Adolescent Master Protocol (AMP)

• Abnormal growth [ Time Frame: Annually for 10 years ] [ Designated as safety issue: No ]
  Assessed via measurement of height, weight, skinfold thickness, mid-upper arm and waist and hip circumference, nutrition and physical activity questionnaires ; subjects meeting growth trigger based on height measurements also have the following laboratory assessments: IGF-I, IGFBP-3, and GHBP. A growth hormone stimulation test may also be required at the recommendation of the endocrinologist.
  
  
• Delayed sexual maturation [ Time Frame: Annually for 10 years except if subject reaches Tanner Stage 5 ] [ Designated as safety issue: No ]
  Assessed via tanner staging; subjects meeting the growth trigger based on the results of the tanner staging will also have the following laboratory assessments: morning LH, FSH, estradiol, and testosterone
  
  
• Abnormal bone mineral density [ Time Frame: Two DXAs, two years apart, per HIV-infected subject; one DXA per uninfected subject; X-ray at same time as DXA unless subject Tanner Stage 5 ] [ Designated as safety issue: No ]
  Assessed via DXA scan and x-ray for bone age; subjects meeting the BMD trigger based on the DXA also have the following laboratory assessments: TSH, calcium, 25-hydroxy-vitamin D, bone-specific alkaline, N-terminal telopeptide of type I collagen phosphatase, and PTH in real time and repository specimens for assay of pro-inflammatory cytokines (IL-1, IL-6, TNF-a)
  
  
• Dyslipidemia [ Time Frame: Annually for 10 years ] [ Designated as safety issue: No ]
  Assessed via lipid testing; subjects meeting the metabolic trigger based on the results of the lipid tests also have the following measurements: endothelial dysfunction (I, E, P-selectins: V, I-CAM-1, endothelin-1, hs-CRP, homocysteine, apolipoprotein B, lipoprotein (a), and vWF antigen)
  
  
• Cardiac abnormalities [ Time Frame: Measured once per subject until study reached 400 echocardiograms ] [ Designated as safety issue: No ]
  Assessed through the administration of echocardiograms and serum biomarkers (ProBNP)
  
  
• Hearing dysfunction [ Time Frame: Once per subject. ] [ Designated as safety issue: No ]
  Assessed via audiologic evaluation conducted by an audiologist.
  
  
• Language dysfunction [ Time Frame: Annually for 10 years ] [ Designated as safety issue: No ]
  Assessed using the Woodcock and CELF IV language tests
  
  
• Neurodevelopmental abnormalities [ Time Frame: Annually for 10 years ] [ Designated as safety issue: No ]
  Assessed via the following neurodevelopmental tests: WISC IV, WAIS IV, BRIEF, Children's Color Trails Test, Trail Making Tests, WIAT-II screen, ABAS, Parent Child Relationship Inventory, BASC-2, Quality of Life Interview, Stressful Life Events Questionnaire, Monitoring the Future
  
  
• Substance Use [ Time Frame: Annually starting at a minimum of 10 years of age for 10 years ] [ Designated as safety issue: No ]
  The assessment of sexual activity is 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.
  
  
• Sexual Activity [ Time Frame: Annually starting at a minimum of 10 years of age for 10 years ] [ Designated as safety issue: No ]
  The assessment of substance use is 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.
  
  
• Pregnancy [ Time Frame: Annually for 10 years ] [ Designated as safety issue: No ]
  Assessed via medical record review to record incidents of pregnancy
  
  
• Sexually Transmitted Infection [ Time Frame: Annually for 10 years ] [ Designated as safety issue: No ]
  Assessed via medical record review to record results of clinically conducted STI and Pap testing and pelvic exams
  
  
• Mitochondrial dysfunction [ Time Frame: Annually for 10 years ] [ Designated as safety issue: No ]
  Assessed via measurement of serum lactate levels, OXPHO immunoassays, mitochondrial specific oxidative stress, mtDNA copies/cell, mrRNA transcripts
  
  
• Lactic acidosis [ Time Frame: Annually for 10 years ] [ Designated as safety issue: No ]
  Assessed through the measurement of blood lactate levels using a point-of-care lactate measuring device; a single venous lactate measurement will be conducted in cases where the POC lactate measure is elevated
  
  
• Renal abnormalities [ Time Frame: Annually for 10 years ] [ Designated as safety issue: No ]
  Assessed through the following laboratory measurements: chemistry panel, urinalysis, protein/creatinine ratio, dip stick urine test
  
  

The primary objectives of AMP are:

1. To define the impact of HIV infection and ART on growth and pubertal development (and their hormonal regulation), along with the cognitive, academic, and social development, of pre-adolescents and adolescents with perinatal HIV infection as they move through adolescence into adulthood.
2. To identify infectious and non-infectious complications of HIV disease, including the toxicities of antiretroviral therapy (ART).

3. To investigate:

   • Cognitive and behavioral changes over time, including medication adherence, family and social function, and high risk behaviors such as risky sexual behavior, licit and illicit drug use, and alcohol use;
   • Changes in language and hearing;
   • Changes in glucose metabolism, body composition, and bone mineralization;
   • Changes in lipid metabolism and other risk factors for cardiovascular disease;
   • Risk factors for secondary transmission of HIV; and
   • The occurrence and clinical course of cervical HPV infections among females.

The domain-specific aims of AMP are:

1. Growth and sexual maturation: To longitudinally track growth and sexual maturation and the factors that influence growth and maturation in HIV-infected children when compared to HIV-exposed but uninfected children.
2. Metabolic risk factors for cardiovascular disease: To characterize the emergence of abnormal glucose metabolism, lipid abnormalities, body composition and other risk factors for cardiovascular disease and identify the contributing influences in HIV-infected children when compared to HIV-exposed but uninfected children.
3. Cardiac function: To estimate the prevalence of cardiac structural and functional abnormalities in HIV-infected children and youth when compared to HIV-exposed but uninfected children.
4. Bone mineral density: To estimate the differences in bone mineral density of HIV-infected children when compared to HIV-exposed but uninfected children and to identify factors contributing to abnormal bone mineralization.

5. Neurologic, neurodevelopment, language, and behavioral function:

   • To examine cognitive and behavioral outcomes of HIV-infected children and adolescents, including high risk behaviors such as risky sexual behavior, licit and illicit drug use, and alcohol use, neurodevelopmental impairment, school achievement and to compare them with an HIV-exposed but uninfected control cohort.
   • To examine non-adherence to antiretroviral therapy and predictors of non-adherence among HIV-infected children receiving ART.
   • To examine family and psychosocial factors associated with emotional and behavioral problems.

6. Adolescent gynecology and STI infection:

   • To evaluate the incidence of and risk factors for acquiring STIs/vaginal infections (C. trachomatis, N. gonorrhea, T. vaginalis, syphilis, genital warts, HPV, and HSV) for males and females, and in addition bacterial vaginosis for females.
   • To evaluate the incidence, predictors, and outcomes of pregnancy.