Efavirenz or Atazanavir/Ritonavir Given With Emtricitabine/Tenofovir Disoproxil Fumarate or Abacavir/Lamivudine in HIV Infected Treatment-Naive Adults

Study Overview
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Brief Summary
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Currently, the preferred anti-HIV regimens used in the United States consist of two nucleoside reverse transcriptase inhibitors (NRTIs) and the nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (EFV). However, with new anti-HIV drugs being approved, alternative regimens need to be tested to determine if new drug combinations have increased effectiveness in treating HIV. The purpose of this study is to test the safety, tolerability, and effectiveness of four different regimens in HIV-infected adults who have never taken anti-HIV drugs.

Detailed Description
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Antiretroviral (ARV) treatment regimens consisting of EFV and two NRTIs are the most commonly prescribed regimens for the initial therapy of HIV-infected people in the United States. Such regimens are popular because the drugs are easy to administer, have overall excellent efficacy, and are well tolerated. However, because of concerns about long-term drug toxicity, the development of drug resistance, and potential complications in pregnant women, it is imperative that other drug combinations be investigated as possible alternative initial regimens. Drugs recently approved by the Food and Drug Administration (FDA) for HIV treatment include the protease inhibitor (PI) atazanavir (ATV) and the two NRTI coformulations emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) and abacavir/lamivudine (ABC/3TC). Data are limited on the efficacy of these new drugs when part of anti-HIV drug regimens. This study will evaluate and compare the safety, tolerability, and efficacy of four different treatment regimens in HIV-infected treatment-naive adults. The treatment portion of this study will last 96 weeks after the last participant is enrolled. Participants will be randomly assigned to one of four arms: Arm 1 participants will receive EFV, FTC/TDF, and placebo for ABC/3TC. Arm 2 participants will receive EFV, ABC/3TC, and placebo for FTC/TDF. Arm 3 participants will receive ritonavir (RTV)-boosted ATV, FTC/TDF, and placebo for ABC/3TC. Arm 4 participants will receive RTV-boosted ATV, ABC/3TC and placebo for FTC/TDF. NOTE: Lopinavir/ritonavir may be used in substitution of other drugs for certain participants. Study visits will occur at study entry; Weeks 1, 2, 4, 8, 16, and 24; and every 12 weeks thereafter. A physical exam, blood collection, and urine collection will occur at most visits. Two pharmacokinetic blood samples will be collected from participants between Weeks 4 and 24. Participants will undergo adherence training at study entry and will be asked to complete adherence questionnaires at selected study visits. Some participants will be asked to participate in ACTG A5224s, a metabolic substudy of ACTG A5202. The Data Safety Monitoring Board (DSMB) for A5202 met in January 2008 to review the study. After reviewing the study information, the DSMB noted that certain study regimens were significantly less effective than others. Specifically, ABC/3TC-containing regimens were not as effective in controlling the virus as TDF/FTC-containing regimens for participants entering the study with high viral loads. The DSMB also commented that participants assigned to ABC/3TC had a shorter time until they experienced side effects than participants assigned to TDF/FTC. The DSMB had no safety concerns for the other drug comparisons. Based on DSMB review, in Feb 2008 participants who started the study with high viral loads were told whether they were taking ABC/3TC or TDF/FTC and offered the option to continue or change their NRTI study drug component, after discussion with their doctor. For participants who started the study with lower screening viral loads, study treatment continued without change. For 74 participant the reason for first treatment modification was unblinded and switched as a consequence of the DSMB results (33 on EFV, ABC/3TC, and placebo FTC/TDF arm; 1 on RTV-boosted ATV, FTC/TDF, and placebo ABC/3TC arm; and 40 on RTV-boosted ATV, ABC/3TC, and placebo FTC/TDF arm).

Official Title
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A Phase IIIB, Randomized Trial of Open-Label Efavirenz or Atazanavir With Ritonavir in Combination With Double-Blind Comparison of Emtricitabine/Tenofovir or Abacavir/Lamivudine in Antiretroviral-Naive Subjects

