Impact of Antiretroviral Therapy on Metabolic, Skeletal, and Cardiovascular Parameters

Study Overview
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Brief Summary
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The U.S. Department of Health and Human Services (HHS) guidelines recommend that HIV-infected people who have never received anti-HIV therapy be treated with a triple drug regimen (commonly called combination antiretroviral therapy, cART). Since the introduction of cART, morbidity and mortality among HIV-infected patients has been dramatically reduced. However, metabolic, skeletal, and cardiovascular diseases have been increasingly reported among HIV-infected patients and may be attributable, in part, to the direct effects of cART. Much of our understanding of the development of these diseases, risk factors, and consequences of these disorders has been derived from clinical studies of HIV-infected persons receiving older antiretroviral agents. A5260s was designed to examine the contributions of HIV-disease related factors and impact of newer antiretroviral drugs on the development of metabolic (such as blood vessels, blood sugar, cholesterol), skeletal, and cardiovascular diseases in people who have never received anti-HIV therapy. A5260s is a prospective substudy of a phase III randomized clinical trial A5257 (see ClinicalTrials.gov identifier: NCT00811954). A5257 was designed to look at different combinations of anti-HIV drugs that do not contain the medication efavirenz (EFV) and how well these drug combinations work to decrease the amount of HIV in the blood and to allow immune system recovery in people who have never received anti-HIV therapy. A5257 also examined drug tolerability and safety for the various drug combinations.

Detailed Description
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A5260s is the optional, metabolic substudy of a phase III, prospective, randomized clinical trial (A5257). For complete details about the parent study A5257, please see ClinicalTrials.gov identifier NCT00811954. Some participants in study A5257 were asked to participate in substudy A5260s. Not all participants were asked since A5260s only took place at a subset of A5257 sites. Participants who agreed to participate in substudy A5260s were enrolled at the same time as their enrollment in A5257. No interventions were given as part of A5260s, but all A5260s participants underwent blood draws, self-administered questionnaire responses (related to physical activity and body image), ultrasound scans to measure the thickness of the carotid artery in the neck and brachial artery flow mediated dilation in the arm, and computerized topography (CT) and dual-energy x-ray absorptiometry (DEXA) scans to measure bone mineral density and body fat. The duration of A5260s study was between 2 and 3 years (96 and 144 weeks), depending on when the participant enrolled. The study was designed to enroll a total of 330 participants with at least 110 per a group; each group represented a different randomized drug combination as defined and assigned by the main study A5257. Cohort A: Atazanavir (ATV) + Ritonavir (RTV) + Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) Cohort B: Raltegravir (RAL) + FTC/TDF Cohort C: Darunavir (DRV) + RTV + FTC/TDF All participants were asked to return for A5260s clinic visits at weeks 4, 24, 48 96 and 144 and participated in all clinical evaluations. No clinical evaluation was restricted to a subset of A5260s participants. If a participant chose to discontinue participation in the substudy, the participant was able to continue in study A5257. However, a participant discontinuing participation from A5257 was also removed from A5260s. Additionally, a participant's decision to discontinue or switch study drugs in the main study did not impact participation and follow-up clinic visits in A5260s.

