When to Start Anti-HIV Drugs in Children Infected With HIV (The PREDICT Study)

Study Overview
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Brief Summary
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The purpose of this study is to determine when HIV infected children should begin taking anti-HIV medications in order to improve both patient quality of life and survival.

Detailed Description
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The use of highly active antiretroviral therapy (HAART) has resulted in a significant reduction in AIDS-related deaths and complications among adults and adolescents. However, the medical management of HIV infected children remains challenging. Access to HIV treatment is limited and early treatment initiation can cause serious complications. Since there is currently no cure for HIV, a balance between treating the disease and maintaining quality of life must be weighed carefully. An evaluation to determine the appropriate time to initiate HAART is necessary to improve both quality of life and survival for HIV infected children. This study will last 144 weeks. All participants will have a CD4 percentage (CD4%) between 15% and 24% and will be randomly assigned to either receive immediate or delayed HAART. The HAART regimen will consist of two nucleoside reverse transcriptase inhibitors, zidovudine and lamivudine. In addition, participants will also receive either one non-nucleoside reverse transcriptase inhibitor, nevirapine or efavirenz, or one protease inhibitor, ritonavir-boosted lopinavir or nelfinavir. Abacavir will replace zidovudine or lamivudine if participants experience toxicity to the regimen. Participants in the immediate treatment arm will receive HAART on Day 1 of the study regardless of their CD4%. Participants in the delayed treatment arm will receive HAART if their CD4% falls below 15 or if they develop a CDC Category C illness. Study visits will occur every 4 weeks for the first 12 weeks and then every 12 weeks until the end of the study. Blood collection, physical exams, and medical and medication history reviews will occur at all visits. Adherence, quality of life, and lipodystrophy assessments will occur every 12 weeks for participants on HAART. Participants will be encouraged to enroll in a related substudy to examine the neurodevelopment of HIV infected children.

Official Title
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An Open Label, Randomized Study to Compare Antiretroviral Therapy (ART) Initiation When CD4 is Between 15% to 24% to ART Initiation When CD4 Falls Below 15% in Children With HIV Infection and Moderate Immune Suppression

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Abacavir
* Drug: Efavirenz
* Drug: Lamivudine
* Drug: Lopinavir/Ritonavir
* Drug: Nelfinavir
* Drug: Nevirapine
* Drug: Zidovudine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infected Antiretroviral naive, defined as never receiving anti-HIV medications, receiving them for less than 7 days, or only receiving them to prevent mother-to-child transmission (MTCT) CD4% between 15 and 24 within 30 days prior to study entry CDC pediatric clinical classification A or B Parent or guardian willing to provide informed consent and willing to follow all study procedures and requirements Exclusion Criteria: Use of systemic chemotherapy, immunomodulators, HIV vaccines, immune globulin, interleukins, or interferons within 30 days prior to study entry Active AIDS-defining illnesses (CDC Category C) within 30 days prior to study entry Certain abnormal laboratory values Known kidney disease Known allergy or sensitivity to study drugs Require certain medications Pregnancy

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 12 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 |
| --- | --- |
| Active Comparator: 1<br>Immediate treatment; individuals receive HAART on Day 1 of the study | Drug: Abacavir<br>* 8 mg/kg (up to 300 mg/dose) take orally twice daily<br>Drug: Efavirenz<br>* 200 to 600 mg taken orally once daily<br>Drug: Lamivudine<br>* 4 mg/kg (up to 150 mg/dose) taken orally twice daily<br>Drug: Lopinavir/Ritonavir<br>* 230 mg/57.5 mg/m^2 body surface area taken orally twice daily with food<br>Drug: Nelfinavir<br>* 45-55 mg/kg taken orally twice daily with food<br>Drug: Nevirapine<br>* 120 mg/m^2 once daily for first 14 days, tehn 200 mg/m^2 (up to 400 mg/day) twice daily<br>Drug: Zidovudine<br>* 180-240 mg/m^2 every 12 hours (up to 300 mg/dose)<br>|
| Active Comparator: 2<br>Delayed treatment; individuals receive HAART if their CD4 percentage falls below 15 percentage OR if they develop a CDC category C illness | Drug: Abacavir<br>* 8 mg/kg (up to 300 mg/dose) take orally twice daily<br>Drug: Efavirenz<br>* 200 to 600 mg taken orally once daily<br>Drug: Lamivudine<br>* 4 mg/kg (up to 150 mg/dose) taken orally twice daily<br>Drug: Lopinavir/Ritonavir<br>* 230 mg/57.5 mg/m^2 body surface area taken orally twice daily with food<br>Drug: Nelfinavir<br>* 45-55 mg/kg taken orally twice daily with food<br>Drug: Nevirapine<br>* 120 mg/m^2 once daily for first 14 days, tehn 200 mg/m^2 (up to 400 mg/day) twice daily<br>Drug: Zidovudine<br>* 180-240 mg/m^2 every 12 hours (up to 300 mg/dose)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AIDS-free survival |  | Week 144 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Direct and indirect cost of treatment per patient |  | Week 144 | 
| Number and duration of hospitalizations |  | throughout study | 
| Time to and number of Grades 3 or 4 HAART-related toxicity and intolerance |  | throughout study | 
| Number of HAART regimen changes |  | throughout study | 
| Number of Grades 1 or 2 infectious episodes |  | throughout study | 
| Number of courses of antibiotics used |  | throughout study | 
| Number of HIV-related clinical events |  | throughout study | 
| Virologic failure, defined as HIV viral load of 1000 copies/ml |  | Week 24 after HAART initiation | 
| Presence of a resistance mutation in participants with virologic failure |  | throughout study | 
| Change of growth in Z scores |  | study entry to Week 144 | 
| Change in CD4% and time-weighted average change |  | study entry and Week 144 | 
| CD4 less than 10% |  | Week 144 | 
| Average scores of the child's quality of life over time |  | Week 144 | 
| Percentage adherence to HAART over time by pill count/weighing liquid medication bottles, self report, and questionnaire |  | throughout study | 
| Presence of iron deficiency anemia |  | study entry and Weeks 24, 48, 72, 96, 120, and 144 | 
| HIV viral sequence |  | study entry and treatment failure | 
| HIV viral replication capacity |  | throughout study | 
| Cytotoxic T-cell (CTL) response |  | throughout study | 
| Percentage of different T-cell subsets |  | study entry and Weeks 48, 96, and 144 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Infant, Treatment Naive, Treatment Initiation, Preschool Child, Child, Zidovudine, AZT, Retrovir, 3TC, Lamivudine, Epivir, Nevirapine, NVP, Viramune, Efavirenz, EFV, Sustiva, Lopinavir/Ritonavir, LPV/r, Kaletra, Nelfinavir, NFV, Viracept, ABC, Abacavir, Ziagen