The overall objective of the EIT 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.
Specific Aim 1: To demonstrate that ART can be safely initiated very early in life after diagnosis of antepartum or peripartum HIV infection, and will result in rapid viral decay in most infants.
Specific Aim 2: To evaluate virologic and immunologic outcomes of very early ART in infancy.
- Describe Viral resistance mutations and genetic sequencing of the virus in enrolled (transmitting) mothers/infant pairs.
- Described Maternal and child HLA typing and other immune system characteristics with comparison between those with and without successful treatment outcomes.
- Develop a model using maternal and infant characteristics associated with peripartum HIV transmission to predict which infants are at risk for peripartum MTCT (and therefore warrant repeat HIV DNA PCR testing following a negative HIV DNA PCR test at birth).
- Evaluate the sensitivity and specificity of point-of-care diagnostics as compared with standard DNA PCR testing.
- Describe long-term virologic and safety outcomes among children in observational follow-up for up to 576 weeks.
Study Design and Population: Open-label phase 2-3 clinical trial of very early ART in HIV-infected infants in Botswana, followed by longer-term observational follow-up for virologic and immunologic outcomes. Approximately 75 infants and young children will be enrolled into three study cohorts: 1) a prospective cohort will enrol up to 40 infants with antepartum infection who initiate ART within the first week of life; 2) a prospective cohort will enrol up to 10 infants with peripartum infection who initiate ART within the first 5-56 days of life; and 3) a control group will enrol up to 25 children aged 24-36 months with either antepartum or peripartum infection whose ART was initiated no earlier than 30 or 57 days after birth (antepartum or peripartum/unknown infection, respectively) and within the first year after birth.
Prospective Cohorts: We will prospectively enrol 50 HIV-infected infants into two parallel early treatment cohorts
- Antepartum Infection Cohort: 30 infants who test HIV-positive within 96 hours after birth (antepartum HIV infection) and are able to initiate ART < 7 days after birth.
- Peripartum Infection Cohort: 20 infants 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 infants who start ART < 21 days after birth.
Control Group: 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.
Study Duration: 5 years with extended observational follow up for up to another 5 years.
Sponsor: The National Institute of Allergy and Infectious Diseases (NIAID).
Study findings so far shows that;
- Cepheid POC assay in the first week of life has a high sensitivity and specificity, despite early infection and antiretroviral prophylaxis and that its use may be a useful approach for adding early infant HIV diagnosis to current testing programs.
- In utero Mother-to-child transmission of HIV (MTCT) occurred only among infants identified as high risk at delivery, using information available from the mother or obstetric record. Birth testing that targets high-risk infants based on maternal ART receipt is likely to identify the majority of in utero HIV transmissions, and allows early ART initiation for these infants.
- Multiple clear benefits of rapid antiretroviral initiation, including an extremely small reservoir of intact proviral sequences, a reduction in abnormal T cell immune activation, a more polyfunctional HIV-1–specific T cell response, and an innate immune profile that displays distinct features of improved antiviral activity and is associated with intact proviral reservoir size, offering a rare insight into the evolutionary dynamics of viral reservoir establishment in neonates while providing strong empirical evidence supporting the immediate initiation of ART for neonates with HIV-1 infection.
- NVP/ZDV/3TC started in the first week of life was safe and effective, even when trough NVP levels were below target. Transient viral increases occurred following transition to LPV/r, but by 12 and 24 weeks most children achieved and maintained viral suppression.
- A DNA PCR cycle threshold value of 33 was predictive of the final HIV status in new-borns, overlap occurred for true positives, false positives, and initial indeterminates. Testing additional samples should be standard practice for positive and indeterminate HIV DNA PCR tests in the first week of life.
- Lower viral reservoir was associated with starting ART at <1 week. Negative serostatus and qualitative DNA were useful markers of sustained viral suppression from 24–84 weeks.
- Defective HIV-1 cell-associated DNA sequences may overestimate the prevalence of drug resistance among early-treated children. The impact of DRMs from intact proviruses on long-term treatment outcomes warrants further investigation.