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

Study Overview
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Brief Summary
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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.

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

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

Conditions
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Antiretroviral Toxicity

Participation Criteria
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Eligibility Criteria
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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
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Static Cohort- closed to enrollment and follow-up<br>HIV-uninfected children < 12 years of age at the time of enrollment, born of HIV-infected mothers | |
| Dynamic Cohort<br>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<br>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<br>Former Dynamic and Static Cohort participants ≥ 18 years of age. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neurologic abnormalities | 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 | 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 | 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 | Assessed through the administration of echocardiograms and serum biomarkers (ProBNP). | Ages 3-5. | 
| Hearing dysfunction | Assessed via audiologic evaluation conducted by an audiologist. | At age 5 and for children of all ages meeting a hearing/language trigger. | 
| Language dysfunction | 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 | 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 | 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 | Assessed through autopsy review. | Annual. | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Conditions and diagnoses potentially related to perinatal exposure to antiretroviral medications