lead to complications such
as heart disease, cancer, liver disease, lung disease, and problems with thinking. Many
HIV researchers are studying the harmful effects of this prolonged immune system
activity and inflammation and possible ways to prevent these complications.

- A drug called dipyridamole is approved by the Food and Drug Administration (FDA) under
the trade name Persantine® for use with other drugs to reduce the risk of blood clots
after heart valve replacement. Laboratory studies have shown that dipyridamole also
lowers the level of immune system activity and inflammation measured in the blood.

Objectives:

- To see how dipyridamole affects blood and lung tests to measure immune system activity
and inflammation and to look at the safety and tolerability of dipyridamole in people
infected with HIV. This use of dipyridamole is investigational, or not approved by the
FDA; however, the dose to be used in this study, 100mg four times a day, is the dose
approved by the FDA.

Eligibility:

- Individuals 18 years of age and older who have HIV infection and are taking medications
to treat it, and have a low viral load (HIV-1 RNA <50 copies/mL) for a minimum of 12
months.

Design:

- Participants will be screened with a physical exam, blood test, and medical history.
Women of reproductive age will also receive a pregnancy test.

- Participants will take either Dipyridamole or a placebo for 12 weeks. Then they will
take Dipyridamole for 12 weeks.

- During the study, participants will have frequent blood and urine tests. Dipyridamole
drug levels, and liver and kidney function tests will be performed. HIV viral load (the
amount of virus in the blood) will also be studied.

- Participants will have a final follow-up visit after an additional 4 weeks.

- Four brachial artery ultrasound images will be taken.

- Four pre- and post-bronchodilator spirometry tests will be performed by participants
enrolled under Version 2.0: after each pre-test spirometry, participants will be asked
to inhale 4 puffs of albuterol, and then to repeat the spirometry for post-testing.

- Participants will receive rectal swabs at screening, and four flexible sigmoidoscopies
with rectal biopsies of the sigmoid colon throughout the study. These studies of the
lower colon and samples of the rectum will be used to explore the effects of
Dipyridamole. Participants can, however, opt out of all rectal procedures.

Inclusion Criteria:

- 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, plasma HIV-1 RNA viral load.

- On ART for at least 12 months prior to study entry with a regimen that includes three
or more antiretroviral medications. More information on this criterion is available in
the protocol.

- Plasma HIV-1 RNA <50 copies/mL by any standard clinical assay at screening and for a
minimum of 12 months prior to entry, confirmed by at least 2 measurements prior to
study entry, one of which must be at least 48 weeks prior to study entry and one of
which must be 61 days and 48 weeks prior to study entry. All plasma HIV-1 RNA
measurements in the 12 months prior to study entry must be <50 copies/mL (with the
exception that a single detectable measurement of ≤ 200 copies/mL is permitted if the
RNA levels immediately before and after are <50 copies/mL).

- Stable ART regimen for at least 8 weeks prior to study entry and no plans to change
ART regimen for at least 6 months following study entry.

- Ability and willingness to provide informed consent.

- In the opinion of the investigator, no medical, mental health or other condition that
precludes participation.

- Laboratory values obtained within 60 days prior to entry.

- Hemoglobin ≥10.0 g/dL

- Platelet count ≥100,000/mm3

- INR ≤ 1.5 (for rectal tissue subset only)

- PTT <2x ULN (for rectal tissue subset only)

- AST and ALT < 2.5 x upper limit of normal (ULN)

- Total bilirubin < 2.5 x ULN (except if hyperbilirubinemia is secondary to
atazanavir).

- Creatinine ≤ 1.5 x ULN

- Hepatitis B surface antigen negative

- Hepatitis C antibody negative (note: subject with HCV Ab positive is eligible if
Hepatitis C RNA PCR (viral load) is undetectable)

- For females of reproductive potential, negative serum or urine pregnancy test at
screening and within 72 hours prior to study entry. Females of reproductive potential
include women who have not been post-menopausal for at least 24 consecutive months,
(i.e., who have had menses within the preceding 24 months, or women who have not
undergone surgical sterilization, specifically hysterectomy and/or bilateral
oophorectomy).

- Females of reproductive potential who are participating in sexual activity that could
lead to pregnancy must agree to use one method of acceptable contraception while
receiving protocol-specified treatment and for 4 weeks after stopping the treatment.
These methods include condoms (male or female) with or without a spermicidal agent;
diaphragm or cervical cap with spermicide; intrauterine device (IUD); and
hormone-based contraceptive.

