Sevelamer for Reducing Endotoxemia and Immune Activation

HIV-infected people can have an increase in inflammation in their body organs, even after
taking anti-HIV medicines. 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, and problems with thinking. Also, HIV-infected
people with high inflammation have lower CD4+ T-cell counts (cells that fight infection).
Many HIV researchers are studying the harmful effects of this prolonged inflammation and
possible ways to prevent these complications.

The increase in inflammation in HIV-infected people may be caused by HIV or by other factors
such as parts of bacteria. These bacterial pieces, called endotoxins, do not cause harm in
the intestine (gut). However, in HIV infection, there is damage to the gut that allows
endotoxins to cross from the gut into the blood. These endotoxins then cause inflammation in
the body. New research is focusing on strategies to reduce the levels of endotoxin as a way
to decrease inflammation.

A drug called sevelamer carbonate is used to bind phosphate in dialysis patients. However,
sevelamer carbonate also binds endotoxin in the gut and lowers endotoxin levels in the blood
of dialysis patients. Sevelamer carbonate also decreases the inflammation endotoxin causes in
dialysis patients. This study will see if sevelamer carbonate can have the same effects in
HIV-infected patients.

A5296 is a phase II, single-arm study to evaluate the effect of 8 weeks of sevelamer
carbonate administration on markers of microbial translocation as well as monocyte and T-cell
activation in the blood in chronically HIV-infected subjects with CD4+ T-cell count ≥ 400
cells/mm3 not receiving ART. This study enrolled 40 subjects. To assess whether there is a
persistent effect of study drug, subjects were observed for an additional 8 weeks off
sevelamer carbonate and changes in biomarkers were monitored.

As A5296 is a phase II study of biologic activity, the primary and secondary analyses are
as-treated, limited to subjects who have data for baseline and week 8 and who remain on study
treatment through week 8. For any subject who initiated antiretroviral treatment (ART),
analyses only included data collected prior to the time ART was started.

Inclusion Criteria:

- HIV-1 infection

- No plans to initiate ART during the course of the proposed study.

- Screening CD4+ T-cell count ≥ 400 cells/mm3 performed in a laboratory that has a
Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent.

- HIV-1 RNA >50 copies/mL within the last 180 days prior to entry.

- Screening serum phosphate > 2.6 mg/dL within 60 days prior to entry.

- Certain laboratory values, as detailed in section 4.1.6 of the protocol, obtained
within 30 days prior to entry

- Female subjects of reproductive potential must have a negative serum or urine
pregnancy test performed within 30 days prior to entry.

- Female subjects participating in sexual activity that could lead to pregnancy must
agree to use at least one of the following forms of birth control for at least 30 days
prior to study entry until the final study visit:

- Condoms (male or female) with or without a spermicidal agent

- Diaphragm or cervical cap with spermicide

- Intrauterine device (IUD)

- Hormone-based contraceptive

- Female subjects who are not of reproductive potential are eligible without requiring
the use of a contraceptive.

- Confirmation of the availability of the stored pre-entry plasma and peripheral blood
mononuclear cell (PBMC) samples for endotoxin, sCD14, and immune activation
determinations, obtained from a fasting sample.

- Ability and willingness of subject to provide informed consent.

- No plans to use probiotics (defined as products that contain significant amounts of
live microorganisms and are ingested for specific health benefits, e.g., yogurt with
live and active cultures, Lactobacillus GG, Saccharomyces boulardii) during the study.

Exclusion Criteria:

- Known diagnosis of acute HIV infection within 180 days prior to study entry.

- Pregnant or breastfeeding.

- Use of any antiretroviral agent within 24 weeks prior to study entry.

- Use of systemic cancer chemotherapy or radiation therapy, immunosuppressive or
immunomodulatory therapy (e.g., interferons, tumor necrosis factor antagonists,
interleukins, systemic corticosteroids) within 24 weeks prior to study entry.

NOTE A: Use of inhaled steroids, nasal steroids, topical steroids, or the equivalent of 10
mg of prednisone or less per day or a less than 2-week course of oral steroids is not
exclusionary.

NOTE B: A single course of 1% hydrocortisone cream applied up to 3 times a day to <10
square inches area for <2 weeks is permitted while on study. Use of all other topical
steroids is excluded.

- Known allergy/sensitivity or any hypersensitivity to components of the study drug or
its formulation.

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

- Serious illness requiring systemic treatment and/or hospitalization within 60 days
prior to study entry.

- Known cirrhosis or severe liver disease (e.g., ascites, encephalopathy, history of
variceal bleeding).

NOTE: Potential subjects with chronic hepatitis B or C virus infection who do not have
known cirrhosis or severe liver disease may participate in the study.

- Severe kidney disease (defined as estimated glomerular filtration rate [GFR] <30
mL/min/1.73m2) at screening.

- History of bowel obstruction or severe GI motility disorders including severe
constipation.

- Severe dysphagia or swallowing disorders.

- Major GI tract surgery within 60 days prior to study entry.

- Intent to initiate or change the dose of lipid-lowering drugs during study. NOTE:
Potential subjects on stable doses of lipid-lowering agents (defined as no change in
preparation or dose within 90 days prior to study entry) are permitted and may be
enrolled.

- Use of investigational therapies within 90 days prior to study entry unless permission
was granted by the A5296 protocol chairs (see Study Management page).

- Currently receiving hepatitis C therapy or anticipation that such therapy will be
started during the study.

- Use of probiotics, for more than 3 consecutive days within the 60 days prior to study
entry.