A Randomized Placebo-Controlled Trial of Atorvastatin in HIV-Positive Patients Not on Antiretroviral Medications With the Specific Aims of Studying the Effects of Atorvastatin on HIV Viral Load and Immune Activation Markers

This protocol is a randomized, double blind, placebo controlled trial designed to study the
effects of the lipid lowering statin, atorvastatin on HIV-1 viremia.

Untreated HIV-1 infection results in an incurable, progressive immunodeficiency and death,
usually from opportunistic infections. Combination antiretroviral therapy (ARV) has been
successful in suppressing HIV replication and reducing morbidity and mortality. Long term ARV
therapy is associated with the development of HIV-1 drug resistance, and significant adverse
side effects including metabolic and cardiovascular complications. Prolonged therapy with
certain antiretrovirals is associated with increased risk of cardiovascular disease and a
number of dyslipidemic syndromes, including increased levels of cholesterol, LDL, and
triglycerides in peripheral blood. New therapeutic strategies to suppress HIV-1 infection are
essential.

Previously, in vitro studies suggested that exposure to cholesterol-lowering statins results
in decreases in HIV-1 replication. The mechanisms of inhibition remain uncertain, but
possibilities include disrupting membrane trafficking or cytoskeletal processes necessary for
intracellular transport of viral proteins, or altering cellular activation state necessary
for viral gene expression. Initial in vivo studies of the effects of statins on HIV-1 have
been largely anecdotal in nature and have yielded conflicting results. Although statin
therapy is commonly used in HIV-1 infection, adverse effects from the combination of
antiretrovirals and statins are possible. A more thorough understanding of the effects of
statins on HIV-1 replication is essential to determine the potential therapeutic effect and
to investigate the risks and benefits of this approach in vivo.

We plan to conduct a double blind randomized placebo controlled trial, with a cross over
design, to study the effects of atorvastatin in 22 HIV-infected patients not currently taking
antiretroviral therapy. Patients will be randomized to receive either placebo or atorvastatin
80mg for 8 weeks. After a 4-week wash out period patients on the atorvastatin arm will
crossover to placebo and, vice versa patients in the placebo arm will cross over to
atorvastatin for an additional 8 weeks. Upon completion of study medications all patients
will be followed for 4 weeks. Each arm will have a minimum of 11 patients each. The primary
outcome measure in this study is the effect of lipid lowering agents on HIV-1 RNA levels;
additional secondary outcome measures include effects of lipid lowering agents on lipid
profile, markers of inflammation and immune activation and investigations of host and viral
genetic factors.

- INCLUSION CRITERIA:

Establish with patient prior to Informed Consent:

- Adults 18 years of age or older.

- HIV-1 infection, as documented by a licensed ELISA test kit and confirmed by a Western
blot assay at any time point prior to study entry or at study entry (May do after
informed consent if no test results are available).

Off all ARV for greater than or equal to three months prior to study entry, no documented
evidence of viral resistance, and no evidence of acute HIV infection. For the purposes of
this study acute HIV infection will be defined as presence of a detectable HIV-1 viral RNA
in the presence of a non reactive HIV-1 or HIV-2 antibody assay or an indeterminate western
blot. For the purposes of this study viral resistance is being defined as having a
genotypic or phenotypic evidence of resistance or in the absence of formal resistance
testing clinical evidence of resistance for e.g. patients with persistent viremia in the
face of adequate adherence.

- Willingness to use a method of contraception during the study period. Adequate methods
of birth control include: condoms, male or female, with or without a spermicide;
diaphragm or cervical cap with spermicide; intrauterine device; any of the methods
that require a prescription (such as contraceptive pills or patch, Norplant,
Depo-Provera, and others) or a male partner who has previously undergone a vasectomy.

- Willingness to have blood drawn.

- No known allergy or contraindication to atorvastatin use.

- Ability to understand and willingness to sign the informed consent.

- Willingness to have blood stored for future phenotyping and genotyping.

After Informed Consent:

- CD4 cell count greater than 350 cells/ml.

- 3 viral loads that average greater than 1000 copies/ml within a 4-week period.

- The viral loads will be done using the bDNA method in the NIH laboratory and must be
within 20% (log10bDNA of each other).

- A fasting total cholesterol lower than 240mg/dl and an LDL cholesterol lower than
130mg/dl.

- Liver function tests (AST or ALT) not greater than 1.5 times the upper limit of
normal. Evidence of active hepatitis B or C will not be considered an exclusion
criteria if the liver function tests are within normal limits.

- Creatine phosphokinase elevations (CPK) not greater than 3 times the upper limit of
normal (ULN) on two sequential determinations and, in the opinion of the investigator,
without clear association with exercise.

- Laboratory values:

Absolute neutrophil count (ANC) greater than or equal to 1000/mm(3).

Hemoglobin greater than or equal to 11.0 g/dL.

Platelet count greater than or equal to 100,000/mm(3).

Creatinine less than or equal to 2 x ULN.

Serum amylase and lipase less than or equal to 1.25 x ULN.

- Negative serum pregnancy test at randomization.

EXCLUSION CRITERIA:

- Pregnancy or breast feeding.

- Active drug use or alcohol abuse/dependence, which in the opinion of the
investigators, will interfere with the patient's ability to participate in the study.

- Serious illness requiring systemic treatment and/or hospitalization within 30 days of
entry.

- Evidence of active opportunistic infections or neoplasms that require chemotherapy
during the study period except cutaneous Kaposi Sarcoma.

- Allergy or hypersensitivity to atorvastatin or any of its components.

- History of myositis or rhabdomyolysis with use of any statins.

- History of inflammatory muscle disease such as poly or dermatomyositis.

- Concomitant use of fibric acid derivatives or other lipid lowering agents including
patients on statins and Ezetimibe.

- Concomitant use of drugs that have significant interactions with atorvastatin. Please
see appendix II for a listing.

- Concomitant use of St.Johns wort.

- Concomitant use of Valproic acid.

- Patients who are on concurrent immunomodulatory agents, including systemic
corticosteroids, will be ineligible for 3 months after completion of therapy with the
immunomodulating agents. Topical, nasal or inhaled corticosteroids use is not an
exclusion criterion.

- Serum LDL cholesterol less than 40 mg/dl.

- Vaccinations within 6 weeks of study entry.

- Vaccinations within 6 weeks of study entry.