Optimizing pediatric HIV-1 therapy

描述（由申请人提供）：儿童HIV-1比成人HIV-1感染更具侵袭性，在生命的前2年内死亡风险超过50%。重要的是要确定优化儿科高效抗逆转录病毒疗法（HAART）的方法，特别是在非洲，世界上大约90%的HIV-1感染儿童居住在那里。本研究的假设为：1.在暴露于奈韦拉平但在基于人群的测序中未检测到奈韦拉平耐药性的婴儿中，含奈韦拉平的HAART的疗效与涉及蛋白酶抑制剂的奈韦拉平保留方案相当，后者与热不稳定性、毒性和不良适口性相关。2.检测低水平耐药性的敏感基因型耐药性检测可能会预测奈韦拉平治疗失败。3.在初次感染期间，早期高效抗逆转录病毒疗法将防止婴儿死亡，恢复免疫功能，并控制病毒血症，此后，鉴于婴儿免疫能力随年龄增长而成熟，从而提高了控制艾滋病毒-1的能力，抗逆转录病毒疗法可推迟到感染后期;这种方法将提供早期HAART的生存益处，而无需终身无限期治疗（与累积毒性、耐药性和治疗疲劳相关）。我们建议在内罗毕按年龄分层的HIV-1感染婴儿中进行临床试验。既往暴露于奈韦拉平单次给药的HIV-1感染婴儿（6- 12月龄）将接受测序，以确定奈韦拉平耐药，之后将无奈韦拉平耐药的婴儿随机分配至含奈韦拉平与不含奈韦拉平的HAART组（每组100例），并在24个月随访期间比较病毒抑制、CD 4%、毒性和临床进展。在该组中，将进行检测低水平奈韦拉平耐药的基因型耐药试验，以确定低水平基因型耐药是否可预测治疗失败。0-3个月大的婴儿（300名）将接受含Pi的HAART治疗24个月，之后将那些正常生长和免疫重建的婴儿随机分为继续治疗和延迟治疗，并在18个月内比较生长和临床发病率。推迟治疗组的儿童将保持停药状态，除非临床或免疫参数要求。将评估其他相关因素，包括依从性、年龄、免疫活化标志物和HIV-1特异性免疫应答对HIV-1进展的影响。这些研究的结合将为改善HIV-1高血清阳性率地区的儿科HAART策略提供关键信息。

DESCRIPTION (provided by applicant): Pediatric HIV-1 has a much more aggressive course than adult HIV-1 infection, with an over 50% risk of mortality in the first 2 years of life. It is important to determine ways to optimize pediatric highly active antiretroviral therapy (HAART), specifically in Africa, where approximately 90% of the world's HIV-1 infected children reside. The hypotheses of this study are: 1. Among nevirapine-exposed infants without detectable nevirapine resistance on population-based sequencing, nevirapine-containing HAART will be comparable in efficacy to nevirapine-sparing regimens that involve protease inhibitors, which are associated with heat-lability, toxicity, and poor palatability. 2. Sensitive genotypic resistance assays to detect low-level resistance may predict nevirapine-treatment failure. 3. Early HAART during primary infection will prevent infant mortality, restore immune function, and contain viremia, after which antiretroviral treatment can be deferred to later stages of infection, given age-related infant immune maturation and the resulting improved capacity to contain HIV-1; this approach will provide the survival benefits of early HAART without obligating life-long indefinite therapy (associated with cumulative toxicity, resistance, and treatment fatigue). We propose clinical trials among age-stratified HIV-1 infected infants in Nairobi. HIV-1 infected infants (6- 12 mos old) previously exposed to single-dose nevirapine will undergo sequencing to identify nevirapine resistance, after which infants without nevirapine resistance will be randomized to nevirapine-containing vs. nevirapine-sparing HAART (100 per arm) and compared for viral suppression, CD4%, toxicity, and clinical progression during 24 mos follow-up. In this group, genotypic resistance assays to detect low levels of nevirapine-resistance will be conducted to determine whether low-level genotypic resistance will predict treatment failure. Infants aged 0-3 mos old (300) will receive Pi-containing HAART for 24 months, after which those with normal growth and immune reconstitution will be randomized to continued vs. deferred treatment and compared for growth and clinical morbidity in an 18-month period. Children in the deferred arm will be maintained off therapy unless clinical or immune parameters require. Additional correlates, including compliance, age, immune activation markers, and HIV-1 specific immune responses, will be assessed for effect on HIV-1 progression. This combination of studies will provide critical information for improving pediatric HAART strategies in high HIV-1 seroprevalence regions.