Adolescent Master Protocol

Study Overview
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Brief Summary
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The advances in treatment to prevent maternal HIV transmission to neonates have been groundbreaking. As a result, the number of new perinatally-infected children in the U.S. is now small. Subsequent improvements in the treatment of HIV-infected infants and children have been equally remarkable, ensuring that most previously infected American children have survived and are approaching adolescence. In addition, the number of HIV-infected adolescents worldwide is growing substantially in both resource-poor countries and in countries with increasing levels of health care. Therefore, there is a global cohort of children who have been living with HIV infection since birth who are aging into adolescence. Little is definitively known about the impact of HIV infection and its treatment on the maturation process in these children. AMP is a prospective cohort study designed to define the impact of HIV infection and antiretroviral therapy on pre-adolescents and adolescents with perinatal HIV infection. Domains to be investigated include growth and sexual maturation, metabolic risk factors for cardiovascular disease, cardiac function, bone health, neurologic, neurodevelopment, language, hearing and behavioral function, and sexually transmitted infections (STI).

Detailed Description
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The primary objectives of AMP are: 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. To identify infectious and non-infectious complications of HIV disease, including the toxicities of antiretroviral therapy (ART). 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: 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. 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. 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. 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. 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. 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.

Official Title
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Adolescent Master Protocol

Conditions
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HIV/AIDS

Participation Criteria
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Eligibility Criteria
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HIV-Infected Cohort Inclusion Criteria: Perinatal HIV infection as documented in the medical record. Age 7 years (7th birthday) up to but not including the 16th birthday at enrollment. Engaged in care and ART history is available. Either: Previous or current enrollment in any of the studies included on the list of approved studies allowing for enrollment into AMP as specified in the protocol. Children participating in other studies may be enrolled with approval of the Protocol Team. Additional approved protocols are listed on the PHACS website; Or: Available medical record documentation since birth of 1)ART exposure history 2)Opportunistic Infection (OI) prophylaxis exposure history 3) Viral load and CD4 count history and 4) Major medical events history Willingness to participate and provide parental/legal guardian permission with assent. Children who do not know their HIV infection status will not be excluded. Exclusion criteria: HIV acquired by other than maternal-child transmission (e.g., blood products, sexual contact, and IV drug use) as documented in the medical record. HIV-Uninfected, HIV-Exposed Control Cohort Inclusion criteria: HIV-uninfected and born to an HIV-infected mother as documented in the medical record. Age 7 years (7th birthday) up to but not including the 16th birthday at enrollment. Previous or current enrollment in any of the studies included on the list of approved studies allowing for enrollment into AMP. Children participating in other studies may be enrolled with approval of the Protocol Team. Additional approved protocols will be listed on the PHACS website; Or: Available medical record documentation since birth of 1)ART exposure history and 2) Major medical events history. Willingness to participate and provide parental/legal guardian permission with assent. Exclusion Criteria: None.

Ages Eligible for Study
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Minimum Age: 7 Years

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 |
| --- | --- |
| Infected Cohort<br>Perinatally HIV-infected adolescents from 7 years of age (7th birthday) up to but not including the 16th birthday at enrollment, engaged in care with ART treatment history available. | |
| Uninfected Cohort<br>HIV-uninfected adolescents from 7 years of age (7th birthday) up to but not including the 16th birthday at enrollment born to HIV-infected mothers. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Abnormal growth | 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. | Annually for 10 years | 
| Delayed sexual maturation | 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 | Annually for 10 years except if subject reaches Tanner Stage 5 | 
| Abnormal bone mineral density | 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) | 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 | 
| Dyslipidemia | 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) | Annually for 10 years | 
| Cardiac abnormalities | Assessed through the administration of echocardiograms and serum biomarkers (ProBNP) | Measured once per subject until study reached 400 echocardiograms | 
| Hearing dysfunction | Assessed via audiologic evaluation conducted by an audiologist. | Once per subject. | 
| Language dysfunction | Assessed using the Woodcock and CELF IV language tests | Annually for 10 years | 
| Neurodevelopmental abnormalities | 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 | Annually for 10 years | 
| Substance Use | 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. | Annually starting at a minimum of 10 years of age for 10 years | 
| Sexual Activity | 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. | Annually starting at a minimum of 10 years of age for 10 years | 
| Pregnancy | Assessed via medical record review to record incidents of pregnancy | Annually for 10 years | 
| Sexually Transmitted Infection | Assessed via medical record review to record results of clinically conducted STI and Pap testing and pelvic exams | Annually for 10 years | 
| Mitochondrial dysfunction | Assessed via measurement of serum lactate levels, OXPHO immunoassays, mitochondrial specific oxidative stress, mtDNA copies/cell, mrRNA transcripts | Annually for 10 years | 
| Lactic acidosis | 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 | Annually for 10 years | 
| Renal abnormalities | Assessed through the following laboratory measurements: chemistry panel, urinalysis, protein/creatinine ratio, dip stick urine test | Annually for 10 years |