PEDIATRIC LATE OUTCOMES PROTOCOL

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。本研究的目的是跟踪目前或曾经参加过儿科ACTG治疗围产期或药物研究的儿童和青少年，以寻找治疗在生长、神经和神经心理功能、长期生存和生活质量方面的任何后期后果。如果儿童目前或以前参加了儿童ACTG方案，或目前参加了在ACTG地点进行的儿童艾滋病基金会长期幸存者研究，则该儿童有资格参加本研究。这包括感染艾滋病毒的母亲所生的婴儿，这些母亲在怀孕时参加了ACTG药物研究，无论婴儿是否明确感染艾滋病毒。所有孩子都有资格被跟踪到21岁生日。下面有几个关键的假设，这些假设是这个晚期结局协议计划解决的与儿科干预有关的问题。此外，预计本方案中收集的纵向数据将使儿科ACTG的研究人员能够回答涉及围产期方案中特定治疗的其他研究问题和假设。围产期组:在子宫内暴露于齐多夫定（或其他研究治疗）的最终未感染婴儿中，与未在子宫内暴露于齐多夫定（或其他研究治疗）的美国儿科人群的患病率相比，晚期器官异常/毒性（重点是高线粒体接触系统-心脏，肝脏，肌肉），出生缺陷或肿瘤（即阴道肿瘤，巴氏涂片异常）的患病率不会显着增加。对于参与ACTG 076的婴儿，与接受安慰剂的未感染儿童的患病率进行比较。对于未来的其他研究，可能需要与国家患病率进行比较。在未感染ACTG 076的婴儿中，与母亲在怀孕期间接受安慰剂的婴儿相比，母亲接受ZDV的婴儿在生长或发育方面没有显著差异：a)生长（体重、身高、头围）b.青春期发育（坦纳分期、第一次月经年龄）c. Bayley和后来的认知测试的平均神经认知得分。在ACTG 185的受感染儿童中，母亲接受hiv感染的儿童与母亲接受IVIG感染的儿童在疾病进展方面没有差异。疾病进展由临床（即艾滋病定义的疾病、死亡）、免疫学（即年龄调整后的CD4+计数）和病毒学（通过检测储存的ACTG 219标本定量中心负荷，检测结果有待确定）参数确定。HIV感染组：与特定药物治疗相关的长期累积剂量相关药物特异性器官系统毒性发生率将存在差异。例如，与其他抗逆转录病毒疗法相比，慢性ZDV疗法更有可能发生肝脏、心脏或肌肉毒性；慢性ddI或使用ddC更容易出现周围神经病变；ddI、ddC或3TC更可能与胰腺异常有关。与单一治疗相比，初始联合治疗（例如，使用随机化治疗方案，如ACTG 152、239和300）将显著增加长期生存率，改善身体生长和生活质量，通过生存期长度、身高、体重和头围的平均生长百分位数以及生活质量仪器的中位数得分来衡量。与最初使用抗逆转录病毒单一疗法相比，在婴儿期（0-24个月）（例如，ACTG 152或239）首次使用联合疗法将导致更少的神经学诊断和4岁和7岁时显著更高的平均神经认知评分。对于方案128中的儿童（在128入组后5-7年随访），治疗组间WISC-R的神经认知评分仍无显著差异。随着时间的推移，药物/生物干预措施、机会性传染病的预防和治疗方案的进展以及支持性护理的改善将显著提高参与ACTG方案的连续儿童群体的生存率、改善生长发育、降低发病率和改善生活质量。这将通过比较连续队列中暴露于ACTG方案中药物/生物制剂的儿科受试者在2、4、7、15和20岁时的生存率、中位数生长百分位数、中位数CD4+百分比和生活质量评分来评估。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The purpose of this study is to follow children and adolescents who are currently enrolled in or were previously enrolled in pediatric ACTG treatment perinatal or drug research studies to look for any late consequences of therapy in growth, neurologic and neuropsychologic function, long term survival, and quallity of life. The child is eligible for this study if the child is currently enrolled in, or was previously enrolled in a pediatric ACTG protocol or is currently enrolled in the Long Term Survivors of the Pediatric AIDS Foundation study being conducted at an ACTG site. This includes infants born to HIV infected mothers who were enrolled in an ACTG drug study when they were pregnant, regardless of whether or not definite HIV infection status in the infant is known. All children are eligible to be followed until their 21st birthday. There are several key hypotheses listen below that this late outcomes protocol plans to address in relation to pediatric interventions. In addition, it is also anticipated that the longitudinal data gathered in this protocol will enable investigators in the pediatric ACTG to answer other research questions and hypotheses specific to treatment in perinatal protocols in which they are involved. Perinatal Group: There will be no signficiantly increased prevalence of late organ abnormality/toxicity (focus on system with high mitochondrial contact - heart, liver, muscle), birth defects or neoplasms (i.e. vaginal tumor, pap smear abnormality) among ultimately uninfected infants exposed to zidovudine (or other study treatments) in utero compared to prevalence rates among comparable pediatric populations in the United States who were not exposed in utero to zidovudine (or other study treatments). For infants enrolled in ACTG 076, the comparison to prevalence rates will be for uninfected children who received placebo. For other future studies, comparison to national prevalence rates may need to be used. Among uninfected infants on ACTG 076, there will be no significant differences in growth or development among infants whose mothers received ZDV compared to those whose mother's received placebo during pregnancy: a.) growth (weight, height, head circumference) b.) pubertal development (Tanner staging, age of first menses) c.) mean neurocognitive scores on Bayley and later cognitive tests. Among infected children from ACTG 185, there will be no difference in disease progession betweent hose whose mothers received HIVIG compared to those whose mothers received IVIG. Disease progression is defined by clinical (i.e. AIDS-defining illness, death), immunologic (i.e. age-adjusted CD4+count), and virologic (quantitative central load via testing of ACTG 219 stored specimens, test to be determined) parameters. HIV Infected Group: There will be differences in rates of long term cumulative dose-related drug specific organ system toxicities related to specific drug therapies. For example, hepatic, cardiac or muscle toxicity will be more likely to occur with chronic ZDV therapy compared to other antiretroviral therapies; peripheral neuropathy will be more likely to be seen with chronic ddI, or ddC use; and ddI, ddC or 3TC will be more likely to be associated with pancreatic abnormalities. Initial combination therapy as compared to montherapy (e.g., using a randomization treatment protocol such as ACTG 152, 239 and 300) will result in significantly increased long term survival and improved physical growth and quality of life, as measured by length of survival, mean growth percentiles for height, weight and head circumference, and median scores on quality of life instruments. Initial use of combination therapy in infancy (0-24 months) (e.g., ACTG 152 or 239) will result in fewer neurology diagnoses and signficiantly higher mean neurocognitive scores at age 4 and 7 years compared to initial use of antiretroviral monotherapies. For children from Protocol 128 (followed up at 5-7 years post enrollment on 128) there will continue to be no significant differences in neurocognitive scores on the WISC-R between treatment arms. Advances in drug/biologic interventions, prophylaxis and treatment regimens for opportunistic infecious diseases and improved supportive care over time will result in significantly increased survival, improved growth adn development, decreased morbidity, and improved quality of life for successive cohorts of children involved in ACTG protocols. This will be assessed by comparing survival, median growth percentiles, median CD4+ percentages and quality of life scores at ages 2, 4, 7, 15, and 20 years for successive cohorts (e.g., assessed serially every 3 to 5 years) of pediatric subjects exposed to drugs/biologics in ACTG protocols.