Early Infant HIV Treatment in Botswana

Study Overview
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Brief Summary
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The overall objective of this study is to determine whether very early antiretroviral treatment (ART) initiation in HIV-infected infants limits the seeding of viral reservoirs and maintains immune responses, potentially allowing future periods off ART.

Detailed Description
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HIV-1 infection during adulthood leads to a stable, long-lasting viral reservoir in CD4 T cells that persists despite suppressive antiretroviral therapy (ART), and is responsible for rapid viral rebound once treatment is stopped in most cases. In neonates, HIV-1 infection occurs at a time when the adaptive immune system is still in development, which may alter the establishment of a long-lasting viral reservoir and offer opportunities to reduce viral persistence through early antiretroviral treatment. Recently, scientific understanding of neonatal HIV infection has been challenged by the description of an infant who tested positive for HIV at birth, was treated with potent combination antiretroviral therapy (ART) within the first 30 hours of life, and achieved long-term remission of HIV infection when ART was stopped approximately 18 months later. Unfortunately, after 2 years off ART, rebound viremia occurred in this child, yet this case raises the provocative question of whether ART initiated within the first days of life for an antepartum infection, or in the first days/weeks of life for a peripartum infection, can prevent the seeding of a long-lasting reservoir of HIV infected cells in some infants (and therefore lead to long periods of HIV remission off ART).

Official Title
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BHP Early Infant Treatment Study: A Clinical Treatment Trial of HIV+ Infants in Botswana

Conditions
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HIV, Pediatric AIDS

Intervention / Treatment
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* Drug: Nevirapine
* Drug: Kaletra
* Drug: Lamivudine
* Drug: Zidovudine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (antepartum infection cohort): Mother/guardian ≥18 years of age and able to provide informed consent Gestational age at birth ≥35 weeks Birth weight ≥2000 grams Age is less than 7 days* HIV-infection identified by testing conducted within 96 hours after birth NOTE: HIV-infection is defined as DNA PCR positive on at least one specimen, with confirmation specimen either positive or pending** Ability to initiate ART within 7 days after birth Eligible for ART through the Botswana government program Ability to be followed in BHP clinic for up to 240 weeks from enrollment# Blood samples collected and submitted for real-time safety lab evaluations; results may be pending at the time of entry. At least half of infants in the antepartum cohort must be < 3 days at enrollment, including 3 of the first 6 infants enrolled. Participants will be offered extended follow-up for up to 576 weeks. However, willingness to participate in optional extended follow-up is not an inclusion criterion. Inclusion Criteria (peripartum infection cohort): Mother/guardian ≥18 years of age and able to provide informed consent Age is greater than 4 days and less than 57 days HIV-negative within 96 hours after birth NOTE: HIV-negative is defined as HIV-negative by DNA PCR on a single specimen or HIV-negative on 2 separate confirmatory specimens following a re-test of an HIV-positive sample HIV-positive between 96 hours and 56 days after birth NOTE: DNA PCR positive on at least one specimen with confirmation specimen either positive or pending repeat draw or result** Ability to initiate ART at enrollment Eligible for ART through the Botswana government program Ability to be followed in BHP clinic for ART for up to 240 weeks after enrollment# Blood samples collected and submitted for real-time safety lab evaluations (results may be pending at the time of entry). An enrolled infant later determined to be HIV uninfected by confirmatory testing will end participation in the study and this enrollment will not be counted against the total number of enrollments planned. Participants will be offered extended follow-up for up to 576 weeks. However, willingness to participate in optional extended follow-up is not an inclusion criterion. Inclusion Criteria (control group): Mother/guardian ≥18 years of age and able to provide informed consent 24-36 months of age HIV-infection documented within 365 days after birth ART initiated within the following timeframe based on timing of HIV-infection diagnosis > 30-365 days after birth if HIV-infection diagnosed within 96 hours after birth OR > 57-365 days after birth if infant was HIV-negative based on testing performed within 96 hours after birth (or if unknown HIV status < 96 hours from birth) and then found to be HIV-positive based on testing performed between 96 hours and 365 days after birth. After 6 months of ART, no more than one HIV RNA measurement > 400 copies/mL Exclusion Criteria (for antepartum and peripartum infection cohort): Hospitalization for life-threatening medical illness Medical condition making it unlikely that the infant will survive to 96 weeks If lab values are available prior to enrollment, the following Division of AIDS 2014 graded results, from samples collected within 7 days prior to entry without subsequent testing, will exclude an infant: Grade ≥3 ALT Grade ≥3 AST Grade ≥4 hemoglobin Note: Baseline lab values may not be available at the time of ART start. However, as soon as these values are available (occasionally within <24 hours), they will be used to make rapid treatment decisions. Neonates with baseline Grade 4 hemoglobin will be called immediately to have ZDV discontinued if the value is confirmed. Neonates with baseline Grade 3 or 4 ALT or AST will be called immediately to stop either NVP or LPV/r if the value is confirmed. Neonates who remain on ART may remain on study. Neonates who discontinue all ART for pre-ART laboratory abnormalities will not be counted against total enrollments. Exclusion Criteria (control group): 1) < 85% reported adherence to prescribed doses or interruption of ART for more than 7 consecutive days since its initiation.

