Optimizing pediatric HIV-1 therapy

描述(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，因为世界上约90%的艾滋病毒感染儿童居住在非洲。这项研究的假设是：1.在人群测序中没有检测到奈韦拉平耐药性的暴露于奈韦拉平的婴儿中，含有奈韦拉平的HAART的疗效与使用奈韦拉平的非奈韦拉平方案的疗效相当，后者涉及酶抑制剂，后者与热不稳定、毒性和适口性差有关。2.检测低水平耐药的敏感基因耐药试验可预测奈韦拉平治疗失败。3.初次感染期间的早期HAART将防止婴儿死亡，恢复免疫功能，并遏制病毒血症，之后抗逆转录病毒治疗可推迟到感染的后期阶段，考虑到与年龄相关的婴儿免疫成熟和由此提高的遏制艾滋病毒-1的能力；这种方法将提供早期HAART的生存好处，而不强制终身无限期治疗(与累积毒性、耐药性和治疗疲劳有关)。我们建议在内罗毕对感染HIV-1的婴儿进行年龄分层的临床试验。之前接受单剂奈韦拉平治疗的HIV-1感染婴儿(6-12个月大)将接受测序，以确定奈韦拉平的耐药性，之后，没有奈韦拉平耐药性的婴儿将被随机分成两组，接受含有奈韦拉平的HAART和不服用奈韦拉平的HAART(每臂100例)，并在24个月的随访期间比较病毒抑制、CD4%、毒性和临床进展。在这一组中，将进行检测奈韦拉平低水平耐药的基因耐药试验，以确定低水平的基因耐药是否将预测治疗失败。0-3个月大的婴儿(300名)将接受为期24个月的含PI的HAART治疗，之后那些生长正常和免疫重建的婴儿将被随机分为继续治疗和延期治疗两组，并在18个月期间比较生长和临床发病率。除非临床或免疫参数需要，否则延期治疗的儿童将被维持在停止治疗的状态。其他相关因素，包括依从性、年龄、免疫激活标志物和HIV-1特异性免疫反应，将被评估对HIV-1进展的影响。这项研究的结合将为改进高HIV-1血清阳性地区的儿科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.