Chloroquine for Reducing Immune Activation in HIV- Infected Individuals

A Phase II, Double Blind, Randomized, Exploratory Study of Chloroquine for Reducing HIV-Associated Immune Activation

HIV is characterized by frequent immune system activation. 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.

Evidence suggests that by decreasing the rate of immune system activation, immune deficiency progression could be prevented. The purpose of this study is to learn how well chloroquine can reduce the level of immune activation and to test the safety and tolerance of chloroquine in people infected with HIV.

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)