Comparative Study of Three NNRTI-Sparing HAART Regimens

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 patients who have never received anti-HIV therapy be treated with a triple drug regimen. The most commonly prescribed and successful regimen contains the medication efavirenz (EFV). However, this regimen may not be an option for everyone, hence alternative regimens are needed. This study was designed to look at how well different combinations of anti-HIV drugs work to decrease the amount of HIV in the blood (viral load) of and allow immune system recovery in people who have never received anti-HIV therapy. This study also examined drug tolerability and safety for the various drug combinations.

Detailed Description
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Of the five anti-HIV drug classes, four were recommended as first-line regimens for patients who have never received anti-HIV treatment before (treatment naive): nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), Integrase Inhibitors (INIs) and protease inhibitors (PIs). The U.S. Department of Health and Human Services (HHS) guidelines recommend that treatment-naive HIV infected patients be treated with a triple drug regimen that includes 2 NRTIs + 1 NNRTI, 2 NRTIs + INI, or 2 NRTIs + 1 PI as their initial treatment regimen. According to data, an efavirenz (EFV)-containing regimen (2 NRTIs + 1 NNRTI, with EFVas the NNRTI) requires fewer pills for the patient, has mild and few side effects, and is more effective in reducing viral load than other regimens, making it the preferred choice for most patients. However, for some patients, an EFV-containing regimen is not feasible due to side effects, acquired NNRTI-resistant HIV virus, or other undesirable effects. For these patients, it is necessary to find alternative regimens with comparable safety and efficacy. This study examined how well different combinations of anti-HIV drugs work, including safety and drug tolerability for various combinations. This was a phase III, prospective, randomized study. Participants was randomly assigned to one of three different groups (treatment arms)-A, B, or C -each representing a different drug combination regimen, none of which contained an NNRTI. Arm A: Atazanavir (ATV) + Ritonavir (RTV) + Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) Arm B: Raltegravir (RAL) + FTC/TDF Arm C: Darunavir (DRV) + RTV + FTC/TDF The duration of this study was between 96 and 192 weeks, depending on when the participant enrolled. There were a total of 1,809 participants, approximately 600 per treatment arm. Screening and pre-entry evaluations must occur prior to the participant starting any study medication, treatments, or interventions. Participants were randomly assigned to their treatment groups at the entry visit and must begin treatment within 72 hours of randomization. Participants was told which group they were in and what medications they were administered. The study drugs were distributed at entry. All drugs were provided by the study with the exception of RTV, which would have to be obtained through the participant's primary care physician (Group A or C). If a participant was unable to tolerate any of the study medications during the course of the study then their doctor could switch them to another regimen. During the study, participants was asked to return to the clinic at Weeks 4, 8, 16, 24, 36, and 48 and then every 16 weeks until the end of the study. They were also contacted by telephone during Week 2 to check on their status. Visits were last about 1 hour. At most visits, participants had a physical exam and answered questions about any medications they were taken. Additionally, participants completed questionnaires addressing their smoking and alcohol habits, had blood drawn, and were asked to give urine samples. At some visits, participants had to come to the clinic without having eaten for 8 hours. If the participant was female and able to become pregnant, a pregnancy test might be given at any visit if pregnancy was suspected. Some participants of A5257 were asked to participate in an optional metabolic substudy A5260s. This substudy took place at only some study sites and continued last up to 144 weeks, including time on A5257. The primary focus of this substudy was to examine carotid artery intima-media thickness (CIMT) as it relates to both RTV- and RAL-containing regimens. Randomization, stratification, treatment assignments, and study visits were as per A5257.

Official Title
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The ARDENT Study: Atazanavir, Raltegravir, or Darunavir With Emtricitabine/Tenofovir for Naive Treatment

Conditions
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HIV Infection

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infected No evidence of any exclusionary mutations defined as any major NRTI or PI resistance-associated mutation on any genotype or evidence of significant NRTI or PI resistance on any phenotype performed at any time prior to study entry. NNRTI-associated resistance mutations are not excluded. More information on this criterion can be found in the study protocol. No prior anti-HIV therapy. More information on this criterion can be found in the study protocol. Viral load is 1000 copies/mL or higher, as measured within 90 days prior to study entry Certain laboratory values obtained within 60 days prior to study entry Ability to obtain RTV by prescription Completed cardiovascular risk assessment. More information on this criterion can be found in the study protocol. Must agree to use acceptable forms of contraception while receiving study drugs and for 6 weeks after stopping the medications. More information on this criterion is available in the protocol. Negative pregnancy test within 72 hours before initiating antiretroviral medication Participating in research at any AIDS Clinical Trial Group (ACTG) clinical research site or select International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) group sites Ability and willingness of subject or legal guardian/representative to give written informed consent Exclusion Criteria: Use of immunomodulators, HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 30 days prior to study entry. Those using stable physiologic glucocorticoid doses, a short course of pharmacologic glucocorticoid, corticosteroids for acute therapy treating an opportunistic infection, inhaled or topical corticosteroids, or granulocyte-colony stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) will not be excluded. Known allergy or sensitivity to study drugs or their ingredients. A history of sulfa allergy is not excluded. Any condition that, in the opinion of the investigator, would compromise the participant's ability to participate in the study Serious illness requiring systemic treatment and/or hospitalization until participant either completes therapy or is clinically stable on therapy, in the opinion of the investigator, for at least 7 days prior to study entry Requirement for any current medications that are prohibited with any study drugs Current imprisonment or involuntary incarceration in a medical facility for psychiatric or physical illness Any prior use of entecavir for treatment of hepatitis B for greater than 8 weeks while the participant was known to be HIV infected Presence of decompensated cirrhosis Pregnant or breastfeeding

