Optimizing pediatric HIV-1 therapy

儿童HIV-1的病程比成人HIV-1感染更具侵袭性，有超过50%的风险 生命头两年的死亡率。确定优化儿科高活性的方法是很重要的。 抗逆转录病毒疗法(HAART)，特别是在非洲，在那里，世界上90%的艾滋病毒-1感染儿童 住下来。 这项研究的假设是：1.在未检测到奈韦拉平的暴露于奈韦拉平的婴儿中 基于群体测序的耐药性，含有奈韦拉平的HAART的疗效将与 奈韦拉平的非治疗方案，包括与热不稳定，毒性， 适口性差。2.检测低水平抗性的敏感基因抗性分析可以预测 奈韦拉平治疗失败。3.初次感染期间早期HAART将防止婴儿死亡，恢复 免疫功能，并包含病毒血症，之后抗逆转录病毒治疗可推迟到后期 感染，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的生存益处，而不需要终身无限期的治疗 (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。感染艾滋病毒-1的婴儿(6- 12个月以前接触过单剂量奈韦拉平的人将接受测序以鉴定奈韦拉平 在此之后，没有奈韦拉平耐药性的婴儿将随机接受含有奈韦拉平的对照组。 奈韦拉平保留的HAART(每臂100例)，并比较病毒抑制、CD4%、毒性和临床 在24个月的随访中取得进展。在这组人中，基因耐药分析检测到低水平的 奈韦拉平的耐药性将被用来确定低水平的基因耐药性是否会预测 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 正常生长和免疫重建将随机分为继续治疗和延期治疗 比较18个月期间的生长发育和临床发病率。延期手臂上的孩子将被 除非临床或免疫参数需要，否则停止治疗。其他相关因素，包括 将评估依从性、年龄、免疫激活标记物和HIV-1特异性免疫反应 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。

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 -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.