Atazanavir/Ritonavir, Once Daily + Raltegravir, Twice Daily, Switch Study in HIV-1-Infected Patients

Study Overview
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Brief Summary
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The purpose of this study is to determine whether HIV-1-infected patients, who are virologically suppressed on a regimen of 2 nucleoside reverse transcriptase inhibitors plus any third agent but are experiencing safety and/or tolerability issues, will maintain virologic suppression after switching to a regimen of heat-stable ritonavir boosted atazanavir, 300/100 mg, once daily plus raltegravir, 400 mg, twice daily.

Detailed Description
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Allocation: Randomized nonstratified Intervention model: Parallel versus comparator

Official Title
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An Open-Label, Randomized Study Evaluating a Switch From a Regimen of Two Nucleoside Reverse Transcriptase Inhibitors Regimen Plus Any Third Agent to Either a Regimen of Atazanavir/Ritonavir Once Daily and Raltegravir Twice Daily or to a Regimen of Atazanavir/Ritonavir Once Daily and Tenofovir/Emtricitabine Once Daily in Virologically Suppressed HIV-1 Infected Subjects With Safety and/or Tolerability Issues on Their Present Treatment Regimen.

Conditions
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HIV, Combination Therapy

Intervention / Treatment
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* Drug: Atazanavir
* Drug: Ritonavir (heat-stable)
* Drug: Raltegravir
* Drug: Tenofovir/Emtricitabine


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria Current treatment regimen of 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus any third agent for at least 3 months immediately prior to screening Virologic suppression (HIV-1 RNA <50 c/mL) for at least 3 months immediately prior to screening Virologic suppression (HIV-1 RNA <40 c/mL) using the Abbott m2000rt® polymerase chain reaction assay during screening period Treatment-related safety and/or tolerability issues to a regimen consisting of 2 NRTIs plus any third agent Key Exclusion Criteria History of switch in highly active antiretroviral therapy due to virologic failure History of genotypic resistance to any component of the study regimen (atazanavir, raltegravir, tenofovir/emtricitabine) History of exposure to atazanavir/ritonavir or raltegravir prior to entering the study Experiencing safety and/or tolerability issues to tenofovir/emtricitabine or raltegravir Switch of any component of HIV antiretroviral medication regimen in the last 3 months immediately prior to or during the screening period