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: ATV/RTV + FTC/TDF<br>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).<br>* Other names: TDF/FTC;Drug: Ritonavir<br>* 100 mg taken orally once daily. A protease inhibitor (PI).<br>* Other names: RTV;Drug: Atazanavir<br>* 300 mg taken orally once daily. A protease inhibitor (PI).<br>* Other names: ATV;|
| Experimental: Arm B: RAL + FTC/TDF<br>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).<br>* Other names: TDF/FTC;Drug: Raltegravir<br>* 400 mg taken orally twice daily. An integrase inhibitor (INI).<br>* Other names: RAL;|
| Experimental: Arm C: DRV/RTV + FTC/TDF<br>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).<br>* Other names: TDF/FTC;Drug: Darunavir<br>* 800 mg taken orally once daily. A protease inhibitor (PI).<br>* Other names: DRV;Drug: Ritonavir<br>* 100 mg taken orally once daily. A protease inhibitor (PI).<br>* Other names: RTV;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Probability of First Virologic Failure by Week 96 | The Kaplan-Meier estimate of the cumulative probability of virologic failure by week 96. Time to virologic failure was defined as the first time from study entry to the first of two consecutive HIV-1 RNA >1000 copies/mL at or after week 16 and before week 24, or >200 copies/mL at or after week 24. Week 16 is defined to occur between 14 (98 days) and 18 weeks (126 days) after study entry, week 24 is defined to occur between 22 (154 days) and 26 (182 days) after study entry, and week 96 is defined to occur between 88 (616 days) and 104 (728 days) after study entry. | From study entry to week 96 | 
| Cumulative Incidence of Discontinuation of the RAL or PI Component of Randomized Treatment for Toxicity by Week 96 | The cumulative incidence of discontinuation for toxicity by week 96 was estimated using competing risks with treatment discontinuation for other reasons considered as a competing event; participants completing the study on the RAL or PI component of their randomized regimen were considered censored at the earliest of the date of last patient contact and off study date. | From study entry to week 96 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Incidence of First Adverse Event by Week 96 | The cumulative incidence of first adverse event (with and without total bilirubin and creatine kinase and measured from study entry) by week 96 was estimated using methods for competing risks. Discontinuation of randomized treatment prior to an adverse event was considered a competing event. The time to the first of any post-entry Grade 2, 3, or 4 sign or symptom, or Grade 3 or 4 laboratory abnormality while on randomization. The protocol required reporting of signs and symptoms and laboratory values as follow: all signs and symptoms grade ≥2 post-entry to week 48, signs and symptoms grade >3 after week 48, and laboratory values grade >3 and all signs, symptoms, and laboratory values that led to a change in treatment, regardless of grade throughout out all post-entry follow-up. | From study entry to week 96 | 
| Cumulative Probability of Time to Loss of Virologic Response (TLOVR) by Week 96 | The Kaplan-Meier estimate of the cumulative probability of TROVR by week 96. A composite TLOVR endpoint defined in the CDER of the FDA document Guidance for Industry - Antiretroviral Drugs Using Plasma HIV RNA Measurements - Clinical Consideration for Accelerated and Traditional Approval (Appendix B, pages 20) http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070968.pdf. If participants never achieved a confirmed HIV-1 RNA≤200 cp/mL (on two consecutive visits) prior to death, permanent discontinuation of randomized treatment, or time of last available HIV-1 RNA evaluation, TLOVR was equal to 0; otherwise, TLOVR was the earliest time of permanent discontinuation of randomized treatment prior to study close-out period, time to confirmed levels >200 cp/mL, or time to death. If TLOVR is immediately preceded by a single missing scheduled visit or multiple consecutive missing scheduled visits, TLOVR is replaced by the first such missing visit. | From study entry to week 96 | 
| Presence of Mutations Associated With NRTI Resistance | The number of participants with NRTI resistance determined by the Stanford resistance scoring algorithm (Version 6.3). All sequencing was performed regardless of status on randomized treatment at the time of virologic failure; no sequencing was performed on subjects not meeting virologic failure. | At the virologic failure at any time throughout the study (up to 213 weeks) | 
| Presence of Mutations Associated With ATV/RTV or DRV/RTV Resistance | The number of participants with ATV/RTV or DRV/RTV resistance determined by the Stanford resistance scoring algorithm (Version 6.3). All sequencing was performed regardless of status on randomized treatment at the time of virologic failure; no sequencing was performed on subjects not meeting virologic failure. | At the virologic failure at any time throughout the study (up to 213 weeks) | 
