Latency and Early Neonatal Provision of Antiretroviral Drugs Clinical Trial

Study Overview
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Brief Summary
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The investigators propose a non-randomized clinical trial of 60 HIV-infected infants identified within 48 hours of birth and their mothers to investigate the consequences of very early ART on the establishment and maintenance of the viral reservoir. The first phase (early ART initiation within 48 hours of birth) will examine the trajectory i.e. changes over time of the viral reservoir and detection of HIV-specific antibody responses in infants testing HIV-positive within 48 hours of birth and initiating early ART. Secondary pathogenesis aims will test whether markers of neonatal immune quiescence are associated with the extent of seeding and rate of decline of the viral reservoir when ART is started at a young age and investigate whether markers in infant stool samples can be used as a non-invasive method of defining relevant immune and HIV-specific parameters associated with viral reservoir size. The investigators hypothesize that developmental characteristics of newborn immunity may make this period the optimal time to begin ART and influence the seeding of the viral reservoir.

Detailed Description
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Prevention of mother-to-child transmission (PMTCT) programs using antiretrovirals (ARVs) have had tremendous success in sub-Saharan Africa. However, HIV transmission continues to occur because (1) implementation of PMTCT is incomplete and (2) ARV interventions are not 100% effective in blocking infection. Thus the challenge of providing treatment to HIV-infected children is far from over. The capacity of early ART treatment to favorably influence the viral reservoir and potentially lead to post-treatment cessation viral control needs to be described in the population of infants, and to identify useful public health strategies.

Official Title
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Latency and Early Neonatal Provision of Antiretroviral Drugs Clinical Trial

Conditions
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HIV

Intervention / Treatment
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* Drug: Nevirapine
* Drug: Zidovudine
* Drug: Lamivudine
* Drug: LPV/r


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Point of care (POC) or laboratory-based test positive on a sample collected within 48 hours of birth. Mother willing and able to provide informed consent. Exclusion Criteria: Expressed intention to leave the Johannesburg area permanently. Co-morbidities, birth defects or other conditions which in the opinion of the clinical team have a greater than 50% risk of mortality in the first days of life. Co-morbidities or conditions which in the opinion of the clinical team advise against initiation of ART within the first 48 hours of life. Active (uncontrolled) maternal psychiatric illness.

Ages Eligible for Study
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Maximum Age: 48 Hours

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Early ART<br>All infants enrolled in the trial, regardless of maternal PMTCT regimen, will be initiated on a triple ARV regimen consisting of nevirapine (NVP), zidovudine (ZDV) and lamivudine (3TC) presumptively based on the initial positive result. This regimen will be continued to 42 weeks post menstrual age (PMA). At this time, infants will be switched to LPV/r, ZDV and 3TC to be continued to 104 weeks or longer unless otherwise preferred by the treating clinician or if any clinical or laboratory contraindications are identified. | Drug: Nevirapine<br>* Standard medication used to treat and prevent HIV/AIDS, specifically HIV-1. It is generally recommended for use with other antiretroviral medication. The initial dose of NVP will be 6 mg per kg per dose orally twice daily until 42 weeks gestational age (2 weeks of age for infants born at term) which is the dosing selected by the NIH International Maternal, Pediatric, Adolescent AIDS Clinical Trials (IMPAACT) Network.<br>* Other names: Viramune;Drug: Zidovudine<br>* An antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use with other antiretroviral. ZDV will be dosed as per standard guideline and routine practices.<br>* Other names: Retrovir;Drug: Lamivudine<br>* An antiretroviral medication used to prevent and treat HIV/AIDS. It is effective against both HIV-1 and HIV-2. 3TC will be dosed as per standard guideline and routine practices.<br>* Other names: Epivir;Drug: LPV/r<br>* Lopinavir is an antiretroviral of the protease inhibitor class. It is used against HIV infections as a fixed-dose combination with another protease inhibitor, ritonavir. LPV/r will be dosed as per standard guideline and routine practices.<br>* Other names: Ritonavir-boosted lopinavir;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of patients with initial viral suppression | Suppression is defined as patients with plasma HIV RNA <50 copies/mL. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of patients maintaining viral suppression | Suppression is defined as patients with plasma HIV RNA <50 copies/mL. | Between 24 and104 weeks | 
| Prevalence of CD4 percentage greater than 30 | Patients that reached a normal CD4% level. | By 24 weeks and sustained through 104 weeks | 
| Prevalence of growth along curve within one standard deviation or upward trend | By comparing viral growth curves. | Up to 104 weeks | 
| Prevalence of detection of specific HIV antibody classes | HIV antibody detection | 24 and 104 weeks | 
| Size of the viral reservoir (copies/million cell) | Quantification of viral reservoir | Up to 104 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, infant, antiretroviral therapy, highly active, antiretroviral agents