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

• Lactic acidosis [ Time Frame: Birth, 1, 3, 5, 7, 9, 11, 13, 15, and 17 years of age. ] [ Designated as safety issue: No ]
  Assessed through the measurement of blood lactate levels using a point-of-care lactate measuring device. Venous lactate and pyruvate levels will be measured for children for whom the point-of-care lactate measurement is abnormal.
• Neurologic abnormalities [ Time Frame: Annually birth through age 5; semiannual thereafter, assessments vary based on age of child. ] [ Designated as safety issue: No ]
  Assessed via head circumference measurement and medical record review for documented clinical diagnoses of seizures, microcephaly, or other neurologic diagnosis.
• Neurodevelopmental abnormalities [ Time Frame: 1, 3, 5, 9, and 13 years of age, assessments vary based on age of child. ] [ Designated as safety issue: No ]
  Assessed via the following neurodevelopmental tests: Bayley Screener, Bayley III, WPPSI-III, BASC-2, WASI, WISC-IV, BRIEF, WIAT II.
• Abnormal growth and metabolic function [ Time Frame: Annually birth through age 5; semiannual thereafter, assessments vary based on age of child. ] [ Designated as safety issue: No ]
  Assessed through the measurement of height, weight, tricep skinfold thickness, mid-upperarm circumference measurements, insulin and glucose, and fasting lipids.
• Cardiac abnormalities [ Time Frame: Ages 3-5. ] [ Designated as safety issue: No ]
  Assessed through the administration of echocardiograms and serum biomarkers (ProBNP).
• Hearing dysfunction [ Time Frame: At age 5 and for children of all ages meeting a hearing/language trigger. ] [ Designated as safety issue: No ]
  Assessed via audiologic evaluation conducted by an audiologist.
• Language dysfunction [ Time Frame: 1, 2, 3, 5, and 9 years of age, assessments vary based on age. ] [ Designated as safety issue: No ]
  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.
• Drug Use and Sexual Activity [ Time Frame: 11, 13, 15, and 17 years of age. ] [ Designated as safety issue: No ]
  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.
• Abnormal organ function [ Time Frame: Birth and age one, semiannual thereafter. ] [ Designated as safety issue: No ]
  Assessed through the measurement of lipase, CPK, ALT, creatinine, glucose, LDH, BUN, WBC, PMN, lymphocytes, platelets, or hemoglobin ( ≥ Grade 3 adverse event).
• Death due to unknown medical condition [ Time Frame: Annual. ] [ Designated as safety issue: No ]
  Assessed through autopsy review.

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.

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 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
4. 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.

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

• Static Cohort
  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
  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

• Tassiopoulos K, Read JS, Brogly S, Rich K, Lester B, Spector SA, Yogev R, Seage GR 3rd. Substance use in HIV-Infected women during pregnancy: self-report versus meconium analysis. AIDS Behav. 2010 Dec;14(6):1269-78.
• Griner R, Williams PL, Read JS, Seage GR 3rd, Crain M, Yogev R, Hazra R, Rich K; Pediatric HIV/AIDS Cohort Study. In utero and postnatal exposure to antiretrovirals among HIV-exposed but uninfected children in the United States. AIDS Patient Care STDS. 2011 Jul;25(7):385-94. Epub 2011 Jun 10.
• Crain MJ, Williams PL, Griner R, Tassiopoulos K, Read JS, Mofenson LM, Rich KC; Pediatric HIVAIDS Cohort Study. Point-of-care capillary blood lactate measurements in human immunodeficiency virus-uninfected children with in utero exposure to human immunodeficiency virus and antiretroviral medications. Pediatr Infect Dis J. 2011 Dec;30(12):1069-74.
• Williams PL, Seage GR 3rd, Van Dyke RB, Siberry GK, Griner R, Tassiopoulos K, Yildirim C, Read JS, Huo Y, Hazra R, Jacobson DL, Mofenson LM, Rich K; Pediatric HIV/AIDS Cohort Study. A trigger-based design for evaluating the safety of in utero antiretroviral exposure in uninfected children of human immunodeficiency virus-infected mothers. Am J Epidemiol. 2012 May 1;175(9):950-61. Epub 2012 Apr 6.
• Siberry GK, Williams PL, Mendez H, Seage GR 3rd, Jacobson DL, Hazra R, Rich KC, Griner R, Tassiopoulos K, Kacanek D, Mofenson LM, Miller T, DiMeglio LA, Watts DH; Pediatric HIV/AIDS Cohort Study (PHACS). Safety of tenofovir use during pregnancy: early growth outcomes in HIV-exposed uninfected infants. AIDS. 2012 Jun 1;26(9):1151-9. doi: 10.1097/QAD.0b013e328352d135.
• Watts DH, Williams PL, Kacanek D, Griner R, Rich K, Hazra R, Mofenson LM, Mendez HA; Pediatric HIV/AIDS Cohort Study. Combination antiretroviral use and preterm birth. J Infect Dis. 2013 Feb 15;207(4):612-21. doi: 10.1093/infdis/jis728. Epub 2012 Nov 29.
• Wilkinson JD, Williams PL, Leister E, Zeldow B, Shearer WT, Colan SD, Siberry GK, Dooley LB, Scott GB, Rich KC, Lipshultz SE; for the Pediatric HIVAIDS Cohort Study (PHACS). Cardiac Biomarkers in HIV-Exposed Uninfected Children: The Pediatric HIV/AIDS Cohort Study (PHACS). AIDS. 2012 Dec 3. [Epub ahead of print]
• Sirois PA, Huo Y, Williams PL, Malee K, Garvie PA, Kammerer B, Rich K, Van Dyke RB, Nozyce ML; for the Pediatric HIVAIDS Cohort Study. Safety of Perinatal Exposure to Antiretroviral Medications: Developmental Outcomes in Infants. Pediatr Infect Dis J. 2013 Jan 21. [Epub ahead of print]
• Himes SK, Scheidweiler KB, Tassiopoulos K, Kacanek D, Hazra R, Rich K, Huestis MA; Pediatric HIV/AIDS Cohort Study. Development and validation of the first liquid chromatography-tandem mass spectrometry assay for simultaneous quantification of multiple antiretrovirals in meconium. Anal Chem. 2013 Feb 5;85(3):1896-904. doi: 10.1021/ac303188j. Epub 2013 Jan 14.

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.

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:

None

Reference Cohort:

• Monolingual Spanish-speaking child or parent/caregiver.

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