Effect of the HIV Protease Inhibitors Atazanavir and Lopinavir/Ritonavir on Cardiovascular Disease Risk Factors

Study Overview
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Brief Summary
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HIV protease inhibitors (PIs) are a class of antiretroviral drugs used to inhibit viral replication. They do so by interfering with a key step in the replication process. Some HIV PIs have been associated with an increased risk of adverse cardiovascular side effects. Further study is needed, however, to assess the full extent of effect of newer HIV PIs, including atazanavir and lopinavir/ritonavir, on cardiovascular disease risk. This study will compare the effects of atazanavir, lopinavir/ritonavir, and placebo on certain cardiovascular disease risk factors in healthy people without HIV.

Detailed Description
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Antiretroviral therapy for HIV, particularly with the use of PIs, is associated with an increased risk of heart attack. Specific cardiovascular side effects seen with the use of some PIs include insulin resistance, abnormal blood lipid levels, and endothelial dysfunction (abnormalities in the cells that line the inner surface of blood vessels). Past studies have shown that treatment with indinavir, an older PI, results in significant endothelial dysfunction, which may be the main cause for the increase in cardiovascular risk. Indinavir is now seldom used in clinical practice, and the newer PIs atazanavir and combination lopinavir/ritonavir now account for nearly 70% of total PI use in the United States. It is not known what effect these new PIs have on endothelial dysfunction. This study will compare the effects of atazanavir, lopinavir/ritonavir, and placebo on certain cardiovascular disease risk factors, including abnormal glucose metabolism and endothelial dysfunction, in healthy people without HIV. Participation in this study will last 4 weeks. All participants will undergo initial assessments that will include various vascular and metabolic evaluations. Body weight, height, basal heart rate, and systolic and diastolic blood pressure will also be measured. Participants will then be assigned randomly to receive 4 weeks of treatment with 400 mg of atazanavir per day plus placebo, 400 mg/100 mg of lopinavir/ritonavir twice per day plus placebo, or placebos for both drugs per day. Upon completing the 4 weeks of treatment, participants will repeat the initial assessments.

Official Title
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Effect of HIV-1 Protease Inhibitors on Endothelial Function and Glucose Metabolism in Normal, HIV-Uninfected Subjects: Atazanavir or Lopinavir/Ritonavir or Placebo

Conditions
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Endothelial Dysfunction

Intervention / Treatment
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* Drug: Atazanavir
* Drug: Lopinavir/ritonavir
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy and lean with normal lipids Not infected with HIV or viral hepatitis Exclusion Criteria:

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Participants will receive treatment with atazanavir and placebo lopinavir/ritonavir. | Drug: Atazanavir<br>* 400 mg of atazanavir (two 200-mg capsules) per day for 4 weeks<br>Drug: Placebo<br>* Daily dose of placebo for 4 weeks<br>|
| Experimental: 2<br>Participants will receive treatment with lopinavir/ritonavir and placebo atazanavir. | Drug: Lopinavir/ritonavir<br>* 400 mg/100 mg of lopinavir/ritonavir (three soft-gel capsules, each containing 133.3 mg lopinavir and 33.3 mg ritonavir) twice per day with food for 4 weeks<br>Drug: Placebo<br>* Daily dose of placebo for 4 weeks<br>|
| Placebo Comparator: 3<br>Participants will receive treatment with placebos for both drugs. | Drug: Placebo<br>* Daily dose of placebo for 4 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Leg blood flow response to the intra-femoral artery infusion of methacholine chloride |  | Measured at Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin sensitivity measured by the hyperinsulinemic euglycemic clamp study |  | Measured at Week 4 |