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.
  
  

• Maternal substance use during pregnancy [ Time Frame: Entry visit. ] [ Designated as safety issue: No ]
  Obtained via interview, toxicology report, and meconium testing.
  
  

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.