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Abacavir/Lamivudine
* Drug: Atazanavir
* Drug: Efavirenz
* Drug: Emtricitabine/Tenofovir disoproxil fumarate
* Drug: Ritonavir
* Drug: Abacavir/Lamivudine placebo
* Drug: Emtricitabine/Tenofovir disoproxil fumarate placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-infected. A resistance assay must be obtained if the participant has evidence of recent infection. More information on this criterion can be found in the protocol. Antiretroviral naive, defined as 7 days or less of ARV treatment at any time prior to study entry. Participants who have received ARVs as part of postexposure prophylaxis or who have received an investigational drug that was not an NRTI, NNRTI, or PI are eligible for this study. HIV viral load greater than 1,000 copies/ml within 90 days prior to study entry Certain laboratory values obtained within 30 days prior to study entry. More information on this criterion can be found in the protocol Willing to use acceptable forms of contraception Parent or guardian able and willing to provide written informed consent, if applicable Hepatitis B surface antigen (HBsAg) negative at study entry Exclusion Criteria: Immunomodulators (e.g., interleukins, interferons, cyclosporine), HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 30 days prior to study entry. Individuals receiving either stable physiologic glucocorticoid doses, corticosteroids for acute therapy for pneumocystis pneumonia, or a short course (2 weeks or less) of pharmacologic glucocorticoid therapy will not be excluded. Known allergy/sensitivity to study drugs or their formulations Active alcohol or drug use that, in the opinion of the investigator, would interfere with adherence to study requirements Serious illness requiring systemic treatment or hospitalization. Patients who have completed therapy or are clinically stable on therapy for at least 7 days prior to study entry are not excluded. Known clinically relevant cardiac conduction system disease Requirement for any current medications that are prohibited with any study treatment. Evidence of any major drug resistance-associated mutation on any genotype or evidence of significant resistance on any phenotype performed at any time prior to study entry. Current imprisonment or involuntary incarceration for psychiatric or physical (e.g., infectious disease) illness Breastfeeding. Women who become pregnant during the study will be unblinded and required to permanently discontinue their study regimens.

