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

June 26, 2025 updated by: Paige Williams, Harvard School of Public Health (HSPH)
SMARTT will estimate the incidence of conditions and diagnoses potentially related to in utero exposure to antiretroviral therapy and/or exposure in the first two months of life among children born of HIV-infected mothers.

Study Overview

Status

Completed

Conditions

Detailed Description

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.

Study Type

Observational

Enrollment (Actual)

5169

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Puerto Rico
      • San Juan, Puerto Rico, 00935
        • University of Puerto Rico Medical Center
      • San Juan, Puerto Rico, 00936-8344
        • San Juan Research Hospital
  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35294
        • University of Alabama
    • California
      • La Jolla, California, United States, 92093
        • University of California San Diego
      • Los Angeles, California, United States, 90033
        • University of Southern California
    • Colorado
      • Aurora, Colorado, United States, 80045
        • University of Colorado Denver Health Sciences Center
    • Florida
      • Fort Lauderdale, Florida, United States, 33316
        • Children's Diagnostic & Treatment Center
      • Jacksonville, Florida, United States, 32209
        • University of Florida Health Science Center
      • Miami, Florida, United States, 33136
        • University of Miami
    • Illinois
      • Chicago, Illinois, United States, 60612
        • University of Illinois, Chicago
      • Chicago, Illinois, United States, 60614
        • Ann and Robert H. Lurie Children's Hospital
    • Louisiana
      • New Orleans, Louisiana, United States, 70112
        • Tulane University Health Sciences Center
    • Maryland
      • Baltimore, Maryland, United States, 21201
        • University of Maryland
    • New Jersey
      • Newark, New Jersey, United States, 07101-1709
        • Rutgers - New Jersey Medical School
    • New York
      • Bronx, New York, United States, 10461
        • Jacobi Medical Center
      • Bronx, New York, United States, 10457
        • Bronx Lebanon Hospital Center
      • Brooklyn, New York, United States, 11203-2098
        • SUNY Downstate Medical Center
      • New York, New York, United States, 10016
        • New York University School of Medicine
      • Stony Brook, New York, United States, 11794
        • SUNY Stony Brook
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104-4318
        • Children's Hospital of Philadelphia
    • Tennessee
      • Memphis, Tennessee, United States, 38105-2764
        • St. Jude Children's Research Hospital
    • Texas
      • Houston, Texas, United States, 77030-3498
        • Baylor College of Medicine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

Yes

Sampling Method

Non-Probability Sample

Study Population

Children aged 0 - < 12 years born of HIV-infected mothers recruited from a clinical setting.

Description

Inclusion Criteria:

Dynamic 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.

Exclusion Criteria:

Dynamic Cohort:

None

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Static Cohort- closed to enrollment and follow-up
HIV-uninfected children < 12 years of age at the time of enrollment, born of HIV-infected mothers
Dynamic Cohort
HIV-uninfected children born of HIV-infected mothers enrolled from prior to birth through ≤ 72 hours of age
Reference Cohort- closed to enrollment and follow-up
HIV-uninfected children born to a mother HIV uninfected at the time of the child's birth enrolled at 1, 3, 5, or 9 years of age(± 3 months) at the time of the study visit
Young Adult Cohort- closed to enrollment and follow-up
Former Dynamic and Static Cohort participants ≥ 18 years of age.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Neurologic abnormalities
Time Frame: Annually birth through age 5; semiannual thereafter, assessments vary based on age of child.
Assessed via head circumference measurement and medical record review for documented clinical diagnoses of seizures, microcephaly, or other neurologic diagnosis.
Annually birth through age 5; semiannual thereafter, assessments vary based on age of child.
Neurodevelopmental abnormalities
Time Frame: 1, 3, 5, 9, and 13 years of age, assessments vary based on age of child.
Assessed via the following neurodevelopmental tests: Bayley Screener, Bayley III, WPPSI-III, BASC-2, WASI, WISC-IV, BRIEF, WIAT II.
1, 3, 5, 9, and 13 years of age, assessments vary based on age of child.
Abnormal growth and metabolic function
Time Frame: Annually birth through age 5; semiannual thereafter, assessments vary based on age of child.
Assessed through the measurement of height, weight, tricep skinfold thickness, mid-upperarm circumference measurements, insulin and glucose, and fasting lipids.
Annually birth through age 5; semiannual thereafter, assessments vary based on age of child.
Cardiac abnormalities
Time Frame: Ages 3-5.
Assessed through the administration of echocardiograms and serum biomarkers (ProBNP).
Ages 3-5.
Hearing dysfunction
Time Frame: At age 5 and for children of all ages meeting a hearing/language trigger.
Assessed via audiologic evaluation conducted by an audiologist.
At age 5 and for children of all ages meeting a hearing/language trigger.
Language dysfunction
Time Frame: 1, 2, 3, 5, and 9 years of age, assessments vary based on age.
Assessed via the following language tests: MCDI, Ages and Stages Communication Scale, PPVT IV, Goldman Fristoe 2, Rice Wexler, TELD-3, TOLD-3, Woodcock, CELF IV.
1, 2, 3, 5, and 9 years of age, assessments vary based on age.
Drug Use and Sexual Activity
Time Frame: 11, 13, 15, and 17 years of age.
The assessment of sexual behavior and substance use will be conducted using an Audio Computer Assisted Survey Instrument (ACASI). ACASI uses computer and voice recordings so that the participant hears (through headphones) and sees (on the screen) each question and response list. The use of ACASI is proven to minimize response bias due to the presence of an interviewer.
11, 13, 15, and 17 years of age.
Abnormal organ function
Time Frame: Birth and age one, semiannual thereafter.
Assessed through the measurement of lipase, CPK, ALT, creatinine, glucose, LDH, BUN, WBC, PMN, lymphocytes, platelets, or hemoglobin ( ≥ Grade 3 adverse event).
Birth and age one, semiannual thereafter.
Death due to unknown medical condition
Time Frame: Annual.
Assessed through autopsy review.
Annual.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Maternal substance use during pregnancy
Time Frame: Entry visit.
Obtained via interview, toxicology report, and meconium testing.
Entry visit.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Harvard School of Public Health (HSPH)

Collaborators

National Institute on Drug Abuse (NIDA)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
National Institute of Allergy and Infectious Diseases (NIAID)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institute of Mental Health (NIMH)
National Heart, Lung, and Blood Institute (NHLBI)
National Institute of Neurological Disorders and Stroke (NINDS)
National Institute of Dental and Craniofacial Research (NIDCR)
NIH Office of AIDS Research (OAR)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Tulane University School of Medicine

Investigators

  • Principal Investigator: Ellen Chadwick, M.D., Ann & Robert H Lurie Children's Hospital of Chicago
  • Principal Investigator: Paige L Williams, Harvard School of Public Health (HSPH)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2007

Primary Completion (Actual)

May 31, 2025

Study Completion (Actual)

May 31, 2025

Study Registration Dates

First Submitted

March 4, 2011

First Submitted That Met QC Criteria

March 4, 2011

First Posted (Estimated)

March 7, 2011

Study Record Updates

Last Update Posted (Actual)

June 27, 2025

Last Update Submitted That Met QC Criteria

June 26, 2025

Last Verified

June 1, 2025

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • 1P01HD103133 - PH100
  • PH100 (Other Identifier: PHACS Protocol Number)
  • 1P01HD103133 (U.S. NIH Grant/Contract)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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