Prospective Evaluation of Anti-retroviral Combinations for Treatment Naive, HIV Infected Persons in Resource-limited Settings

Study Overview
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Brief Summary
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This study compared 3 different three-drug combinations in HIV infected individuals starting their first HIV treatment regimens. Participants were recruited from resource-limited areas in Africa, Asia, South America, Haiti, and also from the United States. The study hypothesis was each of the once daily combinations (PI based, or NNRTI based) would not have inferior efficacy compared to the twice daily NNRTI based combination.

Detailed Description
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In developed countries, standard effective antiretroviral (ARV) therapy for treatment-naive HIV infected people includes three-drug combinations of two nucleoside reverse transcriptase inhibitors (NRTIs) with either a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). However, direct comparisons of ARV efficacy in persons that more closely reflect the worldwide demographics of HIV-1 infection are needed.> > Trial participants were recruited in Africa (Malawi, South Africa, Zimbabwe), Asia (India, Thailand), South America (Brazil, Peru), Haiti, and the United States.> > All participants were randomly assigned to one of three arms, and random allocation was stratified by 2 factors: country, and screening plasma HIV-1 RNA level (< 100,000 copies/mL versus >= 100,000 copies/mL). Participants assigned to the ZDV/3TC+EFV arm received lamivudine/zidovudine twice daily and efavirenz once daily. Participants assigned to the ddI+FTC+ATV arm received emtricitabine, atazanavir, and enteric-coated didanosine once daily. Participants assigned to the TDF/FTC+EFV arm received emtricitabine, tenofovir disoproxil fumarate, and efavirenz once daily. > > > Physical exam and blood collection occurred at entry and at most study visits. Participants experiencing virologic failure were offered a switch to another regimen. > > On May 23, 2008, the ddI+FTC+ATV was closed following a planned interim review by the study's independent Data and Safety Monitoring Board (DSMB). The DSMB recommendation was based upon compelling evidence that this arm had significantly more virologic failure (and therefore was inferior when) compared to the ZDV/3TC+EFV arm . Participants still receiving ddI+FTC+ATV were offered alternative medications, and all participants continued to be followed. > > On November 3, 2009, the DSMB recommended that the study close to all follow-up on May 31, 2010, before the designed termination (based on 30% of participants meeting the primary outcome) was met. The board observed that the recent accumulation of primary efficacy events (i.e. regimen failures) was very slow. Therefore, if the study were to continue another 1-2 years, the precision gained for treatment comparisons would likely be small.

Official Title
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Randomized, Open-Label Evaluation of Efficacy of Once-Daily Protease Inhibitor and Once-Daily Non-Nucleoside Reverse Transcriptase Inhibitor-Containing Therapy Combinations for Initial Treatment of HIV-1 Infected Persons From Resource-Limited Settings (PEARLS) Trial

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Atazanavir
* Drug: Didanosine (enteric-coated)
* Drug: Efavirenz
* Drug: Emtricitabine
* Drug: Emtricitabine/Tenofovir disoproxil fumarate
* Drug: Lamivudine/Zidovudine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria :> HIV-1 infected> CD4 count fewer than 300 cells/mm3 > Viral load test result> Absolute Neutrophil Count at least 750mm3 > Hemoglobin at least 7.5 g/dL> Platelet count at least 50,000/mm3> Calculated creatinine clearance at least 60 mL/min> A , A, and alkaline phosphatase <= 5 times upper limit of normal> total bilirubin <= 2.5 times upper limit of normal> Karnofsky performance score of 70 or higher> Plans to stay in the area for the duration of the study> Agrees to use acceptable forms of contraception for the duration of the study> Exclusion Criteria:> More than 7 days exposure to ARVs (except for single-dose NVP or ZDV for any period for the purpose of pMTCT)> Acute therapy for serious medical illnesses within 14 days prior to study entry> Certain abnormal laboratory values> Radiation therapy or chemotherapy within 45 days prior to study entry. > Any immunomodulator, HIV vaccine, or other investigational therapy within 30 days prior to study entry. > Current alcohol or drug abuse that, in the opinion of the site investigator, would interfere with study participation> Inflamed pancreas within 3 years prior to study entry> Allergy/sensitivity to any of the study drugs or their formulations> Heart rate less than 40 beats/min> History of untreated, active second- or third-degree heart block> Currently detained in jail or for treatment of a psychiatric or physical illness> Vomiting or inability to swallow medications> Pregnancy>