Official Title
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Cardiovascular, Anthropometric, and Skeletal Effects of Antiretroviral Therapy (ART) Initiation With Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) Plus Atazanavir/Ritonavir (ATV/r), Darunavir/Ritonavir (DRV/r), or Raltegravir (RAL): Metabolic Substudy of A5257

Conditions
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HIV Infection

Intervention / Treatment
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* Drug: Emtricitabine/tenofovir disoproxil fumarate
* Drug: Ritonavir
* Drug: Atazanavir
* Drug: Raltegravir
* Drug: Darunavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Enrollment in A5257 and intent to enroll in A5001 (ALLRT) Signed informed consent For A5257 inclusion criteria, please see ClinicalTrials.gov identifier NCT00811954 Exclusion Criteria: Diabetes mellitus, (fasting plasma glucose ≥ 126 mg/dL on two occasions or on hypoglycemic medications). Known cardiovascular disease (history of myocardial infarction [MI], coronary artery bypass graft surgery, percutaneous coronary intervention, stroke, transient ischemic attack, or peripheral arterial disease with ankle-brachial index of less than 0.9 or claudication) Uncontrolled hypothyroidism or hyperthyroidism which in the opinion of the site investigator would affect substudy participation Current use of statins, fish oil (greater than 2 grams per day), fibric acid derivatives, or niacin (more than 1000 mg per day) (NOTE: Current use of fish oil and niacin is defined as receiving treatment in the 8 weeks prior to study entry) Intention to start pharmacological or surgical intervention for weight loss Use of any ART in the 30 days before study entry For A5257 exclusion criteria, please see ClinicalTrials.gov identifier NCT00811954

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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cohort A<br>ATV/RTV + FTC/TDF Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), ritonavir (RTV), and atazanavir (ATV) to be taken orally, once daily. | Drug: Emtricitabine/tenofovir disoproxil fumarate<br>* 200 mg emtricitabine/300 mg tenofovir disoproxil fumarate taken orally daily. A combination drug of two nucleoside reverse transcriptase inhibitors (NRTIs). Other Name: TDF/FTC<br>Drug: Ritonavir<br>* 100 mg taken orally once daily. A protease inhibitor (PI). Other Name: RTV<br>Drug: Atazanavir<br>* 300 mg taken orally once daily. A protease inhibitor (PI). Other Name: ATV<br>|
| Cohort B<br>RAL + FTC/TDF FTC/TDF orally, once daily, and raltegravir (RAL) orally, twice daily. | Drug: Emtricitabine/tenofovir disoproxil fumarate<br>* 200 mg emtricitabine/300 mg tenofovir disoproxil fumarate taken orally daily. A combination drug of two nucleoside reverse transcriptase inhibitors (NRTIs). Other Name: TDF/FTC<br>Drug: Ritonavir<br>* 100 mg taken orally once daily. A protease inhibitor (PI). Other Name: RTV<br>Drug: Raltegravir<br>* 400 mg taken orally twice daily. An integrase inhibitor (INI). Other Name: RAL<br>|
| Cohort C<br>DRV/RTV + FTC/TDF FTC/TDF, darunavir (DRV), and RTV, orally, once daily. | Drug: Emtricitabine/tenofovir disoproxil fumarate<br>* 200 mg emtricitabine/300 mg tenofovir disoproxil fumarate taken orally daily. A combination drug of two nucleoside reverse transcriptase inhibitors (NRTIs). Other Name: TDF/FTC<br>Drug: Ritonavir<br>* 100 mg taken orally once daily. A protease inhibitor (PI). Other Name: RTV<br>Drug: Darunavir<br>* 100 mg taken orally once daily. A protease inhibitor (PI). Other Name: RTV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annual Rate of Change in Right Common Carotid Artery Intima-media Thickness (CIMT) | Right common carotid artery intima-media thickness was measured by ultrasound scan at study entry and weeks 48, 96 and 144. The annual rate of change in right common carotid artery intima-media thickness (CIMT) was estimated over 144 weeks from study entry using mixed effects linear regression model that adjusted for screening HIV-1 RNA level and Framingham risk score stratification factors. | Study entry, week 144 | 
| Change in Brachial Artery (BA) Flow Mediated Dilation (FMD) From Study Entry to Week 24 | Brachial artery flow mediated dilation was measured by brachial artery reactivity tests. All results reflect measures captured from participants who reported fasting and not smoking for at least 8 hours prior to FMD assessments. The change from study entry to week 24 in brachial artery FMD (%) was defined as the maximum FMD (%) calculated from resting heart rate (RH) 60 seconds and RH 90 seconds, relative to resting brachial artery diameter. | Study entry, week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Brachial Artery Flow Mediated Dilation (FMD) From Study Entry to Weeks 4 and 48 | Brachial artery flow mediated dilation was measured by brachial artery reactivity tests. All results reflect measures captured from participants who reported fasting and not smoking for at least 8 hours prior to FMD assessments. The change from study entry to weeks 4 and 48 in brachial artery FMD (%) was defined as the maximum FMD (%) calculated from resting heart rate (RH) 60 seconds and RH 90 seconds, relative to resting brachial artery diameter. | Study entry, weeks 4 and 48 | 
