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
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
Recruiting | Conditions and diagnoses potentially related to perinatal exposure to antiretroviral medications | Multisite
Very Early Intensive Treatment of HIV-Infected Infants to Achieve HIV Remission: A Phase I/II Proof of Concept Study
The purpose of this study is to explore the effects of early intensive antiretroviral therapy
(ART) on achieving HIV remission (HIV RNA below the limit of detection of the assay) among
The study will enroll two cohorts. Cohort 1 will include infants at high risk for in utero
HIV infection. Cohort 2 will include in utero HIV-infected, ART-started infants.
Three early intensive therapy regimens will be assessed. Regimen 1L will include 2 nucleoside
reverse transcriptase inhibitors (NRTIs) plus nevirapine (NVP) plus lopinavir/ritonavir
(LPV/r). Regimen 2R will include 2 NRTIs plus NVP plus raltegravir (RAL). Regimen 2RV will
include 2 NRTIs plus NVP plus RAL plus VRC01 monoclonal antibody.
The study will be conducted in four steps. In Step 1, Cohort 1 infants will be enrolled for
evaluation of HIV infection and initiation of early intensive therapy within 48 hours of
birth. Infants in whom in utero HIV infection is excluded will switch from the study regimen
to standard perinatal prophylaxis per local guidelines within two weeks; these infants will
continue in Step 1 safety monitoring for two additional weeks, undergo final HIV testing at
approximately 12 weeks of age, and then exit the study. Infants in whom in utero HIV
infection is confirmed will enter Step 2 at least two weeks after enrollment in Step 1.
In Step 2, Cohort 1 infants identified with in utero HIV infection and Cohort 2 infants will
receive the study regimen for up to 192 weeks. Beginning at Step 2 Week 84, children who
achieved HIV RNA suppression by Week 24, and maintained suppression thereafter, with no HIV
RNA detected at or after Week 48, will be evaluated for possible treatment cessation.
In Step 3, children in Step 2 who meet criteria for treatment cessation will stop ART, and be
closely monitored for viral rebound for up to five years.
In Step 4, children who experience viral rebound in Step 3 will re-start ART, and be closely
monitored for viral re-suppression on ART until five years of age or six months after
re-suppression, whichever is later.
HIV-uninfected infants will be followed for 12 weeks. HIV-infected infants will be followed
for up to 192 weeks in Step 2 (on ART); those entering Step 3 will be followed for primary
endpoint ascertainment at 48 weeks and for up to a total of five years (off ART) in this