Ages Eligible for Study
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Minimum Age: 0 Days
Maximum Age: 3 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Antepartum Cohort<br>40 children who test HIV-positive within 96 hours after birth (antepartum HIV infection) and are able to initiate ART < 7 days after birth. This cohort will include at least 15 children who start ART < 3 days after birth. All infants in the antepartum cohort will initiate ART with Nevirapine, Zidovudine, Lamivudine, and later switch to Kaletra, Zidovudine, Lamivudine. | Drug: Nevirapine<br> <br> * Other names: NVP;Drug: Kaletra<br> <br> * Other names: LPV/r;Drug: Lamivudine<br> <br> * Other names: 3TC;Drug: Zidovudine<br> <br> * Other names: ZDV;|
| Experimental: Peripartum Cohort<br>10 children who test HIV-negative within 96 hours after birth but test HIV-positive <57 days after birth (peripartum HIV infection) and who are able to initiate ART <57 days after birth. This cohort will include at least 10 children who start ART < 21 days after birth. The majority of infants in the peripartum cohort will be able to start Kaletra, Zidovudine, Lamivudine as their first regimen, but a minority may start Nevirapine, Zidovudine, Lamivudine and then switch to Kaletra, Zidovudine, Lamivudine. | Drug: Nevirapine<br> <br> * Other names: NVP;Drug: Kaletra<br> <br> * Other names: LPV/r;Drug: Lamivudine<br> <br> * Other names: 3TC;Drug: Zidovudine<br> <br> * Other names: ZDV;|
| No Intervention: Control Cohort<br>25 HIV-infected children who initiated ART at later age ranges (30-365 days for antepartum infection, 57-365 days for peripartum infection or for those with unknown timing of infection) will be enrolled for a single visit that will occur between 24 and 36 months of age. These children will serve as a control group for virologic and immunologic comparisons with children in the prospective cohorts. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the proportion of infants who have treatment-limiting adverse events within the first 14 days of treatment |  | 14 days | 
| To determine the proportion of infants who fail to achieve at least a 1.5 log10 copies/mL reduction in HIV-1 RNA by the 14th day of treatment |  | 14 days | 
| To determine the proportion of infants in the antepartum cohort with trough drug concentrations below defined therapeutic ranges at 7 and 14 days of treatment (trough concentrations will be evaluated for NVP, ZDV, 3TC) |  | 14 days | 
| To evaluate virologic and immunologic outcomes of very early ART in infancy | Virologic outcomes after early ART: We will evaluate how the timing of HIV infection and the timing of ART initiation affect the size and composition of the viral reservoir over time. Immunologic outcomes after early ART: We will evaluate how immune activation and immune activity against HIV-1 contribute to the size and composition of the HIV-1 reservoir over time in infants treated early with suppressive ART. Control Group Comparisons. We will evaluate virologic and immunologic outcomes at a single time point in children for whom ART initiation was later than in the prospective cohorts, and compared with immunologic testing of stored specimens from HIV exposed uninfected and HIV unexposed children. | 84-96 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with HIV-1 RNA levels <40 copies/mL |  | up to 576 weeks | 
| Number of participants with reservoir HIV-1 DNA (in copies/million peripheral blood mononuclear cells, PBMCs) below the level of detection for total virus | Threshold of detection is expected to be approximately 5 copies/million PBMCs, but varies by sample volume available. | up to 576 weeks | 
| Median CD4 cell count (cells/mm3) and 95% confidence intervals among participants |  | up to 576 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Botswana, Immunology, Antiretroviral Therapy