Ages Eligible for Study
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Minimum Age: 16 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: EFV, FTC/TDF, and placebo ABC/3TC<br>Participants will receive EFV, FTC/TDF, and placebo for ABC/3TC for at least 96 weeks | Drug: Efavirenz<br>* 600 mg tablet taken orally daily<br>* Other names: EFV;Drug: Emtricitabine/Tenofovir disoproxil fumarate<br>* 200 mg emtricitabine/300 mg tenofovir disoproxil fumarate tablet taken orally daily<br>* Other names: FTC/TDF;Drug: Abacavir/Lamivudine placebo<br>* Placebo tablet taken orally daily<br>* Other names: ABC/3TC placebo;|
| Experimental: EFV, ABC/3TC and placebo FTC/TDF<br>Participants will receive EFV, ABC/3TC, and placebo for FTC/TDF for at least 96 weeks | Drug: Abacavir/Lamivudine<br>* 600 mg abacavir/300 mg lamivudine tablet taken orally daily<br>* Other names: ABC/3TC;Drug: Efavirenz<br>* 600 mg tablet taken orally daily<br>* Other names: EFV;Drug: Emtricitabine/Tenofovir disoproxil fumarate placebo<br>* Placebo tablet taken orally daily<br>* Other names: FTC/TDF placebo;|
| Experimental: RTV-boosted ATV, FTC/TDF, and placebo ABC/3TC<br>Participants will receive RTV-boosted ATV, FTC/TDF, and placebo for ABC/3TC for at least 96 weeks | Drug: Atazanavir<br>* 300 mg tablet taken orally daily<br>* Other names: ATV;Drug: Emtricitabine/Tenofovir disoproxil fumarate<br>* 200 mg emtricitabine/300 mg tenofovir disoproxil fumarate tablet taken orally daily<br>* Other names: FTC/TDF;Drug: Ritonavir<br>* 100 mg tablet taken orally daily<br>* Other names: RTV;Drug: Abacavir/Lamivudine placebo<br>* Placebo tablet taken orally daily<br>* Other names: ABC/3TC placebo;|
| Experimental: RTV-boosted ATV, ABC/3TC, and placebo FTC/TDF<br>Participants will receive RTV-boosted ATV, ABC/3TC, and placebo for FTC/TDF for at least 96 weeks | Drug: Abacavir/Lamivudine<br>* 600 mg abacavir/300 mg lamivudine tablet taken orally daily<br>* Other names: ABC/3TC;Drug: Atazanavir<br>* 300 mg tablet taken orally daily<br>* Other names: ATV;Drug: Ritonavir<br>* 100 mg tablet taken orally daily<br>* Other names: RTV;Drug: Emtricitabine/Tenofovir disoproxil fumarate placebo<br>* Placebo tablet taken orally daily<br>* Other names: FTC/TDF placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time From Randomization to Virologic Failure | Blood samples for determining virologic failure were obtained at visit weeks 16 and 24 , and every 12 weeks thereafter. Virologic failure was defined as a confirmed plasma HIV-1 RNA level >= 1000 copies/mL at or after 16 weeks after randomization and before 24 weeks, or >=200 copies/mL at or after 24 weeks. The 5th percentile for time to virologic failure is the time (in weeks) at which 5% of the participants have experienced virologic failure. | Follow-up time was variable,median follow-up was 138 weeks; see 'Amount of study follow-up' outcome for details | 
| Time From Treatment Dispensation to a Grade 3/4 Safety Event | Grade 3/4 safety event is defined as a grade 3 or 4 sign, symptom, or laboratory abnormality that is at least one grade higher than at baseline, total bilirubin and creatine kinase (CPK) were excluded. Grading used the Division of AIDS (DAIDS) 2004 Severity of Adverse Events Tables. | All follow-up while on initially assigned regimen; the median (25th, 75th percentile) follow-up while on initial regimen was 120 (54, 156) weeks and the range was 0 to 205 weeks. | 
| Time From Treatment Dispensation to Treatment Modification | Treatment modification is defined as the 1st modification of the regimen, including a permanent discontinuation, switch, or substitution. | Follow-up time was variable,median follow-up was 138 weeks; see 'Amount of study follow-up' outcome for details | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time From Treatment Dispensation to Regimen Failure (First Occurrence of Virologic Failure or Treatment Modification) | Blood samples for determining virologic failure were obtained at 16 and 24 weeks, and every 12 weeks thereafter. Virologic failure was defined as a confirmed plasma HIV-1 RNA level >= 1000 copies/mL at or after 16 weeks and before 24 weeks or >=200 copies/mL at or after 24 weeks. Treatment modification was defined as the 1st modification of the regimen, including a permanent discontinuation, switch, or substitution. | Follow-up time was variable,median follow-up was 138 weeks; see 'Amount of study follow-up' outcome for details | 
| The Number of Participants With HIV-1 RNA Levels Less Than 50 Copies/mL |  | At Weeks 48 and 96 | 
| Number of Participants With HIV-1 RNA Levels Less Than 200 Copies/mL |  | At Weeks 48 and 96 | 
| Change in CD4 Count (Cells/mm3) From Baseline | Change was calculated as the CD4 count at Week 48 (or at Week 96) minus the baseline CD4 count (mean of pre-entry and entry values). | At Weeks 48 and 96 | 
| Number of Participants With Virologic Failure and Emergence of Major Resistance | Emergence of resistant virus was assessed by genotypic testing performed at Stanford University for all participants who met criteria for virologic failure and retrospectively on baseline samples from these participants. Major mutations were defined by International AIDS Society-United States of America (2008), as well as T69D, L74I, G190C/E/Q/T/V for reverse transcriptase and L24I, F53L, I54V/A/T/S, G73C/S/T/A, N88D for protease. | Follow-up time was variable,median follow-up was 138 weeks; see 'Amount of study follow-up' outcome for details | 
| Number of Participants Experiencing Certain Targeted Clinical Events, Including Death, AIDS-defining Illness, and HIV-1 Related Events. | AIDS-defining illnesses were defined per CDC category C definition. HIV-1 related events were defined per CDC category B definition. Events underwent study chair review for classification. See link below for more details. http://www.cdc.gov/mmwr/preview/mmwrhtml/00018871.htm | Follow-up time was variable, median follow-up was 138 weeks; see 'Amount of study follow-up' outcome for details | 
| Change in Fasting Total Cholesterol Level From Baseline | Only fasting results are included. The protocol did not require that samples be collected fasting. | At Weeks 48 and 96 | 
| Change in Fasting High-density Lipoprotein (HDL) Cholesterol Level From Baseline | Only fasting results are included. The protocol did not require that samples be collected fasting. | At Weeks 48 and 96 | 
| Change in Fasting Non-high Density Lipoprotein (Non-HDL) Cholesterol Level From Baseline | Only fasting results are included. The protocol did not require that samples be collected fasting. | At Weeks 48 and 96 | 
| Change in Fasting Triglyceride Level From Baseline | Only fasting results are included. The protocol did not require that samples be collected fasting. | At Weeks 48 and 96 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Treatment Naive