Surveillance Monitoring for ART Toxicities Study in HIV Uninfected Children Born to HIV Infected Women

Many antiretroviral therapy (ART) medications given to a pregnant woman cross the placenta
and can be detected in the amniotic fluid and cord blood resulting in substantial fetal
exposure. Therefore, there is concern about toxicity of the drugs in the fetus and infant. It
is noteworthy that none of the currently approved ART medications for the prevention of
maternal to fetal transmission of HIV are in Food and Drug Administration (FDA) Pregnancy
Category A (no fetal risk ascertained in adequately controlled human studies). Thus, there is
continued need to examine the toxicity of ART in HIV transmission prevention for the
short-term toxicity of newer agents and combinations as well as the unanswered questions of
longer term toxicity and subtle adverse effects.

The study will use a registry approach to conduct active surveillance among children < 12
years of age at enrollment. Occurrences of abnormalities from ART exposure in utero and/or in
the first two months of life will be sought in multiple domains, including metabolic, growth,
cardiac, neurologic, neurodevelopmental, behavior, language, and hearing. Clinical and
laboratory data will be examined for abnormalities through a hierarchy of evaluations:
adverse events (AE) will be identified → selected AEs will trigger predefined additional
evaluations → significant observations will be defined as cases → a pattern of significant
study-wide cases will be defined as signals. The incidence of these events of interest will
be monitored over time and by ART regimen, and compared with historical data that may be
suggestive of a signal. Some signals may be testable using existing and/or previously
collected data, while other signals may indicate the need for additional hypothesis-driven
studies outside of SMARTT.

The objectives of SMARTT are:

1. To estimate the occurrence of potential ART-related toxicities through an ongoing
surveillance system among HIV-uninfected children born to mothers with HIV infection
with and without exposure to ART in utero and/or in the first two months of life and
compare the occurrences of these outcomes with other sources of data as well as by ART
exposures; and

2. To actively encourage hypothesis-driven studies to confirm that the signals are due to
ART exposure in utero and/or in the first two months of life. Note that the full design
and execution of these studies may be beyond the scope of the SMARTT study but will be
facilitated by SMARTT.

The specific aims of SMARTT are:

1. To create a Static Surveillance Cohort to extend domain-specific data collection in
children either 1) previously enrolled in any of the approved studies for enrollment
into SMARTT; 2) previously enrolled in another pediatric HIV/AIDS cohort study with
SMARTT Protocol Chair approval, or 3) not previously enrolled in an approved study but
with equivalent data available in the medical record;

2. To create a Dynamic Surveillance Cohort to examine domain-specific data of children
newly exposed to ART in utero and/or in the first two months of life;

3. To create a Young Adult Cohort to study long-term outcomes in SMARTT participants
formerly enrolled in the Static and Dynamic cohorts.

4. To identify a set of "triggers" for each domain that define a "signal" of possible ART
toxicity and compare the occurrence of these signals with previously collected data and
by ART exposure; and

5. To encourage and facilitate the development of hypothesis-driven studies to evaluate
whether a "signal" is the result of ART exposure in utero and/or in the first two months
of life.

Inclusion Criteria:

Static Surveillance Cohort:

- HIV-exposed but -uninfected infants and children; lack of infection must be documented
by medical or research record review. Children exposed and unexposed to ART while in
utero and/or in the first two months of life will be enrolled.

- Previously enrolled in any of the studies included on the list of approved studies for
enrollment into SMARTT or another study with SMARTT Protocol Chair approval if the
study has data on ART exposure by pregnancy trimester, ART exposure during the first 2
months of life, and pregnancy complication data or availability of ART exposure by
pregnancy trimester (including start and stop dates), ART exposure during the first 2
months of life, and pregnancy complication data in the mother and/or child's medical
record.

- Age birth to < 12 years at entry.

- Willingness of parent/legal guardian to provide written permission for child to
participate in study.

Dynamic Surveillance Cohort:

- HIV-exposed living fetus greater than or equal to 23 weeks gestation or a live infant
born after 22 weeks gestation. Infants exposed and unexposed to ART will be enrolled.

- Any infant born of an HIV-infected mother may be enrolled pending determination of the
infant's HIV infection status. However, infants found to be HIV-positive will be
discontinued from the study and will be referred for care outside this study. HIV
infection status will be determined using the Diagnosis of Lack of Infection in
HIV-Exposed Children.

- ART exposure data by trimester of pregnancy must be available if ART exposed.

- Entry prior to birth through < 72 hours of age.

- Willingness of parent/legal guardian to provide written permission for child to
participate in study.

- Willingness of biological mother to enroll at initial enrollment of her child.

Young Adult Cohort:

- 18 years of age or older, and aware of their perinatal HIV exposure status.

- Previously enrolled in the SMARTT Dynamic or Static Cohort.

- Willingness to provide written consent to participate in the study.

Reference Cohort:

- Participants from clinical settings that are similar to participants enrolled in the
PHACS SMARTT Static Cohort.

- Antiretroviral therapy unexposed children born to a mother HIV uninfected at the time
of the child's birth.

- Ages 1, 3, 5, or 9 years (± 3 months) at the time of the study visit.

- Willingness of parent/legal guardian to provide written permission for child to
participate in study.

Exclusion Criteria:

Static and Dynamic Cohorts:

Young Adult Cohort:

- Participants enrolled in the Adolescent Master Protocol for Participants 18 Years of
Age and Older (AMP Up).

- Current prisoner status.

Reference Cohort:

- Monolingual Spanish-speaking child or parent/caregiver.