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 study will examine the effects of atorvastatin, a statin (drug that lowers cholesterol) on the human immunodeficiency virus (HIV). If not treated, HIV infection causes an incurable, progressive deficiency in the immune system that leads to death, usually from disease that takes advantage of weakened immunity. However, previous studies have suggested that if the amount of cholesterol in infected cells is reduced, multiplication of HIV is also reduced. In this study, researchers will examine the HIV viral loads, that is, amount of the virus in the blood. They will evaluate the composition of the strain of the virus that patients carry (HIV genotype), response of the immune system to the virus, and how genes may determine the way in which the drug may or may not work against the strain of virus. Researchers plan to enroll 22 participants, anticipating a study to last 30 weeks for each participant.

Patients ages 18 or older with HIV infection, who are not pregnant or breastfeeding, who do not have a known allergy to atorvastatin use, and who have not had a serious illness or infection that required hospitalization within the 30 days before entering the study may be eligible for this study. They will be assigned to random groups: one that to receive atorvastatin and the other to receive a placebo, which has no effect on cholesterol or ability of the HIV infection to multiply. Patients will remain in their groups and treatments for 8 weeks. At the completion of 8 weeks, no matter the study group, all patients will be required to discontinue all study-related medications for 4 weeks. After that period, the study assignments will be switched, so that those previously taking the placebo will take atorvastatin, and vice versa. The study will proceed for another 8 weeks, followed by a period of stopping study-related medications and patients being observed for 4 weeks. Throughout the study, patients will have regularly scheduled visits at the clinic. At those visits there will be collection of blood samples, assessments of symptoms, physical examinations, and questionnaires to complete. Blood tests may require fasting beforehand, and blood samples will be used in standard tests, including those regarding the liver, kidneys, muscles, blood cells, and pregnancy status. Specialized blood tests will determine viral load, effects of the drug on the immune cells, and genetic influence on the drug's effectiveness. The time spent for procedures during clinic visits...

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.

• Active Comparator: A
  STATIN 80 mg Atorvastatin daily
  Intervention: Drug: Atorvastatin
• Placebo Comparator: B
  PLACEBO control
  Intervention: Drug: Atorvastatin

• Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998 Mar 26;338(13):853-60.
• Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet. 2000 Oct 21;356(9239):1423-30. Review.
• Carr A, Samaras K, Thorisdottir A, Kaufmann GR, Chisholm DJ, Cooper DA. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet. 1999 Jun 19;353(9170):2093-9.

• 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.