Randomized Placebo-Controlled Trial of Atorvastatin in HIV-Positive Patients Not on Antiretroviral Therapy

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:
• Adults 18 years of age or older.
• Human Immunodeficiency Virus -1 (HIV-1) infection, as documented by a licensed Enzyme-Linked Immunosorbent Assay (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 antiretroviral (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.

• Willingness to use a method of contraception during the study period.
• 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.
• Cluster of differentiation 4 (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 branched deoxyribonucleic acid (bDNA) method in the National Institutes of Health (NIH) laboratory and must be within 20% (log10bDNA of each other).
• A fasting total cholesterol lower than 240mg/dl and an Low-density lipoprotein (LDL) cholesterol lower than 130mg/dl.
• Liver function tests (aspartate aminotransferase (AST) or alanine aminotransferase (ALT)) not greater than 1.5 times the upper limit of normal.
• 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.