Elite Controller and ART-treated HIV+ Statin Versus ASA Treatment Intervention Study

Despite dramatic improvements in mortality with antiretroviral therapy (ART), HIV-infected
persons remain at risk of developing non-infectious complications, including cardiovascular,
renal, and neurological disease. A small subset of the HIV-infected population achieve
durable control of HIV virus in the absence of ART. These individuals, termed elite
controllers (ECs), remain ART na(SqrRoot) ve, have stable CD4 T cell counts for many years
and have no history of opportunistic infections. Despite the lack of AIDS complications,
recent evidence suggests ECs may exhibit heightened immune activation that may contribute to
a potentially increased risk for non-infectious complications, similar to successfully
treated progressors.

In the current 2 group, randomized, open label trial, we intend to study the effects of a
lipid lowering agent vs aspirin (ASA) on immune activation in HIV-1 infected participants.
One group will consist of ECs who are HIV-1 infected, maintain HIV-RNA levels of less than
the LLD of commercially available assays in the absence of ART, have no history of ART or
opportunistic infections (OIs) and have stable CD4 T cell counts for greater than 3 years.
The second group will enroll HIV-1 infected Treated Progressors (henceforth referred to as
ART <50) who have maintained HIV-RNA below the limit of detection in commercially available
assays (<40, <48, or <50 copies/mL) for greater than 3 years on ART (treatment duration
greater than 4 years). Up to 2 months after the screening and enrollment visit, each group
will enter a 3 month observation period (to establish baseline values for biomarkers/cellular
markers). After 3 months, participants from each group will be randomized to either ASA, 81
mg PO daily, or atorvastatin (ATV), 40 mg (dose adjusted for subjects on antiretroviral
regimens with significant interactions, and will be treated for 9 months, followed by 3
months of a wash out period (see Figure 1). The primary end point will be change of sCD14
after 9 months of study intervention from Month 3 to Month 12 in each treatment arm, with
groups combined (EC and ART <50). Secondary objectives will be to compare changes in soluble
biomarkers (sCD14, IL-6, D-dimer, hsCRP, sTF, sCD163 and other relevad treatment arms (ASA vs
statin and EC vs ART<50 and with groups combined), to evaluate cardiovascular (CV) disease
prevalence in EC vs ART<50 and with groups combined), to evaluate cardiovascular (CV) disease
prevalence in EC vs ART <50 by MR imaging of carotids, to determine MR measurements and
correlations with biomarkers and cellular activation markers, and to investigate changes in
plasma viremia as measured by single copy assay over time.

- INCLUSION CRITERIA:

EC Arm

1. Age greater than or equal to 18 years.

2. Documented HIV-1 infection confirmed by enzyme-linked immunosorbent assay (ELISA) and
Western blot tests (will not be repeated if performed previously at NIH).

3. Categorized as a long term non-progressor EC as defined by viral loads typically less
than the LLD of commercially available assays and clinical and laboratory criteria (no
OIs, no ART, stable CD4 T cell counts for more than 3 years). Viral load blips are
allowed as long as they are less than 500 copies/mL and flanked by viral load
measurements less than 100copies/mL. Viral load <100c/mL will be acceptable for
eligibility at screening.

4. In women of childbearing potential, with no plans for pregnancy for the next 15 months
and willing to use 2 investigator approved highly reliable methods of birth control
consistently while on the study or in 3 month follow up.

5. Willingness to have samples stored for future research.

6. Not on a statin or ASA for the past 6 months.

ART <50 Arm

1. Age greater than or equal to 18 years.

2. Documented HIV-1 infection confirmed by enzyme-linked immunosorbent assay (ELISA) and
Western blot tests.

3. In women of childbearing potential, with no plans for pregnancy for the next 15 months
and willing to use 2 investigator approved highly reliable methods of birth control
consistently while on the study or in 3 month follow up.

4. On continuous combination ART >4 years.

5. HIV RNA <50 copies/mL (or less than 40 or less than 48 copies/mL, depending on the
lower limit of detection of the assay used; transient periods of low level (<300)
detectable virus, blips, acceptable if isolated and followed by viral loads less than
the lower limit of detection) >3 years and current HIV-RNA less than the LLD of the
commercially available assay used. Subject will be rescreened if HIV is detectable at
screening visit.

6. Willingness to have samples stored for future research.

7. Not on a statin or ASA for the past 6 months.

EXCLUSION CRITERIA

1. Diagnosis of cardiovascular disease or hypercholesterolemia (LDL cholesterol 190
mg/dL).

2. Known hypersensitivity or allergy to ATV or ASA, including a history of myositis or
rhabdomyolysis with statin or ASA use.

3. Other contraindication for ASA or statin therapy (active liver disease, peptic ulcer
disease, etc.).

4. Women who are lactating, pregnant, or actively trying to become pregnant or
considering pregnancy over the likely span of the study (including women of
childbearing potential who are unwilling to use adequate contraception throughout the
study).

5. Any chronic inflammatory condition either requiring anti-inflammatory medication
(systemic corticosteroids, daily NSAID use,immunomodulating medications) which may, in
the opinion of the investigator, confound the interpretation of soluble inflammatory
biomarkers. While on study, short term (less than 5 days) NSAID use will be allowed at
the discretion of the investigator.

6. Active drug use or alcohol abuse that, in the opinion of the investigator, may
interfere with the ability of the subject to participate in the study or that may
unacceptably increase the risk of the study intervention..

7. Safety laboratory cut offs: coagulation (INR >2 upper limit of normal [ULN], PLT<75K),
renal function (GFR<60), liver function (ALT or Alkaline phosphatase or direct
bilirubin >2x ULN), aldolase <1.5 ULN and anemia (Hg <9 mg/dL).

8. Antiretroviral therapy with tipranivir, or any therapy which combines non-nucleoside
reverse transcriptase inhibitors with protease inhibitors.

9. Chronic hepatitis C co-infection. However, if a subject has more than 24 weeks of
sustained virologic response (SVR), the subject can be considered for eligibility.

10. If either MR or apheresis is contraindicated, subject may still participate without
this procedure. In the case of missed apheresis, a 30 mL research blood draw will be
substituted (see Appendices B and C).

- If statin initiation is indicated per current guidelines, subject will be
counseled to consult with their PMD. If the subject then chooses to take part in
the study, we will provide their PMD with all pertinent lab results during the
course of the study, if requested.

Co-enrollment Guidelines: Co-enrollment in other trials will be restricted, other than
enrollment on observational studies. Study staff should be notified of co-enrollment as it
may require the approval of the Investigator.