Lovastatin: Immunomodulatory Value Evaluation

Study Overview
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Brief Summary
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The purpose of this study is to determine whether the long-term administration of statins may benefit the clinical and immunological evolution in HIV-1-infected individuals before the use of antiretroviral therapy is required.

Detailed Description
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Despite the fact that HAART produces a decrease in HIV-1 replication and plasma HIV-1 RNA levels, and allows an increase in the CD4 T-cell count that leads to a diminution in the incidence of opportunistic infections and mortality, the cost and complexity of HAART regimens, the growing list of long-term side effects, and the eventual development of resistance have underscored the immediate need for additional therapeutic approaches. Statins exert pleiotropic effects through a variety of mechanisms, among which there are several immunological effects that are related and unrelated to their cholesterol-lowering activity. HIV-1 requires cholesterol and lipid rafts for several key stages of its replication cycle; statins-mediated depletion of cholesterol alters the capacity of a cell to form lipid rafts and decreases the HIV-1 infectivity. On the other hand, statins may exert significant modulator effects in the balance of the cytokine network, and alter the activity of Rho GTPases and LFA-1 and ICAM-1 adhesion molecules. Preliminary studies showed that statins (Lovastatin) had anti HIV-1 activity, and that its administration was safe and efficient to control HIV-1 infection in chronically infected individuals who did not receive HAART (in terms of decreasing viral load and increasing CD4 T-cell count). Because very limited clinical data are available on this topic, this study will be conducted.

Official Title
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Antiretroviral Effect of Lovastatin on HIV-1-infected Individuals Without Highly Active Antiretroviral Therapy (HAART): A Phase-II Randomized Clinical Trial (RCT)

Conditions
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HIV Seropositivity

Intervention / Treatment
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* Drug: Lovastatin
* Other: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Asymptomatic HIV-1 seropositive individuals, with age ≥ 18 years, who are HAART naive HIV-1 infection confirmed by: positive Western-blot test dated at least six months before admission to the study; a Western-blot test within the last six months, which was also positive for the p31 and p66 bands Detectable viral load < 100,000 copies/ml CD4+ T cell count ≥ 350 cells/ul Exclusion Criteria: Inability or unwillingness of patients to give written informed consent. Main residence outside Medellin and its metropolitan area, or any indication of difficulties in the follow-up period Participation in other clinical trials Evidence that the patient will exhibit low adherence to intervention and follow-up (Morisky-Green test) Pregnancy or breastfeeding Any type of antiretroviral treatment before admission to the study, and therapy with lipid-lowering drugs during the last six months Antecedents of allergy, contraindications or intolerance to statins Patients receiving medications which can generate relevant interactions with lovastatin: clarithromycin, erythromycin, azithromycin, itraconazole, ketoconazole, nefodozone, cimetidine, rifampin, phenobarbital, carbamazepine, phenytoin. Unwillingness to avoid the consumption of Citrus paradise (grapefruit juice) or Saint John's Wort (Hypericum) Opportunistic infections or any type of AIDS-defining disease Chronic active hepatitis (B or C) Any hepatocellular disease, indicated by elevation of liver enzymes (AST or ALT) more than twice the reference value Renal failure, indicated by serum creatinine ≥ 2 mg/dl Myopathy, indicated by an elevation of creatine phosphokinase (CPK) more than five times the reference values Infection or acute disease that requires in-patient treatment Active substance-related disorders

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>In this arm, subjects will receive 40 mg of Lovastatin (2 tablets of 20 mg each, p.o.), in a daily doses, during twelve months | Drug: Lovastatin<br>* Lovastatin 40 mg daily (2 tablets of 20 mg each, p.o.), during twelve months until the end of the study, or before the end of the study if any AIDS defining disease or toxicity appear<br>* Other names: statin;|
| Placebo Comparator: 2<br>In this arm, subjects will receive placebo (2 tablets which will look externally identical to lovastatin: wrapped in the same way, with the same size, shape and color) | Other: placebo<br>* Placebo will be administered daily (2 tablets which will look externally identical to intervention: wrapped in the same way, with the same size, shape and color), during twelve months until the end of the study, or before the end of the study if any AIDS defining disease or toxicity appear<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1. HIV-1 viral load measured as RNA copies per ml of peripheral blood 2. CD4 T-cell count measured as cells per ul of peripheral blood |  | Before, 6 and twelve months after the intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CD8+ T cell count, CD4/CD8 ratio, Expression of CD38 and HLA-DR, Total serum cholesterol, Cellular cholesterol, Activity of LFA-1 and ICAM-1, Activity of Rho GTPases, Monthly frequency of AIDS defining diseases, hospitalization and mortality |  | Before, 6 and twelve months after the intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 1 human immunodeficiency virus infection, Lovastatin, Adaptive Immunity, Cellular cholesterol, Rho GTPases, Lymphocyte function-associated antigen-1