| Change in Absolute Flow Mediated Dilation (FMD) From Study Entry to Weeks 4, 24 and 48 | The change in absolute FMD was defined as the maximum absolute FMD from the RH 60 and 90 second measurements, from study entry to weeks 4, 24, and 48 (unit of measure millimeters). All results reflect measures captured from participants who reported fasting and not smoking for at least 8 hours prior to FMD assessments. | Study entry, weeks 4, 24 and 48 | 
| Percent Change in Bone Mineral Density (BMD) of the Hip From Study Entry to Week 96 | Bone mineral density (BMD) of the hip was evaluated by dual-energy x-ray absorptiometry (DXA) scans at study entry and study week 96. The percent change was calculated as ((week 96 value - study entry value) / study entry value)) x 100. | Study entry, week 96 | 
| Percent Change in Bone Mineral Density (BMD) of the Lumber Spine From Study Entry to Week 96 | Bone mineral density (BMD) of the lumber spine was evaluated by dual-energy x-ray absorptiometry (DXA) scans at study entry and study week 96. The percent change was calculated as ((week 96 value - study entry value) / study entry value)) x 100. | Study entry, week 96 | 
| Percent Change in Bone Mineral Density (BMD) of the Total Body From Study Entry to Week 96 | Bone mineral density (BMD) of the total body was evaluated by dual-energy x-ray absorptiometry (DXA) scans at study entry and study week 96. The percent change was calculated as ((week 96 value - study entry value) / study entry value)) x 100. | Study entry, week 96 | 
| Percent Change in Total Limb Fat From Study Entry to Week 96 | Total limb fat was evaluated by dual-energy x-ray absorptiometry (DXA) scans at study entry and week 96. The percent change was calculated as ((week 96 value - study entry value) / study entry value)) x 100. | Study entry, week 96 | 
| Percent Change in Trunk Fat From Study Entry to Week 96 | Trunk fat was evaluated by dual-energy x-ray absorptiometry (DXA) scans at study entry and week 96. The percent change was calculated as ((week 96 value - study entry value) / study entry value)) x 100. | Study entry, week 96 | 
| Percent Change in Lean Mass From Study Entry to Week 96 | Lean mass was evaluated by dual-energy x-ray absorptiometry (DXA) scans at study entry and week 96. The percent change was calculated as ((week 96 value - study entry value) / study entry value)) x 100. | Study entry, week 96 | 
| Percent Change in Visceral Abdominal Fat (VAT) From Study Entry to Week 96 | Visceral abdominal fat (VAT) was evaluated by single slice abdominal computerized tomography scans at study entry and week 96. The percent change was calculated as as ((week 96 value - study entry value) / study entry value)) x 100. | Study entry, week 96 | 
| Percent Change in Subcutaneous Abdominal Fat (SAT) From Study Entry to Week 96 | Subcutaneous abdominal fat (SAT) was evaluated by single slice abdominal computerized tomography scans at study entry and week 96. The percent change was calculated as ((week 96 value - study entry value) / study entry value)) x 100. | Study entry, week 96 | 
| CD4+ T-cell Count at Study Entry and Weeks 24, 48, 96 and 144 | The absolute levels of CD4+ T-cell counts (cells/mm^3) measured at study entry and weeks 24, 48, 96 and 144. | Study entry, weeks 24, 48, 96 and 144 | 
| Change in CD4+ T-cell Count From Study Entry to Weeks 24, 48, 96 and 144 | Change was calculated as (CD4+ T-cell count at week 24, 48, 96, or 144) - (CD4+ T-cell count at study entry). | Study entry to weeks 24, 48, 96, and 144 | 
| Change in Fasting Total Cholesterol (TC) From Study Entry to Weeks 4, 24, 48 and 96 | Total cholesterol (TC, unit of measure mg/dL) was measured at study entry and weeks 4, 24, 48 and 96 from participants who reported fasting for at least 8 hours prior to assessment; all results were centrally laboratory tested in batch. Change in TC was calculated as (week 4, 24, 48 or 96 result) - (study entry result). | Study entry, weeks 4, 24, 48 and 96 | 
| Change in Fasting Triglyceride (TG) From Study Entry to Weeks 4, 24, 48 and 96 | Triglyceride (TG, unit of measure mg/dL) was measured at study entry and weeks 4, 24, 48 and 96 from participants who reported fasting for at least 8 hours prior to assessment; all results were centrally laboratory tested in batch. Change in TG was calculated as (week 4, 24, 48 or 96 result) - (study entry result). | Study entry, weeks 4, 24, 48 and 96 | 