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: ZDV/3TC+EFV<br>ZDV/3TC+EFV participants will receive lamivudine/zidovudine and efavirenz | Drug: Efavirenz<br>* 600 mg taken orally daily<br>* Other names: EFV;Drug: Lamivudine/Zidovudine<br>* 150 mg/300 mg taken orally twice daily<br>* Other names: 3TC/ZDV;|
| Experimental: ddI+FTC+ATV<br>ddI+FTC+ATV participants will receive emtricitabine, atazanavir, and enteric-coated didanosine | Drug: Atazanavir<br>* 400 mg taken orally daily<br>* Other names: ATV;Drug: Didanosine (enteric-coated)<br>* 400 mg taken orally daily<br>* Other names: ddI;Drug: Emtricitabine<br>* 200 mg taken orally daily<br>* Other names: FTC;|
| Experimental: TDF/FTC+EFV<br>TDF/FTC+EFV participants will receive emtricitabine/tenofovir disoproxil fumarate and efavirenz | Drug: Efavirenz<br>* 600 mg taken orally daily<br>* Other names: EFV;Drug: Emtricitabine/Tenofovir disoproxil fumarate<br>* 200 mg/300 mg taken orally once daily<br>* Other names: FTC/TDF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Treatment Failure (PI Comparison) | Time from randomization to the earliest of: scheduled week of first plasma sample meeting virologic failure (two consecutive plasma HIV-1 RNA values 1,000 copies/mL or higher, regardless of whether ARV medications being taken at the time); scheduled week of first AIDS defining diagnosis (WHO Stage 4 (2005), plus microsporidiosis, cyclospora gastroenteritis and Chaga's disease), not attributed to Immune Reconstitution Inflammatory Syndrome (reviewed by chairs); date of death (due to any cause). Plasma drawn every 8 weeks (except confirmation samples could be drawn earlier). | Virologic failure starting 14 weeks following randomization; disease progression starting 12 weeks following randomization; and death occurring at any time following randomization. Follow-up until ddI+FTC+ATV arm closed (May 22, 2008). | 
| Time to Treatment Failure (NRTI Comparison) | Time from randomization to the earliest of: scheduled week of first plasma sample meeting virologic failure (two consecutive plasma HIV-1 RNA values 1,000 copies/mL or higher, regardless of whether ARV medications being taken at the time); scheduled week of first AIDS defining diagnosis (WHO Stage 4 (2005) plus microsporidiosis, cyclospora gastroenteritis and Chaga's disease), not attributed to Immune Reconstitution Inflammatory Syndrome (reviewed by chairs); date of death (due to any cause). Plasma drawn every 8 weeks (except confirmation samples could be drawn earlier). | Virologic failure starting 14 weeks following randomization; disease progression starting 12 weeks following randomization; and death occurring at any time following randomization. Follow-up through study closure (May 31, 2010). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Discontinuation of Initial Antiretroviral (ARV) Therapy (PI Comparison) | Time is measured from date of treatment initiation to earliest of the following: date of last participant contact (premature discontinuation of study follow-up); date all ARV medications were held (if all medications held for at least 8 weeks, for any reason); date that any ARV medication was changed (excluding the following single ARV substitutions: stavudine or tenofovir for zidovudine, nevirapine for efavirenz, or didanosine for tenofovir). | Throughout follow-up until ddI+FTC+ATV arm closed (May 22,2008) | 
| Time to Immunologic Failure (PI Comparison) | Time from randomization to the first scheduled study visit (week 48 or later) with a CD4+ cell count fewer than 100 cells/mm3. | At or after Week 48 (including only follow-up until ddI+FTV+ATV arm closed - May 22,2008) | 
| Change in CD4 Count From Screening to Weeks 24, 48, 96 (PI Comparison) | Available pre-randomization CD4 cell counts were limited to the single CD4 cell count used for study eligibility (and therefore must have been fewer than 300 cells/mm3). | weeks 24, 48 and 96 (including follow-up until ddI+FTC+ARV arm closed - May 22, 2008) | 
| Time to First Dose Modification or Grade 3 or 4 Adverse Event (PI Comparison) | Time from treatment dispensation to the first occurring of the following: week of first ARV medication change; week of first grade 3 or higher sign/symptom or laboratory abnormality (total bilirubin was excluded) that was at least one grade higher than baseline. Grading used the Division of AIDS (DAIDS) 2004 Severity of Adverse Events Tables. | Throughout study follow-up until ddI+FTC+ATV arm closed (May 22, 2008) | 
| Plasma HIV-1 Viral Load Fewer Than 400 Copies/ml (PI Comparison) | Number of participants with plasma HIV-1 Viral load fewer than 400 copies/mL at study visit weeks 24 and 48. Closest observed result between 20 and up to 28 weeks (for week 24), and between 44 and up to 52 (for week 48) used if multiple results available. Missing values excluded, and both study treatment status and history ignored. | At Weeks 24 and 48 (including only follow-up until ddI+FTC+ARV arm closed - May 22, 2008) | 
| Time to Loss of Virologic Response by Week 48 (Defined by FDA TLOVR Algorithm - Excluding Study Allowed ARV Substitutions)(PI Comparison) | Time from randomization to any of the following events occurring prior to week 48: discontinued ARV regimen (see time to discontinuation of initial ARV therapy above); discontinued study follow-up or died; absence of virologic suppression defined as 2 consecutive plasma HIV-1 RNA values < 400 copies/mL; two consecutive plasma HIV-1 RNA values > 400 copies/mL following virologic suppression. | Week 48 (using follow-up only until closing of ddI+FTV+ATV arm on May 22,2008) | 