- Females not of reproductive potential (girls who have not reached menarche, women who
have been post-menopausal for at least 24 consecutive months, or women who have
undergone surgical sterilization, e.g., hysterectomy, bilateral oophorectomy, or
bilateral tubal ligation or salpingectomy) are eligible without requiring the use of a
contraceptive. Self- report is acceptable documentation of sterilization, other
contraceptive methods, and menopause.

- Rectal Tissue Subset only: Willing to abstain from receptive anal intercourse and
practices involving insertion of anything in the rectum (drug, enema, penis, or sex
toy) for 72 hours prior to rectal biopsy and for 7 days post-biopsy to minimize risk
of bleeding complications.

Exclusion Criteria:

- Pregnancy or breast-feeding.

- Known allergy/sensitivity or any hypersensitivity to components of study drug(s) or
their formulation.

- Known cardiovascular disease (history of MI, coronary artery bypass graft surgery,
percutaneous coronary intervention, stroke, transient ischemic attack, peripheral
arterial disease with ABI <0.9 or claudication).

- Uncontrolled type II diabetes mellitus.

- Known chronic inflammatory conditions such as, but not limited to, rheumatoid
arthritis, systemic lupus erythematosus, sarcoidosis, inflammatory bowel disease
(i.e., Crohn's disease or ulcerative colitis), chronic pancreatitis, or autoimmune
hepatitis, myositis, or myopathy.

- History of asthma requiring medical treatment within 2 years prior to study entry with
the exception of the use of albuterol inhaler for mild intermittent asthma.

- Serious illness requiring systemic treatment and/or hospitalization within 14 days
prior to entry.

- Use of any of the following medications for more than 3 consecutive days within the 60
days prior to study entry:

- Immunosuppressives (e.g., azathioprine, corticosteroids [physiologic replacement
doses are allowed], cyclosporine, mycophenolate, NSAIDs (nonsteroidal
anti-inflammatory drugs), sirolimus, sulfasalazine, tacrolimus)

- Immune modulators (e.g., cytokines [e.g., IL-2], granulocyte colony stimulating
factor, growth hormone, tumor necrosis factor antagonists, thalidomide)

- Antineoplastic agents

- Anticoagulants (e.g., warfarin and heparin)

- Anti-platelet drugs (e.g., clopidogrel and aspirin)

- Vaccinations within 1 week prior to the pre-entry or study entry visits. Routine
standard of care vaccinations including hepatitis A and/or B, influenza, pneumococcal,
and tetanus are permitted if administered at least 7 days before pre-entry and entry
evaluations.

- Participation on any HIV immunotherapy or therapeutic vaccination trials within 6
months prior to study entry.

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

- Use of investigational therapies within 30 days prior to study entry.

- Rectal Tissue Subset only:

- Abnormalities of the colorectal mucosa or significant colorectal symptom(s),
which in the opinion of the study investigator represent a contraindication to
biopsy (including but not limited to presence of any unresolved injury,
infectious or inflammatory condition of the local mucosa, and presence of
symptomatic external hemorrhoids.

- NOTE: Abnormalities of the colorectal mucosa will be assessed at the time of the
enrollment flexible sigmoidoscopy. If no significant colorectal abnormalities or
symptoms are present then the participant will undergo the enrollment procedures.
If abnormalities are present then no biopsies will be performed and the
participant will not be enrolled into the rectal tissue subset but will continue
participation in the main study.

- Active untreated gonorrhea, or chlamydia infection within 30 days prior to study
entry (subjects diagnosed with rectal gonorrhea or chlamydia infection at
screening may be treated during the screening period provided the treatment is at
least 30 days prior to entry).

- Exclusions for spirometry testing (for participants enrolled under Version 2.0)
Participants will not undergo pre- and post-bronchodilator spirometry if they have any
of the following: - Abdominal or cataract surgery within 3 months.

- Myocardial infarction or stroke within the past 3 months.

- Acute onset of shortness of breath, cough, fever or heart condition such as
tachycardia, angina or arrhythmias with 4 weeks prior to enrollment.

- Increasing respiratory symptoms or febrile (temperature >100.4°F [38°C]) within 4
weeks of study entry.

- Uncontrolled hypertension defined as systolic > 160 mm Hg or diastolic > 100 mm
Hg from an average of two or more readings. Participant with controlled
hypertension may undergo spirometry.

- Prior history of adverse reaction to albuterol.