| Presence of Mutations Associated With INI Resistance | The number of participants with INI resistance determined by the Stanford resistance scoring algorithm (Version 6.3). All sequencing was performed regardless of status on randomized treatment at the time of virologic failure; no sequencing was performed on subjects not meeting virologic failure. | At the virologic failure at any time throughout the study (up to 213 weeks) | 
| CD4+ T-cell Count | The absolute levels of CD4+ T-cell counts (cells/mm3) | At Weeks 24, 48, 96, and 144 | 
| CD4+ T-cell Count Changes From Baseline | Change was calculated as the CD4+ T-cell count at week (24, 48, 96, and 144) minus the baseline CD4+ T-cell count | Study entry to weeks 24, 48, 96, and 144 | 
| Incidence of Death or AIDS Defining Events (CDC Category C) | The incidence of death or AIDS defining events (CDC category C) was estimated as number of incident events over total person years of follow-up. Multiple new events for a single subject were counted toward events totals in estimation of event incidence; generalized estimating equations were used to estimation of robust standard errors for the incidence. | Study entry to off-study at any time throughout the study (up to 213 weeks), participant follow-up time was variable | 
| Incidence of Targeted Serious Non-AIDS Defining Events (Renal Failure, Liver Disease, Serious Metabolic Disorder, and CVD) | The incidence of targeted serious non-AIDS defining events was estimated as number of incident events over total person years of follow-up. Multiple new events for a single subject were counted toward events totals in estimation of event incidence; generalized estimating equations were used to estimation of robust standard errors for the incidence. | Study entry to off-study at any time throughout the study (up to 213 weeks), participant follow-up time was variable | 
| Change in Fasting Total Cholesterol Level From Baseline | Only fasting results are included. Change was calculated as the fasting total cholesterol at week (48, 96, and 144) minus the baseline fasting total cholesterol. | Study entry to weeks 48, 96, and 144 | 
| Change in Fasting HDL Cholesterol Level From Baseline | Only fasting results are included. Change was calculated as the fasting HDL cholesterol at week (48, 96, and 144) minus the baseline fasting HDL cholesterol. | Study entry to weeks 48, 96, and 144 | 
| Change in Fasting Triglycerides Level From Baseline | Only fasting results are included. Change was calculated as the fasting triglycerides at week (48, 96, and 144) minus the baseline fasting triglycerides. | Study entry to weeks 48, 96, and 144 | 
| Change in Fasting Plasma Glucose Level From Baseline | Only fasting results are included. Change was calculated as the fasting plasma glucose at week (48, 96, and 144) minus the baseline fasting plasma glucose. | Study entry to weeks 48, 96, and 144 | 
| Change in Framingham 10-year Risk of MI or Coronary Death From Baseline | Only risk score estimated with fasting lipid results were included. Change was calculated as the Framingham 10-year risk of MI or coronary death at week (48, 96, and 144) minus the baseline Framingham 10-year risk of MI or coronary death. Framingham 10-year risk of MI or coronary death was calculated using Hear Coronary Heart Disease (10-year risk) found at https://www.framinghamheartstudy.org/risk-functions/coronary-heart-disease/hard-10-year-risk.php. Framingham 10-year risk of MI or coronary death was calculated according to age, laboratory values of total cholesterol and HDL cholesterol, smoking status, systolic blood pressure, and treatment for hypertension. The Framingham 10-year risk of MI or coronary death was calculated as: for males: <0 point (<1 percent risk) up to ≥17 points (≥30 percent risk); whereas for females: <9 points (<1 percent risk) up to ≥25 points (≥30 percent risk). Higher scores indicate high cardiovascular risk. | Study entry to weeks 48, 96, and 144 | 
| Change in Waist Circumference From Baseline | Change was calculated as the waist circumference (based on mid-waist circumference) at week (48, 96, and 144) minus the baseline waist circumference. | Study entry to weeks 48, 96, and 144 | 
| Change in Waist:Height Ratio From Baseline | Change was calculated as the waist:height ratio at week (48, 96, and 144) minus the baseline waist:height ratio. | Study entry to weeks 48, 96, and 144 | 
| Self-reported Adherence | Self-reported percentage of anti-HIV medications participant had taken during the last month at weeks 4, 24, 48, 96, and 144. | At Weeks 4, 24, 48, 96, and 144 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Treatment naive, Treatment inexperienced