| Time to Loss of Virologic Response at Week 48 (Defined by FDA TLOVR Algorithm - Including All ARV Substitutions)(PI Comparison) | Time from randomization to any of the following events occurring prior to week 48: changed any ARV medication (including permanent discontinuation of all medications); discontinued study follow-up or died; absence of virologic suppression defined as 2 consecutive plasma HIV-1 RNA values < 400 copies/mL; two consecutive plasma HIV-1 RNA values > 400 copies/mL following virologic suppression. | Week 48 (using follow-up only until closing of ddI+FTV+ATV arm on May 22,2008) | 
| Time to Discontinuation of Initial Antiretroviral (ARV) Therapy (NRTI Comparison) | Time is measured from date of treatment initiation to earliest of the following: date of last participant contact (premature discontinuation of study follow-up); date all ARV medications were held (if all medications held for at least 8 weeks, for any reason); date that any ARV medication was changed (excluding the following single ARV substitutions: stavudine or tenofovir for zidovudine, nevirapine for efavirenz, or didanosine for tenofovir). | Throughout follow-up until study closed (May 31,2010) | 
| Time to Immunologic Failure (NRTI Comparison) | Time from randomization to the first scheduled study visit (week 48 or later) with a CD4+ cell count fewer than 100 cells/mm3. | At or after Week 48 (including all follow-up through study closure - May 31,2010) | 
| Change in CD4 Count From Screening to Weeks 24, 48, 96 (NRTI Comparison) | Available pre-randomization CD4 cell counts were limited to the single CD4 cell count used for study eligibility (and therefore must have been fewer than 300 cells/mm3). | weeks 24, 48 and 96 (including all follow-up through to study closure on May 31, 2010) | 
| Plasma HIV-1 Viral Load Fewer Than 400 Copies/ml (NRTI Comparison) | Number of participants with plasma HIV-1 Viral load fewer than 400 copies/mL at study visit weeks 24 and 48. Closest observed result between 20 and up to 28 weeks (for week 24), and between 44 and up to 52 (for week 48) used if multiple results available. Missing values excluded, and both study treatment status and history ignored. | At Weeks 24 and 48 (including follow-up through to study closure on May 31, 2010) | 
| Time to Loss of Virologic Response at Week 48 (Defined by FDA TLOVR Algorithm - Excluding Study Allowed ARV Substitutions)(NRTI Comparison) | Time from randomization to any of the following events occurring prior to week 48: discontinued ARV regimen (see time to discontinuation of initial ARV therapy above); discontinued study follow-up or died; absence of virologic suppression defined as 2 consecutive plasma HIV-1 RNA values < 400 copies/mL; two consecutive plasma HIV-1 RNA values > 400 copies/mL following virologic suppression. | Week 48 (using follow-up through study closure on May 31,2010) | 
| Time to Loss of Virologic Response at Week 96 (Defined by FDA TLOVR Algorithm - Excluding Study Allowed ARV Substitutions)(NRTI Comparison) | Time from randomization to any of the following events occurring prior to week 96: discontinued ARV regimen (see time to discontinuation of initial ARV therapy above); discontinued study follow-up or died; absence of virologic suppression defined as 2 consecutive plasma HIV-1 RNA values < 400 copies/mL; two consecutive plasma HIV-1 RNA values > 400 copies/mL following virologic suppression. | Week 96 (using follow-up through to study closure on May 31,2010) | 
| Time to Loss of Virologic Response at Week 48 (Defined by FDA TLOVR Algorithm - Including All ARV Substitutions)(NRTI Comparison) | Time from randomization to any of the following events occurring prior to week 48: changed any ARV medication (including permanent discontinuation of all medications); discontinued study follow-up or died; absence of virologic suppression defined as 2 consecutive plasma HIV-1 RNA values < 400 copies/mL; two consecutive plasma HIV-1 RNA values > 400 copies/mL following virologic suppression. | Week 48 using follow-up through study closure on May 31,2010 | 
| Time to Loss of Virologic Response at Week 96 (Defined by FDA TLOVR Algorithm - Including All ARV Substitutions)(NRTI Comparison) | Time to any of the following events occurring prior to week 96: changed any ARV medication (including permanent discontinuation of all medications); discontinued study follow-up or died; absence of virologic suppression defined as 2 consecutive plasma HIV-1 RNA values < 400 copies/mL; two consecutive plasma HIV-1 RNA values > 400 copies/mL following virologic suppression. | Week 96 using follow-up through study closure on May 31,2010 | 
| Time to First Dose Modification or Grade 3 or 4 Adverse Event (NRTI Comparison) | Time from treatment dispensation to the first occurring of the following: week of first ARV medication change; week of first grade 3 or higher sign/symptom or laboratory abnormality (total bilirubin was excluded) that was at least one grade higher than baseline. Grading used the Division of AIDS (DAIDS) 2004 Severity of Adverse Events Tables. | Throughout study follow-up until study closure (May 31, 2010) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Treatment Naive, Adherence, Drug Resistance, Treatment Failure