Chloroquine for Reducing Immune Activation in HIV- Infected Individuals

HIV is characterized by persistent immune system activation, and early in the course of
infection the body establishes an immune activation "set point" related to the amount of HIV
in the blood stream. This set point affects the rate of CD4 cell loss. Without CD4 cells, or
with very low levels of CD4 cells, the body cannot fight off illness. This is known as
immunodeficiency. If left untreated HIV can lead to extreme immunodeficiency and AIDS.

Immune system activation includes activating the CD8 cells. These cells attack body cells
infected with viruses. Because of this, CD4 cells infected with HIV are frequently destroyed
by CD8 cells. The purpose of this study is to learn how well chloroquine reduces the level of
activation of CD8 cells in people infected with HIV. Increased activation of CD8 cells is
thought to lead to a more severe path of disease in HIV infection.

The constant immune activation observed in HIV- infected patients has also been linked to
higher levels of byproducts from certain naturally occurring bacteria found in the gut that
are known to be immune stimulants. By decreasing the stimulation from these byproducts with
chloroquine treatment, HIV disease may be slowed.

The purpose of this study was to learn how well chloroquine reduces the level of activation
of CD8 cells and lowers the levels of bacteria byproducts in people infected with HIV, either
off antiretroviral therapy (ART) (protocol version 1.0 dated December 17, 2008) or on-ART
(protocol version 2.0 dated October 1, 2010). The off-ART (Arms A and B) and on-ART (Arms C
and D) participants were enrolled during different time periods, and the study was designed
to analyze the two study populations separately. This study also looked at how well
chloroquine was tolerated and its safety in HIV- infected participants.

Off-ART participants in the study were randomized with equal probability to one of two
treatment arms:

Arm A: Participants received 12 weeks of chloroquine treatment followed by 12 weeks of
placebo

Arm B: Participants received 12 weeks of placebo followed by 12 weeks of chloroquine

On-ART participants in the study were randomized with equal probability to one of two
treatment arms:

Arm C: Participants received 12 weeks of chloroquine treatment followed by 12 weeks of
placebo

Arm D: Participants received 12 weeks of placebo followed by 12 weeks of chloroquine

Study treatment was given once a day for a full 24 weeks. There was an additional 4 weeks of
follow-up for purposes of safety. After treatment has started, participants were asked to
come to the clinic on Weeks 4, 10, 12, 16, 22, and 24. At each visit participants were given
enough study treatment to last until the next visit. Each visit lasted between 30 and 60
minutes. At most visits, participants had a physical exam, answered questions about any
medications they were taking and how they are feeling, and had blood drawn for safety to
assess CD4/CD8 cell counts and viral load. Some additional blood were also stored for
immunology testing. At some visits, participants were asked questions about their medication
and medical history, had pupils dilated, had a hearing test, and had an electrocardiogram
(EKG). Some visits required participants to arrive fasting. Pregnancy tests were also
conducted if the participant is able to become pregnant or if pregnancy was suspected.

Inclusion Criteria:

- HIV-1 infected

- Certain specified laboratory values obtained within 30 days prior to study entry. More
information on this criterion can be found in the study protocol.

- Documentation that pre-entry specimen for the primary immune activation endpoint
responses has been obtained

- Female participants of reproductive potential must have a negative pregnancy test
performed within 24 hours prior to study entry

- If engaging in sexual activity, female participants must use adequate forms of
contraception while receiving study treatment and for 4 weeks after stopping the
treatment. More information on this criterion can be found in the study protocol.

- Ability and willingness to provide informed consent

Additional Inclusion Criteria for Off-ART Participants:

- No antiretroviral therapy (ART) for at least 6 months prior to study entry and not
likely to start within the 6 months after study entry

- CD4 cell count greater than or equal to 400 cells/mm3 at screening, obtained within 30
days prior to study entry

- For participants with previous ART use, documentation or recall of nadir CD4 cell
count greater than or equal to 200 cells/mm3

- HIV-1 RNA viral load greater than or equal to 1,000 copies/mL obtained within 30 days
prior to study entry

- No history of CDC category C AIDS-related opportunistic infections

- Karnofsky performance score greater than or equal to 70 within 30 days prior to study
entry

Additional Inclusion Criteria for On-ART Participants:

- Receiving ART, defined as a regimen that includes three or more antiretroviral
medications, for at least 24 months prior to study entry

- Required documentation that all HIV-1 viral loads (at least two) were below 400
copies/mL. More information on this criterion can be found in the study protocol.

- Screening HIV-1 RNA <200 copies/mL within 30 days prior to study entry. More
information on this criterion can be found in the study protocol.

- CD4 cell count <350 cells/mm3 at screening, obtained within 30 days prior to study
entry

Exclusion Criteria:

- Continuous use of certain specified medication for more than 3 days within 30 days
prior to study entry. More information on this criterion can be found in the study
protocol.

- Use of chloroquine or hydroxychloroquine within 3 months prior to study entry

- Known history of hypersensitivity to 4-aminoquinoline compounds (such as chloroquine
or hydroxychloroquine)

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

- Serious illness requiring systemic treatment and/or hospitalization within 30 days
prior to study entry

- Renal insufficiency, defined as serum creatinine greater than 1.5 mg/dL, within 30
days prior to study entry

- History of retinal disease (i.e. confirmed retinopathy by ophthalmologic examination)

- History of neoplasm, within 5 years prior to study entry, other than treated in situ
carcinoma or basal-cell or localized squamous cell carcinoma of the skin

- Glucose-6-phosphate dehydrogenase (G6PD) deficiency at screening

- History of porphyria

- History of psoriasis

- History of cirrhosis

- History of seizure disorder

- History of tinnitus (ear and/or head noise lasting more than 5 minutes that occurs
more often than once per week) or history of sudden hearing loss

- History of myopathy

- History of cardiac conduction abnormality or cardiomyopathy. More information on this
criterion can be found in the study protocol.

Additional Exclusion Criteria for On-ART Participants:

- Plans to change ART regimen with the 6 months after study entry (change in ART regimen is
only permitted if due to toxicity)