| Change in Fasting High-density Lipoprotein Cholesterol (HDL-C) From Study Entry to Weeks 4, 24, 48 and 96 | HDL cholesterol (unit of measure mg/dL) was measured at study entry and weeks 4, 24, 48 and 96 from participants who reported fasting for at least 8 hours prior to assessment; all results were centrally laboratory tested in batch. Change in HDL-C was calculated as (week 4, 24, 48 or 96 result) - (study entry result). | Study entry, weeks 4, 24, 48 and 96 | 
| Change in Fasting Calculated Low-density Lipoprotein Cholesterol (LDL-C) From Study Entry to Weeks 4, 24, 48 and 96 | Calculated LDL-C (unit of measure mg/dL) was measured at study entry and weeks 4, 24, 48 and 96 from participants who reported fasting for at least 8 hours prior to assessment; all results were centrally laboratory tested in batch. Change in calculated LDL-C was calculated as (week 4, 24, 48 or 96 result) - (study entry result). | Study entry, weeks 4, 24, 48 and 96 | 
| Change in Fasting Glucose Level From Study Entry to Weeks 4, 24, 48 and 96 | Glucose (unit of measure mg/dL) was measured at study entry and weeks 4, 24, 48 and 96; all results reflect measures captured from participants who reported fasting for at least 8 hours prior to assessment. Change was calculated as (fasting result during at week 4, 24, 48 or 96) - (fasting result at study entry). | Study entry, weeks 4, 24, 48 and 96 | 
| Change in Fasting Insulin Level From Study Entry to Weeks 4, 24, 48 and 96 | Insulin (unit of measure uIU/dL) was measured at study entry and weeks 4, 24, 48 and 96; all results reflect measures captured from participants who reported fasting for at least 8 hours prior to assessment. Change was calculated as (fasting result during at week 4, 24, 48 or 96) - (fasting result at study entry). | Study entry, weeks 4, 24, 48 and 96 | 
| Fold Change in D-dimer From Study Entry to Weeks 48 and 96 | D-dimer was measured at study entry and weeks 48 and 96 (unit of measure ug/ml). Fold change from study entry to week 48 or week 96 was calculated as (week 48 value or week 96 value) / (study entry value). Results identified above or below the limit of quantification were imputed at the quantification limit of the respective assay. | Study entry, weeks 48 and 96 | 
| Fold Change in High Sensitivity C-reactive Protein (hsCRP) From Study Entry to Weeks 48 and 96 | hsCRP was measured at study entry and weeks 48 and 96 (unit of measure ug/ml). Fold change from study entry to week 48 or week 96 was calculated as (week 48 value or week 96 value) / (study entry value). Results identified above or below the limit of quantification were imputed at the quantification limit of the respective assay. | Study entry, weeks 48 and 96 | 
| Fold Change in Interleukin-6 (IL-6) From Study Entry to Weeks 48 and 96 | IL-6 was measured at study entry and weeks 48 and 96 (unit of measure pg/ml). Fold change from study entry to week 48 or week 96 was calculated as (week 48 value or week 96 value) / (study entry value). Results identified above or below the limit of quantification were imputed at the quantification limit of the respective assay. | Study entry, weeks 48 and 96 | 
| Fold Change in Soluble CD14 From Study Entry to Weeks 48 and 96 | Soluble CD14 was measured at study entry and weeks 48 and 96 (unit of measure ng/ml). Fold change from study entry to week 48 or week 96 was calculated as (week 48 value or week 96 value) / (study entry value). Results identified above or below the limit of quantification were imputed at the quantification limit of the respective assay. | Study entry, weeks 48 and 96 | 
| Fold Change in Soluble CD163 From Study Entry to Weeks 48 and 96 | Soluble CD163 was measured at study entry and weeks 48 and 96 (unit of measure ng/ml). Fold change from study entry to week 48 or week 96 was calculated as (week 48 value or week 96 value) / (study entry value). Results identified above or below the limit of quantification were imputed at the quantification limit of the respective assay. | Study entry, weeks 48 and 96 | 
| Fold Change in Percent Expression of CD38+HLADR+ on CD4+ (Percent) From Study Entry to Weeks 24 and 96 | Percent expression of CD38+HLADR+ on CD4+ was measured at study entry and weeks 24 and 96 (unit of measure percent). Fold change from study entry to week 24 or week 96 was calculated as (week 24 value or week 96 value) / (study entry value). | Study entry, weeks 24 and 96 | 
| Fold Change in Percent Expression of CD38+HLADR+ on CD8+ (Percent) From Study Entry to Weeks 24 and 96 | Percent expression of CD38+HLADR+ on CD8+ was measured at study entry and weeks 24 and 96 (unit of measure percent). Fold change from study entry to week 24 or week 96 was calculated as (week 24 value or week 96 value) / (study entry value). | Study entry, weeks 24 and 96 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ART, Antiretroviral therapy, Treatment naive, Highly active antiretroviral therapy (HAART)