Pediatric Urgent Start of Highly Active Antiretroviral Treatment (HAART)

Study Overview
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Brief Summary
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Design: Randomized clinical trial involving hospitalized HIV-1 infected children. Children will be randomized to randomized to urgent (<48 hours) versus early antiretroviral therapy (7-14 days). This trial will be unblinded. Population: Hospitalized HIV-1 infected children who are antiretroviral therapy (ART) naïve ≤ 12 years of age. Sample size: 360 children will be randomized (180 per arm). Treatment: All infants will be treated with ART according to World Health Organization (WHO) and Kenyan national guidelines. Study duration: Enrollment into the study will occur over the course of 36-48 months and each infant will be routinely followed for a maximum of 6 months. Study site: Kenyan hospitals. Primary hypothesis: HIV-1 infected children hospitalized with severe co-infection either may be unsalvageable due to too far advanced immunosuppression/co-infection or may benefit from urgent ART. Secondary hypotheses: Urgent ART during an acute infection could potentially result in increased risk of immune reconstitution inflammatory syndrome (IRIS) or drug toxicities/interactions. Specific aims: To compare the 6 month all-cause mortality rate, incidence of immune reconstitution inflammatory syndrome (IRIS), and incidence of drug toxicity in HIV-1 infected children (≤ 12 years old) presenting to hospital with a serious infection randomized to urgent (<48 hours) versus early ART (7-14 days). To determine co-factors for mortality, IRIS, and drug toxicity. Potential cofactors will include: baseline weight-for-age, height-for-age, weight-for-height (Z-scores), CD4, HIV-1 RNA, type of co-infection, age, rate of viral load and CD4 change following ART, immune activation markers, pathogen and HIV-1 specific immune responses. Secondary aim: To determine etiologies of IRIS and to compare immune reconstitution to HIV, TB, EBV and CMV following ART overall and in each trial arm.

Detailed Description
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Children will be followed and compared for 6-month mortality.

Official Title
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Urgent Versus Post-Stabilization ART in HIV-1 Infected Children With Severe Co-Infections

Conditions
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Human Immunodeficiency Virus, Immune Reconstitution Inflammatory Syndrome

Intervention / Treatment
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* Other: Urgent ART
* Other: Early ART


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged ≤ 12 years old (reported) HIV-1 positive (for example, two rapid HIV-1 antibody tests for children >18 months and not breastfeeding, or one HIV-1 DNA/RNA test for children ≤18 months or who are breastfeeding) Not currently receiving antiretroviral therapy (history of pMTCT does not affect eligibility) Eligible to receive ART, according to current WHO guidelines Caregiver plans to reside in study catchment area for at least 6 months (reported) Caregiver provides sufficient locator information Exclusion Criteria: Suspected meningitis, any other central nervous system infection, or encephalitis

Ages Eligible for Study
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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 |
| --- | --- |
| Experimental: Urgent ART<br>Initiation of highly active antiretroviral therapy (HAART) within 48 hours of enrollment. Antiretroviral therapy will include regimens recommended by the Kenyan Ministry of Health. | Other: Urgent ART<br>* Children will be started on HAART <48 hours after enrollment.<br>* Other names: HAART regimens recommended by WHO and Kenya MOH.;|
| Active Comparator: Early ART<br>Initiation of HAART 7-14 days after enrollment. | Other: Early ART<br>* Children will be started on ART after stabilization 7-14 days after enrollment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause Mortality |  | 6 months post-HAART initiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Evidence of Immune Reconstitution and Inflammatory Syndrome (IRIS) | Confirmed, possible or likely IRIS based on external independent review | 6 months post-HAART initiation | 
| Number of Participants With Potential Drug Toxicity | Participants with adverse events that are deemed to be potentially related to medications. | 6 months post-HAART initiation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV-1, IRIS