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

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

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.

Study Overview

• Status: Completed
• Conditions: Endothelial Dysfunction
• Intervention / Treatment: Drug: Atazanavir; Drug: Placebo; Drug: Lopinavir/ritonavir

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Healthy and lean with normal lipids
• Not infected with HIV or viral hepatitis

Exclusion Criteria:

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; Participants will receive treatment with atazanavir and placebo lopinavir/ritonavir.	Drug: Atazanavir; 400 mg of atazanavir (two 200-mg capsules) per day for 4 weeks; Drug: Placebo; Daily dose of placebo for 4 weeks
Experimental: 2; Participants will receive treatment with lopinavir/ritonavir and placebo atazanavir.	Drug: Placebo; Daily dose of placebo for 4 weeks; Drug: Lopinavir/ritonavir; 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
Placebo Comparator: 3; Participants will receive treatment with placebos for both drugs.	Drug: Placebo; Daily dose of placebo for 4 weeks

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Indiana University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Michael P. Dubé, MD, Indiana University School of Medicine

Publications and helpful links

General Publications

• Dube MP, Shen C, Greenwald M, Mather KJ. No impairment of endothelial function or insulin sensitivity with 4 weeks of the HIV protease inhibitors atazanavir or lopinavir-ritonavir in healthy subjects without HIV infection: a placebo-controlled trial. Clin Infect Dis. 2008 Aug 15;47(4):567-74. doi: 10.1086/590154.

Study record dates

Study Major Dates

• Study Start: November 1, 2003
• Primary Completion (Actual): September 1, 2006
• Study Completion (Actual): October 1, 2006

Study Registration Dates

• First Submitted: July 21, 2008
• First Submitted That Met QC Criteria: July 21, 2008
• First Posted (Estimate): July 23, 2008

Study Record Updates

• Last Update Posted (Actual): October 25, 2017
• Last Update Submitted That Met QC Criteria: October 23, 2017
• Last Verified: July 1, 2008

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Ritonavir; Lopinavir; Atazanavir Sulfate
• Other Study ID Numbers: 573; R01HL072711 (U.S. NIH Grant/Contract); R01HL072711-01 (U.S. NIH Grant/Contract)