RAltegravir Switch STudy: Effects on Endothelial Recovery

Study Overview
=================
Brief Summary
-----------------
Treatment with HIV-infection with protease inhibitors is associated with high blood lipids and higher chance for cardiovascular complications. The RASSTER study aims to investigate the effect of switching the protease inhibitor lopinavir/ritonavir to raltegravir on vessel wall function and inflammation,and activation of the immune system. we hypothesize that with this intervention these parameters will improve. Since decreased vessel wall function and inflammation are initial steps in the process of atherosclerosis, it is important to know this data when treating HIV-infected patients.

Detailed Description
-----------------
Fixed dose combination lopinavir/ritonavir (LPV/r) is a widespread used antiretroviral drug belonging to the class of protease inhibitors (PIs). PIs are associated with an increased risk of myocardial infarction. However, data is available suggesting increased levels of plasma lipids are not the sole explanation for this observation. Treatment with LPV/r might lead to a decrease of endothelial function as well, thus explaining the increased risk of myocardial infarction besides increased plasma lipids. Raltegravir is a registered antiretroviral drug with no known cardiovascular side effects. We hypothesize that switching LPV/r to raltegravir in HIV-infected patients with suppressed plasma viral load (<50 copies/ml) will lead to an improvement of endothelial function. Objective: First, to assess the effect of the switch of lopinavir/ritonavir to raltegravir on endothelial function. Second, to assess the effect of the intervention mentioned above on markers of endothelial function; immune activation; chronic inflammation; and, on plasma HIV-RNA below the cut-off of 50 copies/ml.

Official Title
-----------------
Phase IV, Randomized, Open Label, Crossover, Intervention Trial to Investigate the Effect of the Switch of Lopinavir/Ritonavir to Raltegravir on Endothelial Function, Chronic Inflammation, Immune Activation and HIV Replication <50 Copies/ml

Conditions
-----------------
HIV Infection, Endothelial Dysfunction

Intervention / Treatment
-----------------
* Drug: raltegravir


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 years HIV-1 infection Treatment with antiretroviral regimen containing lopinavir/ritonavir for at least the previous 3 months No other protease inhibitors besides lopinavir/ritonavir in antiretroviral regimen Subjects must have a minimum period of viral suppression (plasma HIV-RNA < 50 copies/ml) of 6 months Subjects will not have a history of virological failure on antiretroviral therapy Results of previous resistance testing allowing replacement of lopinavir/ritonavir by raltegravir CD4+ cell count > 200 cells/µL Signed informed consent Exclusion Criteria: Pregnancy Breastfeeding Raltegravir hypersensitivity Treatment of underlying malignancy Renal insufficiency requiring dialysis Acute or decompensated chronic hepatitis (Child-Pugh score C) Modification of antiretroviral regimen in the previous 3 months

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Raltegravir<br>At baseline, lopinavir-ritonavir will be switched to raltegravir (cross-over after 8 weeks). | Drug: raltegravir<br>* Switch of lopinavir/ritonavir to raltegravir 400 mg BID (duration 8 weeks)<br>* Other names: Isentress;|
| No Intervention: Lopinavir/ritonavir<br>Subjects will continue lopinavir/ritonavir (cross-over after 8 weeks) | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in flow mediated dilatation (FMD) of the brachial artery | Change in flow-mediated dilatation (FMD) of the brachial artery after 8 weeks of raltegravir treatment as compared to the control group (treatment with lopinavir/ritonavir) | week 8, week16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in markers of chronic inflammation |  | Baseline, week 2, week 4, week 8, week 10, week 12 and week 16 | 
| Change in markers of immune activation |  | Baseline, week 2, week 4, week 8, week 10, week 12 and week 16 | 
| Change in markers of endothelial function |  | Baseline, week 2, week 4, week 8, week 10, week 12 and week 16 | 
| Changes in plasma HIV-RNA below 50 copies/ml |  | Baseline, week 8, week 16 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Anti-HIV Agents, Anti-Retroviral Agents, Antiviral Agents, Anti-Infective Agents, Lopinavir/ritonavir