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: Atazanavir/Ritonavir + Raltegravir<br>Atazanavir + Ritonavir (heat-stable) + Raltegravir | Drug: Atazanavir<br>* Capsules, Oral, 300mg, Once daily, 48 weeks<br>* Other names: Reyataz;Drug: Ritonavir (heat-stable)<br>* Tablets, Oral, 100 mg, Once daily, 48 weeks<br>* Other names: Norvir;Drug: Raltegravir<br>* Tablets, Oral, 400 mg, Twice daily, 48 weeks<br>* Other names: Isentress;|
| Other: Atazanavir/Ritonavir + Tenofovir/Emtricitabine<br>Reference Atazanavir + Ritonavir (heat-stable) + Tenofovir/Emtricitabine | Drug: Atazanavir<br>* Capsules, Oral, 300mg, Once daily, 48 weeks<br>* Other names: Reyataz;Drug: Ritonavir (heat-stable)<br>* Tablets, Oral, 100 mg, Once daily, 48 weeks<br>* Other names: Norvir;Drug: Tenofovir/Emtricitabine<br>* Tablets, Oral, 300/200 mg, Once daily, 48 weeks<br>* Other names: Truvada;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With HIV-1 RNA Level <40 c/mL at Week 24 | HIV-1 RNA level was measured with the Abbott m2000rt® polymerase chain reaction assay. Response rates were assessed using an intent-to-treat algorithm, with numerator representing patients meeting the response criteria, and denominator representing all randomized patients. Randomized patients not meeting the criteria for treatment failure (eg, discontinuation of study therapy or virologic rebound at or before Week 24) were considered responders. Virologic rebound was defined as 2 consecutive on-treatment HIV-1 RNA levels ≥40 c/mL or the last on-treatment HIV-1 RNA level ≥40 c/mL followed by discontinuation. Patients who experienced treatment failure or had missing Week 24 HIV-1 RNA levels were considered failures. RNA=ribonucleic acid; HIV=human immunodeficiency virus. | From Day 1 to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With HIV-1 RNA Level <40 c/mL at Week 48 | Percentages of patients with HIV-1 RNA levels <40 c/mL were summarized at each scheduled visit. Longitudinal plots were created to display proportion versus visit week through Weeks 24 and 48 with error bars representing 95% confidence intervals. | From Day 1 to Week 48 | 
| Number of Participants With Virologic Rebound at Weeks 24 and 48 | Viral genotypic and phenotypic resistance profiles were assessed for virologic rebound (HIV-1 RNA level ≥40 c/mL). Only patients with HIV-1 RNA levels ≥500 c/mL met the criteria for resistance testing. Genotypic substitutions at baseline were summarized for virologic rebound. The genotypic resistance profile presented patients with genotypable isolates, those with protease inhibitor substitutions from genotypable isolates, those with integrase substitutions from genotypable isolates, and those with selected reverse transcriptase substitutions from genotypable isolates using the most current version of the International AIDS Society-USA list and Stanford HIV Drug Resistance Database. Newly emergent genotypic substitutions were summarized analogously for virologic rebound without baseline phenotypic resistance to atazanavir, ritonavir, or raltegravir, using all on-treatment isolates. | Day 1 to Weeks 28 and 48 | 
| Number of Participants With Genotypable/Phenotypable Isolates, Emergent Genotypic Substitutions in Patients With Genotypable Isolates, and Phenotypic Resistance in Patients With Phenotypable Isolates at Week 24 | Viral genotypic and phenotypic resistance profiles were assessed for virologic rebound (HIV-1 RNA level ≥40 c/mL). Only patients with HIV-1 RNA levels ≥500 c/mL met the criteria for resistance testing. Genotypic substitutions at baseline were summarized for virologic rebound. The genotypic resistance profile presented patients with genotypable isolates, those with protease inhibitor substitutions from genotypable isolates, those with integrase substitutions from genotypable isolates, and those with selected reverse transcriptase substitutions from genotypable isolates using the most current version of the International AIDS Society-USA list and Stanford HIV Drug Resistance Database. Newly emergent genotypic substitutions were summarized analogously for virologic rebound without baseline phenotypic resistance to atazanavir, ritonavir, or raltegravir, using all on-treatment isolates. pts=patients | Day 1 to Week 24 | 
| Number of Participants With Genotypable/Phenotypable Isolates, Emergent Genotypic Substitutions in Patients With Genotypable Isolates, and Phenotypic Resistance in Patients With Phenotypable Isolates at Week 48 | Viral genotypic and phenotypic resistance profiles were assessed for virologic rebound (HIV-1 RNA level ≥40 c/mL). Only patients with HIV-1 RNA levels ≥500 c/mL met the criteria for resistance testing. Genotypic substitutions at baseline were summarized for virologic rebound. The genotypic resistance profile presented patients with genotypable isolates, those with protease inhibitor substitutions from genotypable isolates, those with integrase substitutions from genotypable isolates, and those with selected reverse transcriptase substitutions from genotypable isolates using the most current version of the International AIDS Society-USA list and Stanford HIV Drug Resistance Database. Newly emergent genotypic substitutions were summarized analogously for virologic rebound without baseline phenotypic resistance to atazanavir, ritonavir, or raltegravir, using all on-treatment isolates. pts=patients | Day 1 to Week 48 | 
| Number of Patients With Death as Outcome, Serious Adverse Events (SAEs), Treatment-related SAEs, Treatment-emergent Adverse Events (AEs) Leading to Discontinuation, and Treatment-emergent AEs | AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Related=having certain, probable, possible, or unknown relationship to study drug. | Day 1 to Week 48 | 
| Mean Changes in Fasting Lipid Levels From Baseline to Week 48 | LD=low-density lipoprotein; HDL=high-density lipoprotein. | From Baseline to Week 48 |