Early Infant HIV Treatment in Botswana

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).

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.