Optimizing pediatric HIV-1 therapy

描述（由申请人提供）：儿童HIV-1的病程比成人HIV-1感染更具侵袭性，在生命的头两年有超过50%的死亡风险。重要的是确定优化儿科高效抗逆转录病毒治疗（HAART）的方法，特别是在非洲，世界上约90%的艾滋病毒1型感染儿童居住在那里。本研究的假设是：1。在人群测序中未检测到奈韦拉平耐药的奈韦拉平暴露婴儿中，含奈韦拉平HAART的疗效将与使用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、毒性和适口性差有关。2. 检测低水平耐药的敏感基因型耐药试验可预测奈韦拉平治疗失败。3. 在初次感染期间早期进行HAART治疗将预防婴儿死亡，恢复免疫功能，并控制病毒血症，此后抗逆转录病毒治疗可推迟到感染的后期阶段，因为与年龄相关的婴儿免疫成熟以及由此提高的控制艾滋病毒-1的能力；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。先前暴露于单剂量奈韦拉平的HIV-1感染婴儿（6- 12月龄）将进行测序以确定奈韦拉平耐药性，之后，无奈韦拉平耐药性的婴儿将随机分为含奈韦拉平和不含奈韦拉平的HAART组（每组100例），并在24月龄随访期间比较病毒抑制、CD4%、毒性和临床进展。在该组中，将进行基因型耐药试验以检测低水平的奈韦拉平耐药，以确定低水平的基因型耐药是否可以预测治疗失败。0-3个月大的婴儿（300岁）将接受含pi的HAART治疗24个月，之后生长和免疫重建正常的婴儿将随机分为持续治疗组和延迟治疗组，并比较18个月期间的生长和临床发病率。除非临床或免疫参数需要，延迟组的儿童将保持不接受治疗。其他相关因素，包括依从性、年龄、免疫激活标记物和HIV-1特异性免疫反应，将被评估对HIV-1进展的影响。这些研究的结合将为改善HIV-1血清高患病率地区的儿童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.