Assessing the Impact of INSTI to PI Switch on Insulin Sensitivity and Fat Metabolism

Study Overview
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Brief Summary
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A substudy of TMC114FD2HTX4004 that will perform glucose tolerance testing, adipose testing and MRI scan at baseline, 12 and 24 weeks post switch of ART medications.

Detailed Description
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Synopsis Full study title: Assessing the impact of integrase strand transfer inhibitors (INSTI) to protease inhibitor (PI) switch on insulin sensitivity and fat metabolism (ADIPOSITY): a sub-study of DEFINE Endpoints and objectives: The following endpoints will be determined 12 and 24 weeks after switch from an INSTI-based antiretroviral therapy (ART) regimen to a PI-based regimen: Primary endpoint: Change in insulin sensitivity (SI) at 12 weeks assessed by using a 3-hour frequently sampled oral glucose tolerance testing (fsOGTT). Secondary endpoints: 1) Change in insulin sensitivity (SI) at 24 weeks assessed by using a 3-hour frequently sampled oral glucose tolerance testing (fsOGTT); 2) Change in insulin secretion during the fsOGTT assessed by using C-peptide deconvolution; 3) Change in intrahepatic triglyceride (IHTG) content measured by magnetic resonance imaging (MRI); 4) Change in adipocyte size by the osmium tetroxide fixation technique; and 5) Change in expression of genes associated with adipose tissue development, lipogenesis, inflammation and endocrine function by RNA sequencing. Hypothesis: Insulin sensitivity will improve following switch from INSTIs to PIs

Official Title
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WU 360: Assessing the Impact of Integrase Strand Transfer Inhibitors (INSTI) to Protease Inhibitor (PI) Switch on Insulin Sensitivity and Fat Metabolism (ADIPOSITY): a Sub-study of DEFINE

Conditions
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HIV I Infection, Adiposity

Intervention / Treatment
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* Procedure: Frequently sampled glucose tolerance testing
* Procedure: abdominal subcutaneous adipose tissue biopsy
* Procedure: MRI scan to assess intrahepatic triglyceride content


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: • Must be enrolled in the DEFINE study TMC114FD2HTX4004 Must sign an ICF indicating that they understand the purpose of, and procedures required for, the study and are willing to participate in the study. Exclusion Criteria: • Contraindication to magnetic resonance imaging as determined by institutional policy. Current diagnosis of diabetes mellitus

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: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Immediate switch<br>Immediate switch | Procedure: Frequently sampled glucose tolerance testing<br>* Frequently sampled glucose tolerance testing<br>Procedure: abdominal subcutaneous adipose tissue biopsy<br>* abdominal subcutaneous adipose tissue biopsy<br>Procedure: MRI scan to assess intrahepatic triglyceride content<br>* MRI scan to assess intrahepatic triglyceride content<br>|
| Active Comparator: Delayed switch<br>Delayed switch | Procedure: Frequently sampled glucose tolerance testing<br>* Frequently sampled glucose tolerance testing<br>Procedure: abdominal subcutaneous adipose tissue biopsy<br>* abdominal subcutaneous adipose tissue biopsy<br>Procedure: MRI scan to assess intrahepatic triglyceride content<br>* MRI scan to assess intrahepatic triglyceride content<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin Sensitivity measured by homeostatic model assessment for insulin resistance {HOMA_IR} | Change in insulin sensitivity (SI) at 12 weeks assessed by using a 3-hour frequently sampled oral glucose tolerance testing (fsOGTT).to calculate HOMA_IR | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intrahepatic triglyceride (IHTG) content measure by magnetic resonance | Change in intrahepatic triglyceride (IHTG) content measured by magnetic resonance imaging (MRI | 12 weeks | 
| Intrahepatic triglyceride (IHTG) content measure by magnetic resonance | Change in intrahepatic triglyceride (IHTG) content measured by magnetic resonance imaging (MRI | 24 weeks | 
| Adipocyte size measured by osmium tetroxide fixation technique | Change in adipocyte size by the osmium tetroxide fixation technique | 12 weeks | 
| Adipocyte size measured by osmium tetroxide fixation technique | Change in adipocyte size by the osmium tetroxide fixation technique | 24 weeks | 
| Adipocyte gene expression correlated with adipose tissue development | Change in expression of adipose tissue genes correlated with adipose tissue development, lipogenesis, inflammation and endocrine function measured by RNA sequencing | 12 weeks | 
| Adipocyte gene expression correlated with adipose tissue development | Change in expression of adipose tissue genes correlated with adipose tissue development, lipogenesis, inflammation and endocrine function measured by RNA sequencing | 24 weeks | 
| Insulin Sensitivity measured by homeostatic model assessment for insulin resistance {HOMA_IR} | Change in insulin sensitivity (SI) at 12 weeks assessed by using a 3-hour frequently sampled oral glucose tolerance testing (fsOGTT).to calculate HOMA_IR | 24 weeks |