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Early Infant HIV Treatment in Botswana (EIT)

This study is currently recruiting participants.
See Contacts and Locations
Verified March 2017 by Roger Shapiro, Harvard School of Public Health
Sponsor:
Collaborators:
Ragon Institute of MGH, MIT and Harvard
Brigham and Women's Hospital
University of California, San Diego
Information provided by (Responsible Party):
Roger Shapiro, Harvard School of Public Health
ClinicalTrials.gov Identifier:
NCT02369406
First received: February 12, 2015
Last updated: March 13, 2017
Last verified: March 2017
  Purpose
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.

Condition Intervention Phase
HIV Pediatric AIDS Drug: Nevirapine Drug: Kaletra Drug: Lamivudine Drug: Zidovudine Phase 2 Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: BHP Early Infant Treatment Study: A Clinical Treatment Trial of HIV+ Infants in Botswana

Resource links provided by NLM:


Further study details as provided by Roger Shapiro, Harvard School of Public Health:

Primary Outcome Measures:
  • To determine the proportion of infants who have treatment-limiting adverse events within the first 14 days of treatment [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 14 days ]
  • To evaluate virologic and immunologic outcomes of very early ART in infancy [ Time Frame: 192 weeks ]

    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.



Estimated Enrollment: 70
Study Start Date: February 2015
Estimated Study Completion Date: February 2019
Estimated Primary Completion Date: February 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Antepartum Cohort

30 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
Other Name: NVP
Drug: Kaletra
Other Name: LPV/r
Drug: Lamivudine
Other Name: 3TC
Drug: Zidovudine
Other Name: ZDV
Experimental: Peripartum Cohort

20 children who test HIV-negative within 96 hours after birth but test HIV-positive within 42 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
Other Name: NVP
Drug: Kaletra
Other Name: LPV/r
Drug: Lamivudine
Other Name: 3TC
Drug: Zidovudine
Other Name: ZDV
No Intervention: Control Cohort
20 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.

Detailed Description:
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).
  Eligibility

Ages Eligible for Study:   up to 56 Days   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria (antepartum infection cohort):

  1. Mother/guardian ≥18 years of age and able to provide informed consent
  2. Gestational age at birth ≥35 weeks
  3. Birth weight ≥2000 grams
  4. Age is less than 7 days*
  5. 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**
  6. Ability to initiate ART within 7 days after birth
  7. Eligible for ART through the Botswana government program
  8. Ability to be followed in BHP clinic for up to 192 weeks from enrollment
  9. 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.

Inclusion Criteria (peripartum infection cohort):

  1. Mother/guardian ≥18 years of age and able to provide informed consent
  2. Age is greater than 4 days and less than 57 days
  3. 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
  4. HIV-positive between 96 hours and 42 days after birth NOTE: DNA PCR positive on at least one specimen between 96 hour and 42 days after birth, with confirmation either positive or pending**
  5. Ability to initiate ART at enrollment
  6. Eligible for ART through the Botswana government program
  7. Ability to be followed in BHP clinic for ART for up to 192 weeks after enrollment
  8. 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.

Inclusion Criteria (control group):

  1. Mother/guardian ≥18 years of age and able to provide informed consent
  2. 24-36 months of age
  3. HIV-infection documented within 42 days after birth
  4. 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 42 days after birth.
  5. After 6 months of ART, all documented HIV RNA measurements < 400 copies/mL

Exclusion Criteria (for antepartum and peripartum infection cohort):

  1. Hospitalization for severe medical illness
  2. Medical condition making it unlikely that the infant will survive to 96 weeks
  3. If lab values are available prior to enrollment, the following Division of AIDS 2004 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 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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02369406

Contacts
Contact: Roger L. Shapiro, MD, MPH 617-771-0040 rshapiro@hsph.harvard.edu

Locations
United States, Massachusetts
Harvard School of Public Health Active, not recruiting
Boston, Massachusetts, United States, 02115
Brigham and Women's Hospital Active, not recruiting
Cambridge, Massachusetts, United States, 02139
Ragon Institute of MGH, MIT and Harvard Active, not recruiting
Cambridge, Massachusetts, United States, 02139
Botswana
Botswana Harvard HIV/AIDS Institute Partnership Recruiting
Gaborone, Botswana
Contact: Joseph Makhema, MD    +267-390-2671    jmakhema@bhp.org.bw   
Sub-Investigator: Joseph Makhema, MD         
Sponsors and Collaborators
Harvard School of Public Health
Ragon Institute of MGH, MIT and Harvard
Brigham and Women's Hospital
University of California, San Diego
  More Information

Additional Information:
Publications:

Responsible Party: Roger Shapiro, Principal Investigator, Harvard School of Public Health
ClinicalTrials.gov Identifier: NCT02369406     History of Changes
Other Study ID Numbers: U01AI114235 ( U.S. NIH Grant/Contract )
Study First Received: February 12, 2015
Last Updated: March 13, 2017

Keywords provided by Roger Shapiro, Harvard School of Public Health:
Botswana
Immunology
Antiretroviral Therapy

Additional relevant MeSH terms:
Lamivudine
Zidovudine
Nevirapine
Lopinavir
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Anti-HIV Agents
Antimetabolites
Cytochrome P-450 CYP3A Inducers
Cytochrome P-450 Enzyme Inducers
HIV Protease Inhibitors
Protease Inhibitors
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors

ClinicalTrials.gov processed this record on September 25, 2017