Treatment Options for Protease Inhibitor Exposed Children

描述(由申请人提供)：新的儿科治疗指南建议开始对所有感染艾滋病毒的婴儿进行抗逆转录病毒治疗，无论他们的免疫学或临床特征如何。由于在使用奈韦拉平(NVP)预防母婴传播(PMTCT)后对非核苷类逆转录酶抑制剂(NNRTI)产生耐药性，建议开始使用洛比那韦/利托那韦(LPV/r)治疗。对于所有感染艾滋病毒的儿童是否应该从小开始治疗，指南没有具体的建议(通常建议作为二线方案，但这里建议作为一线方案)。无限期、长期使用LPV/r疗法有几个风险，包括其适口性差(增加了幼儿和较大儿童的依从性挑战)、与用于结核病联合治疗的利福平的相互作用、缺乏任何合适的二线方案，以及对其用于发育中儿童的长期代谢毒性的不确定性。我们提出了一项非盲目随机临床试验，以评估一种简化的、省去蛋白酶抑制剂(PI)的治疗策略，用于最初接受LPV/r治疗的NVP暴露的HIV感染儿童。主要目标是测试在接受LPV/r治疗的受抑儿童中，当儿童切换到基于efavirenz(EFV)的治疗时，病毒抑制的持久性是否相同。基于EFV的治疗是一种有吸引力的替代疗法，因为它已经被推荐用于3岁儿童的治疗，被广泛使用，适合每天一次的儿科配方，毒性很低，并被推荐与利福平联合治疗。我们建议在南非约翰内斯堡的一个诊所招募300名3至5岁的艾滋病毒感染儿童。纳入标准将包括作为预防母婴传播的一部分暴露于NVP，在生命的头36个月开始基于LPV/r的治疗，以及病毒载量为50拷贝/毫升。这些儿童将被随机分为两组，一组用EFV替代LPV/r，另一组继续接受基于LPV/r的方案。随机化后，儿童将接受为期48周的定期病毒载量和其他临床测试。在试验组中，在EFV方案中出现突破性病毒血症的儿童将立即重新启动LPV/r方案。次要目标包括比较免疫保存、毒性、耐药突变的选择以及两个手臂的粘附性。将调查抗逆转录病毒药物的浓度和依从性，作为对这种简化方案效果的可能解释。这项研究的总体目标是为证据基础作出贡献，以便在资源匮乏的情况下扩大艾滋病毒感染儿童的治疗选择。 公共卫生相关性：我们建议进行一项随机临床试验，以评估在接受奈韦拉平治疗的HIV感染儿童中，在3至5岁时改用基于洛比那韦/利托那韦的抗逆转录病毒治疗是否能与继续使用基于洛比那韦/利托那韦的治疗类似地维持病毒学抑制。

DESCRIPTION (provided by applicant): New pediatric treatment guidelines recommend starting all HIV-infected infants on antiretroviral treatment regardless of their immunologic or clinical profile. Treatment initiation with Lopinavir/ritonavir (LPV/r) is recommended because of concerns about resistance to non-nucleoside reverse transcriptase-inhibitors (NNRTI) following use of nevirapine (NVP) in prevention of mother-to-child HIV transmission (PMTCT). Guidelines offer no specific advice about whether LPV/r-based therapy (usually recommended as a second- line regimen but here recommended as first-line) should be continued life-long for all HIV-infected children starting therapy at a young age. There are several risks associated with indefinite, long-term use of LPV/r- based therapy, including its poor palatability (raising adherence challenges in toddlers and older children), interactions with rifampicin used for co-treatment for tuberculosis, the lack of any suitable second-line regimens, and uncertainty about its long-term metabolic toxicities when used in developing children. We propose an unblinded randomized clinical trial to evaluate a simplification, protease-inhibitor (PI)-sparing treatment strategy among NVP-exposed HIV-infected children treated initially with LPV/r. The primary objective is to test, among children suppressed on LPV/r-based therapy, whether the durability of viral suppression is equivalent when children are switched to efavirenz (EFV)-based therapy. EFV-based therapy is an attractive alternative as it is already recommended for treatment of children >3 years, is widely used, palatable with once daily pediatric formulations, a low, well-described toxicity profile, and is recommended for co-treatment with rifampicin. We propose to recruit 300 HIV-infected children aged 3 to 5 years at a clinical site in Johannesburg, South Africa. Inclusion criteria will include exposure to NVP as part of PMTCT, initiation of LPV/r-based therapy in the first 36 months of life and a viral load < 50 copies/ml. These children will be randomized to either substitute EFV for LPV/r or to continue on their LPV/r-based regimen. Children will be followed with regular viral load and other clinical tests for 48 weeks after randomization. Children in the experimental arm who have breakthrough viremia on the EFV-based regimen will promptly reinitiate the LPV/r regimen. Secondary aims include comparison of immune preservation, toxicities, selection of resistance mutations, and adherence across the two arms. Antiretroviral drug concentrations and adherence will be investigated as possible explanations for the effects of this simplification regimen. The overall goal of the study is to contribute to the evidence base to allow expansion of treatment options for HIV-infected children in low resource settings. PUBLIC HEALTH RELEVANCE: We propose a randomized clinical trial to evaluate, among nevirapine-exposed, HIV-infected children initiated and suppressed on lopinavir/ritonavir-based antiretroviral therapy, whether switching to efavirenz-based therapy at the age of 3 to 5 years leads to comparable maintenance of virologic suppression as continuation of lopinavir/ritonavir-based therapy.